^t THE LIBRARY OF THE UNIVERSITY OF CALIFORNIA LOS ANGELES GIFT OF SAN FRANCISCO COUNTY MEDICAL SOCIETY THE BIOLOGY AND TREATMENT OF VENEREAL DISEASES. 4 \m. l' ^v ^ -hi ^ f % ^(^r-- ^b ^SK:^:^ <^ ^-^ :•; Plate 1. — Frontispiece. » ' J ' I ' VENEREAL DIS. ^^^^ .till 1JKIW0H8 .aHAjO OITAHIM/J 0ITIJ1H1Y8 A 10 MOlTOairi- .1 STA.l'l .noiiiiaiiiJTol •^jiji laui oJaraJig oliina*? .U JaifO OToqei .0 .rKt'jnoaual inelounonorn at-ii;! ni o)YnoJ)mijg olr.tn gniiioIavaCE .Q[ .oJv.ooouel iBsIaijfionoai oginl xii lioo Ij;)oi;riooiiq8 .M .Jajo 3ioq8 .1 .lioo iBJomlooiiqB .0 ,IIoo IjsilejJJobn'j ni seJiosoism sniqoIsveCt .H ')UN A()!l, '■' y'-.^yj^cie^oUme'i .1 .llaj eiii; it-'ivWo'SfmVro nioJioswriqoiJ gniqolevoCE .H .9^1e lolhi-o .olJiQ .J .aeJ^ooJejuBs sUaial M '"! I I. ., Plate 1. — Section of a Syphilitic Lymphatic Gland, showing the VARIOUS PHASES OF THE LEVCOCYTOZOON SYPHIUDIS, STAINED WITH Pyronin and Methyl Greek. A. Binary fissioa of zygote. B. Female gamete just after fertilisation. C. Spore cyst. D. Developing male gametocyte in large mononuclear leucocyte. E. Spirochaetal coil in large mononuclear leucocyte. F. Spore cyst. G. Spirochaetal coil. H. Developing meiozoites in endothelial cell. J. Female gamete. K. Developing trophozoite in conncotivo-ti«sue cell. L. Ditto, earlier stage. M. Female gametocytes. Fronlinpiere. THE '249 BIOLOGY AND TEEATMENT VENEREAL DISEASES AND THE BIOLOGY OF INFLAMMATION AND ITS RFLATIONSIIIP TO MALIGNANT DISEASE BY J. E. R. McDONAGH, F.R.C.S. SURGEON TO OTJT-PATIENTS, LONDON LOCK HOSPITAL, ETC. LEA & FEBIGER PHILADELPHIA AND NEW YORK 191 (j Biomed'cil Likraiy CONTENTS. Part I. THE BIOLOGY AND TREATMENT OF VENEREAL DLSEASES. CHAPTEE. PAGE. L History of the Organism of Syphilis ... ... ... ... ... ... 1 IL The Life-Cycle of the Organism of Syphilis (ieMcocj/fozoow (SypMidis) ... 8 III. Aberrant Development of the Life-Cycle and Cocc/fZjosJs ^I'enerea ... ... 11 IV. Errors to be avoided in examining Syphilitic or other material ... ... 21 V. Arguments against ieucocj/tozooft (Syy/ji7irfis ... ... ... ... ... 23 VI. Chemistry of the Leucocylozoon Syphilidis ... ... ... ... ... 25 VII. The Light which the Chemistry of the Leucocylozoon Syphilidis flirows upon previously unexplamcd phenomena ... ... ... ... ... ... 55 VIII. Tlie cultivation of the Spirochaeta Pallida and the methods of demonstrating this Organism ... ... ... ... ... ... ... ... ... 59 IX-. Technique of the Wassermann Reaction ... ... ... ... ... ... G5 X. The Rationale or Modus operandi of the Wassermann Reaction and Abder- halden's Test 09 Xl^-^riie significance of the Wassermann Reaction and the way in which it is influenced by treatment ... ... ... ... ... ... ... 100 XIL The Cutireaction 113 XIII. The Biology of the various stages of Syphilis ... ... ... ... ... 119 XIVA The Cbnical Aspect of the SyphiUtic Cutaneous Lesions ... ... ... 124 XV. SyphiUs of the Lympho- and Hacmopoetic Systems ... ... ... ... 144 XVI. SyphUis of the Male Genito-urinary Tract 152 XVn. SyphiUs of the Eyes and Ears ■ ... 155 XVIIL Syphilis of the Mouth and Throat 162 XIX: Syphilis of the Bronchi and Lungs ... ... ... ... ... ... 166 XX. Syphilis of the Bones and Joints ... ... ... ... ... ... ... 169 XXI. SyphiUs of the Abdominal Viscera 174 XXII. Esamination of the Cerebro-SpLnal Fluid 182 XXin. The Biology of SyphiUs of the Nervous System 200 1 XXIV. The Clinical Aspect of Syphilis of the Nervous System 231 XXVt SyphiUs in Women 248 XXVL Congenital SyphiUs 260 XXVII. Chemotherapy and its mode of action in the case of Syphilis 276 XXVIII. Toxic Symptoms of Salvarsan and Neo-salvarsan 294 XXIX. The Treatment of Syphilis 321 XXX. Drugs LTsed in the Treatment of Syphilis and the Methods of administering them 337 XXXL CTctM- J/oHe (Soft Sore) 358 XXXIL Gonorrhoea '. ... 371 60349S ( vi ) Contents — cnntiii ncrl. CHAPTER. PAGE. XXXIII. Comiilications of Urethritis Gonorrhoica due to direct extension of the Organism ... ... ... ... ... ... ... ... ... 388 XXXIV. Complications of Gonorrhoea due to a spread by Metastasis of the Organism 406 XXXV. Non-Gonococcal Urethritis ... ... ... ... ... ... ... ... 416 XXXVI. Gonorrhoea! Diseases of the Eyes 420 XXXVII. Gonococcal Rashes 424 XXXVIII. Gonorrhoea in Women ... ... ... ... ... ... ... ... 427 XXXIX. The Treatment of Gonorrhoeal Infections by Vaccines and the Application of the Complement fixation test in Gonorrhoea ... ... ... ... 435 XL. Phimosis, and Paraphimosis... ... ... ... ... ... ... ... 401 XLI. Balanitis, Condyloma Acuminatum, Molluscum Contagiosum, Herpes Geni- talis, Granuloma Inguinale, Induratio Penis Plaslica, and Pediculosis Pubis ... ... ... ... ... ... ... ... ... ... 464 XLII. Sexual Neurasthenia... ... ... ... ... ... ... ... ... 478 XLIII. Venereal Disease and Marriage 485 XLIV. Venereal Disea.se and Public Health 493 Part II. THE BIOLOGY OF INFLAMMATION AND ITS RELATIONSHIP TO MALIGNANT DISEASE. Introduction ... ... ... ... ... ... ... ... ... ... 49'J XLV. The Role played by an Epithelial Cell in Inflammation and its probable relationship to Malignant Epithelioma , ... ... ... ... ... 501 XLVI. The Role played by a Lymphocyte in Inflammation and its probable relation- ship to Sarcoma ... ... ... ... ... ... ... ... 520 XL VII. The Role jjlayed by an Endothelial Cell in Inflammation and its probable relationship to Sarcoma ... ... ... ... ... ... ... 563 XLVIII. The Role played by other Oells in Inflammation and their probable relation- ship to Malignant Disease 580 ILLUSTRATIONS. Part I. Plate 1 (coloured). — Phases of the Leucocylozoon si/philidis in section ... Frontispiece. Plate 2. — Schematic representation of the jiliases of the Leucocylozoon syjMlidis Facing page 8 Plates 3-11. — Photographs (X 1,500) of the phases of the Lencoojiozoon syphilidis Facing page 10 Plate 12 (coloured). — 1. Developing trophozoite in a vessel in the cerebral cortex. 2. Development of the male gametocyte in a late cutaneous syphilide Facing 2'('9^ ^^ Plate 13 (coloured). — 1. Polar body formation in a chancre. 2. Spore cyst in a vessel wall Facing page 10 Plate 14. — Aberrant development of the ieacocy/ozoon syphilidis ... ... Facing page 12 Plate 15. — ^Low power section of a papule from a case of Coccidiosis avenerea „ ., 18 Plate 16-17. — Photographs (X 1,500) of the phases of the avenereal cocoidium „ ,, 18 Plate 18 (coloured). — High power section of a pajiule from a case of Coccidiosis avenerea, showing the parasitic phases Facing page 18 Plate 19. — Bodies seen in vivo, when examining fresh tissue, stained with borax methylene blue Facing imge 20 Plate 20. — Various forms of the aminoplasma cells as seen in in vivo staining. . . Facing page 22 Plate 21. — Photographs (X 1,500) of lymphocytes developing in endothelial ccUs Facing page 22 Plate 22 (coloured). — Twelve methods for differentiatmg the phases of the Leucocylozoon syphilidis in section Plate 23. — Aminoplasma cells as seen in sections Plate 24 (coloured). — Section specially treated to show only the phases of the Leucocylozoon syphilidis ... Plate 25 (coloured). — Papulo-erosive chancre Plate 26 (coloured). — Papulo-erosive chancre on the skin of the penis Plate 27 (coloured). — Painilo-crosive chancre in corona Plate 28 (coloured). — Papulo-erosive chancre on the under surface of Plate 29 (coloured). — A chancre of the frocnum ... ... Plate 30 (coloured). — ^A chancre in one of the furrows of the prepuce Plate 31 (coloured). — A papulo-ulcerative chancre Four diagrams of the early syphihtic skin lesions ... Diagrammatic representation of the origin of syphilitic alopecia Two diagrams of the recurrent syphilitic skin lesions Plate 32 (coloured). — Diffuse pajiular syphilitic eruption on the genitals Four diagrams of the recurrent syphilitic skin lesions Barker's lumbar puncture needles ... Facing page 30 34 Leucocylozoon Facing page 40 124 126 128 the prepuce Facing page 130 132 134 ., 134 . . . Page 135 137 ,, 138 Facing page . . . Page 138 139 182 ( viii ) Illustrations — continued. Plate 33. — 1. (Coloured) Female gametocyte in the pia-arachnoid. 2. Schematic repre- sentation of the phai?es of the icucoci/Zozoo?! sj/^/iiZirfi.s ... Fachxg jjage 210 Two diagrams of McDonagh's sjrringe ... ... ... ... ... Page 343 Plate 34 (coloured). — A single soft sore... ... ... ... ... ... Facing page 358 Plate 35. — 1. Low power section of the soft sore depicted on Plate 34. 2. Higher power section of the same sore ... ... ... ... ... ... Facing page 358 Plate 36 (coloured). — Higher power section still of sore depicted on Plate 34, showing the streptobacillus ... ... ... ... ... ... Facing page 358 Plate 37 (coloured). — Ulcus molle elevatum ,, „ 360 Plate 38. — 1. Low power section of sore depicted on Plate 37. 2. Higher power section of the same sore ... ... ... ... ... ... ... Facing page 360 Plate 39 (coloured). — Ulcus molle serpiginosum ... ... ... ... ... ,, ,, 362 Plate 40. — Section of Ulcus molle serpiginosum ... ... ... ... ... „ ,, 362 Plate 41 (coloured). — Keralodermia blennorrhagica ... ... ... ... ,, „ 424 Plate 42 (coloured). — Section of Qranuloma inguinale, showing the phases of its causative organism ... ... ... ... ... ... ... ... Facing page 472 Part II. Plate 43 (coloured). — 1. Section of a malignant prickle-celled epithehoma, stained with pyronm and methyl green. 2. Same tissue stained with EhrUch's triacid mixture ... ... ... ... ... ... ... Facing page 500 Plate 44 (coloured). — Pseudo-parasitic bodies from a case of malignant prickle-ceUed epithelioma ... ... ... ... ... ... ... Facing page 506 Plate 45. — 1. Section of a milium. 2. Trichoepdtlielioma papulosum ... „ ,, 514 Plate 46. — A section of a rodent ulcer, showing presence of a sebaceous adenoma and a milium ... ... ... ... ... ... ... ... Facing page 514 Plate 47. — 1. Section of a sjTingoma. 2. SjTuigoma with trichoepitheliomatous elements ... ... ... ... ... ... ... ... Facing page 518 Plate 48. — Syringoma ... ... ... ... ... ... ... ... ., ., 518 Plate 49. — A mixed tumour, showing simultaneous appearance of trichoepithehoma, sebaceous adenoma and syringoma ... ... ... ... Facing page 518 Pl.ate 50 (coloured). — 1. Crystalline form of aminoplasma cells. 2. Section of a lymphatic gland from a rat, which died of sleeping sickness... ... Facing page 532 Plate 51 (coloured). — Three sections taken from different cases of intermediary lymphatic aleucaemic lymphocytomata, showing the changes from the innocent to the malignant form Facing page 552 Plate 52 (coloured). — 1. A section from a recurrent case of intermediary cutaneous aleu- caemic lymphooytoma, following X-rays. 2. A section of a sarcomatous ulcer (plasmo-sarcomatosis) ... ... ... ... ... Facing page 554 Plate 53. — Sections from a case of Naevo-xantho-endothelioma taken at various periods during-its metamorphosis ... ... ... ... ... Facing page 568 Plate 54. — Sections from cases of Naevo-xantho-endothehomata ... ... ,, „ 572 Part I. THE BIOLOGY AND TREATMENT OF VENEREAL DISEASES. CHAPTER I. HISTORY OF THE ORGANISM OF SYPHILIS. Several observers described what they considered to be the cause of syphilis, but none attracted much attention until, in the year 1884, Lustgarten^ described a bacillus which resembled the tubercle bacillus. Koch had discovered the tubercle bacillus two years previously, and at that time the opinion was widely held that sjnphilis and tuberculosis were closely related to each other ; therefore Lustgarten's work was eagerly received, and was quickly confirmed from several sources. Belief in Imstgarten's theory was, however, short lived, as in a year or two's time, first Alvarez and Favel,^ then Klemperer,^ and many others showed that the bacillus described was probably only the smegma bacillus. During the next few years, certain cocci, granules, etc., were brought forward in turn as the casuative agents of syphilis, but confirmation was lacking. The next in the field was van Niessen,* with his Syphilomyces, a polymorphic bacillus which he succeeded in culturing from the blood of syphilitic patients. After the Spirochaeta pallida had been discovered, van Niessen stated that he believed the latter was a developmental form of his bacillus. That the pathogenic agent of syphihs -was a protozoon, was first suggested by Doehle,^ who described movable, flagellated protoplasmic bodies, in the secretion from chancres, in the tissue juice of congenital syphilitic organs, and in the blood. Then Clarke,® Schiiller,' ^and others described protozoa, which they took to be the syphilitic organism. Although they did not describe any organism, Metschnikofi and Roux,'^" in 1903, made the important discover)^ that apes could be inoculated with syphilis, and, in the following year, Klingmiiller and Baermann^^ showed that the syphilitic A 2 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. virus would not pass through a filter, and, therefore, that the cause was not an ultramicroscopic organism. Soon after these two very important observations had been made, Siegel^^ ^^ came forward with his Cytorrhydes luis. The name cytorrhyctes was used, because Siegel found that his bodies closely resembled bodies which Guarnieri had discovered in small-pox, and had called cytorrhyctes. Some of the bodies which Siegel described were actively motile, 0'5 to 25 n in diameter, and were easily distinguished from other structures by their powerful refractility : others were bodies which Siegel later called spores, containing 2 to 16 nuclei. Although Siegel's work received confirmation, it passed into obHvion when Schaudimi and E. Hofimann^* published their joint paper on an organism named by them the Spirochaeta pallida. No sooner had the Sjnrochaeta pallida been discovered, than one paper appeared after another confirming Schaudinn and Hofltmann's discovery. At the Pasteur Institute in Paris, Metschnikoft' and Roux* ^^ found the Spirochaeta pallida in the lesions they produced by inoculating chimpanzees with human syphilitic material : and Levaditi, by means of silver nitrate impregnation, succeeded in demonstrating the Spirochaeta pallida in sections of congenital syphihtic organs. So many observers took up this work that, in a very short time, the Spirochaeta pallida had been found in, broadly speaking, every known type of syphihtic lesion. While searching for the Spirochaeta pallida, many other spirochaetae were observed, and at one tune there was a great discussion as to whether these extraneous spirochaetae were distinct organisms, or whether they were aberrant, or even developmental forms of the Spirochaeta pallida. The other spirochaeta to which most attention was directed, was the Spirochaeta refringens, and many well-trained observers stated that they had found it only in syphilitic material, in company with the Spirochaeta pallida. TQis valuable observation was, I believe, somewhat unjustifiably set aside, and the Spirochaeta refringens was stated, both to be utterly imrelated to the SpirocJuieta pallida, and to be unspecific for syphihs. At first the Spirochaeta pallida was generally considered to be a protozoon. Others held that it belonged to the bacteria, an opinion which Meirowsky^^ has lately strenuously attempted to maintain. Dobell^' also holds the view that spirochaetae are vegetable organisms, but the Spirochaeta pallida was not amongst the spirochaetae studied by him. The third opinion was that the spirochaetae held a position of their own, THE HISTORY OF THE ORGANISM. 3 midway between the bacteria and the protozoa ; and most elaborate families and sub-families were drawn up, to include all the known forms. Meirowsky^* describes branching, with chib formation occurring at the end of the branches, in fact in almost any part of the Spirochaeta pallida. These branches appear to resemble the mycelium and spores seen in fungi, and he suggests therefore that the syphilitic organism belongs to the class including the leprosy and tubercle baciUi. Summarising his views, Meirowsky states that the absence of a nucleus, of an un- dulating membrane, and of a blepharoplast, are strong arguments against the Spiro- chaeta pallida being a protozoon. That the Spirochaeta pallida divides transversely, is, according to him, also no proof that it is a protozoon, since transverse fission is the general method of dividing in bacteria. Finally, Meirowsky states, that " it is mere waste of time to elaborate analogies between spirochaetae, and the flagellata, or other protozoa with sexual differences, and reproductive cycles." I find myself unable to agree with Meirowsky, and his last statement is, in itself, sufficient to throw considerable doubt upon the value of his work. With one or two exceptions, the Spirochaeta pallida, as has already been stated, was universally accepted as the cause of syphihs ; but de Korte,i^ who worked at the London Lock Hospital for some time, was strongly opposed to the general view. Although the illustrations accompanying de Korte's paper are not good, there can be little doubt that some of the bodies described are the same as Siegel's spore cysts. In his last article, Hoffmann^'' states very positively that the Spirochaeta pallida is the sole cause of syphihs. The result of this is, that no disciple of Hoft'mann has repeated any of the work which has been done to prove the existence of a hfe-cycle of this organism. Naturally, Hoffmann and his disciples consider the existence of the life-cycle to be fundamentally impossible. If the Spirochaeta pallida is the sole cause of syphihs, it is difficult to explain why the incubation period of syphihs is so long, why division is not seen in every specimen examined, and why one or two injections of salvarsan do not always effect a cure. ^ I was aware that, in most known protozoal diseases, the organism had several phases, and that recurrences of the diseases were common. I was also aware of the similarity between syphilis and malaria. In the fight of these facts, it occurred to me, in 191 1, that the obscure points in syphihs, connected with the Spirochaeta pallida, could be cleared up, only if the spirochaeta itself could be regarded as merely a phase ^ in the life history of some unknown protozoon. Seeing that svphilis could be conveyed from person to person, there was no reason to assume that an intermediary host was required, as is, for instance, the a2 4 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. case in malaria. Therefore, if there were other phases, I expected to fuid them all in the patient himself. Owing to the motiUty of the Spirochaeta 2Mttida, and to its resemblance to a spermatozoon and to the male gametes of the various protozoa, it occurred to me that perhaps it was the adult male body of a protozoon. My chief reason for thinking that the Spirochaeta pallida was an end phase, was the fact that, in spite of the numerous examinations which I had made of spirochaetal tissue, I had never succeeded in seeing the organism divide. It had been suggested, some time previously, that the Spirochaeta jmllida had a resting stage — in fact, Schaudinn was at work on this very point just prior to his untimely death. V. Prowazek^^ was under the impression that the Spirochaeta pallida rolled up into a ball. Similar circular bodies were also found by Hoffmann,^'' in the spleen of a congenital syphilitic, and intermediate stages in unrolhng and rolling-up were described by him. The resting stage, as just described, was held to be responsible for the long incubation period of svphilis. Kryzsztalowicz and Siedlecki^^ '-'* described a sexual development, and in that, short, thick, nucleated bodies, which the}' looked upon as macrogametes, gave rise, by a process of division, to microgametes ; but these authors afterwards altered their views. As a result of my investigations, I am firmly of the opinion that the organism of syphilis has a sexual development, but different from that just described. Full details of my work will form the matter of the next chapter. Within the last two or three years Balfour, ^^ Fry,^^ Kanken,^^ and others have described a granular stage in the development of certain spirochaetae and try- panosoraes, which they have called the " infective granule." Balfour, working with infected chickens (spirochaetosis), in which a natural crisis had occurred, or in which an artificial crisis had been induced by salvarsan, found, by use of the dark ground illumination, that the spirochaetae broke up into granules. Whether the granule described by Balfour is the same phenomenon as the bulbous extremity of the Spirochaeta pallida, first described by Herxheimer,^* is not, however, clear. Henry^* has described the infective granule as the initial phase in the life history of a haemogregarine, which maj' or may not be the same as that described by Balfour in the spirochaetosis of Sudanese fowls, and by Fry and Eanken in certain trypanosomes. These so-called " infective granules," especially as described by Balfour, owing to their close similarity to cell detritus, require fiu'ther study before authori- tative statements can be made about them. THE HISTORY OF THE ORGANISM. 5 One wonders whether these granules are the same as the knobs occurring on the branches of the Spirochaeta pallida, described by Meirowsky. If so, then the opinions of Lipschiitz^* and Kreibich** must be taken into consideration. Both these observers maintain that Meirowsky's figures are the results of chemico-physical changes, which have taken place in the organism, probably of the nature of a lipoid degeneration. There are many pathological conditions in man caused by spirochaetae, which differ at once from syphilis, because they are very amenable to treatment, and they do not tend to recur. Therefore, it is only reasonable to expect that there is a difference in the development between the Spirochaeta balanitidis, for instance, and the Spirochaeta pallida . The infective granule, described by Henry, is probably the trophozoitic stage of the protozoon. Even if this infective granule be proved to be the cause of certain spirochaetal diseases, recurrent fever and yaws, for example, it would not necessarily follow that the protozoon causing syphiHs had a similar development. Relapsing fever and yaws respond very rapidly to treatment with salvarsan, whereas syphilis shows a strong tendency to recur, in spite of such treatment. These two facts strongly suggest that the parasite of s3rphiUs has some developmental form, of far greater resistant capacity than that found in relapsing fever or yaws. In December, 1911, I began to examine lymphatic glands from the region draining the site of the initial lesion. These glands had been removed early in the generalisation stage. In .January, 1912, I found some bodies which I thought might be parasitic in nature. These bodies had special staining properties, and could not be demon- strated in the control material. In October, 1912,2^ I published my first paper on the life history of the organism of syphilis, and it was succeeded by several more in different journals.^' ^* ^' ^° In September, 1912, prompted by some observations which he had made with spirochaetae from guinea-pigs, E. H. Ross conducted some experiments, with material which I had placed at his disposal. In December he pubhshed a paper-* on some phases in the development of the Spirochaeta pallida. At about the same time my assistant Moolgavkar,^^ and Jennings,-'' working with Ross's jelly method, confirmed his observations. Some discussion as to priority in discovery then arose. This subject need not be revived here. The whole matter is summed iip in The Medical Press and Circular,-^ to which I would refer all inquirers. Although both Ross and myself have described life-cycles, there appear to be b THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. some wide differences in the descriptions of the various phases. This is doubtless due to the fact, that Ross has not observed the phases which he has described, in the living state ; and that he has altogether neglected to examine the fixed tissue. Up till the present, two observers — Peyri Rocamora*i and Klausner*^ — have repeated some of my work, and both have substantiated my discoveries. Reschad^*^ and Kyrle, Mucha and Ketron,*^ working in Finger's laboratory, repeated Ross's work, using his jelly method, and found that the bodies which Ross had described could also be found in non-syphilitic material. Roddy*^ worked at the same subject in America, and his results confirm those of the last-mentioned observers. I have had occasion to use the jelly method, which, as Herxheimer and Reinke'^ rightly point out, is a modification of Carrel's method. I have not found this method very successful. The cells are distorted, they stain unevenly, and are soon killed, so that impregnation cannot be studied by this means. I have employed the borax methylene blue method, by which the organism is stained aUve. By using this method the act of impregnation may be witnessed. To have seen impregnation is important, since thereby the female cell can be definitely ascertained, and a clue is gained as to the relative position of the other phases in the life-cycle. This life- cycle is fuUy described in the next chapter. 1 Lustgarten (1884), " Wien med. Woch," xxxiv, 1389. ~ Alvarez et Favel (1885), " Arch, de physiol. norm, et path.," iii, 303. 3 Klemperer (1885), " Deutsoh. med. Woch," xi, 809. * van Niessen (1908), " Der Syphihsbacillus ; seine Geschichte, Literatur, Kiiltur, etc." (Leipzig.) 5 Doehle (1905), "Med. Klinik," i. 590. « Clarke (1907), '■ Lancet," i, 91. ' SohuUer (1905), " Deutsche Arzteztg." « SchuUer (1905), " Berl. Win. Woch.," xlii, 1275. " Metscliiiikoft' et Rous, Etudes experinientales sur la Syphilis. " Aiui. de I'fnst. Past.," 1903-1907. i» Metsehnikof=f etRoux(1905), "Bull, de I'Acad. de Med.," liii, 468, et " Le Bull. MM.," 441. '1 KJinginiiller u. Baermann (1904), " Deutsch. med. Woch," xxi, 766. '2 Siegel (1906), " Miinch. med. Wocli.," liii, 63. " Siegel (1906), " Centralblatt f. Bakt," xlii, 128, 225, 321. ■* Schaudinn u. HofEmaim (1905), " Arb. a. d. Kais. C4esundheitsamte," xxii, 527 •5 Meirowsky (1914), " Dermat. Woch.," Iviii, 225. '« de Korte (1906), " Practitioner," Ixxvi, 786. ■' DobeU (1912), " Arcli. f. Protistenkunde," xxvi, 117. ■» V. Prowazek (1907), "Arb. a. d. Kai.s. Gesundheitsamte," xxvi, 23. THE HISTORY OF THE ORGANISM. 7 '" Kryzsztalowicz u. Siedlecki (]90o), " M. f. prakt. Derm." xli, 231. ^ '0 Kryzsztalowicz u. Siedlecki (1900), " M. f. jirakt. Derm.," xliii, 1. V -' Balfour (1911), " Fourth Report, Wellcome Res. Lab.," Khartoum, 7(5. " Fry (1912), " Proc. Roy. Soc," Ixxxiv (Ser. B.), 79. =3 Raiiken (1912), " Brit. Med. .Journ.," ii. 408. " Henry (1914), " Brit. Med. Joum.," ii, 1G.'54. " Ross (1912), " Brit. Med. Journ.," ii, 16,51. -' Moolgavkar (1912), - Brit. Med. Journ.," ii, 16.5.5. =' Jennings (1912), " Brit. Med. Journ.," ii, 1655. 2s McDonagh (1912), " Lancet," ii, 1011. =9 Editorial (1913), " ]\Ied. Press and Circ," ii, 660. '" Reschad (1913), " Arch. f. Derm. u. Syph.," cxviii, 578. 31 Kyrle (1914), " Arch. f. Derm. u. Sj^ph.," cxis, 213. ^- Herxheimer u. Reinke(1912), " Lubarsch u. OstertagErgeb. d. Path. u. Anat.," Jahrg. 16, Abt. II, 45. ''^ Hoffmann (1912), " Handb. d. Geschlechtskranldieiten," ii, 784. '^ Herxheimer (1905), " Munch, med. Woch.," lii, 1861. ^^ Lipschiitz (1914), " Archiv. f. Derm. u. Syph.," cxix, 213. 3" Kreibich (1914), " Archiv. f. Derm. u. Syph.," cxix, 213. 3' McDonagh (1913), '" Proc. Roy. Soc. Med." (Path. Sec), vi, 8.5. '8 McDonagh (1913), " Dermat. Wocb.," Ivi, 413. 39 McDonagh (1914), "Dermat. Woch.," Iviii, 4.5. " McDonagh (1914), " Arcliiv. f. Derm. u. Syph.," cxix. 20.5. •" Peyri Rocamora (1913), " Revista de Med. Cir. y EspeciaUdades," vii, 1. *' Klausner (1914), " Archiv. f. Derm. u. Syph.," cxix, 214. " Roddy (1914), "New York Med. Jnurn.," xcix. 424. CHAPTER IT. THE LIFE-CYCLE OF THE ORGANISM OF SYPHILIS. {LEVCOC YTOZOON S YPHILIDIS.) The life-cycle commences with a spore, or, as it is generally called, a sporozoite. The sporozoite, when examined in vivo, remains for some time unstained. Later it stains very deeply, but its motility is not thereby impaired. It is seen in two forms — (a) circular, (6) renal-shaped — -its size is about 1'5 microns in diameter, and it is actively motile. Besides being found in the scrapings from syphilitic lesions, it may be found in the blood withdrawn from the healthy skin surrounding a chancre, and also in the general blood-stream, during the stage of general infection. The sporozoite then becomes intracellular. On two occasions, I have seen it in a small mononuclear leucocyte : it remained actively motile while within, and it ultimately left the cell. It chooses a connective-tissue cell or an endothelial cell as its host, and, when inside, it undergoes important changes, which can best be described under two headings : — (1) The sporozoite steadily increases in size, and, by a process of budding, gives rise to several bodies, which later become differentiated into male and female elements. By this time, the cell is a sac, as all the reserve material has been used nj) by the merozoites ; the niicleus still remains, although degenerated, but finally it dis- appears, when the sac gives way and frees the male and female merozoites. Not all the bodies formed in this way are sexually differentiated ; there are others which become free with the sexual merozoites, and are able, no doubt, to start the cycle again, by seeking fresh connective-tissue cells or endothehal cells. (2) The sporozoite increases in size, but not to the dimensions met with in the previous case. Having reached a certain size, it divides into two, and again into four. These four masses, by a process of further subdivision, form a ring, and migrate to the periphery of the body, when a picture is given as if the ring had stones mounted in it, the whole way round. By this time, the host cell is almost completely degenerated, and one might imagine that the parasite had become extracellular, but it does so only when the host cell is no more. In the centre, and around the SCHEMATIC EEPEESENTATION OF THE VARIOUS PHASES OF LBVCiK 'YTO'/JXIX S milL WIS. TlIK 3(;rp)— --(.150^--. ASEXUAL STAGE 27 ^ O 0-* 28^ ■e-'-b- ..®;. -<-SL....-X|' J -5. G- -13. 1- -13. U- -1:1. U. 1.x Iti, 17. 18, 19. •-'0 -ih. 23. 24. 2.=). 26 -29. iii,jc 10, ^1 *? V Troplio/Aiitu iu couiiectivu-t issue cull. liiiiary lission (if tiYtjtlKizuitc in (.'niiiiL'otivc-tissiU' cell. First siiliilivisi(»n of iisuxual sjior ti'ophozuiU' tnwiirds funimtimi u[ cyst ill (Mirlntlu'lial cell. Fiiiilicr stage of pvoceiling' plu coiiimonoinp; (Ict^enoration of itog^rapli. Nnte host's cell. Plate 4. Asexiuil spi.iro cyst. Note contpK^tc degoiiuratioii o[ the host's cell. Asexual spore cyst ■\\'ith daugliter spore cyst. Endothelial cell almost degenerated. Asexual spore cyst witli daughter spore cysts. Host's cell lias quite degcuerated. Male g.nmctocyte after it has left counective-tissue cell. Plate .'i. I 1 13. H. M:ili- i;ami-toovtc iiisitli' a hivge iiuniiiinii-li-iir li-ii.ocyte. Malo gametocyte with tbref uucli-ar Ixidies. Nucleus of mouonuclear shows, but it is out of focus. #* ^ if % '-A l.V III- Devolojiuieut of the thi-co uuch-ar bodies of tlie mah- Further developiueiit of the three uuch'ar bodies gametocyte iu the protoplasm of a large uiouuiiuelear towards formatiou of spirocbtetal coil. Nucleus leucocyte. of uiououuclear is tii riglit and out of foeiis. Pl..\TE G. / Jl '^ 4 f Spii-oclio?tiil coil. IS. Kxtvai't'Iliilar .levi'Iopniriit nt male' gainc'tooytu. / Fm-t.liiT stage of iiviM-i'ilini; iiliofogniijli. Further stagi.' of procnling pliotograpli. Plate 21. 2-.'. Feniali' ganu'tocyti' "with (.nn- lilcplinroiilast. Fi'iiiale ^■aiui'tm^yto. 23. 24. Female gamete. rai-tlii'inigciictii: (lovelopmeiit vi fi'iiialr gamete. Plate 8. I ^r--J^ e • 1 ■J.'l. ■ill. Fuinale yaiiicti; after iiiipvfjfiiatiou. Note skuiu Zyguto. bctWL'oii iiialo auf-1 fomalo cletiients. jp •• «? < r.inary Hssiou of zygote. Stage after biliary ti,ssi<.ii of zygote. 4 ■20. S}n'rulilnst fnnnatiitn nf zyg'utr. Fni'tlirr cli'vcliipiiic'iit (if siHii-ol)I:isti ^«< (f5 •% «! t wldcli "wiJl funii ^■p^'l■(lzuit^.s. 34, Escaped sporoblast with a spnruzuite. •n % • * Biuary fissiou of sporoblast. Sporozoites developed from a sporolilast. Plate U. I Plate 12. 1. Section of the cerebral cortex from a case of degenerative encephalitis, stained with pyronin and methyl green. A. Developing trophozoite in a connective-tissue cell. B. Aminoplasma cell. C. Nucleolus from a degenerated nerve cell. Section of a late recurrent cutaneous pnpular sj-philide, stained witli pyronin and methyl green. A. Male gametocyte. B. Male gametocyte in a large mononuclear leucocyte. C.D.E. Intracellular and extracellular spirochaetal coils. ®) ti" bunw;ta ,oioiu;iio j> lo noiioyfci naoig lijiliam odi ofdiins oi lobio ni Jorioolfi biofi oM9db ni bsnabieri w// iailo prepuce. I have had the opportunity of thoroughly examining five such sores, four were primary sores, and the fifth was a chancre redux. In the case of the chancre redux, the patient had contracted syphilis 29 years previously, and in the mean- time had never had a syphilitic symptom. Around the chancre redux were smaller satellite sores, all of which had the same clinical features. Neither salvarsan nor mercury had the slightest influence on these five cases. Histologically, no spirochaetae could be found, but the asexual phases of the leucocytozoon were easily demonstrable in section. From the cases just mentioned, it would appear that when only the asexual ABERRANT DEVELOPMENT OF THE LEUCOCYTOZOON SYPHIUDIS. 15 stage of the Leucocytozoon syphilidis develops, the course nui by the disease is a chronic one, and the Wassermann reaction is of no value as a diagnostic agent, since, out of the last five cases mentioned, the reaction was negative in four, and was positive in the chancre redux case only. The histological appearances of the sections from these cases resemble very closely those seen in Granuloma inguinale — indeed, the parasitic bodies are very similar [vide Plate 42). The lesion of Granuloma inguinale is essentially a chronic one ; the Wassermann reaction is not positive, and, as a rule, the condition is not improved by salvarsan — three points which tally exactly with the syphilitic lesion, when only the asexual stage of the parasite develops. Sequeira* recently had a very remarkable case, the microscopic pictures of which were not at all unlike those of the lesions under discussion. The patient was a boy, aged 7, thin and anaemic. He complained of a rash which had only recently developed, and which was diagnosed as Lichen jjkmus. Some months later, the rash further developed, and each lesion of it was distinctly xanthomatous in appearance. About the same time, Diabetes insipidus ensued, soon after which the patient died. Unfortunately, a Wassermaim reaction was not done, as Diabetes insipidus in children is very commonly a symptom of congenital syphilis, and is due to a lesion in the posterior lobe of the pituitary body. Curiously enough, the case in hand had a lesion in this gland. With Dr. Sequeira's kind permission, I am able to give here the report on the histology of the sections which I submitted to the Pathological Committee of the Dermatological Section of the Eo}-al Society of Medicine. Epidermis. — The epidermis is thinned in some parts, but the processes are markedly elongated, and, in between some of the epithelial cells, are a few stray leucocytes. The basal la}'er of the epidermis over the cellular infiltration of the corium is depigmented. A similar picture is to be seen in sections of most syphilitic and tubercular skin lesions. Corium. — The cellular infiltration reaches as far up as the epidermis. It is especially noticeable in the papillae, and ^this arrangement no doubt accounts for the prolongation of the epidermal processes on either side. Laterallj-, the infiltration is not circumscribed, but below, it does not reach as far down as the sweat glands. The topography of the cellular infiltration strongly suggests a parasitic infection, which has reached the skin by way of the blood stream. The cellular infiltration consists mainly of endothelial cells. There are several polymorphonuclear leucocytes, fewer lymphocytes, and only a few embryo lympho- cytes and eosinophile cells. I could find no cells which I took to be plasma cells. 16 THE BIOLOGY, CLINICAL ASPECT AND TEEATMENT OF SYPHILIS. The endothelial cells are, for the most part, normal, the protoplasm behig perhaps a little irregular and degenerate. There is no nuclear or nucleolar activity. Most of the endothelial cells have only one nucleus, and each micleus has only one imcleolus. Hence, so far as the endothelial cells are concerned, the lesion is an inflammatory one, and not a new growth. Several of the endothelial cells have coalesced to form giant cells. Some of the endothelial cells recpiire very special mention. The protoplasm is sacculated. The outline of the sack is very distinct, and is attached to the nucleus at its two ends. Between the attached portions, the outline of the nucleus is concave. The groundwork of the sack is unstained. In the sack one or more cells are to be seen, the morphology of which varies in the different cells examined. In some, the cell is very small, and appears to consist of nuclear material only ; in others, the nuclear material is much bigger, stains very darkly, is homogeneous, and lies in a mass of protoplasm, which is perfectly circumscribed, regular, and slightly refractile. In other endothelial cells, instead of one mass of nuclear material, there appear to be four masses, and each of the four divisions consists of two masses of nuclear material, with protoplasm between each. In still other cells, six or more bodies are to be seen. Each one is either made up of the two nuclear masses just described, or these two nuclear masses have increased to three or four, as if they had undergone division. Similar bodies in groups, and occasionally single, are to be seen extracellularly situated. I have seen bodies siniilar to these in Granuloma iropicum. In the case of the tropical granuloma, by emploj^ing various micro- chemical tests, I have come to the conclusion that they are parasitic bodies, and that they are probably phases in the asexual development of a coccidial protozoon (vide Plate 42). The sacculation of the protoplasm of the endothelial cells, and the very deep staining of the nucleus of the included bodies are very suggestive of parasitism. In the section stained with haematox3'lin and Sudan III, fat is demonstrable, both outside and inside the endothelial cells. This is probabh' to be regarded as a degeneration product of the protoplasm of the endothelial cells. It is likely that xanthoma is not a disease sui generis, but merely granulation tissue, composed of endothelial cells, in which the protoplasm has undergone fatty degeneration. When an enormous number of endothelial cells is formed, as in this specimen, they must ultimately either degenerate or become malignant. They certainly have not become malignant. They have degenerated, and, in the process, have , formed a substance which stains with Sudan III. Such a degeneration is commonly to be met with in endothelial cells. ABERRANT DEVELOPMENT OF THE LEUCOCYTOZOON SYPHILIDIS. 17 It should be borne in mind that Sequeira's patient was seriously affected by his disease, and died of it, and this probably accounts for the reason why the cellular infiltration is mainly endothelial. I have noticed, in examining syphilitic lymphatic glands, that the severer the case of sj^jhilis, the more endothelial in character the infiltration, and the less lymphocytic it was. The histology of the sections of this case appears, to me, to be extremely similar to that met with in very severe cases of syphilis, and, in nn^ opinion, the section represents a granuloma, which is most probably of protozoal origin. AVhether the parasitic bodies represent the asexual stage of the Leucoajtozoon syphilidis, or of some other coccidium, I am unable to saj*. As the boy had Diabetes insipidus, and since we know that this condition is commonly met in con- genital syphilis, it is very suggestive at first sight that this case is an acute case of syphilis, in which only the asexual stage of the parasite has developed. When more light has been thrown upon this interesting point, the question will naturally arise, does the organism develop in a pecuhar way, because the patient's resistance compels it to do so, or because the organism conies of a breed that never forms male and female gametes ? If the syphihtic organism is cultured, one knows that only the Spirocliaeta pallida grows, and, further, that it will grow only under anaerobic conditions. It is also a well known fact that the processes of fertihsation and subsequent develop- ment of the zygote require oxygen, therefore it is not likely that bodies other than the male will develop under anaerobic conditions. This point is mentioned here, because the distribution of oxygen in the body might have an effect in influencing the development of the Leucocytozoon syphilidis. As will be seen later, when the chemistry of the Leucocytozoon syphilidis is discussed (Chapter VI), the entrance of the male gamete into the female cell causes certain chemical reactions. An ovum, during and after fertilisation, stains in vivo with the methylene red moiety of the borax methylene blue, and this signifies the formation of some strongly reducing substance, which was not present prior to fertilisation. If the same cells be examined in fixed specimens, it is found that the fertilised female cell has a greater affinity for basic dyes. This indicates that the reducing substance is of an acid nature. Loeb^ found that a fertilised ovum takes up neutral red more readily than an unfertilised ovum does. Neutral red is a base ; therefore another point is gained in favour of the view that, during fertilisation, there is an increase of acid in the female cell. This acid appears to be of fundamental importance, since the slightest alteration B 18 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. in the hydroxyl-iou couceiitration of the fluid, in which the process of fertilisation is taking place, is sufficient to check further development. Loeb, in his most fascinating work on artificial parthenogenesis, found that the female cell did not develop a mantle until he had added acetic, propionic, or butyric acid to the sea water in which the cell was developing. Mineral acids would not take the place of the above-mentioned monobasic fatty acids, except when sodium acetate or sodium butyrate was added. The action of the mineral acid is to break up the salt, and set free a fatty acid ; therefore it is clear that fatty acids play an important role in fertilisation. There is little doubt that salts also exert an influence upon the process of fertilisation, for instance, potassium and calcium salts have a stimulating effect. Although these are chemical points, I mention them here. I do so in order to show how important certain chemical substances are, for one of the most important functions in the development of any organism in which there are male and female bodies. This also shows how little is the alteration required to upset the natural sequence of events. I have also laid great stress upon the question of aberrant development, because, if the body can change the mode in which the organism develops, we might be able to find out how it is done, and in this way either find a preventive against the disease, or a cure which is more certain than any which we have at present, and what is still more important, we may be able to give aii exact prognosis in those cases in which we can see the primary sore. Since the above was written I have had a case under my care, which I take to be one of coccidiosis, in which the coccidium is certainly not the Coccidium sypkilidis. Case 2. — The patient, a big and healthy-looking man, aged 22, consulted me for a rash on his elbows and penis. When the rash appeared the patient was stationed in the North-West Frontier Province (India), and the follo\A;ing is the history of the case : — In August, 1914, the patient was playing hockey, when he fell and cut both knees and the right elbow. A dressing was applied to the knees, but as the elbow wound was trivial no attention was paid to it. The knees healed quickh-, but although the wound healed in time on the elbow, a rash developed outside it, and this has been gradually spreading since. In September, 1914, the patient had what he called a " go of temperature," whicl lasted for three weeks. The patient had never had fever before, so the diagnosis made at that time was fever following a frontier sore. Many doctors saw the sore on the elbow, and most were of the opinion that it was a frontier sore. Section of a papule from a case of Cvrcidlos'is Avenerea magnified fifteeu times. The papule is seeu to be situated in the corium, to be perfectly circumscribed, aud to have produced uo reaction iu its jjeriphery. Plate 15. Facing p. 18. PHUTUGllAPHS. X 1500 Tru|iliozi.)iti- First division of tiuiilio/.(.itc Development of tropliozoite into niorozoito. Plate IC. Folhu$ Plate 15. ys ..^^p ^* # ^' Dt'veltipmi.'iit L'f irn'rozuitu iutu spores. i lutrncrllnhir ili-vi'Iopinoiit of .sporor^ ,n ExtracL'Uiibir ilrvL'lopnu'ut of sxiores. Platk 17. Fullous Plate 16. Plate IS. Section through a papule froui a case of Coccidiosis Avcncrca (vide Plate 15) stained with pyronui and methyl green. A. Spore cyst. B. Trophozoite in an endothelial cell. C. Ballooned endothelial cell. D. Spore cyst in an endothelial cell. E. K. Foam cells. F. First subdivision of trophozoite in an endothelial cell. G. The same, but the body is extracellularly situated. H, L. Binary fission of trophozoite in endothelial cells. J. Trophozoites extracellularly situated. Folhivs riaic 17. .81 aTAja (51 oiel'I '(bVi) nsiaiwjii, 8«oi¥»»o'J Jo asBO e uio'il aliiq^q j> /lyuoiHi noiioofi .i?.Xo 3ioq8 .A .IIoo IciloxIJobno aa ni sJiosodqoiT .S .IIoo l*iIoriJoba9 banoollBS .0 .Ilao l*ilod,>obng nc ni Jg^o 3ioq8 .Q .pIIso (a£o1 .3 ,f[ .Iloa iBiladiobna n* ni oJioso/lqoiJ lo noiwvibJuB Jaiil .1 .bslfiuiia i^hBloll90Biix6 bi yBoiI nrii ii;d ,9m£g 9riT .0* .8l[99 liiilodlobna ni gJiosoiIqoil lo noisgil yi'SniS .J ,H .baJeuJis ihiAMooniiy.-j asJiosoriqo-iT .1 TI yaM i'»«l\u'i I Cro Q ** »2^ V i ° "* a -, '^Si t o^ ^ IJ^ ^ o\c 1^ , ^fkSc^M.*-.- . Plate 18 ABERRANT DEVELOPMENT OF THE LEUCOCYTOZOON SYPHILIDIS. 10 111 November, 1914:, a rash appeared on the penis, and a month later the left elbow became affected. The patient was treated with arsenic internally, and various ointments were apphed locally without any result. The lesion on the right elbow was a little bigger than a five-shilling piece ; it was purple-blue coloured, slightly crusted in parts, and here and there were small depressed scars. The patch looked not unlike a Sarcoid. Outside the patch were several irregularly distributed but discrete papules. The papules were about the size of a hemp-seed, red-brown in appearance, with somewhat of a transparent look, hke the apple-jelly nodules in lupus. Some of the papules were crusted, a few had coalesced, but the base upon which they were situated was not inflamed. The rash on the penis and on the left elbow was papular, and indistinguishable from the papules just described. The papules on the penis affected the glans, the corona and the under-surface of the prepuce. WTien the under-surface of the prepuce was stretched several papules were seen to be developing, so a portion of the tissue in this region was excised for a microscopical examination. The patient had no enlargement of his lymphatic glands, nothing else abnormal could be discovered, he had never had sexual connection, and the Wassermann reaction was negative in all dilutions. Thinking the case was one of an infective granuloma, and probably protozoal in origin, I gave the patient potassium iodide internally and unguentum iodex externally, with the result that, in four days' time there was a very distinct improvement. Histological examination of an early papule. — Situated in the deeper layers of the corium is a circular cellular infiltration, about 1 mm. in diameter (Plate 15), The mass is perfectly circumscribed, and there is no surrounding cellular infiltration. The mass may be said to consist of three parts : an outer layer of plasma cells, then a layer of mixed plasma cells, lymphocytes and endothelial cells, while the centre is mainly occupied by lymphocyte-producing endothelial cells. Hence the mass was not unlike a lymphoid follicle, in a chronically inflamed lymphatic gland. Mainly in the intermediary zone were to be found some intracellular bodies, which were markedly pjToninophile, suggesting at once that they were parasitic. The cell affected was the endothelial cell, and the following are the phases which could be discerned (Plates 16, 17, 18) : — 1. A bright pyroninophile mass lying in its own unstained protoplasm, and the whole, situated in a sac, outlined by the edge of the protoplasm of the endothelial cell, and in one part by the concave inner surface of the nucleus (Trophozoite). 2. An inclusion body in which the pyroninophile mass had become divided into two (Merozoite). b2 20 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. 3. Inclusion bodies in which the pyroninophile masses had further divided into four, eight, and so on (Spores). The further developed was the inclusion body, the more degenerated was the endothelial cell, so that when the body had formed what appeared to be spores, it looked as if it were extracellular. The inclusion bodies are ojDtically active, and give the same micro-chemical reactions as the phases of the Leucocytozoon sypMlidis, to the asexual stage of which they closely correspond. From what has been said about this case, the most reasonable explanation to offer would be, that the organism entered the wound on the right elbow from the earth, developed in situ, gained entrance to the circulation, caused fever, and then settled down in various areas to produce lesions. Considering how common coccidiosis is in animals, it is surprising that many varieties have not already been described in man. Just as sporotrichosis has laid claim to some cases of infective granuloma, which were wrongly diagnosed as syphilis, coccidiosis will probably soon be found to do the same. In the meantime, the name of Coccidiosis avenerea can be given to those cases of coccidiosis, in which the Leucocytozoon syphilidis is not the cause. 1 McDonagh (1914), " Brit. Journ. of Dermatol.," xxvi. 1. 2 McDonagh (1914), " Brit. Journ. of Dermatol.," xxvi, 85. ' Loeb, " Handbuch der Biochemie," ii, 80. * Sequeira (1914), " Brit Journ. of Dermatol.," xxvi, 20, 332. o o o € ^ 10. 12. Q 13. 14. >m IG. 17. 4,^ 18. ^/ 19. 20. ? ■_'l. Lorlirs seeu in rico staiufd with borax mi-ili\irii<' hliic in imnual ami iullaiiu'd ylauds. 1-14 arc developing lymphocytes. 1."). 10 ;ire developing granular leucocytes. 17, 18 are red blood corpuscles. 11)-"21 are adult leucocytes. Platk 1!). Facing ;>. 20. CHAPTER IV. ERRORS TO BE AVOIDED IN EXAMINING SYPHILITIC OR OTHER MATERIAL. It may be as well to mention here the various pitfalls which must be avoided, before one is able to discriminate normal from parasitic cells. I. — In vivo. — 1. Dark-staining motile dots, which are either bacteria or granules from leuco- cytes, are frecjuently to be seen. As a rule they are smaller than, and do not stain so deeply as the sporozoites. 2. Circular bodies, of all sizes from 1 to 7 microns, are invariably to be found in every inflamed tissue. They superficially resemble the female garaetocytes, but may be distinguished by the fact that they contain no chromatin network. The darkly staining masses, of which they are made up, are mostly situated in the circumference of the cell itself, so that one or more of these darkly stained masses will be crescentic in shape. From Plate 19, it will be noticed that there is a close resemblance between the mature lymphocytes and the small circular bodies with the crescentic masses, since in both the most deeply stained part of the lymphocyte and tiny body is the periphery. In the former, the periphery may be stained in its entirety, or, more generally, irregularly, with a preference for one pole, where deeply staining masses are to be found, which ultimately become extracellular. I think it is highly probable that the small bodies referred to are immature lymphocytes. (For further details, vide Chapter XL VI.) 3. Small granular cells, varying in size, Hke the immature lymphocytes, might be mistaken for small spore cysts (Plate 19 (15, 16) ). The granules in the immature leucocytes are smaller than the sporozoites in the spore cyst, less actively motile, not so metachromatic, and they prefer the methylene red, to the methylene violet moiety of the borax methylene blue. These cells are probably embryo mast cells (vide Chapter XL VIII). 4. The fertilised female cell, or zygote, might possibly be mistaken for cells of the same size, which also have an affinity for methylene red. 22 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. If these cells are closely studied, it will be noticed that the affinity for methylene red is very much more pronounced than it is in the case of the parasitic cells. More- over, other cells, both larger and smaller, will be seen to exhibit the same phenomenon, and finally, hardly any two of the cells are exactly aUke ; some have no nucleus, others have their chromatin distributed unevenly about the cell, either in small masses or in strands (Plate 20). These cells will later be found to be degeneration forms of plasma cells, or, in short, aminoplasma cells {vide Chapter VI). 5. Female gametes might possibly be mistaken for a certain form of red blood corpuscle, the centre of which stains with the same dyes as does the nucleus of the parasitic cell (Plate 19 (18) ). These red blood corpuscles are poor in haemoglobin, therefore the similarity between them and the female gametes becomes the closer. The following points will serve to enable a distinction to be made. The red blood corpuscles are found only in cases of pronounced anaemia. Their staining is imeven, i.e., in some parts it is very faintly marked, while in others it is deep. Occasionally, here and there, an area may be seen which has taken the methylene red and not the methylene violet part of the stain. Finally, the stained portion may be in the form of strands, or dots, or masses, not unlike that seen in the aminoplasma cells. II. — Fixed. — Endothehal cells which contain circular masses of varying sizes in their j)rotoplasm may be mistaken for connective tissue syphilitic bodies. The cells ultimately burst, and these masses escape. It is in Giemsa-stained specimens, and in sections, that these masses are most likely to be mistaken in this way. In the case of the former, no bodies should be taken for parasitic, unless they have a background, which, in my specimens, closely resembles the colour of a red blood corpuscle. In sections, the distinction is more apparent. The endothelial masses stain a dazzling transparent red (pyronin), and look as if they had no depth in them ; the centre is usually clear, or, it woidd be better to say that, the most deeply stained part of the mass is the periphery ; furthermore, some of the masses stain green (methyl green), which is some evidence of their not being parasitic {vide Chapter VI and Plate "21). Far and away the most distinguishing feature is the fact, that the syphilitic bodies are massed together in one clear encapsuled space, while the endothelial masses are scattered irregularly about the cell. The syphilitic bodies, as will be seen from Plate 1, have a rose-pink to red background, with their nuclear structure, situated more or less at one pole, appearing eccentrically placed, and very deeply stained, sometimes to a very dark red, or even brown. Most of the syphilitic bodies have a clear space or halo surrounding them. 4 ik 1. ^ 2/iD •t*c^i \ ^ Q^ ^^ 10, i v^-s^^^. 1-2. lo. Varii,>iis forms of ainiooplasma colls to be mot with in hi vivo staininj? with borax iiiotliylone blvio from any plasiuomatoiis losion. Plate 20. Facmg p. 22. PHOTOGRAPHS. X 1500 An eudotliolial cell iu a flxed section from a lympliatic gland. Tlio lymphocytes iu the developing granoplasm of the coll are clearly discernible. This is a later stage of tlie pri'i-.Mling-, in wliicli most of the lym|ihcieyti's to be formed have been formed and Irft tlir cell. The endothelial ell iu consequence has begun to degeuiTale. Platk 21. Fnllmis Villi,- 211. CHAPTER V. ARGUMENTS AGAINST LEUCOCYTOZOON SYPHILIDIS. I may here mention the objections which have been raised to my discover}- of the life-cycle. These objections are purely theoretical, for no observer, other than the two already mentioned (Page 6), has attempted to repeat any of the work. The objections which have been raised can be quite shortly mentioned. It is contended that the Spirochaefa pallida has been obtained in pure culture, and that animals have been infected with such cultures. I have, however, been able to culture the Spirochaeta pallida, and, from my experiments, it is evident that the Spirochaeta pallida in culture develops cxtracellularly. It is possible to lay too much stress upon cultures, especially in the case of protozoa. With bacteria and fungi, the greatest morphological differences exist between the same organism in the body, and in cultures, not to mention the variations produced by the different media upon which they are grown. The difference is hkely to be greater when the growth in culture of a highly developed organism like a protozoon, is compared with its growth in vitro. The statement that animals can be infected with syphilis from cultures of the Spirochaefa pallida, is no objection to my life-cycle, for the following reasons : — (1) In many instances, if a sufficient quantity of a certain organism be injected into an animal, inflammation will result, and some of the organisms may be found in the urine and blood-stream. This is not evidence that the animal is suffering from the specific disease caused by that organism. It must not be forgotten that, if a sufficient quantity of wax or fat be injected into a rabbit's testicle, fine particles of the same may be found later in the blood- stream and in the urine. (2) Considering the resistance of the spores, and their small size compared with that of the spirochaetae, they can be easily overlooked and injected with the latter, when only spirochaetae were .supposed to be present. If looked for in cultures of the Spirochaeta pallida, these small bodies can alwaj's be found. Therefore, 24 THE BIOLOGY, CLINICAL ASPECT AXD TREATMENT OF SYPHILIS. what is happening in the test animal's body, may be no more than what is taking place in a culture tube. The other points are, that the phases described and depicted are cell degenera- tions, nuclear degenerations, or korpereigene structures. The next chapter on the chemistry of the Leucocytozoon syphilidis will show that these views are untenable. Still another argument against my view being correct was, that, in some pro- tozoal diseases, an intermediate host was necessary for the full development of the organism, e.g., malaria, trypanosomiasis, etc. Because an intermediate host, such as the mosquito, has been found necessary for the complete development of the Plasmodium nialariae, it does not follow that an intermediate host should be required by all protozoa. This searching for an intermediate host in all protozoal diseases is doubtless hampering many discoveries. Syphilis is a disease conveyed from person to person, and therefore it cannot be compared with malaria, which cannot be spread in this wise. Owing to the difficulty in doing animal experiments in England, I decided to try an entirely new path, and to attempt to prove, by chemical means, that the bodies described could not be protoplasmic or nuclear degenerations, or, as Hoffmann called them, horpereigene structures. In this work I was ably assisted by R. L. Mackenzie Wallis, and we received valuable assistance from Unna's writings upon the biochemistw of the skin. CHAPTER VI. CHEMISTRY OF THE LEUCOCYTOZOON SYPHILIDIS. The Physical and Chemical Properties of the Staining Reagents Used. In all micro-chemical iiivestigation.s, full consideration must be given to the chemical and physical properties of the staining reagents, before any conclusions are drawn as to the chemical nature of the structures under observation. Ahnost all the members of the group of dyes are colloidal in nature, that is to say, they do not readily diffuse through animal membranes. Like other colloids, they have high molecular weights, and they are amorphous. In solution these dyes form typical colloidal suspensions, the size of the particles varying in different cases ; consequently some stains appear quite homogeneous, whilst others show the well-marked characters of suspensions. Further, many dyes are eliminated by filtration, and they may be separated by this means ; for example, methylene blue occurs in the urine after subcutaneous injection. Owing to their colloidal nature, the small particles of a dye in suspension become electrically charged, and, for convenience, dyes may be divided into negatively and positively charged colloids. The negatively charged colloidal particles of a dye will, therefore, show electrical migration to the anode, whilst positively charged colloids will travel towards the kathode. It follows from this also, that on mixing a positive dye with a negative dye, the charges will be neutrahsed, and the resulting colloidal mixture will then exist in an uncharged condition ; e.g., the eosine-methylene blue mixture, the former being negatively charged whilst the latter is positively charged. The most notable feature common to all dyes is that they exhibit the pheno- menon of adsorption (Bayhss ®). By adsorption is meant a " combination " between two substances which is not strictly in the nature of a chemical union, that is to say, in which there is no direct proportionality between the concentration of the solution and the amount adsorbed. There is some kind of physico-chemical affinity between the bodies adsorbed, and those which take them up, but this affinity is more of a 26 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. mechanical than of a tnie chemical nature. To take an example, if a series of solutions of Congo red be taken, of different concentrations, and the same amount of filter paper be placed in each, a part of the dye is taken up, but in relatively larger proportions in the more dilute solutions of the dye. There are, however, instances where the combination of the dye with the material acted upon, is in the nature of a true chemical combination ; but these are rather exceptional cases, e.g., the staining of nuclei with rongalit white. The presence of electrolytes is a most important factor in the process of pre- paring histological specimens. As regards their adsorptive capacities, the dyes, as a whole, are very sensitive to electrolytes, and the effect appears to be propor- tional to their colloidal nature. Electro-negative dyes, like Congo red, are increased in adsorptive power by the addition of kations, such as lithium, potassium, sodium, ammonimn, magnesium and calcium. On the other hand, anions such as hydroxyl, acetate, chloride, oxalate, sulphate and phosphate depress adsorption. With electro-positive dyes, such as toluidine blue, the reverse is the case, namely, anions increase, and kations depress the adsorptive capacity. The effect of electroh^tes, however, is much more marked in the case of kations than in that of anions. The salts of those heavy metals which form positively charged colloidal hydroxides — for example, iron — have a very powerfid effect on the adsorptive capacity of electro- negative dyes. In every case, the ion promoting adsorption of the dye is carried down with it. If attention be now paid to histological preparations, perhaps it may be possible, in the light of these observations, to interpret the changes induced in the act of staining. In the living cell, the substance to be stained has a negative charge, for the reaction of the tissues always tends towards the alkaline side of neutrahty. It is known that protein solutions, in an alkaline mediimi, are always negatively charged ; it follows, therefore, that hving cells will take up basic dyes, and that electrolytes are not essential to the process. When the cells die, the electrolytes attached to the protein constituents of the cell are split off, with the result that the cells now readily take up acid dyes. Farther, the fixation of a dye is facilitated by heat, and this fact has been utihsed in Altmann's method of acid fuchsin staining. Mayer has also shown, that the affinity of the Nissl bodies of nerve cells for basic dyes is destroyed by previous treatment with neutral salts. This ob.servation further emphasises the importance of electrolytes in the process of staining. If similar observations now be made upon the syphilitic parasite, it can be seen whether the results obtained may be interpreted in the light of these views of staining. In the first place, chief consideration will be given to the two principal stains used, viz., pyronin and methyl green. Both these dyes are positively charged colloids. CHEMISTRY OF THE LEUCOCYTOZOON .SYPHILIDIS. 27 and, in consequence, their staining action will be facilitated by the presence of anions, particularly of hydroxyl and siilphanion. The pyronin will, therefore, act as a basic dye ; and this explains why it is precipitated by nigi'osine and also by diamine green, but not by diazine green. By considering the chemical characters of the dyes used, and by reviewing, in the light of this knowledge, all the results obtained, it is obvious that much useful and valuable information of the micro- chemistry of the cells under investigation may be gained. The specific staining pro- perties of the s}^hihtic parasite will be referred to again, and all that need be pointed out here, is the importance of regarding pyronin as a positively charged colloid, and as one influenced by anions. The Characters of the Syphilitic Bodies, when Stained " In Yivo." The simplest and best way to use a reagent for vital staining, is to spread a solution of it on a shde free from fat and alkali, and to allow this to dry in the air. The film should be made just before it is required, and should not be kept for several days. The material to be examined is placed upon a cover shp, and the latter is so adjusted to the shde that no air remains between them, and so that the fluid to be examined exudes at the sides as little as possible. Examination is possible until the fluid has dried, that is, for several hours. The process is greatly facilitated by ringing the cover shp with wax. The shdes used for hanging drop preparations are useless, but a warm stage may sometimes be employed ■with advantage. I have used all the stains which have been from time to time advocated, but I have not obtained the results promised by the literature on these stains. I may at once state that neutral red, neutral violet, Bismarck brown, auramine, diazine green, malachite green, tropaeohn 00, and Congo red, do not give good vital staining. Owing to the use which is now being made of the azo-dyes, in determining the functional activity of certain cells in the body, I tried several for my method of staining in vivo, but with poor .success. They have feeble staining i)roj)erties, and are general protoplasmic stains, without possessing preferential affinity for certain structures. Moreover, they do not possess metachromatic properties. The dyes which gave the best results were aqueous solutions of borax methylene blue, Jjoly- chi'ome methylene blue, brilhant crystal blue, Nile blue sulphate, and alcoholic solutions of toluidine blue, thionine and azure II. The disadvantage of the alcoholic solutions is, that they must be well diluted before use, as crystals form so readilj- ; this is especially the case with thionine. Azure II stains deeply, but unfortunately it has no metachromatic properties. The intracellular stages are perhaps better depicted by the alcoholic stains ; but, on the whole, the results are not so good as 28 THE BIOLOGY. CLINICAL ASPECT AND TREATMENT OF SYPHILIS. when the aqueous solutions of either borax methylene blue or brilliant crystal blue are used. Of the last two, the former is superior. The metachromatic properties of borax methylene blue are dependent upon the basic sodium biborate. The latter acts upon methylene blue to produce both methylene violet, which, as a basic dye, shows affinity for acid substances, and methylene red, which is an acid dye, and so shows affinity for basic substances. I tried various other bases with methylene blue, with the hope of obtaining greater metachromatic action by substituting for the borax a base of higher valency. For this purpose colloidal aluminium hydroxide was employed. The methylene blue remained unaltered, no doubt owing to the fact that the aluminium hydroxide did not contain sufficient free hydroxyl-ions, and that it was itself an unstable colloid, which therefore had no action upon the positively charged methylene blue. Borax methylene blue, when freshly prepared, has practically no metachromatic action, but, the longer the stain is kept, the more this property increases. Finally the methylene red becomes the stronger dye, and stains the cells just as the methylene violet does. Borax methylene blue appears to be at its best when it has been kept for a year or two. As the methylene red scarcely comes into play in the fresh solutions, no harm is done by adding 0' 1 grm. eosine to 100 c.c. borax methylene blue, for a true chemical compound results. The eosine picks out the granules in the poly- morphonuclear leucocytes, and it brilhantly stains the eosinophile granules, but does not afiect any one of the stages of the syphihtic organism. I learnt that the sj^hiUtic organisms contained lecithin in the form of a lecithin-globulin complex. I was aware of the affinity of this complex for dextrose, so it struck me that it might be possible to increase the staining properties of the organism, by adding dextrose to borax methylene blue. Although the dextrose did not carry the colloidal dye particles to the organism, it nevertheless was taken up by every cell which contained the lecithin-globulin complex, since the protoplasm of such cells swelled and absolutely refused to stain, but, owing to the swelling, they were as easily discernible as if they had stained, consequently the plasma cells and syphihtic bodies could be well studied, as their nuclei were not prevented from staining. I witnessed the act of impregna- tion in a dextrose-borax methylene blue specimen, so I was able to compare it with what I had previously seen. The nucleus of the female appeared to float about, surrounded by the clear ring of mistained protoplasm ; when first seen, one end of the spirochaeta had already entered, as one extremity was fixed to the nucleus ; the spirochaeta was also thickened (due to the dextrose). The one end of the spirochaeta remained fixed to the female nucleus, and, in spite of impact with other cells in its progress, it remained attached to the sanie spot, but did not enter any further. Suddenly the female cell became stationary and the SpirocJiaeta pallida CHEMISTRY OF THE LEUCOCYTOZOON SYPHILIDIS. 29 completely entered it, but 55 iniinites had elapsed before this hai:)pened. No further change was noticed in the female cell, as it had not stained very well, but about four minutes later it became very active and discharged a clear non-staimng polar body, which seemed to be emitted with some force. A few seconds later, another clear polar body was extruded, and then the female cell came to a standstill again. It is possible that the dextrose made these jjolar bodies appear bigger than they really were, as each appeared to be certainly 2-3 fj. in diameter. From what has been stated, it will be easily seen that a description of the syphilitic organism iji vivo, frona its reactions, will entirely depend upon the characters of the borax methylene blue which is used. Now, as impregnated female cells do not stain with eosine, or with the methylene red of freshly prepared borax methylene blue, the increase in the basicity resulting from impregnation cannot be very great. It is far more probable that little change in reaction occurs, and that the reason for staining with methylene red, a fact which I have frequently observed, is due to an increase in the reducing action, as will be shown later. The sporozoites may remain for some time unstained, or they may immediately stain a dense violet. The intracellular phases stain late, and the early ones show an affinity for the methylene violet moiety, whilst the late ones, viz., the coils, take up the methylene red. The females, before fertilization, remain unstained, except their chromatic network and blepharoplasts, which immediately stain with methylene violet. The Spirochaeta pallida stains pink, and when it has impregnated a female cell and when the whole cell has come to a sudden standstill, a pink diffuse stain comes over the cell like a mantle. The sporozoites, while in the spore cysts, show a greater affinity for methylene red than for methylene violet, and some sj^ore cysts are seen which stain distinctly metachi-omatically. In staining in vivo with a negatively charged colloid, it follows that basic dyes will react best, and this has been found to be the case. The reason why neutral red, neutral violet, Bismarck brown, auramine, diazine green, malachite green, tropaeoliu 00, and Congo red, were found not to give good results, is simply due to the fact that they are negatively charged dyes, and therefore they cannot stain cells, which contain colloids in solution with a negative charge, and which exist in a medium on the alkaline side of neutrality. It follows that good staining can be obtained only by using dyes with a positive charge, hence the reason why borax methylene blue and polychrome methylene blue serve so admirably, for it is only under such conditions that adsorption can come into play. Summary. — Basic stains are the most suitable for in vivo work, and, of these, borax methylene blue is the best. Owing to the presence of a lecithin-globuhn envelope, the syphilitic bodies can be made to stand out more clearly by adding dextrose 30 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. to the stain. The varied affinity shown by the different bodies, on the one hand for methylene violet, and on the other hand for methylene red, is due to the pre- valence of a substance which has strong reducing properties (lecithin-globulin), and not so much to a change in the reaction. The Characters of the Syphilitic Bodies when Stained in Fixed Specimens. Both Pappenheim and Martin Heidenhain explained the specific action of methyl green for chromatin, as being due to the breaking down of the weak basic salt by the strong nucleic acid radicle. The nucleus, however, did not stain with pyronin, which they regarded as being a more strongly basic salt. As a matter of fact, since methyl green is a triamino-stain, it is by far a stronger base than the diamino-stain pyronin, the basicity of which is also diminished by its extra oxygen atom. Furthermore, acetic acid increases methyl green staining, and if acids combine with the free amino group of the salt, acetic acid would have done this before the nucleic acid could do so. Therefore, this explanation of its action, which had held sway for some years, cannot be the correct one. A stain which had been largely used by Unna,, namely, rongalit white, was found to resemble methyl green in many respects, and was only known to stain the oxygen positions of the tissues. Rongalit white is the leuco-base of methylene blue, and it is prepared with sodium sulphite and formalin. It is, therefore, a colourless and basic mixture, and the methylene blue is only brought out as a dye in the presence of oxygen. As rongalit white stains the nuclear part of the cell, Unna concluded that methyl green also picked out the oxygen foci of the tissue, and that it was, therefore, a reduction-sensitive stain. By a series of experiments, Unna showed that methyl green was far more sensitive to reducing substances than methylene blue was, and that malachite green came in between, but that such reducing agents as grape sugar and hydroxyl- amine were without effect, i.e., they did not decolourise methyl green. Another difference between methyl green and methylene blue, and malachite green was, that the leuco-bases of the last two could be reconverted into their coloured bases by the addition of hydrogen peroxide, but this could not be done in the case of methyl green. Until Unna enunciated his theory of staining by oxidation and reduction, we were under the impression that staining depended upon reaction ; in other words that acid substances stained with basic dyes, and were therefore termed basophihc ; and that basic substances stained with acid dyes, and were therefore termed ~1 vco- \ Plate 22. — Twelve Ready Methods for DiPPERENTLiTiNG the Phases or the Le CYTOzoox SyriiiiJDis in Section. 1. — Section of sypliilitic lymphatic gland, fixed in 50 per cent, alcohol, and stained with equal parts of freshly prepared 1 per cent, solutions of potassium ferricyanide and ferric chloride, mixed imnrediately before use. The syphilitic body is a zygote. Owing to the reducing action of the parasitic lipoid-globulin, which is most marked over the nucleus, the protoplasm stains a light Berlin blue, while that part of the protoplasm over the nucleus stains a dark Berlin blue. The other cells stain green. Aminoplasma cells, owing to the strong reducing action they exhibit, because of the tjTosine they contain, also stain dark Berlin blue, but these can easily be distinguished from the sypliilitic parasites. The female gametocyte is indistinguishable from a plasma cell, because the reducing action of the lipoid-globulin does not become marked until after fertilisation. 2. — Section of syphilitic lymphatic gland, hardened in 50 per cent, alcohol, and, befoio being stained with pyronin and methyl green, left for twelve hours in a mixture of a 1 per cent, solution of potassium ferrocyanide and equal parts of normal acetic acid. If the tissue is hardened in 50 per cent, alcohol and treated with the potassium ferrocyanide solution only, every trace of lipoid-globulin vanislies. If the tissue is hardened in absolute alcohol and treated with the potassium ferrocyanide solution, only the most resistant lipoid-globulin remains behind. The addition of acetic acid to the 50 per cent, alcohol hardened specimen, prevents the destruction of the more resistant lipoid-globulin, and therefore serves as an excellent means of differentiating the Leiicocijlozoon syphilidis. The phase shown in this specimen is the binary fission of a zygote. Note the admirable preservation of the syphilitic lipoid-globulin, the less preserved pyroninophile properties of the nucleoli, and the still less preserved pyroninophile properties of the protoplasm of the plasma cells. 3. — Section of syphilitic lymphatic gland fixed in absolute alcohol, and treated for twelve hours with a 1 per cent, solution of potassium ferrocyanide, before being stained with pjTTonin and methyl green. The phase shown is a female gametocyte. It should be noted that the protoplasm of the plasma cells scarcely stains, and that even a small portion of the syphilitic lipoid-globulin has been destroyed, since the protoplasm of the syphilitic cell stains only a pale rose-pink and the nucleus a deeper red. 4. — Section of syphilitic lymphatic gland, fixed in 50 per cent, alcohol, and treated with normal saline for twelve hours, before being stained with pyronin and methyl green. The phase represented is a spore cyst. In the spore cyst it will be noted that three bodies are stained red, while seven smaller bodies are stained dark green. Three bigger bodies stain red, because they have not lost their lipoid-globulin membrane. They are therefore sporoblasts. The smaller bodies, which have lost their lipoid-globulin membrane, are sporozoites. The lipoid-globulin of the plasma cells and of the nucleoli has vanished. 5. — Section of a syphilitic lymphatic gland, fixed in 50 per cent, alcohol, and stained with rongalit white II. The phase sho\vn is a female gamete, just after fertilisation. It will be noted that the protoplasm of the plasma cells does not stain, only the nuclei and the nucleoli. The protoplasm of the syphilitic phase stains pale blue, while that covering the nucleus stains a very dark blue, much darker than the chromatin of the nuclei of the j^lasma cells and of their nucleoli. This shows that the oxygen content of the syjihilitic body is much greater than that of the nuclei or the nucleoli of the other cells. 6. — Section of a syphilitic lymphatic gland, fixed in 50 per cent, alcohol, and stained with Ehrlich's triaeid stain. The phase shown is a developing trophozoite in a connective-tissue cell. It will be noted that the protoplasm of the plasma cells does not stain, nor do their nucleoli, with the acid fuchsin, while the protoplasm of the syphilitic j'arasite does. 7. — Section of a syphilitic lymphatic gland, fixed in absolute alcohol, and stained with pyronin and diazine green. The phase shown is a female gametocyte. It should be noted that the nucleus of the sj-philitic parasite stains with pyronin, while the nucleoli of the other cells stain with the diazine green. Diazine green is not nearly so sensitive to reducing substances as is methyl green, and since the nucleus of the syphilitic cell stains ■nith pjTonin, while the nucleoli of the plasma cells stain with diazine green, it jjroves that the reducing action of the syphiUtie bodies is greater than that of the normal cells. 8. — Section of a syphilitic lymphatic gland, fixed in absolute alcohol, and stained with safra- nin and methyl green. The phase showni is a female gametooj'te. It should be noted that the syphilitic body shows a greater affinity for safranin than does the protoplasm of the plasma cells. Further, the nucleoli stain with methyl green. The picture presented by this specimen might at first sight appear paradoxical, because so much has been said of the pyroninophile properties of the Leucocytozoon syphilidis. Pyi'onin is a basic stain, safranin is an acid stain. As the syphihtic parasite stains so well with safranin, it is clearly shown that amphoterism only plays an insignificant part in the staining of fixed material, while reducing action plays a greater part. The reducing action of the nucleoli is not sufficient to overcome their basophilic properties, consequently they stain with methyl green. In the syphilitic parasite, on the other hand, the reducing action of the lipoid-globulin membrane of the nucleus so strongly outweighs its baso- philic properties, that it stains with safranin rather than with methyl green. 9. — Section of a sjrphilitic lymphatic gland fixed in 50 per cent, alcohol and treated with human serum for twenty hours before being stained with pyronin and methyl green. The phase sho\\ii is a spore cyst. It will be noted that only a portion of the lipoid-globulin has been destroyed, wliile that of the plasma cells and nucleoli has completely vanished. 10. — Section of syphilitic lymphatic gland, fixed in 50 per cent, alcohol and treated for twelve hours with 25 per cent, alcohol, before being stained with pyronin and methyl green. The phase shown is a trophozoite, in a connective-tissue cell. It should be noted that more lipoid- globulin has been destroyed than in the following specimen, that the protoplasm of the syphihtic body stains with about the same intensity as that of the plasma cells, while the lipoid-globulin covering the nucleus is still markedly pyroninophile. As some of the lipoid-globulin covering the nucleus has been destroyed, one sees a trace of the chromatin network arrangement of the nucleus in an early trophozoite. II. — Section of a s\-philitic lymphatic gland, fixed in 50 per cent, alcohol and treated with 50 per cent, alcohol for twelve hours, before being stained with pyronin and methyl green. The phase shown is a trophozoite, in a connective-tissue cell. It will be noted that the proto- plasm of the plasma cells stains better than in the preceding specimen, and the syphihtic parasite also stains better, but comparing it with the following specimen, one can see that even a portion of its lipoid-globulin has been destroyed. 12. — Section of a syphilitic lymphatic gland, fixed in 50 per cent, alcohol and treated for twelve houre with 70 per cent, alcohol, before being stained with pyronin and methyl green. The phase shown is a trophozoite, in a comiective-tissue cell. It will be noted that the pyronino- phile properties of the syphihtic parasite are unimpaired, while those of the protoplasm of the plasma cells and the nucleoli are faintlv diminished. (0 ^- 9 0) Qj •^ ^% ^ ^ Q i^ (i^ ^ • ••: ^^ Q © O ^ ^ 9 ^'i Plate 22. CHEMISTRY OF THE LEUCOCYTOZOON SYPHILIDIS. 31 acidophilic. No doubt, in part this conception is correct, but there is also no doubt that it was carried very much too far. After all, fixed protoplasm is an amphoteric substance, i.e., it can act as a base or as an acid ; for instance, the proto- plasm of plasma cells stains well with acid fuchsin, which is an acid dye, or with pyronin, which is a basic dye. Although it stains with both, it stains better with the latter than with theformer ; therefore, under ordinary circumstances, it may be stated that protoplasm, using the word in a very general sense, prefers to act as an acid. From my description of the Lencocijtozoon syphilidis, and from the coloured plates which illustrate this book, it will be seen that, by using Pappenheim's stain (a mixture of pyroniu and methyl green), the syphilitic bodies stain with pyronin ; but that they differ from all other cells, in that the nucleus also apparently stains with pyronin, and with a much deeper red than the rest of the cell. Working on the reaction hypothesis, or on the electrolytic theory, one must assume then, that the protoplasm, and especially that of the nucleus of the syphilitic organism, is strongly basophilic, and is negatively charged. It has, however, already been shown to be partly acidophihc, from the in vivo examinations, when it was pointed out that certain phases showed an affinity for methylene red. We have, then, a paradox, and a solution to the problem can be found only if we adopt Unna's theory of oxidation and reduction. Methylene violet, like methyl green, is a reduction-sensitive dye, although not to the same degree. The reason why certain phases stain with methylene red, is not because the protoplasm is acidophilic, but because it has reducing properties ; and, as methyl green is far more sensitive than methylene violet, every phase stains with pyronin, while, only in those in which the reducing action is greatest, is the affinity of methylene violet for nucleic acid overcome. The result of this is, that the reducing substance stains with methylene red. This reducing sub.stance does not stain very readily with acid dyes in fixed specimens, should a basic dye be present as well ; because if pyronin is supplanted by acid fuchsin, most of the nuclei of the syphihtic organisms .stain with methyl green (Plate 22 (6) ). Therefore, this characteristic pjToninophile .substance of the syphihtic organisms is a strong reducing agent, is basophihc, and ,so is negatively charged, according to the electro- lytic theory ; but the action of its electric charge is overshadowed by its reducing action. Therefore, we have another extremely important factor coming into play in the act of staining. Seeing how sensitive a stain methyl green is, it at once appears obvious that great caution must be taken in choosing the most suitable fixing reagent, and that any fixing reagent which robs the nucleus of its oxygen will naturally prevent staining with methyl green, and will also alter the action of the medium. Fixing c 32 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. tissue for 24: hours in a 1 per cent, solution of platinum chloride increases the capacity of the nuclei for methyl green, but it is an expensive solution, and it does not give such good results as some other fixing reagents. Mercuric chloride has the disadvantage that the sections may stain unevenly, since it increases the capacity for methyl green staining only in the situation where it remains, and diminishes it in those situations where it is reduced by the tissue. If mercuric chloride is employed in an alcoholic solution as a fixing reagent, quite good sections may be obtained with Pappenheim's stain, and the effect is enhanced if a little acetic acid is added to the mixture. Chrome salts destroy the staining properties of pyronin and methyl green. Osmic acid alone, or in conjunction with other acids, diminishes the receptivity of protoplasm to most dyes. Formalin, owing to the formic acid which it so frequently contains as an impurity, not only diminishes the staining properties of protoplasm, but also markedly reduces the power of the nuclei to stain with methyl green. Including other fixing reagents which are seldom used, and are not available for obtaining satisfactory sections with Pappenheim's stain, practically only alcohol remains. From several experiments I have undertaken, I have been convinced that alcohol is far and away the finest fixing reagent we possess at present, as it allows staining with most of the stains in general use, it fixes by coagulation, and forms no chemical compound with the cells. Therefore it is extremely well adapted for the purpose of micro-chemical research, when fresh sections are not employed. I employ either absolute alcohol, or 50 per cent, alcohol ; the former causes shrinking of the intercellular tissue, but not so much shrinking of the individual cells, and its main advantage is that coagulation is immediate. The moment the tissue is removed from the body, it is put into absolute alcohol, and allowed to rest on wool. Whenever alcohol is used, a pad of wool should rest on the bottom of the bottle, so as to allow the alcohol to remain approximately the sanje strength throughout, while the water extracted from the tissue sinks through the wool. This simple device also leads to a great saving of alcohol. The tissue remains for 12 hours in absolute alcohol, and it can then be changed into two further lots of absolute alcohol for 12 hours each, or be put back to 50 per cent, and gradually taken up, in the usual way. Cedar wood oil is used for clearing, as it does not harden the tissues to the same extent as xylene. Before the tissues are put into wax, two changes of xylene are used, for 1-2 hours each, as wax penetrates better after the tissue has been through xylene. The wax used is a mixture of : — Paraffin (melting point 60' ('.)... ... ... 8i parts. Stearin ... ... ... ... ... ... 1 part. Wax ... ... ... ... ... ... i jiart. CHEMISTRY OF THE LEUCOGYTOZOON SYPHILIDIS. 33 The melting point of the prepared article is 53° C, and the tissue is left in three changes of this, for about six hours altogether. The whole of the secret of getting good paraffin sections, is to be absolutely certain that the tissue is fully dehydrated. The tissues can also be fixed in 50 per cent, alcohol, if allowed to remain in the solution for 2i hours, and then for 24 hours each in 70 and 90 per cent., and 12 hours each in three changes of absolute alcohol, and so on as before. There is not so much shrinkage of the tissue, and most excellent Pappenheim- stained sections may be obtained. For some tests of minor importance, celloidin sections are preferable, but, for general purposes, I much prefer paraffin, as thinner sections can be obtained. They can be more easily fixed to the cover shps, and one does not have to go through the troublesome procedure of removing the celloidin, as is necessary when anihne dyes are being used, owing to the intense avidity which celloidin has for many of them. If Pappenheim's stain is to be used, I proceed as follows : Eoughly three parts of a saturated aqueous solution of pyronin are mixed with one part of a saturated aqueous solution of methyl green, immediately before use. This mixture assumes a red-purple colour. In this stain, the sections may be left from 5 minutes indefinitely, as overstaining is impossible. After being in the stain, the sections are transferred to a freshly prepared distilled water solution of resorcinol, which is merely used for washing off the stain. Here they are left for about a minute, and then they are put into a freshly prepared absolute alcoholic solution of resorcinol, and are kept in it until all the superfluous stain has come awa)^ These resorcinol solutions are absolutely essential, as they act as mordants, and I regard mordanting after staining as superior to Uima's method, which consists in adding carbolic acid to the stain, so enabling the stain to be prepared and always to be ready for use. The stain is sold under the name carbol-pyrouiu- methyl green. The great disadvantage of the ready prepared stain is, that the pyronin comes out too cpiickly in the dehydrating process, while, if resorcinol be used, this is not the case. The amount of resorcinol crystals used in the first watch glass is about 0" 3 grm., and in the absolute alcohol watch glass, just double the quantity. From the resorcinol, the sections go through three changes of absolute alcohol, two of xylene, and are then mounted in balsam. As ethyl alcohol may abstract the pyronin stain from the sections, such clearing fluids may be used to take its place as chloroform, lavender oil, or bergamot oil. Clove oil should never be employed, owing to its powerful reducing action. Xylene fortunately acts indifferently, but Canada balsam, in time, owing to its reducing and acidic action, destroys the staining effect. Dammar, dis.solved in xylene, forms a better medium for preserving the section. For a year or two, or C 2 o 34 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. even longer, sections stained in the above method and mounted in Canada balsam, show a much sharper contrast of colour ; the pyronin stands out clearer, the orange colour of the mast cells is more distinct, but the methyl green staining is somewhat weaker, and, as time proceeds, it is the methyl green stain which first disappears. Some sections, prepared seven years ago, are as good as, and in many respects o\ving to increase of sharpness, better now than then. In a Pappenheim-stained section, the protoplasm of the groundwork and connective-tissue cells stains a rose-pink, and has a finely granular appearance, whereas the protoplasm of the plasma cells stains a clear red (Plate 1). All nuclei stain green, the nucleoli a brilliant red, the mast cell granules orange, and all bacterial and protozoal bodies red. The protoplasm of the syphilitic bodies stains a rose pink to red, and the nuclei, stain a deeper red. The difference in the rose-pink to red of the protoplasm is most marked in the female cells, and depends upon whether they have been impregnated or not, as the fertilised female cells and zygotes always stain more deeply. At first sight, one might conclude that the supposed nuclear part of the sj-philitic organism, because it contains no nucleic acid, stains deeply with pyronin ; but I have endeavoured to prove that such a surmise is incorrect. I added acetic acid to the alcohol in which the tis.sues were fixed, in the propor- tion of 1 c.c. glacial acetic acid to 7-5 c.c. either absolute or 50 per cent, alcohol, with the hope that, if any nucleic acid was present, the acetic acid would precipitate it. When the sections were stained, I found that the general pyronin staining had not been interfered with, that the methyl green staining was strongly intensified, and that some of the nuclei of the syphilitic bodies stained a brilliant green, which at once proved that they contained nucleic acid (Plate 13 (1) ). The addition of acetic acid to the alcohol used for fixing in ordinary staining with pyronin and methyl green, gives better residts than if alcohol is used alone, owing to the fact that, apart from the nucleic acid being precipitated, the swelHng action of the acetic aeJd on the cells is counterbalanced by the shrinking action of the alcohol, and ince versa. For special staining, as when the demonstration of micro-organisms is required, alcohol alone is the one and only fixing reagent. As methyl green is one of the ingredients of Ehrhch's triacid .stain, and as the red dye, acid fuchsin, is an acid dye in contradistinction to pyronin, which is basic, I stained some sections with this mixture, with the result that the protoplasm of the s}T)hilitic bodies' stained red, while the nuclei stained green, another proof that the nuclei contain nucleic acid (Plate 22 (6) ). It can, therefore, be assumed that there is some substance either in or over the nucleus of the sj'philitic parasites which is a strong reducing agent, as it prevents the methyl green from getting at the nucleus, and that it prefers basic to acid dyes. ^««» # ■•# \t? ^ <5 « e5> <@s> t ^ ■\ n IV ■ ^ » '^ ■^ .>^ 4 ) «%, % A (^ K- Aniiuoplasnia cells in fixed tissue. 1. Shows a luultiloculatotl aminoplasma cell iu tlie ceuti'o. 2. Shows two bilobed amiuoplasma cells, one on each side. Plate 23. cing p. r!4. CHEMISTRY OF THE LEUCOCYTOZOON SYPHILIDKS. 35 My next step was to try to determine the reducing action of this substance, and also its degree of sohibihty in various reagents. Reducing action. — («) Sections were stained for 1-2 minutes in a freshly prepared 1 per cent, solution of potassium permanganate, then they were washed in water, decolourised in oxalic acid if overstained, dehydrated, and mounted ins balsam. All protoplasm has a reducing action, and consequently it stains browu' with potassium permanganate, while the nuclei remain unstained. The protoplasm, of the syphihtic bodies has a greater reducing action than ordinary granoplasm,. and some of the nuclei stain a dark brown. If the section be counterstained with methyl green, it is found that the nuclei of the parasitic cells do not stain so well as those of the ordinary cells, and in those parasitic cells the nuclei of which stain least with methyl green, a clear halo appears to surround the nucleus. These cells have the strongest reducing action. (6) Sections were placed for 5 minutes in a mixture of equal parts of a 1 per cent, solution of ferric chloride and of a 1 per cent, solution of potassium ferri- cyanide. It is imperative that these two solutions shall be mixed only immediately before use, as, if allowed to stand, a blue precipitate is slowly formed. The reducing action of the granoplasm converts the ferricyanide into ferrocyanide, with the result that, where the reduction is greatest, a beautiful Berlin blue colour is formed in the presence of the ferric chloride. Ordinary granoplasm has a weak reducing action, and so stains green ; the granoplasm of plasma cells and of the syphilitic bodies has a stronger reducing action, and so stains darker green, while the nucle of the ordinary cells do not stain, but some of the nuclei of the syphilitic bodies do stain a faint Berlin blue colour (Plate 22 (1) ). Red blood corpuscles also give the Berlin blue reaction, and so do the aminoplasma cells, both to a more marked degree than the nuclei of the syphilitic bodies. Ordinary nucleoli have likewise a reducing action on ferric ferricyanide, and they tend to stain a very faint Berlin blue colour. There is something quite characteristic in the appearance of the syphilitic bodies stained with potassium permanganate, and of those stained with ferric ferricyanide, because in the former, when counterstained with methyl green, the nucleus appears smaller than it really is ; there is less nucleus exposed to take the methyl green. In both it appears to be irregular, and, scattered here and there about the nuclei, are small non-staining transparent areas. I will deviate somewhat from my course here, and dwell upon the aminoplasma cells (Plates 20, 23). The aminoplasma cell is a form of plasma cell, which Unna has called, from his examinations thereof in fixed specimens, hyaline plasma cell. The term " Hyahne " rather suggests some relationship to cartilage, although it is very 36 THE BIOLOGY, CLINICAL ASPECT AND TREATMEXT OF SYPHILIS. largely used for substances of which the obserYer has no knowledge. Now, hyaline cartilage is a strongly basophihc substance owing to its chondroitin-sulphuric acid radicle, and therefore it possesses great affinity for basic dyes. Unna's hyaline plasma cells are, on the other hand, acidophihc, and they contain no acid radicle ; furthermore, they have very strong reducing properties, and so cannot stain with methyl green, and, as I shall show presently that this reducing action is due to tyrosine, I consider that the best name for them is aminoplasma cells. The cell is frequently to be met with in syphilitic material, but it is also to be found in any very chronic inflammatory lesion, viz., Rkinoscleroma and Ulcus molle serpiginosum. In in vivo specimens, an aminoplasma cell is apt to be mistaken for a zj-gote, owing to the affinity which both have for methylene red. The distinction becomes clear, when it is borne in mind, that the former may vary in size from 7-14 // or more in diameter, that it may have no nucleus, that the nucleus stains homogeneously with meth3dene vnolet, that it may be situated in the centre of the cell or at the periphery, and that it sometimes possesses the power of motion, and may be extruded, and finally excluded, from the cell altogether. In the amino- plasma cells, dots are also generally to be seen, and masses or strands may be situated anywhere and irregularly scattered about the cell, but they have no connection with the nucleus, although they stain deeply with methylene \nolet (Plate 20). In fixed specimens, the appearance of these cells is very different, and instead of being round, homogeneous cells, they are often irregular in shape and divided up into irregular sized loculi or balls of protoplasm, many of which become loose and scattered about in the tissue. These balls stain with safranin, and acid fuchsin, and give a Berhn blue reaction with ferric ferricyanide. They do not stain well with pyronin, but, in some specimens, strands of protoplasm are to be noticed in between the loculi, and they do stain with pyronin. The strands are, no, doubt, the same as the dots, masses, and strands, which were described in the in vivo method as showing an affinity for methylene violet (Plate 23). These ballooned plasma cells have, in some cases, lost their nuclei, whilst, in other cases, the nucleus is lengthened out and fits one apex of the cell as a cap does the head, and, not infrequently, sends string-hke processes down over the cell protoplasm. These cells are, no doubt, degenerated cells, because the protoplasm gives amino-acid reactions, and, in the most degenerated cells, the nucleus gives the histone reaction, and fails to stain with methyl green. From what has been said, it will at once be seen that the sj^hilitic bodies bear points of resemblance to the aminoplasma cells, but that they differ in the very striking point, that the most reducing part of the s'V'philitic body stains deeply CHEMISTRY OF THE LEUCOCYTOZOOX SVPHILIDIS. 37 with pyroiiin, whilst the most reducing part of the aniinoplasnia cell stains faintly with pyrouin. As I have shown that the reducing substance of the former is basophilic, it at once appears obvious that that of the latter is more acidophilic. The Berhn blue formation is a fixed chemical process between tissue and reagent, since, although the colour can be caused to vanish with alkalis, it immediately returns on the addition of an acid. As the feeble reduction areas are more quickly decolourised than the firm Berlin blue areas, weak alkalis may be used to decolourise the former, and the protoplasm of the cells can then be counterstained with an aniline dye. (c) The third reaction I tried was with tetranitrochrysophanic acid (Ci5H80j(NOJj). It is a crystalline product, obtained from chr3-sarobin, which is dissolved in acetic acid, and treated with nitric acid. The reagent is insoluble in water, and, owing to the reducing power of ethyl and methyl alcohol, it has to be dissolved and kept in chloroform or xylene. After staining for 10 minutes, the sections are returned to chloroform, put through three changes, and through xylene, and then mounted in balsam. Weak reducing agents stain a pale red-rose, strong reducing agents stain red. The protoplasm stains pale rose-red, nuclei remain unstained, syphilitic bodies stain a deeper red, but the contrast is not so clear as in {a) and (b). In tissues there are four chief classes of bodies : — 1. Proteins. 2. Carbohydrates. 3. Fats. 4. Cholesterol, lecithin and allied lipoids. All four groups possess reducing properties in varying degrees, but the second may be ruled out in the present discussion, as will be shown later. Therefore, the reducing substance must be a protein, a derivate of a protein, a fat, or a lipoid. Speaking generally, pure proteins, fats (olein excepted), and lipoids, are not strong reducing agents, but derivates of proteins are, especially the amino-acids, and here is appended a list of amino-acids, with their action on potassium perman- ganate, and on the ferric ferricyanide mixture (after Unna) : — Amino-acids. OlnO^. Iron mixture Asparagiue — - -Manine... — — Phenylalanine — — Leucine _i_ -t- Glutaminic acid -1- -1- Glycokoll -t- + - Cystine -l-H- - TjTOsine and Tryptophane ... + + + -i- + -|- 38 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. The amino-acids which -par excellence give the Berlin bhie reaction are tyrosine and trj'ptophaue, and, to prove that these plasma cells contained tyi'osine, some sections were stained in Millon's reagent, with the result that the recognised reaction was obtained. Millon's reaction was, on the other hand, not given by the syphihtic bodies ; therefore, the reducing substance of the syphilitic bodies is not dependent upon tyrosine for its action. So far as amino-acids are concerned, it may be said that the syphilitic bodies contain none in the free state. Feehng that the protein molecule existed as such, attention was first directed towards this substance, and all Unna's experiments, which led him to divide the proteins into albumoses, were repeated. {«) Tlte protoplasmic portion of the syphilitic organism. Eecent work has proved to me that Unna's arbitrary division of albumoses is not justifiable. To say that granoplasm is a very special albmnose, as Unna ventures to do, can scarcely be correct, since the granoplasm of connective-tissue cells behaves differently froni that of plasma cells. The greatest difference is also to be noticed in the individual plasma cells themselves, depending upon their stage of development and degeneration, and, lastly, the behaviour of organisms and protozoa is as different again, and all behave differently according to the method of fixation. Unna states that granoplasm is a deuteroalbmnose, and not a primary albumose. Although it differs from the former, owing to its greater insolubihty, and in this respect resembles an acroalbumose which belongs to the latter group, the assumption is made that granoplasm is a deutero-albimiose, which has probably been formed from an acroalbumose. The opinion is now generally held that albumoses are degeneration products of protein, and that the protein of a cell consists of albumin, globidin and Upoid-globulin. The albumin is the most easily destroyed by reagents, then the globulin, and finally the Hpoid-globuhn. The last is practically insoluble in most of the reagents used. Owing to the insolubility of Hpoid-globuhn, it was always regarded as nucleo-protein, but later on it will be seen that such a conception is incorrect. Unna, and most other observers, treated the sections beforehand with alcohol and ether, to extract the lipoids, but, as this work will show that adsorbed hpoids cannot be so extracted, naturally the inter- pretation of their conclusions cannot be correct. To make this very complicated part of the subject as clear as possible, it may be said that the most soluble granoplasm is that met with in the connective-tissue cells and groundwork, then comes the granoplasm of some plasma cells, then of other plasma cells, then of the embryonic lymphocytes and nucleoli, and finally CHEMISTRY OF THE LEUCOCYTOZOON SYPHILIDI8. 39 of the syphilitic bodies. Here we must halt for a moment, as in the syphilitic bodies ■we are dealing with two distinct proteins, one which stains pink to red with pyronin, the other highly refractile, which stains deep red with pjTonin. The former of these proteins is the groundwork or granoplasm of the cell, and resembles ordinary granoplasm ; the latter may cover the whole cell, or only the nucleus, and it is extremely resistant to reagents, and therefore does not resemble ordinary granoplasm ; this is the protein which may be called the pyroninophile substance. As the granoplasm of the syphilitic bodies resembles ordinary granoplasm, the protein of the syphihtic bodies will be referred to as the pjToninophile substance, since it is the chemistry of this substance that is to be imi-avelled. Unless otherwise stated, the following experiments were undertaken with sections which had been fixed in 50 per cent, alcohol, and which were placed in the different reagents for 12 hours at room temperature, and then stained with pjTonin and methyl green. 1. In distilled water, granoplasm begins to dissolve, the action is very much quicker at .37°, but the syphihtic bodies remain unaltered. If kept in water for several days, the avidity for pyronin disappears, and the nucleic acid is left behind to stain with methyl green. One may say that the protein of the syphilitic bodies is insoluble in water. If normal sahne is substituted for distilled water, the action is much the same, and the syphilitic bodies are still insoluble (Plate 18 (4) ). 2. 30 per cent, alcohol behaves like normal saline, and dissolves a greater por- tion of the granoplasm, but has no action on the syphihtic bodies. In 60, 70, 80, 96 per cent., and absolute alcohol, the granoplasm remains mostly intact, depending upon the concentration, as no granoplasm is soluble in absolute alcohol. In no percentage of alcohol are the parasites dissolved (Plate 22 (10-12) ). 3. In a 10 per cent, solution of metaphosphoric acid, granoplasm and the syphilitic bodies are insoluble, owing, no doubt, to the precipitation of all proteins by the acid ; this is hkewise the case with 1 per cent, phosphomolybdic acid, either alone, or with 1 per cent, hydrochloric acid, 1 per cent, phosphotungstic acid, picric acid, and weak solutions of the mineral acids. It is very difficult to work with the above acids, owing to the fact that they all prevent staining with methyl green, and everything stains a diffuse red with pyronin. 4. Granoplasm and the proteins of the syphihtic bodies are insoluble in all strengths of acetic acid. The fact that the nuclei stain green, giving the first impression that the pyroninophile substance, over, or in them, has been dissolved, is only due to the marked precipitating action of acetic acid on micleic acid. 40 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. 5. Graiioplasm is very soluble in a 1 or 2 per cent, solution of boric acid, but is insoluble in a 5 per cent, solution ; the syphilitic bodies, on the other hand, retain their affinity for pyronin. Such a pretty and instriictive picture is obtained by leaving a section in 1 per cent, boric acid for 12-20 hours at ordinary temperature, and then staining in the usual way with pyronin and methyl green, that more than a passing mention is desirable. The grauoplasm of all the cells has dissolved, the nucleoh have vanished, those embryo l}anphocytes which stain red, and ■which might be confounded with certain phases of the syphilitic organism, now all stain a brilliant green, and the only bodies which stand out a brilUant red colour, are the syphilitic parasites. So, in this very simple method, we have as fine a differential stain as the Ziehl Niellsen for tubercle bacilli (Plate 24). 6. In 1 per cent, potassium ferrocyanide, not only does the ordinary grauo- plasm disappear, but the protein of the syphilitic bodies does so also, with the result that only the nuclei stain with methyl green. If acetic acid is added to the potassium ferrocyanide, the granoplasm and protein of the syphilitic bodies remain unaltered, and stain in the ordinary way (Plate 22 (2) ). 7. In a 2 per cent, solution of copper sulphate, the granoplasm has gone, nuclei remain, nucleoli have disappeared, as also the granoplasm of the amino- plasma cells ; the groundwork protoplasm of the .syphiUtic female bodies has vanished, but the pyroninophile substance over the nucleus remains intact, and stains with pyronin, and most of the spore cysts stain red. 8. In 1 per cent, caustic potash, nuclei and all have dissolved. 9. In mercuric chloride and alcohol, there is no change. 10. The syphilitic bodies remain unchanged after treatment with a 1-10 per cent, solution of lead acetate ; nucleoli are hkewise not dissolved in this reagent. From these experiments, it is clear that the pyroninophile protein of the syphilitic parasites is not ordinary granoplasm, it is not an albiunin, albumose or peptone ; this leaves us with only globuhn. So, when the insolubility of the protein imder question is considered, I think I am justified in saying that it is a globulin, or, as will be seen later, a globuhn complex. If the sections have been fixed in absolute alcohol, which prevents the extraction of salts, and acts as a very powerful coagulant, many of the above-mentioned substances fail to make any alteration ; boric acid, for instance, is innocuous, and the syphilitic protein does not dissolve in potassiurii ferrocyanide. To produce the similar results, sections must be left in the reagents for several days (Plate 22 (3) ). 50 per cent, alcohol can extract electrolytes from the cells, hence the}' become less negatively or positively charged, and the charge may be still further diminished by reagents, and, as electrolytes are essential for the staining of fixed specimens, I Plate 21. Section of ti syphilitic Ijmphatic gl:incl, which has been treated with a 1 per cent, sokition of boraoic acid, Ijulore being stained with pyionin and methyl green. The section shows a developing trupliozoite in an endothelial cell. Facing p. 40. .1-S axjia'l ban iiino'ix" Muhleus (1910), " Klin. Jahrb. ' xxiii, 339. " Hoffmann (1911), " Deut. med. Woch." xxxvii, 1546. 12 Hoffmann (1911), " Zeitschr. f. Hyg." Iviii, 27. '3 Tomasczewski (1912), " Berl. klin. Woch." xlix, 1556. " Sowade (1914), "Arch. f. Derm. u. Syph." cxix, 189. 1" Nakano (1912), " Deut. med. Woch." xxxix, 13.33. "■■ Shamine (1912), " Zentralbl. f. Bakt." Ixv, 311. " Bruckner et Galasescb (1910), " Compt. reud. Soc. Biol." Iviii, 684. . — 15 Boas (1911), " Nord. Med Archiv." ii, 53. 13 Proca, Danila et Stroe (1912), "Compt. rend. Soc. Biol." Ixxii, 495. ^MoLeod and Soga (1914), "Journ. of Path, and Bact.' six. 210. -'I Fontana (1913), "Dermatol. Woch." hi, 301. ■■'S Noguchi (1913), "Miuich. med. Woch." Ix, 737. CHAPTER IX. TECHNIQUE OF THE WASSERMANN REACTION. Patient's Serum. The blood is best withdrawn from a vein. Antiseptics used for cleansing the skin should be allowed to dry, before the needle is inserted, since a trace of alcohol or ether in the serum may alter the reaction. Blood should not be withdrawn while the patient is under an anaesthetic, as anaesthetics tend to make negative sera give a positive reaction — chloroform especially has this effect. The blood should be allowed to stand in a warm place, until the serum separates off. The serum should then be taken, and inactivated in an incubator or a water bath at 57° C. for half an hour. If a blood is to be sent by post, only the serum should be sent. When the test is to be carried out, the serum should be diluted 1 in 10, or 1 in 5, with saline (0"9 per cent.). Antigen. The best antigen is an alcoholic extract of a congenital s'y-philitic liver. As so many are on the market, it is not worth while to prepare one's own. For some time past, I have used the antigen supplied by the SachsLsches Serumwerk, and it has always given constant results. Before use, it is diluted with saline 1 in 10. The saline should be added gradually, and the diluted liquid should be gently agitated after each addition. Complement. Complement is best obtained from a guinea pig. As deep anaesthesia destroys complement, the best plan is to render the guinea pig unconscious by a knock on its head. An incision is made down the middle line of neck, the carotids are dissected out, cut, and allowed to bleed into a tube. This procedure will bleed the anhnal to death. The blood is put into an incubator at 37° C, and allowed to remain until the serum separates off. It is best not to centrifuge complement. Complement, as a rule, will not remain fresh longer than 36 hours. E 2 66 the biology, clinical aspect and treatment of syphilis. Amboceptor. Amboceptor is the serum of rabbits which have been immunised against the red blood corpuscles of the sheep. Owing to the trouble entailed in immunising rabbits, the best plan is to use the dried amboceptor prepared by the Sachsisches Serumwerk. It is packed in tubes containing O'l grm., and the titer is constant, namely, 0"0003. The dried serum, before use, is added to 2 c.c. of distilled water, and then made up to 10 c.c. with saline. The dried senmi dissolves slowly, and it should be shaken briskly. Solution will take place more rapidly, if some fragments of the containing tube are allowed to fall into the test-tube in which the solution is made. These fragments of glass break up the pieces of dried serum, and so a larger surface is offered, a condition highly favourable to rapid solution. Sheep's Red Blood Corpuscles. Sheep's blood is obtained from the slaughter-house, mixed with saline and then centrifuged. The fluid is then pipetted off, and the deposit is shaken again with saline, and centrifuged. This process is repeated about half-a-dozen times, until the supernatant fluid is quite colourless, which shows that the red blood corpuscles in the deposit are well washed. Before use, the red blood corpuscles are diluted 1 in 20 with saline, i.e., a 5 per cent, emulsion. It is well to add the corpuscles to some saline, and then add the remainder of the saline. In this way, the tendency of the corpuscles to cling to the tube, is overcome. Before the test can be carried out, the strength of the complement must be ascertained. Two tubes, A and B, are taken. A contains complement 1 in 30, and B con- tains complement 1 in 40. Six tubes are placed in a row and numbered 5, 10, 15, 20, 30, 40. "6 c.c. of the contents of tube A are transferred to tube 5. To this are added '1 c.c. of the 1 in 10 dilution of amboceptor, "1 c.c. of 1 in 20 emulsion of sheep's red blood corpuscles, ' 1 c.c. of 1 in 10 dilution of antigen. The contents of tube 5 are then made up to 1 c.c. by adding " 1 c.c. of saline. Therefore, the 1 c.c. of fluid in tube 5 contains "6 c.c. of 1 in 30 complement, that is, 6/30 of complement ; there- fore, in tube 5 the dilution of complement is 1 in 5. In tube 10, "3 c.c. of the contents of tube A are placed. 1.5 "2 A. ,, oO, "1 ,, ,, A ,, „ 20, -2 „ „ B „ 40, -1 „ „ B TECHNIQUE OF THE WASSERMANN .S REACTION. 67 To each of these are added antigen, amboceptor and red blood corpuscles, as to tube 5 above, and the total content in each is made up to 1 c.c. by adding saline. Therefore : — Tube 10 contains 3/30 of complement = dihition 1 in 10. = „ 1 „ 30. = ,. 1 „ 20. = „ 1 :, 40. The operation may be expressed shortly : — Tube A "1 c.c. complement + 2"9 c.c. saline. ,, B '1 c.c. „ +3*9 c.c. ,, 15 >) 2/30 30 j» 1/30 20 yt 2/40 40 n 1/40 Tube— 5. 10. 15. 20. 30. 40. c.c. c.c. c.c. c.c. c.c. c.c. From tube A 0-6 0-3 0-2 01 From tube B ... 0-2 01 Amboceptor ... 1 01 01 01 01 01 Antigen 01 01 01 01 01 01 Corpuscles 0-1 01 01 0-1 ! 0-1 01 Saline 01 0-4 0-5 0-5 j 0-6 OG Total 10 10 10 10 10 10 The test tube rack is then placed in an incubator at 37° C, for from 20 minutes to half-an-hour. If the complement is good, in 20 minutes there should be complete haemolysis in tube 30, and in half-an-hour complete, or nearly complete, haemolysis in tube 40. If this is the case, the strength of complement to be used in the test should be 1 in 12. If there is haemolysis in tube 20 in 20 minutes, and in tube 30 in half-an-hour, the complement should be diluted 1 in 10. If there is haemolysis in tube 15 in 20 minutes and in tube 20 in half-an-hour. the complement should be diluted linS. If there is haemolysis in tube 10 in 20 minutes and in tube 20 in half-an-hour, the complement should be diluted 1 in 5. With complement so weak as this, very unsatisfactory results are obtained, since guinea-pig's serum not infrequently has a strong haemolytic action on sheep's red blood corpuscles. Under such circimistances it is best to kill another guinea-pig. 68 IHE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. Before any series of tests the complement should always be most carefully titrated. A rack is then obtained, marked A, 1, lA, 2, 2A, etc., and the tubes should always have a diameter of not less than 1 centimetre, so that the contents can be easily shaken and mixed. In A is placed 1/10 c.c. of a 1 in 10 dilution of antigen and 1/10 c.c. of the titrated complement dilution. In 1 is placed 1/10 c.c. of serum No. 1, diluted 1 in 10, or 1 in .5, and 1/10 c.c. of the titrated complement dilution. In lA is placed 1/10 c.c. of serum No. 1 diluted 1 in 10, or 1 in 5, 1/10 c.c. of antigen diluted 1 in 10, and 1/10 c.c. of the titrated complement dilution. To each tube 5/10 c.c. of saline is added. The tubes are then shaken, and the rack is placed in an incubator at 37° C. for f to IJ hours. After incubation, to each tube is added 1/10 c.c. of amboceptor diluted 1 in 10, and 1/10 c.c. of the 5 per cent, emulsion of sheep's red blood corpuscles. The tubes are well shaken, and the rack is replaced in the incubator for from 10 minutes to half-an-hour. Only experience can enable one to judge the correct time at which to read the residts, but, broadly speaking, one is safe in doing so when tubes A, 1, 2, etc., are completely haemol^^sed. There must always be complete haemolysis in A, which proves that the complement is not being fixed by the antigen alone. There should always be complete haemolysis in tubes 1, 2, etc., which proves that the serum alone is not fixing complement. A few syphilitic sera have this property, and they are, therefore, called amphoteric. If the reaction is positive, there should be no haemol3'.sis in tubes lA, 2A, etc., while if the reaction is negative, there should be complete haemolysis in these tubes. Between haemolysis and precipitation there are several intermediary stages, and one can interpret these by experience only, and by comparing the result with the clinical history of the case. CHAPTER X. THE RATIONALE OR MODUS OPERANDI OF THE WASSERMANN REACTION AND ABDERHALDEN'S TEST. History. Bordet and Geugou^ were the first actually to demoustrate the occurrence of an antibody, by means of the complement-fixation test. Wassermann did much work on these lines, and, in conjunction with Bruck,- he published several papers referring to tuberculosis and other diseases, from this aspect. Wassermann's next step was to apply this test to syphilis, but he was confronted with the difficulty that the SpirocJiaeia jMllida had, up to that time, resisted all attempts fo be cultured, and so he was forced to use an extract of a viscus which was rich in these organisms. Consequently an extract of a foetal syphilitic Uver was used as antigen. As such an extract was found to act perfectly well, Wassermann and Bruck^ brought out their serum diagnosis of syphilis, which has since gone by the name of the Wasser- mann reaction. Owing to the labour entailed in carrying out the complement fixation test, various workers attempted to supplant it by precipitation tests. Fornet and Schereschewsky,*and Michaelis^ claimed that they got a definite precipitate by the action of a syphilitic serum on an extract containing a large amount of syphilitic antigen. Forges and Meier,* instead of using a syphihtic antigen, employed a 1 per cent, solution of sodium glycocholate. Klausner' merely diluted the sera with distilled water. None of these precipitation tests was ultimately found to give satisfactory results. The next step was Schiirmann's* colour test. Schiirmann was under the impression that s)rphilitic sera contained lactic acid, and he attempted to demon-strate this with UfEelmann's reagent, and later with perhydrol mixed with phenol and ferric chloride. This test was soon found to be fallacious. Assuming that the modus operandi of the AVassermann reaction depended on a precipitation, JacobsthaP suggested a method which he termed the " optic serodiagnosis of syphilis." The 70 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. patient's serum is mixed with au alcoholic extract of syphilitic liver, and the resulting precipitate is examined by the dark ground illumination method. A strong positive reaction appears as a clumpy precipitate, and a negative reaction as a thick emulsion of very fine particles. As Jacobsthal's observation throws some light upon the rationale of the Wassermann reaction, it will be referred to later. As no tests could be found to supplant the reaction, various attempts were made to simplif)^ the technique. Levaditi and Yamanouchi,^" instead of using immunised rabbit's serimi as the amboceptor in the haemolytic system, rehed upon the human serum already present, because human serum contains a natm'al amboceptor to sheep's blood. The natural complement was also used by Hecht^^ and Fleming.^^ Laudsteiner, Miiller and PotzF^ next found that an efficient antigen could be prepared from tissues which had never harboured a Spirochaeta jiallida. As both amboceptor and complement retain their active properties if dried, measured quantities of these were taken up by measured sizes of filter paper, dried, and dissolved in salme, when required. Modifications in the reaction were also made, in order to diminish the number of negative results obtained in syphilitic cases. Cholesterol^* -" was added to the antigen, and Wechselmann^^ advocated shaking the sera beforehand with barium sulphate, to precipitate what he called " complementoid bodies." Another test which requires mention, as it has some bearing upon the rationale of the reaction, is the Meiostagmine * reaction suggested by Ascoli,^* used by him. as a diagnostic procedure in typhoid fever, and apphed by Izar^' to syphihs. The test is a physico-chemical reaction of immunity, depending on a change in surface tension when an antibody is brought in contact with its own antigen. The consensus of opinion is, that no test for syphilis is so valuable as the Wassermann reaction, and that all modifications of the original technique detract from the reliabihty of the test. The attempt to sharpen the reaction, by adding cholesterol to the antigen, has met with great approval, although the view that non-specific reactions are obtained is fast gaining ground. Wechselmann's method has not received much attention, but Lange^^ obtained good results in a series of cases in which both methods were simultaneously performed. As these modifications to sharpen the Wassermann reaction help to explain the rationale of it, a fuller description of them will be found later. ■-■ /jLf'ioiv (smaller), (TTd(a (drop). RATIONALE OF THE WASSERMANN AND ABDERHALDEN TESTS. 71 The Modus Operandi or Rationale of the Wassermann Reaction. Ill the Wasseriuami reaction we are concerned with four factors : — (1) Antigen. (2) Complement. (3) Antibody. (4) Haemolytic system. As the haemolytic system is common to all complement fixation tests, it is necessary, at present, to discuss the first three factors only. Moreover, the explana- tion to be given of the )nodus operandi of these three factors will also clear up the rationale of the haemolytic system, because in both we are dealing with an antigen, complement and an antibody. Since the antigen need not necessarily be an extract of syphilitic material, the reaction ceases to fall in line with the bacterial complement fixation tests originated by Bordet and Gengou.^ Owing also to the fact that a positive Wassermann reaction may be obtained in conditions other than syphiUtic ones, the reaction ceases to be a specific reaction. Therefore the third factor ought not to be called an antibody, since it is in no wise specific, hence it is best called reacting substance, or Reagin, for short. Antigen. It is now a well-known fact that one, if not the main, principle in the antigen, is a Upoid, and that the hpoid which has the best action is that in which the ratio between nitrogen and phosphorus is as Ni:Pi (lecithin), as demonstrated by Thiele and Embleton.^-' Although we know that the antigen is a Upoid, this knowledge is of no great service, as the term " lipoid " embraces so many substances, some of which have no antigenic properties, and all of which are extremely complex. Therefore, there must be some active substance, or combmation of substances, in the lipoid, which is primarily responsible for the antigenic action. For a substance to have antigenic properties, it appears to be necessary for it to contain nitrogen in its molecule. The nitrogen, in the form of amino-acid, appears to be the active part of the hpoid, since artificial antigens can be prepared, provided they contain amino-acid groups. Tested by Van Slyke's method with nitrous acid, but without previous precipitation with 72 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. alcohol, the antigen which I have always used (extract of congenital syphilitic liver), gave the following amino-acid value : — Vol. of Antigen diluted 1 in 10 with Saline. Vol. of N. collected. Vol. of N. Vol. of N. from solution. from 100 c.c. Weight of N. from 100 0.0. c.c. 5 c.c. 100 C.C. 0-50 0.0. 10 00 mgm. 11 -70 Temperature ... ... ... ... 15° C. Pressure of gas ... ... ... ... 750 mm. Weight of 1 c.c. of N. at 15" C. and 750 mm. ... ... ... ... 117 mgms. If a trace of formalin be added to an antigen, the antigenic properties are increased ; and, at the same time, the amino-acid content is decreased by about half. Formalin increases the antigen action, because the replacement of the amino groups by a methane group increases the size of the colloidal particle — • H.COH + E.NHj = R.N.CH, + H.O. The proof that the colloidal particle is increased in size is shown by the fact that the R.N.CHj molecule requires about three times as much ammonium sulphate to precipitate it as the E.NHj molecule does. Therefore, although an amino group is primarily responsible for the action of antigen, it is not wholly responsible, since the formalised jsroduct will act as an antigen, and this leads me to the conclusion that the size of the colloidal particle plays an important part in the reaction. Three c.c. of antigen were taken, and were divided into three parts. To 1 c.c. 1 drop of a 40 per cent, solution of formaUn was added (antigen B.), and to another 1 c.c. 1 drop of a 1 in 10 of a 40 per cent, solution of formalin was added (antigen C), antigen A being the control. Antigen Antigen Antigen. Antigen + Complement + Complement + Complement. + SyphiUtic + Normal Serum. Serum. A.— Iin5 _ + + + + A.— 1 in 10 — + + + — A.— 1 in 20 — + + + — B.— Iin5 + + + + + + + + + B.— linlO + + + + + + + + B.— Iin20 — + + + + + C— linS — + + + + + C— linlO — + + + — C— lin20 — + + + — RATIONALE OF THE WASSERMANN AND ABDERHALDEN TESTS. 73 A few days were allowed to elapse before the experiment was carried out, so as to be quite sure that no free formalin was present which might fix complement. These same antigens, tested one week, and two weeks later, gave approximately the same results. It must be stated that the antigen is neither specific nor absolutely necessary for the Wasserniann reaction. As the Wassermann reaction is generally performed, for the fixation to be complete, the tube must contain antigen, complement, and a serum containing reagin ; but it occasionally happens that reagin and complement alone are sufficient to produce fixation, and to such a phenomeyion the term amphoterism or Eigen- hemmung is given. Amphoteric sera are practically always syphihtic sera. They are more commonly met with in late than in early cases of syphilis, and occur not infrequently in the cases of Ipnphocytomata of syphihtic origin, although the patient may no longer be in an active syphilitic condition. The amphoterism is due to an excess of lipoid, which is attached to the globulin molecule. The more lipoid there is attached to the globulin molecule, the larger is the molecule, and the greater its adsorptive capacity. Therefore, from the few remarks already made, it looks as if the Wassermann reaction was not a specific reaction, but merely an adsorption or precipitation reaction, depending partly upon the size of the lipoid-globulin (reagin) molecule. Although, in my opinion, an extract of foetal syphilitic tissue gives the best results, there is not very much to choose between this and an alcoholic extract of ordinary, or, better, autolysed material. An extract of spirochaetae acts very indifferently as an antigen, owing to the fact that the emulsion contains sufficient free fatty acid or, what is more probable, that the parasitic lipoid-globulin molecule contains an unsaturated fatty acid group, and that this prevents adsorption. WTien it became generally known that the antigen's active principle was a lipoid, several observers manufactured artificial antigens, and the chief substance added was cholesterol,^* -" ^^ although none of these observers appeared to have any reason for adding this substance. At the present time, great differences of opinion prevail as to whether the addition of cholesterol does not, in sharpening the reaction by reason of its great adsorptive powers, cause positive results to be obtained with sera which should have given negative reactions. At first, cholesterol antigens found great favour, but several observers in Germany, France and Italy-^ have recently given them up, owing to the fact that normal sera were found to give positive results. In England, Thiele and Embleton^' have come to the conclusion that the addition of cholesterol gives non-specific reactions, and in my research work on the 74 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. rationale of the Wassermaun reaction I have carried out several experiments with cholesterol, about which a few remarks may be stated here. Provided that the patient's serum is inactivated within forty-eight hours of its withdrawal, and that the serum is neither kept longer than twenty-four hours in an ice incubator, nor longer than ten days at room temperature — and here the time of year plays a r6le — the risk of obtaining a positive reaction in a non-syphilitic case is remote, but possible, when an antigen is used which is made up with an aqueous solution of cholesterol, and which has been properly standardised. If, on the other hand, the precautions mentioned above are not observed — often they cannot be, and usually they are not observed — the risk referred to becomes very great. If it be necessary to make the reaction sharper, there must be grounds for so doing. For diagnosis the reaction should be seldom required. Failing diagnosis, its next use is to regulate treatment. Making the reaction sharper means the administration of more treatment, until, in the majority of early cases of sj'phihs, it is impossible to obtain a negative reaction, even two or three years after the most vigorous treatment has been given, when cHnically we assume the patient to be cured. Summing rip the points which the addition of cholesterol brought to my notice, it will be seen that temperature has an influence upon the reaction, and that a serum is more easily affected if it be from a patient who formerly had syphilis, even if he be now cured of the disease. Consequently, the next series of experi- ments I undertook was to gauge the influence temperature had upon sera. Effect of Temperature. All sera kept at room temperature, sooner or later, give a positive reaction. A negative serum from a patient who has had syphilis will tend to become positive earher than a serum from a normal patient. No rule can be laid down as to when sera become positive, as no two require the same time. I have found a normal serum to give a positive reaction after it had been kept four days, but this is an exception. If kept longer still, when bacterial action has autolysed the reagin, even strongly positive syphilitic sera will give negative reactions. If the sera are diluted with saline, and then kept, they do not tend to become more positive ; but syphilitic sera may become negative, owing to precipitation of the reagin molecules. For the same reason, neither antigen nor complement will keep when diluted. The protein molecules in diluted sera quickly become deionised, and this results in their precipitation. If kept in an ice incubator, all sera develop RATIONALE OF THE WASSERMANN AND ABDERHALDEN TESTS. 75 reagin at a quicker rate than when kept at room temperature. Inactivating beforehand prevents this, to some degree. I have had two cases in which normal sera developed reagin, after having been in an ice incubator for only twenty-four hours. The action of heat also influences the reaction. Many S3'philitic sera when inactivated, i.e., heated for half an hour at 57° C, become negative, whereas before being heated they gave strong positive reactions. Heating sera for longer than half-an-hour and at a higher temperature than 57° C, causes them to develop reagin. Freezing Point. The freezing point of sera was next tested, as I thought that perhaps s^^philitic sera might give a different reading to normal sera, but such was not the case. All that one could say was that, generally speaking, the freezing points of syphilitic sera were slightly lower than those of normal sera ; but the differences were too small to allow one to separate a normal from a syphihtic case, and even these small differences showed no regular variation when compared with the degree of positivity of the Wassermann reaction. The factor upon which the freezing point of sera is dependent is the concentra- tion of the free salts. The concentration of the free salts begins to vary after the sera have been kept for twentv-four hours ; hence no reading is accurate unless it is made before that time. The freezing point of normal sera, according to Rona-^ varies from — 0"517°C. to — 0"562° C. If the sera are kept, after twenty-four hours the freezing point becomes lower, which suggests that the concentration of the free salts increases. Sera which have been tested for the freezing point may be used for the Wassermann reaction afterwards, provided they are only frozen once, and for as short a time as is practicable. If the first reading is inaccurate, and another is required, i.e., if the serum is frozen twice, the second reading has a tendency to be lower than the first, and such a serum may have developed reagin. Freezing sera for a longer period than is required for ordinarily reading the freezing point, will often make a negative serum give a positive Wassermann reaction. Active Sera. Since inactivat'on may destroy reagin, I have tested over 2,000 sera side by side, active and inactive, with the result that a far greater percentage of positive reactions were obtained in syphihtic sera when they were used active ; a few 76 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. syphilitic sera reacted positively only when inactivated ; and, very occasionally, a normal serum gave a positive reaction in the active condition (five cases). Theoretically, it might be imagined that if a serum were used active, the additional complement would suffice to give a negative rather than a positive reaction. Practically, that is not the case, the reason being that complement and anti- body (reagin) are the same substance chemically ; and since complement becomes antibody no hard and fast Une can be drawn between them. Moreover, when complement becomes antibody, it often loses its complementary properties, for frequently syphiUtic sera are to be met with, in which no complement can be demon- strated. It may occasionally happen that a serum will give a more positive reaction when inactivated than when used active. This is probably due to the fact that free fatty acid molecules exist in the active serum, and that when the serum is heated, more fatty acid molecules and, in addition, amino-acid molecules are also set free from the reagin particle, and either of them, if in excess, can fix complement. Inactivation injures the reagin molecule. The action of reagin, as will be later shown, is one of adsorption and consequent precipitation. The adsorptive capacity of a molecule is partly dependent upon its peripheral atoms, or, in other words, ions. Therefore, it will at once be seen that, so far as the pure complement fixation test is concerned, sera should always be used active. The reagin molecule, when in the active condition, is more as it is when in the body, and the so-called complement which is attached to it only increases its anti-complementary action, and vanishes in the process. Pressure. The next experiment was to test the effect of pressures, both greater and less than that of the atmosphere. For minus pressure sera were left for fortj--eight hours under 500 mm. of Hg., instead of 760 mm., at 10° C. For plus pressure sera were kept for forty-eight hours under 850 mm. of Hg., instead of 760 mm., at 10° C. The action of both was the same, so they can be considered together. Normal sera tended to develop reagin, the degree of fixation depending, as was found throughout this work, upon how long the sera had been kept, upon the temperature at which they, were kept, and upon whether the antigen contained cholesterol or not. Syphilitic sera which gave a negative -or a weak positive reaction become very positive, and those giving a positive reaction become amphoteric. RATIONALE OF THE WASSERMANN AND ABDERHALDEN TESTS. 77 Neither a miuus nor a plus pressure was able to convert an amphoteric serum into a negatively reacting serum. The action of a minus pressure upon sera is probably to increase the size of the colloidal particles by precipitating them. The action of a plus pressure upon sera is probably to cause partial hydrolysis, which would result in there being an excess of amino and fatty acid molecules. The lowering of the surface tension is more marked in those sera, which have been subjected to a minus pressure, a point in favour of precipitation as against hydrolysis. Wechselmann's Barium Suplhate Modification. As Wechselniann'^5 some years ago had shown that shaking a negatively reacting serum with barium sulphate often resulted in the sermn becoming positive, I tried a series of experiments with this salt, and also with kaolin, Kieselguhr, silicic acid (Kieselsnure), and iron hydroxide. Barium sulphate is non-colloidal. Kaolin (HjO, AljO.,, 2SiOj) is only partially colloidal. Kieselguhr is practically SiOj, and therefore colloidal. Kieselsi'iure is Si(OH)^, and therefore strongly colloidal, and so is iron hydroxide, which is Fe(OH)o. The more colloidal the body, the less influence it had in causing an alteration in the reactions, and vice versa. Barium sulphate tends, but shghtly only, to make normal sera positive ; time, temperature and cholesterol are, as usual, influencing factors. Syphilitic sera giving a negative reaction become positive ; those giving a feeble positive reaction become markedly positive ; those giving a positive reaction become amphoteric ; while primarily amphoteric sera remain unchanged. Kaohn has a similar action, but to a much less degree. Kieselguhr is feebler still, while Kieselsdure and iron hydroxide are without action. Therefore the degree of activity varies inversely as the colloidal nature of the body added. Now comes the question as to how barium sulphate acts. Barium sulphate cannot carrj^ down ions, since it is itself non-ionisable. It can take down some fatty acid, but this alone would not suffice to account for the increased positive reaction, which, in some cases, is often considerable. Barium sulphate, being non-colloidal, no doubt increases the size of the colloidal particles, and in this way acts as a very slight protein-precipitant. The more vigorously the barium sulphate serum is shaken, and the longer the salt is kept in contact with the serum, the more positive will the reaction be, as protein precipitation is increased. Polarimeter readings carried out at different intervals confii-m this. 78 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. To prove that barium sulphate acted by precipitation, I examined with the stalagmometer a series of sera, before and after treatment with barium sulphate. The stalagmometer measures the surface tension. The surface tension of a colloidal solution is maintained by the colloidal particles in the solution. Hence it will follow, that if the colloidal particles are precipitated, the surface tension must be lowered. The barium sulphate-treated sera were found to have a slightly lower surface tension than the plain sera. Here it may also be stated that plain syphilitic sera cannot be differentiated from plain normal sera by measuring their surface tension. Ascoli and Izar^^ ^' showed that the surface tension of syphilitic sera was lowered when antigen and complement were added thereto, but not when the two latter were added to normal sera, a fact which proves that the mixture of antigen reagin and complement results in a precipitation of certain colloidal particles, and this could not have come about without previous adsorption. Reagin. The question now arises as to what reagin is. If my work on the chemistry of the Leucocytozoon syphilidis be referred to'^ '^ ^* (Chapter VI), it will be seen that the phases of the parasite are rich in lecithin-globulin, and that the protoplasm of the plasma cells also contains this substance. It is a well-known fact that the host protects itself with weapons of the same nature as those with which it is attacked. It is, moreover, common knowledge, that protective substances, although originating in cells, do not remain intra- cellular ; they circulate in the blood, or, more strictly speaking, in the serum. Wassermanu and Lange^* recently showed that the reagin substance in the cerebro-spinal fluid came from the cells which constituted the lymphocytosis. That is true, so far as it goes, but it is not only from the lymphocytes that the reagin originates — it also comes from the epithelial cells of the choroid plexuses, and from the nerve cells, especially in the parenchymatous nerve lesions. The epithelial cells of the choroid plexuses, and Nissl's granules are made up of lipoid-globuHn adsorption complexes. If the reagin in the cerebro-spinal fluid comes from these cells, it rather suggests that the reagin is a Hpoid-globulin. One of the functions of these lipoid- globulins in syphihs is, as I have shown elsewhere,-* ^^ to carry oxygen ferments. Now, the cerebro-spinal fluid in cases of degenerative encephalitis is rich in oxydases ; the epithelial cells of the choroid plexuses, and Nissl's granules give marked oxydase reactions ; therefore, the proof is strong that the reagin is the same substance as the lipoid-globulin of certain cells. It becomes still stronger, when RATIONALE OF THE WASSERMANN AXD ABDERHALDEN TESTS. 79 attention is called to the fact, that the amount of globulin in the cerebro-spinal fluid is increased in cases of syphilitic lesions of the central nervous system, and that this globulin is frequently to be found in an adsorption complex with a lipoid. Thinking it highly feasible, then, that the reagin was lecithin-globulin, I next tried a series of experiments to find out the action of pure lecithin-globuhn upon complement, and then added it to sera and repeated the same experiments with butyric, palmitic, stearic and oleic acids, alone, with normal sera (human, and equine) and with lecithin-globulin. Similar experiments were conducted with tripalmitin, tristearin, and triolein, and also with other nitrogen and phosphorus-containing hpoids, namely, cerebrin and protagon. As very similar results were obtained, space may be saved by giving a general statement of them. The lecithin-globulin used in these experiments was obtained from a case of pseudo-chyclous ascites, and it was kindly given to me by Dr. Mackenzie-Wallis. A saline emulsion of this lecithin-globuhn did not deviate compleuient, and, when added to normal serum, it produced no change in the reaction. When added ta syphiUtic sera, in some it made no alteration, in others it either increased or decreased the reaction. Its most usual effect was considerably to decrease the reaction in all stages of s)'philis ; in fact, a serum amphoteric under ordinary circumstances often gave a negative reaction, on the addition of lecithin-globuhn. In only the minority of instances was a negative reaction converted into a positive one, and the only cases in which this happened were those of patients in the latent stage of syphilis. The reason why positive sera became negative, was probably because the lecithin- globulin emulsion contained some free fatty acid, which, if not too great in amount, can readjust complement, or prevent adsorption. The reason why negative syphilitic sera became positive was probably because the reagin contained free fatty acid groups, which primarily were responsible for the negative reaction, and these free fatty acid groups, plus those contained in the lecithin-globulin emulsion, were sufficient to fix complement, since excess of fatty acids has this action. All the fatty acid mixtures had a similar action, although they differed in degree, the action of oleic acid being the most pronounced. Normal sera tended to develop reagin, a phenomenon dependent upon the length of time during which the fatty acid had been in contact with the serum. Syphilitic sera giving a negative reaction usually became markedly positive. Syphilitic sera giving a feeble positive reaction often became amphoteric. Sera giving a strong positive reaction, and those which were primarily amphoteric, often became completely negative. F 80 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. The differeut results depend, as in the previous case, upon the amount of free fatty acid : if in excess, then fixation of complement ; if not in excess, then readjustment of complement followed. The fatty acid esters or triglycerides had a strong anti-complementary action, and all sera became positive or amphoteric. Occasionally, most contradictory and irregular results were obtained with the triglycerides, and I found later these results were due to the powerful action certain sera had in breaking down the triglycerides into their corresponding fatty acids. Cerebrin, broadly speaking, behaved like a fatty acid, while protagon acted like a triglyceride. Both were easily broken down into free fatty acids. From the behaviour of the saline emulsion of lecithin-globuUn in the preceding experiment, doubts might be cast upon my view that the reagin is of a lecithin- globulin nature. Lecithin-globulin cannot be extracted from the fluid in which it is, unless it is precipitated ; therefore, in the process of precipitation, some change may have taken place which would alter its physical properties. Precipitated globuhn will fail to give the goldsol reaction, because, in the process of precipitation, theglobuUn has lost its electric charge, or, in other words, has had its ions detached. The same is the case with the lecithin-globulin. When the lecithin-globulin is added to a normal serum, the reaction becomes positive, which proves that the hpoid-globuhn in the serum has adsorbed the lecithin-globuhn, with the residt that its molecules are increased in size, and are made to resemble reagin. It is only the lipoid-globulin molecule in the serum which is capable of forming adsorption complexes ; therefore, it would appear that reagin is lipoid-globulin, the molecule of which has reached a certain size, and is a molecule which is capable of adsorbing other similar substances, owing to the ions which are attached thereto. Complement. All we know about complement is that it quickly vanishes when kept, that it is thermolabile, that it can be preserved for a jieriod in concentrated salt solutions, that when once destroyed it cannot be rejuvenated, that it can be destroyed by shaking and by continued centrifuging, and that it is probably a mixture of lipoid and globulin, as Dean had already suggested. To these, a few more facts may be added : — • (1) That complement is often better when it has stood a few hours than when the blood has been freshly drawn. (2) That giving the animal too much anaesthetic destroys its action. (3) That it keeps better at room temperature than in an ice incubator. RATIONALE OF THE WASSEEMANN AND ABDERHALDEN TESTS. 81 (4) That its action is increased by the preseuce of a trace of either au amino or of a fatty acid. (5) That no protein, no aniino-acid, no fatty acid, no triglyceride, no lipoid, uo salt, nor any combination thereof will restore destroyed complement. (6) That lipoid solvents destroy complement. (7) That alterations of pressure destroy complement. (8) That formalin destroys complement. "What light do these facts throw upon the action and being of complement ? The fact that it vanishes when kept, suggests that some alteration has taken place in its colloidal particles. From analogy to what takes place in the reagiu particles, it is possible that the complement particle is robbed of some of its salts. If this is correct, then a point is gained in favour of the complement molecule being an adsorptive molecule. That destruction on keei^ing is still more probably due to the abstraction of salts, is shown by the fact that complement may be preserved in a contentrated solution of sodium chloride, and in a 1 in 3 solution of magnesium sulphate, which prevents their abstraction. That it is thermolabile points neither here nor there, since a multitude of things may be caused by keeping sera at 57° C. Delicate ferments may be destroyed, the concentration of the free salts may be altered, some lipoid-globulin complexes may be spht up, an alteration in the concentration of the free fatty acids may ensue, etc. That" when once destroyed it cannot be rejuvenated, favours the adsorptive molecule view, since there is something vital in all these hpoid-globuhu colloidal compounds, as no hpoid-globuhn complex has as yet been artificially prepared. That it can be destroyed by shaking, by continued centrifuging, and by altering the pressure at which it is kept, are all points in favour of complement being an adsorptive complex, since these measures are capable of precipitating and hj'drolysing such complexes. That complement is destroyed by giving the animal too much anaesthetic, throws additional hght upon its nature. Chloroform ansesthesia destroys com- plement more effectually than ether anaesthesia. Both chloroform and ether are hpoid solvents, and both have an avidity for oxygen. Normal sera, when withdrawn while the patient is under deep narcosis, are liable to give positive Wassermann reactions, owing to the fact that narcosis causes an excess of lipoid in the serum. ^* We know that the lipoids largely exist as adsorption complexes with globulin. Therefore, the evidence grows that complement is a lipoid-globulin colloidal molecule. f2 82 THE BIOLOGY, CLINICAL ASPECT AST) TREATMENT OF SYPHILIS. From what has just been stated, it looks very much as if complement aud antibody are similar substances, and I am of the opinion that they are. Every serum contains lipoid-globulin particles, which vary in size. In normal sera these particles are, to m)- mind, complement. If the size of these particles be compared, it will be found that they are larger in syphilitic than in normal sera. These particles are, to my mind, complement which has increased the size of its colloidal particles, so as to carry more protective substances to overcome the infection ; hence they become antibody. If a lipoid, such as antigen, is added to a normal sermu, the ultra-microscopic particles increase in size, as JacobsthaP was the first to demonstrate ; in other words, the complement molecule has taken up a lipoid, a phenomenon well known in lipoid-globuhn complexes. The ultra-microscopic particles are still further increased in size if the antigen is added to a sj'philitic serum, especially if the senmi be fresh, i.e., if it contain complement. This signifies that the lipoid-globuHu in a syphilitic serum has a greater adsorptive capacity than that in a normal serum, which would be natural if it were larger in size, but it also shows that the adsorptive capacity is greater if complement be present. In other words, the adsorptive capacity of a lipoid- globuhn complex is greatest when the molecules which make up the particles have not been disturbed. While in the body, the molecules are not likely to be disturbed for long, since the rapidity with which the blood balances a change is phenomenal. This accounts for the failure experienced in differentiating normal from syphihtic sera b}' testing them when fresh for their freezing point, their viscosity and their hydrogen-ion concentration. Soon after the blood is drawn, the vital part of the lipoid-globuhn vanishes, and its adsorptive capacity diminishes. The suggestion that complement is the forerunner of antibody does not throw full hght upon the active principle of complement. Since the hpoid-globuhn complexes are vehicles for oxydases, and since the opinion has been frequently expressed that the Wassermann reaction was of a ferment nature, it struck me that perhaps oxydases played an important role in the reaction. If so, then it could only be the complement which held the oxydases, because they are destroyed at 57° C, the temperature at which sera are inactivated, and by alcohol, with which the antigen is prepared. Several points can be brought forward in favour of complement being the ferment holder, and of the view that the ferment is an oxydase. Physical and chemical factors which destroy ferments destroy complement. Anaesthetics act RATIONALE OF THE WASSERMANN AND ABDERHALDEX TESTS. 83 ill virtue of their avidity for oxygen, which they get from both the serum and the cells. Complement gives oxydase reactions, which disappear when complement action vanishes. Although it is highly suggestive that complement action is due to oxydases, no actual proof is forthcoming, since I have failed to replace complement by other oxydase-bearing substances, and all attempts at re-oxygenating inactivated com- plement have, so far, met with no success. Summing up, we see that complement and antibody are the same. They con- stitute the lipoid-globub'u of the serum, and the size of the particle to some extent determines whether it is complement or antibody. Also that, probably, complement acts in virtue of its oxydases, the action of which is primarily to aid adsorption. Further Proofs and Mode of Action of these Lipoid-GJlobulin Complexes. From what has just been stated, certain inferences may be drawn. My biochemical work^^ ^° ^- ^* ^® on the Leucocytozoon syphilidis led me to believe that the protective substance, elaborated by the host to overcome the parasite, was lipoid-globulin, which carried the ferments (oxydases) which destroyed the parasite. Complement is also lipoid-globulin, to which there is no doubt that oxygen ferments are attached. Complement is, then, the ever-ready or normal resisting substance of every animal, without which the host would doubtless quickly succumb to any disease by which it might be attacked. So long as complement remains complement, it behaves as an oxydase, but, when complement is destroyed, its oxydase reactions vanish. Therefore there is some ground for suggesting that the vital part of the lipoid-globuhn (complement) is an oxydase. As the existing protective substance is often not powerful enough to over- come the parasite, it is only logical to suppose that the host will increase it in some way. Broadly speaking, one of two things happens when the body is attacked by organisms : either the polymorphonuclear leucocytes or tjie mononuclear leucocytes are increased. As we are concerned with syphihs, it will only be necessary to dwell upon the latter, since the former play no part in combating the infection. At the same time as the mononuclears increase, the protective substance in tlic serum increases. Sufficient evidence has already been produced to prove that, not only is this protective substance lipoid-globulin, but also that it has a cellular 84 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. Complement has just been shown to be a lipoid-proteiu, and to be identical with the protective substance, which happens, when it is increased, to be called antibody ; therefore the suggestion at once arises that complement has a cellular origin. This I have proved to be the case, as an extract of a lymphatic gland will act as complement. The proofs I have for the statement made, that the colloidal particles are larger in S3^hilitic than in normal sera, and that their adsorptive capacity is greater, should now be given. For the colloidal particles to be larger, either one of two things must happen : there must be more protein, or the protein present must be in a less ionised con- dition, i.e., less colloidal, more like a precipitated protein. That the latter is not the case can easily be seen, since it would be impossible for the particles to act as protective substances, unless they were in a perfectly colloidal condition and electrically charged. To prove that the protein was increased in syphilitic sera, I estimated the total nitrogen, and found that a higher value could be obtained in syphilitic than in normal sera, an observation which Folin had previously made. The increase of nitrogen is, presumably, not entirely protein nitrogen. Some of it doubtless emanates from the lipoid which is attached to the globulin. Unfortunately, an accurate estimation of the lipoid nitrogen cannot be made, since precipitation of the protein, by alcohol or mercuric chloride, also results in the carrying down of the adsorbed lipoid. Moreover, all the lipoid, while in the adsorbed condition, cannot be extracted with alcohol and ether, and any substance which frees the lipoid, hydrolyses the protein to which the Upoid is attached, with the result that amino-acids are set free, and, at the same tmie, the lipoid breaks up, with the result that elementary nitrogen is set free. Although a method could doubtless be devised to estimate the lipoid nitrogen, the amount of lipoid can be better judged by other means, such as by measuring the optical activity, and staining properties of the colloidal particles, etc. By employing these methods, it can be sho^^l that there is an excess of lipoid-protein in syphiHtic sera ; that this protein is a globuhn, since lipoids do not form adsorption complexes with albumin ; that the lipoid is proved to be in an adsorption complex, since it cannot be entirely removed by ether and alcohol, and that the excess of lipoid is most marked in the late or so-called tertiary cases of syphilis. This increase of lipoid in late cases of syphihs may be proved in the following ways : — The so-called albuminuria of the generalisation stage of syphilis may, as is well known, be very pronounced, without there being any clinical signs of kidney disease. RATIONALE OF THE WASSERMANN AND ABDERHALDEN TESTS. 85 If the uriiie be examiued, it will be found that the protein is not albumin but globulin. The globulin comes from the blood, and not from the kidney cells. The kidney merely acts as a filter, and is not diseased. Such a urine will give a positive Wasserraann reaction. On further examination, no blood or casts are demonstrable in the urine. The colloidal particles (globulin) are neither so large, nor do they exhibit so pronounced an optical activity as the colloidal particles obtained from a similar urine from a very late case of syphihs. Late syphiHtic lesions dii?er front early syphilitic lesions, in that, in the former, the degeneration of the host's cells is far greater than in the latter, although the number of parasites present is overwhehningly larger in the latter. The degeneration is of a hpoid nature. To give two examples : If the pyramidal cells of the brain cortex, from a case of degenerative encephalitis, are examined, it will be found that varying portions of the protoplasm have become finely granular, and that they stain orange to yellow with p3'ronin. If stained in fresh sections, the granules stain violet with Nile blue sulphate, and orange with Sudan III. If the aorta from a case of syphilitic aortitis be examined, masses of lipoid material are seen in the walls, and this is never the case in an early and acute endarteritic lesion. For this important observation I am indebted to Dr. Andrewes.^^ Moreover, this hpoid degeneration is peculiarly locaHsed to the area affected. This excess of hpoid doubtless accounts for the deficiency in calcium salts which Andrewes has observed in his ash analyses of syphihtic aortae. This strongly suggests that salts have made way for lipoids, as they do in sera, when the hpoid- globulin molecule increases in size. This means, then, that larger lipoid-globulin molecules exist in the sera from late cases of sj'philis, than in those from early cases. The larger the molecule, the greater its anti-complementary action. Hence, no relationship exists between the positivity of the reaction and the number of organisms present in the host. The Wassermann reaction is stronger in late syphihtic cases than in early ones, because there is an excess of lipoid. As hpoids can easily have fatty acid molecules set free from their particles, and as fatty acids may increase the action of complement, this is probably the explanation of the not infrequent occurrence of negative Wassermann reactions in late cases of s^'phihs, especially when the lesions are hmited to vessels. Bisgaard^^ showed that, during death agony, and for some time after, the total nitrogen in the cerebro-spinal fluid was increased, and that the main excess 86 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. was non-proteiu nitrogen. Those who have worked with the AA'assermann reaction, have long since been aware that, even in people who have never had syphilis, the blood taken just before death, or just after death, is Uable to give a positive Wassermann reaction. From these few remarks, it will be seen that, although the globulin ma}' be partly responsible for the reaction, the lipoid is still more so. This statement is still further proved by the fact that neither the blood nor the urine from a case of non-syphilitic functional albuminuria, in which the jirotein in the urine is globulin and not albumin, gives a positive Wassermann reaction. The reason is because the globulin from such a case has no lipoid attached to it, and that it comes from the glomeruli of the kidneys and is not filtered through from the blood, therefore it is in an isoelectric condition. Having proved that the reagin is a lipoid-protein, it must now be explained how it acts. Lipoid-proteins have large molecules. They can be seen when examined ultra-microscopically, i.e., by the dark groimd illumination method. They possess, moreover, strong adsorptive properties, and, by their presence, can render soluble a substance which is, under ordinary circumstances, insoluble in a certain medium. Their adsorptive capacity is partly dependent upon, and regulated by the ions and other groups which are attached to the molecules. Neither pure Upoid-globuUn nor, still less, pure globulin has a sufficient anti- complementary action to cause as strong a positive reaction as that given by a syphilitic serum. Both pure lipoid-globulin and pure globulin are, practically speaking, isoelectric. In their preparation, they have been robbed of their ions, and although ions are necessary for the reaction they only play a subordinate role. I undertook a series of experiments with all the salts that could be supposed to be found in normal serum, and tested them in various strengths as to their anti-complementary and haemolytic actions, and tested their influence upoii the Wassermann reaction itself. Broadl}' speaking, all the salts had a strong anti-complementary action if they were used in much stronger concentrations than those in which they would naturally exist, while in their approximately normal strengths they had neither an anti-complementary nor a haemolytic action, nor did they in any way influence the Wassermann reaction. Therefore it cannot be the ions themselves upon which the action of reagin depends. If, then, the adsorptive capacit}' of the reagin molecule is partly dependent upon its ions, it might be expected that, the larger the molecule, the greater the RATIONALE OF THE WASSERMANN AND ABDERHALDEN TESTS. 87 power with which the ions are attached thereto. The following experiments proved this to be the case : — Some lymphatic glands were removed from syphilitic and normal patients, each divided into two portions, dried and weighed. The first portion was incinerated and the chlorides estimated as sodium chloride in the ash. The second portion was thoroughly extracted with alcohol, the alcoholic extracts collected, dried, weighed and the chloride content determined. The residue of gland substance was then submitted to dialysis and the chlorides estimated in the dialysate. The difference between the two estimations gave the amount of chlorides fixed to the proteins in the tissue under investigation, and this was found to be greater in the syphilitic than in the normal glands. The larger the molecule, not only the greater is the power of attachment of the ions, but also there will be more salts in the ionised condition. The proof of this is seen in the greater rapidity for clotting exhibited by syphilitic sera. My friend, Dr. Myers, ^^ has recently estimated the amount of calcium in sera, and, from the experiments he has made, there appears to be an excess of ionised calcium salts in sjqjhilitic sera. These last few remarks apply only to the early stages of syphilis, because in the late stages the excess of lipoids causes a diminution of the salts. In the so-called tertiary stage, the calcium content of the blood does not vary much from the normal. Those who have followed the recent literature on syphilis will remember two papers by Kaplan,-* on the amino content of syphilitic sera. Estimating the amino-acids by Van Slyke's method, Kaplan found that the amino content of syphilitic sera was less than that of normal sera. Kaplan's explanation for the difference was, that the syphilitic parasites required a considerable quantity of amino-acids for their development, and that the serum lost what they used. Before stating the results I obtained by Van Slyke's method, it would be as well to di'aw attention to a few points which Van Slyke-'^ himself pointed out, before any interpretation is given of the fall of amino-acids in syphilitic sera, as mentioned by Kaplan. In Van Slyke's gasometric estimation of the primary aliphatic amino nitrogen, the various kinds of amino derivates do not give off their nitrogen in the same time. The natural amino-acids, i.e., the amino groups which are attached to the carboxyl groups in the a-position, react in five minutes. The e-amino groups in lysine require half an hour, therefore lysine is the only natural amino acid which requires more than five minutes. Ammonia and methylamine require 1-0-2 hours, and urea requires 8 hours. Therefore, these substances can be excluded from having any influence on the 88 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. results obtained. The same applies to the amino groups in the purine and pyrimidine bodies, which require 2-5 hours before they react. Taking the amino-acids individually, Van Slyke found that glycocoll, alanine, valine, leucine, phenylalanine, tyrosine, aspararginic acid, glutaminic acid and cystine, which contain a-amino nitrogen only, gave up all their nitrogen in five minutes. Lysine takes longer, because it contains E-amino groups. Although the guanidine bodies contain nitrogen atoms, the^y do not react. Arginine contains four nitrogen atoms, but only one reacts, i.e., the nitrogen atom in the a-position. The nitrogen of the indol ring in trj'^ptophane, and of the pyrrholidine rings in proline and oxyprohne, and of the imidazole nucleus in histidine, does not react ; therefore tryptophane reacts with only half its nitrogen atoms, histidine with only a third, arginine with only a quarter, and proline and oxyproline do not react at all. One explanation of the diminution of amino-acids in sypliilitic sera might easily be, that there is a predominance of those which do not react with all their nitrogen. Therefore it w'ould be worth while to undertake a series of experiments to prove if there be an excess of tryptophane, histidine and arginine in syphilitic sera. A very important consideration which Kaplan appears to have overlooked is: How do the amino-acids exist in senun ? That a few occur free, there can be no doubt, as a constant synthesis and analysis of the protein molecules is taking place in the serum. That more occur combined in the protein molecules is also true, because, as Eniil Fischer said long ago, proteins are chains consisting of amino-acid L'nks. It will follow from this, that the larger the protein molecule, the greater the nrunber of combined amino groups ; therefore, the larger the molecule, the smaller the number of amino groups which will react wuth nitrous acid. Hence a ready explanation of Kaplan's results would be that the amino nitrogen is less in syphilitic than in normal sera, because the protein molecule is larger in the former than the latter. The proof that the larger the protein molecule, the fewer the amino-acids which react, is forthcoming from Van Slyke's important observations that natural proteins only reacted with a trace of their nitrogen, that the albumoses reacted with more, and that the polypeptides reacted with practically all. This proves that the albuinoses are degeneration products of proteins, as I have already suggested, ^^ ^* and it confirms Fischer's theory of the structure of protein, w'hich is that, the smaller the molecule, the greater the quantity of nitrogen that exists in the form of free amino-acids. In untreated cases of syphilis I found, as Kaplan did, that the free amino content was less, but I failed to trace any direct ratio between the free amino content and the result of the Wassermann reaction. RATIONALE OF THE WASSERMANN AND ABDERHALDEN TESTS. 80 If the protein is not precipitated beforehand with alcohol, I found that syphilitic sera, taken from patients wlio had received no treatment, gave a smaller amino-acid figure than normal sera. But again, no direct ratio existed between the amino-acid content and the result of the Wassermann reaction. As I was more concerned with the study of the protein molecule than with the free amino- acids, in the following experiments I did not precipitate the protein with alcohol, before testing it by Van Slyke's method. If the amino content of sera, half of which have been kept in an ice incubator, half at room temperature, is tested, the amino content may be either raised or diminished. If raised, the difference is only slight; while if lowered, the difference is considerable. Serum. Vol. of Serum. Vol. of N. CoUected. Vol. of N. from Serum. Vol. of N. from 100 c.c. Serum. Weight of N. (mgras.) from 100 c.c. Serum. 1— Room temperature ... Ice incubator 2 Room temperature ... Ice incubator 3— Room temperature ... Ice incubator 4— Room temperature ... Ice incubator c.c. 3 3 3 3 2 3 3 3 c.c. 3-70 4-40 3-30 4-00 2-70 2-90 4-70 2-90 c.c. 1-85 2-20 1 -65 2-00 1-35 1-45 2-35 1-45 c.c. 61-70 73-30 55 -00 66-60 67-50 48-30 78-30 48-30 mgms. 71-40 84-86 63-68 77-20 78-10 55-90 90-65 55-91 Temperature Pressure of gas ... Weight of 1 c.e. of N. at 19° C. and 747 mm. 19° C. 747 mm. 1-17 mgms. The fact that the difference is great when the amino-acid content is lowered, suggests that cold increases the size of the colloidal (protein) molecule. Cold undoubtedly increases reagin formation, as stated before ; therefore, there is still more evidence that reagin depends upon the size of the colloidal particle. The reason why the amino-acid content is sometimes increased in the cold, is probably that fatty acids are thrown out of combination, and that they have the power of liberating some of the amino-acids from the protein molecules. Salvarsan raises the amino content of sera, but the Wassermann reaction 90 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. may be either positive or negative. The rise begins almost immediately after the injection has been given, and may persist for some weeks. Vol. of Serum. Vol. of N. Collected. Vol. of N. from Serum. Vol. of N. from 100 c.c. Weight of N. (mgms.) from 100 c.c. Serum before " 006 "— 2 Serum one hour after " 606 "— 3 c.c. 2-25 3-45 c.c. 112 1-72 c.c. 56-25 57-50 mgms. 65-80 67-25 Temperature 15° C. Pressure of gas ... ... ... ... 750 mm. Weight of 1 c.c. of N. at 15^ C. and 750 mm. 1 -17 mgms The addition of fatty acids to sera increases the amino content, especially the addition of oleic acid, which may increase it sevenfold. Triglycerides, on the other hand, considerably depress it. Triglyceride emulsions in sera give very marked positive Wassermann reactions, but fatty acid emulsions may also exhibit a strong anti-complementary action. Serum (Horse). jVol. of Serum. Vol. of N. Collected. Vol. of N. from Serum. Vol. of N. from 100 c.c. Serum. Weight of N. from 100 c.c. Serum. c.c. c.c. c.c c.c. mgm. I. Stearic acid 1 0-6 0-3 30 35-37 II. Triolein 2 0-2 0-1 5 5-89 III. Oleic acid 2 2-4 1-2 CO 70-74 IV. Normal 2 0-4 0-2 10 11-79 V. Protagon 2 0-2 0-1 5 5 -89 VI. Tristearin 2 0-2 0-1 5 5-89 VII. Cerebrin 1 0-4 0-2 20 23-58 Temperature 14° C. Barometer ... ... ... ... 763 mm. Pressure of gas ... ... ... ... 751mm. Weight of 1 c.c. of N. at 14° and 751 mm. 1 -179 mgms. The explanation of the fact that fatty acids increase, and triglycerides decrease the amino-acid content, is that the amino-acids are amphoteric, i.e., that they dissociate in an aqueous solution both as bases and as acids. EATIONALE OF THE WASSERMANN AND ABDERHALDEN TESTS. 91 This would make their acid power very wealv, aud most possibly the fatty acids — weak as they are — relatively stronger. This being so, the stronger acids would tend to replace the weaker, so that the amino-acids would be liberated from their compounds, just as, for example, hydrochloric acid would, with a sidphite, form a chloride and liberate sulphurous acid. The triglycerides, being condensation products of glycerol and the fatty acids, would have no acid power, and would not displace the amiuo-acid from their compounds. Bariiun sulphate raises the amino content, but this may be due to the air which gets into the sera. Serum (Horse) Treated with Barium Sulphate. Vol. of Serum. Vol. of X. Collected. Vol. of N. from Serum. Vol. of N. I Weight of N. per 100 c.c. from 100 c.c. Serum. Serum. c.c. c.c. c.c. c.c mgm. I. Stearic acid 1 1-2 0-6 60 68-7 II. Trlein 2 3-2 1-6 80 91-6 III. Oleic acid 2 1-9 0-95 47-5 54-39 IV. Normal 2 2 -2 11 55 62-97 V. Protagon 2 2-2 11 55 62-97 VI. Tristearin 2 1-4 0-7 35-0 40-07 VII. Cerebrin o 1-6 0-8 40 45-8 Formalin markedly increases the amino content, and all sera which have been treated with formalin have a very strong anti-complementary action. Vol of N Weight of N. Vol. of Serum. ! Vol. of N. Vol. of N. from Seruiu. from 100 c.c. Serum. (mgms.) from 100 c.c. Serum. c.c. c.c. c.c. c.c. mgms. Serum A alone 3 2-90 1-45 48-30 56-10 Serum A treated with formalin (1 drop 40 j per cent, solution to I 1 c.c. serum)... ... 3 1-80 0-90 30-00 34-80 Serum B alone 3 4-00 2-00 66-60 77-30 Serum B treated with '• formahn 2 1-30 0-65 32-70 37-90 Temperature Pressure of gas . . . Weight of 1 cc. 738 mm. N. at 16° C. and 16° C. 738 ram. 1 -16 mgms. 92 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. From these few remarks, it will be seen that there is no direct ratio between the amino content of the serum and the result of the Wassermann reaction. The decrease of amino nitrogen in syphilitic sera, as shown in Van Slyke's method, is largely owing to the fact that the amino-acids are more combined or adsorbed in syphilitic, than in normal sera. It does not mean that there are fewer amino-acids in syphihtic sera, since, if such sera are hydrolysed, an increase of amino nitrogen is obtained in syphihtic sera. There is an increase of globulin complexes in syphilitic sera, which means that the protein molecules are bigger, hence the explanation for the diminished amino nitrogen content. It is interesting here to note the influence which the addition of amino-acids to sera had upon the Wassermann reaction. The results of adding amino-acids dissolved in sahne to sera, gave some important and interesting results. The three used were tyi'osine, leucine, and glycocoll, in the strengths of 1 in 1,000, 1 in 10,000, 1 in 100,000 and 1 in 1,000,000. The stronger solutions had an anti-complementary action, and therefore tended to make normal sera positive. Some sera rich in reagin became negative. The weak dilutions increased the action of complement, and caused positive sera to become negative ; glycocoll had the strongest action in tliis respect. If the amino-acids are, on the other hand, dissolved in sera, quite different results are obtained. The tendency is for all the sera to become very positive. Should a positive serum containing an amino-acid (O'OOl per cent.) be added to another serum, the reaction is less positive in the mixture of the sera, one of which contains the amino-acid, than in a mixture of the same two sera, to neither of which an amino-acid had been added, and this shows that some of the acid has become adsorbed by the lipoid-protein molecules of the serum containing no amino-acid, and therefore there was less to fix the complement. If a free fatty acid be present in addition, the activity of the amino-acid is markedly increased, and a negative reaction is the result. A stearic acid s^um, giving & + + -^ + reaction, when mixed in equal parts with a glycocoll serum giving a -I- + + reaction, gives a negative result. Fatty acids in excess have an anti-complementary action ; in weak dilutions, they appear to aid complement. Fatty acids frequently cause positive sera to become negative, but if they have been previously added to normal sera, and the fatty acid normal sera are mixed with the positive sera, the reaction usually remains positive, which points to the fact that normal sera can adsorb fatty acids. Normal sera may give positive reactions on the addition of fattv acids, as they did with amino-acids. RATIONALE OF THE WASSERMANN AND ABDERHALDEN TESTS. 93 Triglj'cerides increase the reagin all round, and always give rise to a positive reaction. When in sera, they are liable to become split np into fatty acids. This splitting up must be borne in mind, since just sufficient fatty acid may be split off to make the reaction negative. From these experiments, the influence of salvarsau upon the Wassermanu reaction can be explained. Salvarsan increases the amino content of syphihtic sera, and this suggests that it breaks up the lipoid-globuhn (reagin) molecule, a suggestion which is supported by the fact that salvarsan decreases the clotting time of sera ; and this would be the case if the calcium salts were split off from the lipoid-globulin molecules, thereby diminishing their ionic action. If the molecules are rendered smaller, it would at first sight appear that the Wassermann reaction after salvarsan would always be negative, which is not the case, at any rate in earl}'- syphihs. If a syphilitic plasmoma be examined histologically before and after salvarsan treatment, it will be noticed that the protoplasm of the plasma cells in the latter case is completely broken up, but each fragment still retains its chemical and physical properties. If the protoplasm is broken up, the area over which it can act is greater than w'hen the masses are crowded together. Therefore, it would appear to be an advantage to break up the reagin particles. Because they are broken up, it does not necessarily follow that each smaller particle does not possess the properties of lipoid-globulin. It is only after several injections that actual hydrolysis occurs, i.e., that the hpoid fraction is split up into fatty acids, and the globulin fraction into amino-acids. So long as the reagin particles are hpoid-globuUn, they will retain their adsorptive capacity ; and as the area over which they act is greater, it follows that the total action will be increased, i.e., that more complement will be fixed, and that the Wassermann reaction will be more marked. As I pointed out two years ago,^^ it is only after the first two or three injections of salvarsan that the Wassermann reaction becomes more positive, and then, after the subsecjuent injections, it gradually diminishes, until it becomes negative. Salvarsau at first increases the adsorptive capacity of the reagin molecule by breaking it up, and then decreases it by causing hydrolysis. That such an explanation is probably correct, is shown by the fact that the increase of the free amino-acid content of the serum is most marked, not after the first three injections of salvarsan, but after the later injections. Often a positively reacting serum — and this is especially the case in the so-called tertiary stage — wiU become negative after an injection of salvarsan. 94 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. In the late cases of syphilis, the lipoid portion of the lipoid-globulin molecule is greater than it is in the early cases, and, the larger the lipoid fraction, the greater the ease with which an unsatisfied fatty acid molecule is set free. As stated before, a trace of a free fatty acid will prevent adsorption ; an excess will fix complement. Therefore, the first action which salvarsan has in such cases, is to set free just sufficient fatty acid from the reagin molecule to readjust complement. Further injections split up the large hpoid-globuhn molecules into smaller ones, with the residt that the reaction will be more positive ; and finally hydrolysis occurs, when the reaction becomes negative. Therefore it at once becomes evident that a negative Wassermann reaction after treatment can be no indication as to the number of parasites killed, or as to whether any are left behind or not. The question which now arises is, whether there is any specificity in the reagin molecule, or whether its action depends entirely upon physical conditions which are naturally present in syphilis, but which, when brought into play outside the body, can make a normal serum give a positive Wassermann reaction. The mere fact that an antigen is not absolutely necessary, at once rules out the Wassermann reaction as being a specific reaction, but from this it does not necessarily follow that the reagin molecule, when in the body, has no specific action. Further hght can be thrown upon this point if Abderhalden's test is considered for a moment. The serum of a pregnant woman will break down placental extract — according to Abderhalden^' — owing to the i^resence of a specific proteolytic ferment in the serum. It will necessarily follow that the placental extract, for the sera of pregnant women, will also be specific. From this it follows that specificity can lie in the peptones, polypeptides, amino-acids and amines. There is a hmit to the number of these substances, but there is no limit to specificity. There is also no hmit to the variation of the physical configurations of the molecules of the above substances, although there is a limit to their chemical molecular configurations. Therefore there would appear to be some relationship between specificity and the physical configuration of the foundation molecule, upon which are built up the other atoms wliich go to constitute the protein molecule. Hence a physical homology exists between the molecules of the serum and those of the placental extract. For the serum of a pregnant woman to break down placental extract, it is necessary that the serum should be fresh, or, in other words, should contain complement. Interpreted, this means that a serum cannot break down its specific antigen, unless its molecules are ionised, and have oxydases attached to them. RATIONALE OF THE VVASSERMANN AND ABDERHALDEN TESTS. 95 In the preceding pages, it was shown that complement was lipoid-globulin, therefore it is the lipoid-globulin molecules in the sera of pregnant women which break down the placental extract. Hence an analogy exists between these molecules and the reagin molecules in syphilitic sera. I have already shown that the action of reagin is one of adsorption. Therefore, on the same principles, there is no reason why adsorption should not take place between the lipoid-globulin particles of the sera of pregnant women and those of the placental extract. Reagin adsorbs complement because both have the same physical molecular configuration. Reagin will only adsorb an antigen which contains amino-acid atoms, since a variation in physical configuration of molecules can only affect those of proteins, or those upon which proteins are built up. Adsorption of homologous molecules results in precipitation, and further dialysis results in hydrolysis. If complement be dialysed, its action is destroyed ; and it is so, too, with reagin, owing to the fact that the lipoid-globulin molecules spUt up. In Abderhalden's test, my view is that, adsorption between homologous molecules takes place, and this results in their precipitation and subsequent hydrolysis owing to dialysation, which allows sufficient amino-acid to get through the fish bladder to give a positive ninhydrin reaction. At first sight, it looks as if Abderhalden's test is specific, but not infrequently a syphihtic sermn from a non-pregnant woman will, with placental extract, give a positive ninhydrin reaction. Therefore, as a test, it can be no more specific than the Wassermann reaction. The fact that a syphilitic serum will give a positive ninhydrin reaction with placental extract, to my mind, throws a great deal of hght upon both the Abderhalden and Wassermann reactions. There is a close similarity between the sera of pregnant women and syphilitic women, because pregnant women seem to be very httle affected by — and some even to be immune from — syphihtic symptoms. Unfortunately, syphilitic sera will give a positive ninhydrin reaction, with an extract of ahnost any organ. Therefore it looks very much as if neither of these two reactions is specific, but that they are merely group reactions, which depends upon certain physical conditions of the protein molecules, and do not necessarily simulate the processes which take place in the body. There is a marked analogy between the interchange of action between antigen, antibody and complement, and the interchange of action between sheep's red blood corpuscles, amboceptor and complement (haemolytic system). Therefore there must be an analogy between the modus operandi of Abderhalden's test and of the haemolji:ic system. 96 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. That haemoglobin becomes free, when complement and a specific amboceptor is present, is no proof that the red blood corpuscles have been broken down by proteolytic ferments ; it is only a proof that the colloidal membrane has been altered by the abstraction of certain chemical groups attached to it, and therefore rendered more pervious by an alteration of the osmotic pressure. Syphilitic sera without any extract at all, provided complement be present, will sometimes give a positive ninhydi-iu reaction, which can be explained in this way : complement may be fbced by reagin in the Wassermann reaction, without there being any antigen present. Owing to the fact that the reagin and complement molecules are homologous, adsorption results, and then precipitation. Precipitated complement is not necessarily destroyed. A ratio exists between the degree of precipitation and the loss of action, since, if the precipitation be only slight, the complement can be collected, and its action proved by placing it in a haemolytic system. Should, on the other hand, the complement be precipitated in a dialysing apparatus, hydrolysis of both the complement and the precipitating substance (reagin) takes place, with the result that an excess of amino atoms is formed, and it dialyses through the fish bladder, and gives a positive ninhydrin reaction. Therefore, in the Wassermann reaction, we are dealing with a pure precipitation, and in Abderhalden's test, with precipitation and h)'drolysis. The proofs for the statements just made are to be found in the following experiments :— Colloidal solutions have a surface tension which decreases, if the colloidal particles are precipitated. If normal sera are mixed with antigen and complement, and then tested with the stalagmometer, there is no diminution in the surface tension. If syphihtic sera are treated in the same way, there is a diminution of surface tension, and this proves that when reagin, antigen, and complement are mixed, a precipita- tion occurs, or, in other words, the solution in which they are present becomes less colloidal. From the above it would appear, that there is some relationship between Surface tension and the Wassermann reaction ; that such is really the case is proved by the fact that the surface tension of sera is lowered by the addition of barium sulphate, Kieselguhr and formalin, all of which increase the anti-complementary action of sera. The addition of silicic acid or iron hydroxide to sera does not lower the surface tension, and does not cause sera to give a positive Wassermann reaction. Therefore there is strong evidence in favour of the precipitation theory for the Wassermann reaction. The proof that Abderhalden's test is primarily a precipitation, and finally a hydrolysis, is shown by the fact that, if fresh syphilitic RATIONALE OF THE WASSERMANN AND ABDERHALDEN TESTS. 97 sera are dialysed, the reagin is partly destroyed, and the complement is completely destroyed. Summary. It will be seen from what has been stated, that once a serum has had its adsorptive capacity increased, as occurs to the lipoid-globulin molecules (reagin) in a syphihtic case, it is always liable to exhibit the same phenomenon, should circumstances arise which give it the opportunity. Most of these opportunities arise only after the blood has been withdrawn. Moreover it will be seen that several factors may be responsible for a positive reaction. An increase in the size of the protein molecule, an excess of hpoid over the protein, a breaking down of the large lipoid-globuUn molecule into several smaller ones, and an excess of fatty acids and amino-acids. These various factors may be at work without the observer's knowledge, and they cannot be prevented or differentiated ; therefore, it must be v\Tong to state that a positive Wassermann reaction is necessarily indicative of active sypliilis. Since a free amino group, or a free fatty acid group, can prevent what would have been a positively reacting serum from giving a positive reaction, it can be easily understood, that a negative reaction can neither exclude syphilis, nor be taken as an indication of a cure. It must be obviously incorrect to say that a positive Wassermann reaction means that there are spirochaetae in the body, because, if true, a ratio would exist between the positivity of the reaction and the number of spirochaetae present. This is by no means the case, since the most positive reactions are obtained from those patients who are suffering from diseases caused by syphihs, such as the inter- mediary cutaneous and visceral lymphocytomata in which no parasites are present, and then in late cases in which only a few parasites are present. The fact that one may obtain a very strong positive Wassermann reaction in a case of cutaneous IjTiiphocytoma occurring in a patient who has had syphihs, but is, as far as one can tell, cured, throws, to my mind, a great deal of light upon the aetiology of certain chronic dermatoses, and even on that of malignant disease itself. Once the body has had to form protective substances, should the call upon them have been a prolonged one, in many instances, in spite of the fact that the attacking force has vanished, the body still goes on forming these protective sub- stances, and in an ever-increasing degree, until the protective substances them- selves become parasitic, so to speak, upon the host that formed them. In the case of syphilis, the protective substances are Upoid-globulin complexes G 2 98 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. which emanate from the lymphocytes. The production of these substances can go on, in spite of the fact that there are no more organisms to vanquish, and in an ever-increasing rate, until the lymphocytes are strained to their utmost to furnish these substances, and, in their efiorts, they become malignant. It looks to me as if there is no one cause of the leucaemic and aleucaemic lymphocytoniata^® and mahgnant disease, but that they are the results of the host's own protection against parasites, etc., of which the Leucocytozoon sijpMlidis is one. Still further proof in this direction is the degree of positivity which is not infrequently witnessed in sera, taken post-mortem. As oxydases are quickly destroyed post-mortem, and as the sera of some of the late cases of syjihilis fail to give oxydase reactions, no ratio can exist between the positivity of the reaction and the oxydase content. Therefore, a strongly positive reaction need not neces- sarily signify that a grave or widespread active syphilitic condition exists. What applies to the Wassermann reaction, in my opinion, applies to Abderhalden's test. It is not tlie lipoid-glolnilin itself which is primarily responsible for the breaking down of the organ. The active agent is the oxydase contained in the complement, which is necessary for the reaction, and is linked to the hpoid- globulin, which itself may have a specific configuration. Furthermore, there is no evidence that the breaking do-rni of the organ is due to a proteolvtic or peptolytic ferment. I should not be at all surprised if in time all ferments are found to be oxydases, and that the differences in action rest in the stereo-chemical molecular configuration of the radicles to which the oxydases are attached by means of the ions. The above points to the fact that the complement is the most important factor in the reaction; therefore, any modification which rehes upon the patient's own complement must be fallacious, as the action of the complement is altered by the behaviour of the radicles to which the complement is attached. Some modifications rely upon the patient's own complement and sheep's blood amboceptor. Results obtained by such modifications must be untrustworthy, since the action of amboceptor upsets its complement action, and vice versa, for both exist in the same molecule. Hence the reason why so many positive reactions are obtained in patients who have never had syphilis. Furthermore, the com- plementary action of different sera varies enormously ; therefore, it is essential that a standardised strength of complement be employed, which means, in other words, that only the original Wassermann technique is reliable. Finally, since normal sera will, under certain conditions, give a positive reaction, any attempt to sharpen the reaction will increase the number of positive results RATIONALE OF THE 'WASSERMANN AND ABDERHALDEN TESTS. 99 to be obtained with normal sera ; therefore cholesterolised antigens had better not be emploA'ed. For valuable assistance in this work I wish to express my thanks to Dr. R. L. Mackenzie Wallis, Mr. J. Patterson and Mr. W. H. Collier. ' Bordet et Gengou (1901), " Ann. de I'lnstitut Pasteur," xv, 289. - Wassermann u. Bruck (1905), " Mediz. Kliiiik.," 1409. '■' Wassermann u. Bruck (1906), " Deutsch. med. Woch.," sxxii, 450. ' Fornet u. Schereschewsky (1907), " Miinch. med. Woch.," liv, 1471. 5 Miohaelis (1907), " Berl. kUn. Woch.," xliv, 1477. " Forges u. Meier (1908), " Wien. klin. Woch.," xxxi, 206. ' Klausner (1908), " Wien. klin. Woch.," xxi. 214. 8 Sohtirmann (1909), "Deutsch. med. Woch.," xxxv, 616. » Jacobsthal (1909), " Jliineh. med. Woch.," Ivi, 2607. " Levaditi et Yamanouchi (1907), " Comptes Rendus de la Soc. de Biol.," hx, 740. " Hecht (1908), " Wien. khn. Woch.," xxi, 1742. '^ Fleming (1909), " Lancet," i, 1512. " Landsteiner, Muller u. Potz] (1907), " Wien. klin. Woch.," xx, 1421. " Sachs (1911), " Berl. khn. Woch.," xlviii, 2066. '^ Wechselmann (1909), " Ztsohr. f. Immunitatsforsch.," iii (orig.), 525. 1'^ Ascoli (1910), "Miinch. med. Woch.," Ivii, 63. " Izar (1910), " Miinch. med. Woch.," Ivii, 182. " Lange (1910), " Deutsch. med. Woch.," xxxvi, 217. "9 Thiele and Embleton (1914), " Lancet," i, 526. 20 Browning (1914), " Lancet," i, 740. " Mackintosh and Fildes (1912), " Zeitschr. f. Chemotherapie," i, 79. " Rona, " Handbuch der Bioch. Arbeitsmethoden," v, 328. " McDonagh and Mackenzie Walhs (1913), " Biochemical Journal," \'ii, 517. " Wassermami u. Lange (1914), "Berl. klin. Woch.," li, 527. =^ Mantovani (1914), " Giorn. Ital. d. Malat. Vener. e. d. Pelle," Iv, 759. " Kaplan (1913), " Xew York Med. Journ., " xcvii, 1172, and xcvii, 1267. -' Van Slyke, " Handbuch der Bioch. Arbeitsmethoden," v, 995. -' Landsteiner u. Rook (1912), "Zeitschr. f. Immunitatsforschung," xvi (orig.), 14. -' McDonagh (1914), " West London Med. Journ.," xix, 1. '" McDonagh (1914), "A Report upon the Biology of Sj-philis " (Harrison & Sons, London). " Bisgaard (1914), "Bioch. Zeitschr.," Iviii, 1. 2= McDonagh (1914), " Archiv. f. Derm. v. Syph.," cxix, 205. '' Andrewes (1914), "Local Gov. Board. Report of the Medical Officer," xliii. ^* McDonagh (1914), " Arcliiv. f. Derm. v. Syph.," cxx, 289. ^' McDonagh (1912), " Brit. Med. Joum.," i, 1287. «« McDonagh (1914), " Brit. Journ. of Dermatology," xxvi, 283. " Abderhalden (1914), " Abwehrfermente," 4'" Aufiage. (J. Springer, Berlin.) '» Nerking (1909), " Miinch. med. Woch.," Ivi, 1475. '' Myers (1914), " Lancet," i, 767. CHAPTER XI. THE SIGNIFICANCE OF THE WASSERMANN REACTION, AND THE AVAY IN WHICH IT IS INFLUENCED BY TREATMENT. A negative Widal does not invariably mean that a patient is not sufiering from enteric fever, and similarly for a negative Wassermann. As a positive Widal proves that the patient has had, or has tj^phoid, so does a positive Wassermann prove that he has had, or has syphilis, although it must be remembered that positive reactions may be obtained in leprosy, trj^panosoniiasis, and in some cases of malaria. Sporadic cases have been described, where a positive Wassermann has been obtained in diseases other than syphilis ; in over 16,000 tests I have had 17 undoubted instances. It is very difficult to exclude syphilis, say of some 10, 15 or 20 years' standing, history being untrustworthy. For instance : — Case 3. — A man was admitted into hospital for pains in the stomach region, and vomiting. Diagnosis, mahgnant disease. Wassermann positive ; no history or sign of syphilis. Operation was advised but patient refused. About a year later patient came up to hospital complaining of pains in his legs. Again the reaction was positive. He was found to have Argyll-Robertson pupils, and the case proved to be one of degenerative myelitis. Although a positive reaction is a proof of syphihs, it must not be forgotten that the trouble for which the patient seeks advice is not necessarily svpliihtic. Syphilitic patients are by no means immune to tuberculosis, mahgnant disease, and the various forms of lymphocytomata, all of which may produce symptoms which are clinically very difficult to distinguish from those of syphilis. Moreover, a positive reaction does not necessarily mean that the patient has active sjrphilis. Therefore, the only certain thing that one can say about a positive Wassermann reaction is, that the usual factors excluded, it signifies that the patient has had syphilis. The many modifications of the reaction which have been made, have increased the incidence of positive reactions in persons who have never had syphilis. The reaction which Wassermann described is laborious, but nevertheless is the most trustworthy. Since the reaction is empirical, all efforts should be made to do INTERPRETATION OF REACTION AND INFLUENCE OF TREATMENT UPON IT. 101 away with the empiricism, before attempting to simplify the technique. The reader will find in chapter X an attempt to achieve the former. The interpretation of a positive and negative Wassermann reaction will be as follows, according to the various stages of the disease : — Stage of the Initial Lesion. In this stage the reaction is alwa3^s negative. Should a positive reaction be obtained in a case of a doubtful sore, it is tolerably certain that the sore is syphilitic, and it means that the patient has entered the generalisation stage. Stage of the Generalisation of the Virus. The Wassermann reaction becomes positive, as a rule, before any signs or symptoms of this stage manifest themselves. The Wassermann reaction may become positive as early as the fifteenth day after the first appearance of the sore, but, as a rule, it does not become positive until about the thirty-fifth day. In 6'5 per cent, of cases, in spite of obvious sj'mptoms, the Wassermann reaction is negative. Recurrent Stage. If the reciu:rence occurs before the fourth year, or thereabouts, and if the patient has received no treatment within the last six months, the reaction will be positive in practically every case. The longer the interval that intervenes, from the fourth year until the appearance of the recurrence, the greater the chance of the Wassermann reaction being negative, so that, in the stage of the late recurrences, the Wassermann reaction may not be positive in more than 75 per cent, of the cases. This is due, as may have been seen in the last chapter, to a free fatty acid particle existing in the lipoid-globulin or reagin molecule. The effect of treatment upon this molecule often makes itself felt for a few months, hence a careful interpretation of a negative AVassermann reaction should be made, if any treatment has been administered during the last six months. Latent Stage. This is one of the most important stages of the disease, and is one in which the Wassermann reaction is of the least value. The latent stage is the stage in which the patient has had syphilis, has been treated, and shows absolutely no symptoms of the disease after a very careful clinical examination. To give accurate figures per cent., in which the Wassermann reaction is positive in this stage, is impossible, since so many factors come into play, such as the kind of infection, 102 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. the time that has elapsed since the infection, the amount of treatment the patient has had, the stage in which the patient was when the treatment was commenced, the date when the patient last had treatment, and whether he has had a recurrence or not. Let us take each of these factors in turn, and assume that in every case the syphilis was contracted not less than four years prior to the date when the patient seeks advice, as this is about the period at which the latent stage can be said to have begun. (a) The hind of infection. — If the infection was mild, the check upon the production of antibodies will have probably commenced about the fourth 3'ear, and therefore the Wassermann reaction will be negative. This does not necessarily mean that the patient is cured, as he may develop a degenerative nerve lesion or even a systemic lesion, later. If the infection was severe, the production of reagin often continues throughout the patient's life time, hence, about the fourth year, the Wassermann reaction will be positive. This does not necessarily mean that the patient has active syphilis. \h) The amount of treatment. — The more treatment the patient has had, the greater the likelihood that the Wassermann reaction, about the fourth year, will be negative, and vice versa, but the results can convey no meaning, as a negative reaction is not definite proof that the patient is cured, and a positive reaction may only be an indication of the patient's protective capacity against the disease. (c) The stage of the disease at which treatment teas commenced. — If the Wasser- mann reaction was negative before treatment was started, and negative again about the fourth year, the patient can almost certainly be assured that he is cured. If the Wassermann reaction was positive before treatment was begun, neither a positive nor a negative Wassermann reaction, about the fourth year, means anything. (d) The date when the paiient last had treatment. — The more recent the treatment, the greater the likelihood of the reaction being negative, and the less the reliUnce that can be placed upon the test. (e) Whether the patient has had a recurrence or not. — If the patient has had a recurrence, the chances are that the reaction will be positive, in spite of treatment. If negative, on the other hand, the chances are that the patient is cured, but there are several traps that await the physician who feels sure himself that the patient is cured. The chemical configuration of the reagin molecule may be such that it will prevent adsorption of complement in vitro, and this is a condition which is very apt to occur in the sera of those patients who have had a recurrence. I now practically never do a Wassermann reaction in this stage, for the simple INTERPRETATION OF REACTION AND INFLUENCE OF TREATMENT UPON IT. 103 reason that a positive reaction may only mean that the patient's protective mechanism is working well, and requires no stimulus ; treatment is by no means indicated — indeed, it may even be a contraindication, as I have seen several cases in which I am certain that a degenerative nervous lesion was precipitated, owing to the check which treatment put upon the production of systemic antibodies {vide Chapters XXIII and XXIV). I examine the patient thoroughly, and if I can find nothing wrong, I assure him that all is well, and send him out a happier man than he came in. If I am the least bit suspicious, and I pay particular attention to any nervous signs or symptoms, I examine the cerebro-spinal fluid, and base my advice to the patient upon the conditions found therein {vide Chapter XXII). Syphilis in Women. The infection of women can be divided into two classes, («) ordinary infection, (b) conceptional infection. Only the latter need be discussed, as the former does not differ from the infection of the male, but it must always be remembered that, broadly speaking, the sera of women, during the child bearing period, have a tendency to give negative Wassermann reactions. In what may be called con- ceptional syphihs, that is when the mother and embryo are infected by the contaminated semen, the Wassermann reaction is often negative. I have fre- quently had cases in which the mother has given birth to an undoubted syphilitic infant, and yet her blood has given a negative reaction. Pregnancy no doubt retards or prevents the development of the Leucocytozoon syphilidis for the time being. Some time after a pregnancy, should another not supervene, or after the child bearing period is over, the reaction frequently becomes positive. In some cases repeated pregnancies have undoubtedly resulted in a spontaneous cure of the disease. Congenital Syphilis. It may be mentioned first, that when one wishes to get blood from a new born infant, it is best to puncture the heel. Infants born with S3Tnptoms of the disease always give a positive reaction. Syphilitic infants, born without symptoms of the disease, may not give a positive reaction until symptoms appear. The reaction is always positive in Syphilis congenita tarda, and it may remain so throughout life, although, in the majority of cases, the tendency is for it to become negative in time. Case 4. — A girl aged 23, unmarried, had signs of an old bilateral interstitial keratitis, she was stone deaf in both ears, she had Hutchinson's teeth, and marked 10-i THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. signs of old osteoperiostitis, but, in spite of all this, her blood was negative on every occasion it was tested. I have had almost similar cases, in which the blood of congenital syphilitics between 40 and 50 3^ears of age has been positive, and I have had two cases in which a congenital syj^hilitic mother has given birth to children, whose blood has given a positive Wassermann reaction. Usually the blood of infants born of congenital syphilitic parents gives a negative reaction. Treatment has very little influence upon the reaction in congenital syphilis. Syphilis of the Nervous System. In early arterial lesions, the blood is almost invariably positive, while in late arterial cases, it is frequently negative. In meningeal syphilis, the blood may be either negative or positive. As in many of the cases of .syphilitic meningitis, symptoms do not arise until the host has ceased to form protective bodies in his systemic portion, it will naturally follow that the blood will often be negative. In degenerative nerve lesions, when the condition first commences, the blood may be positive or negative. If positive, the chances are that the patient has a systemic vascular lesion, which not infrequently accompanies degenerative nerve lesions. In those cases in which the blood is negative at first, it usually becomes positive later, especially is this the case in degenerative encephalitis, when sufficient reagin, which is formed in the nerve tissue, percolates into the general blood stream. As more reagin gets formed in degenerative encephaUtis, than in degenerative myelitis, it naturally follows that, in the former the blood more often gives a positive Wassermann reaction. If later still, the blood becomes negative, and the case is one of degenerative encephalitis, it generally means that the patient is in a quiescent period. If the case is one of degenerative myelitis, the chances are that spontaneous cure has resulted — a by no means uncommon sequence to the condition. , Differential Diagnosis. The Wassermann reaction is sometimes useful, when one is dealing with a differential diagnosis, but it is perfectly true to say that, the more it is used for this purpose, the less the clinical knowledge of the physician who uses it. Clinical knowledge is the highest attainment in medicine, hence, the present, and all future generations would be better advised to place less reliance upon this, and all other tests, and to regard them as mere adjuncts to a clinical diagnosis. I have been carrying out Wassermann tests since early in the year 1908. I have had the clinical history of most of the cases examined, and I have in all done INTERPRETATION OF REACTION AND INFLUENCE OF TREATMENT UPON IT. 105 over 16,000 tests. Early in the year 1915, I am able to say that scarcely ever an opportunity arises in which the performance of the reaction is called for, and even in those cases in which the result is positive, in the majority of instances, it is impossible to say, whether it means that the patient has active syphilis, or only that he has had the disease. The Wassermann Reaction as Influenced by Treatment. In the primary stage, when the reaction is negative before treatment with salvarsan is commenced, most cases give a positive reaction after treatment. This is most marked about the forty-eighth hour, but commences to show itself about the seventeenth hour. In some cases, on the other hand, the reaction does not become positive until the fifth day. Although it may remain positive for several days, the degree diminishes generally about the third week, till it becomes negative before the eighth. If the reaction is only slightly positive after the injection, it becomes negative much earlier. If the serum is tested in diminishing strengths, to estimate its reagin* content, one can form an approximately accurate opinion as to how close to the generalisation stage the patient is, and, roughly, how many subsequent injections will be necessary to produce a possible cure. If the first injection gives rise to only a weak reaction, then three or four more will undoubtedly suffice to make the reaction negative ; if, however, the reaction is strong, then the patient is in the generalisation stage, and will require at least 3 grams of salvarsan or neo-salvarsan, before the desired effect is obtained. Case 5. — Intra-urethral chancre, 14 days' duration, six weeks after inter- course ; slight inguinal adenitis ; spirochaetae found. No. of Injection, and Result. 24 Hours 48 Hours 5th 10th after. after. Day. Day. + + + + + + + + + + + — + + + + + + — — + — + 14th Day. 1st injection ... ...[ — 2nd injection (8th day after 1st) ...'-|- + -|- 3rd injection (21.st day after 2nd) . . . j + + + 4th injection (8th day after 3rd) ...' + + + 5th injection (14th day after 4th) ... — 6th injection (8th day after 5th) ... + + + + The reaction was tested on the seventh, fourteenth, twenty-first and twenty- eighth days after the last injection, and was negative on each occasion. Patient * Since the reacting substance in the Wassermann reaction is not a true antibody, it has received the name of " reagin." ]06 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. was put on mercury for a year, and six months afterwards Wassermann reaction was positive. Patient has never developed a recurrence. The blood has been tested several times since it was last positive, and sometimes it gives a negative reaction and sometimes a positive one. Paradoxical sera are not uncommonly met with in patients, who have been well treated. Case 6. — Two chancres on penis, two on scrotum ; no adenitis ; date of infection not clear ; spirochaetae found. Xo. of Injection, and Result. 24 Hours after. 48 Hours after. 5th Day. 1st injection 2ncl injection {8th day after 1st) 3rd injection (8th day after 2iid) 4th injection (8th day after 3rd) + + + + + + + + + + The reaction was tested on the seventh, fourteenth, twenty-first and twenty- eighth days after the last injection, and was negative on each occasion. The reaction was tested again, one and two years later, with negative results. Case 7. — Chancre, internal canthus of eye ; adenitis, pre-auricular and cervical ; date of infection uncertain ; spirochaetae found. No. of Injection, and Result. 24 Hours after. 48 Hours after. 5th Day. 10th Day. 17th Day. 1st injection 2nd injection (8th day after 1st) 3rd injection (17th day after 2nd) ... 4th injection (8th day after 3rd) 5th injection (21st day after 4th) ... -I--I--H + + -|--t- + + + + + + + -I- 4--t- + + + On testing the reaction on the seventh, fourteenth, twenty-first and twenty- eighth days after the last injection, it was found to be negative ou each occasion. Mercury was given for one year, and blood was tested again six months and a year later ; on the latter occasion it gave a positive result. This patient has had no recurrence, and the blood tested since has sometimes been positive and sometimes negative. Unfortunately, it is rare to get a case so early that the reaction does not become positive as the result of an injection. I have had some cases however, but nevertheless I give three or four more injections of neo-salvarsan, for safety. In every case, mercury should be prescribed, for from 12 to 18 months. INTERPRETATION OF REACTION AND INFLUENCE OF TREATMENT UPON IT. 107 WTien the reaction becomes strongly positive after an injection, and in cases in which it is markedly positive before treatment is commenced, it may be assumed at once that the patient is in the generalisation stage, and that he should receive the treatment mapped out for this stage {vide Chapter XXIX). Case 8. — Chancre on penis, general adenitis, and headaches at night time. No. of Injection, and Result. 24 Hours after. 48 Hours after. 5th Day. 1st injection 2nd injection {8th day after 1st) 3rd injection (8th day after 2nd) 4th injection (8th day after 3rd) + + + + + + + + + + + + + + + + + + + + + - + The reaction was also found to be negative on the seventh, fourteenth, twenty- first and twenty-eighth days after the last injection. Mercury was prescribed for 18 months, but six months later Wassermann reaction was positive. Patient has since developed a meningo-myelitis, in spite of the fact that the "Wassermann reaction in the blood has been negative for some time past. Case 9. — A typical case of early generalised syphilis, rash, sore throat, etc. No. of Injection, and Result. 24 Hours after. 48 Hours after. 5th Day. 1st injection 2nd injection (8th day after 1st) 3rd injection (8th day after 2nd) 4th injection (8th day after 3rd) 5th injection (8th day after 4th) 6th injection (8th day after 5th) 7th injection (8th day after 6th) + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + The reaction was also found to be negative on the tenth, fourteenth, and twenty-eighth days after the last injection. Mercury was taken for six months only ; six months later Wassermann reaction was negative, but a year later it had become positive again. In the late stages, the Wassermann reaction behaves much in the same way as it does in the primary and generalisation stages, except for one peculiar phenomenon, which is occasionally to be noted, that is, that a case with a strong positive reaction, before treatment, may become negative immediately after an injection, and remain so from 2-1 to 72 hours, and then become quite positive again. On repeating the injection, the same thing may happen, but more often it is quite the reverse, namely. 108 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. that the reaction becomes more positive, au occurreuce which is seen in the early stages. The opposite also frequently occurs, i.e., a patient with late lesions, giving a negative reaction, gives a positive reaction after an injection of salvarsan. Case 10. — The patient contracted syphihs 25 years ago, for which he took mercury at irregular intervals for four years. For the past five years he had been troubled with cutaneous gummata, which disappeared under mercury and iodides, to reappear quickly after treatment was discontinued. In 1911 the patient had three intramuscular injections of salvarsan, and he came up for a Wassermann test just after Christmas of the same year. There were no s)Tiiptoms at the time. No. of Injection, and Result. 24 Hours after. 48 Hours after. 5th Day. 1st injection 2nd injection (8th day after 1st) 3rd injection (8th day after 2nd) ■4th injection (8th day after 3rd) 5th injection (8th day after ith) 6th injection ( 8th day after 5th) + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + Six months and a year later, although patient was under mercury, the Wasser- mann reaction was positive, but since then it has remained negative. Case 1 1 . — A man, aged 42, 18 years ago contracted syphihs, for which he was treated with mercury (pills) internally for three years. A few years later he was much troubled with headaches, which were only relieved by mercury and iodides ; and the moment treatment was stopped, the headaches commenced again. From time to time, the patient had cutaneous gummata and some soft nodes (gimimatous pericranitis) on his skull. When he came up for advice he had a gumma over his frontal bone, and it had eroded a portion of the external table ; headaches were bad, and the patient complained bitterly of losing his memory. No. of Injections, and Result. 24 Hours after. 48 Hours after. 5th Day. lat injection 2nd injection 3rd injection 4th injection 5th injection 6th injection 7th injection 8tli injection 9th injection (8th day after 1st) (28th day after 2nd) (8th day after 3rd) (8th day after 4th) (8th day after 5th) (8th day after 6th) (8th day after 7th) (8th day after 8th) + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + INTERPEETATION OF REACTION AND INFLUENCE OF TREATMENT UPON IT. 101) On testing the reaction on the seventh, fourteenth, twenty-first, and twenty- eighth days after the last injection, it was found to be negative on each occasion, and has remained negative for three years. When approaching the end of treatment, and when all the reactions are negative, and in cases in which the amount of reagiu is normally small, namely, in cases of arteriosclerosis, cerebro-spinal syphiUs, sj'phihtic epilepsy, and hemiplegia, each serimi should be tested in gradient increasing strengths. When a serum stronger than normal is used, controls should never be omitted, to show that it has no haemolytic power on the sheep's blood corpuscles, an occur- rence which is not at all uncommon, especially when the serum has been allowed to remain with its corpuscles for a few days. Therefore it is desirable to pipette ofi the serum as soon as possible after the blood has been withdrawn, and it is always better to inactivate the serum as soon as possible, since sera left at room temperature, or, more especially, in an ice incubator, soon acquire the property of fixing complement. It sometimes happens that cases nearing the end of treatment, for instance, after the fourth or fifth injection, give a weak positive reaction only between the third and fom'th week, and it becomes negative within a few hours of repeating the injection. Patients who have had syphilis, and give a negative Wassermanu reaction, are either cured or in the latent stage ; which of the two can sometimes be ascertained by giving a provocative injection of salvarsan, and then testing the blood. Case 12. — A man, aged 29, contracted syphihs five years ago. The attack was very mild, but nevertheless the patient continued his mercury treatment (pills and injections) for four years. A recurrence never appeared. On three different occasions the blood had given a negative Wassermann reaction, but the patient being anxious to marry was desirous of an injection of " 606 " to make things sure. Xo. of Injection, and Result. 1st injection... 2ud injection (8th day after 1st) ... 3rd injection (8th day after 2nd) ... 4th injection (8th day after 3rd) ... 5th injection (21st day after 4th)... 6th injection (8th day after 5th) ... 7th injection (8th day after 6th) ... 24 Hours after. 48 Hours after. 5th Day. 14th Day. ' + -f-n- _ — + -1- + + -f-l- — + -1- + + . -1- + + + . + . +- — — — - — 110 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. The reaction was also negative on tlie seventh, fourteenth, twenty-first, and twenty-eighth days after the last injection. Mercury was prescribed for a year, and up to the second year the reaction was negative every time it was tested. If the previous treatment has been recent — that is, only a few months ago — the appearance of a positive reaction may be delayed, or, as happened in several cases, may be positive in the IS hours blood, and negative again on the fifth or even the third day, to become only definitely positive on each occasion after the second injection. In a few cases, the reaction was not positive at all, until after the second injection — cases of arterial syphilis. Not only is the reaction determined by the time of the previous treatment, but also largely by the quality of that treatment. If the treatment has been good, then the occurence of a positive reaction may also be delayed, and only a few injections are required to produce a negative reaction. Several of my patients, who had been treated with mercury for from three to four years, and who had given a negative Wassermann reaction on several occasions, gave a positive one after a provocative injection of salvarsan, and required from four to six injections before a negative reaction was obtained. Whether a positive reaction after a provocative injection of salvarsan means that the patient has an active lesion, a hidden focus, or only signifies that he has had syphilis, I am not at present able to state definitely. My own opinion is, that it only means that the patient has had syphilis, therefore it is very seldom that I now give a provocative injection. I rely upon a clinical examination, or upon an examination of the cerebro-spinal fluid, to guide me as to whether further treatment is required or not. If no treatment is required, most patients assume that they are cured, and do not ask the question. If they do, I explain the whole situation to them, with the result that the visit ends happily. Giving a provocative injection and doing a series of tests in which absolute faith cannot be put, only tend to make the patient suspicious and more concerned about himself, a state of mind which no venereal patient should be allowed to develop. In cases of cerebro-spinal meningitis, in which the cerebro-spinal fluid gives a positive Wassermann reaction, repeated injections of salvarsan may convert the positive into a negative reaction, and at the same time cause the lymphocytosis to disappear, but, in the majority of cases, the reactions become positive again, sooner or later. As the cerebro-spinal fluid is weak, both in its reagin content and in complement-fixing capacity, it should invariably be tested in increasing strengths up to 1,000 per cent. In cerebro-spinal syphihs, it is not at all uncommon to find that the INTERPRETATION OF REACTION AND INFLUENCE OF TREATMENT UPON IT. Ill Wassermann reaction is negative in the blood, and positive in the cerebro- spinal fluid, becoming positive in the former only after treatment. In degenerative nerve lesions, treatment, however drastic it is, is, in the majority of cases, quite unable to render a positive Wassermann reaction in the cerebro-spinal fluid negative ; the globulin reaction seldom disappears, but the lymphocytosis may vanish. However many injections of salvarsan be given, it is always wise to supplement them with at least one year's treatment by mercurial injections and iodides. Even then one may not be successful in preventing a recurrence from appearing later, as no test exists which will prove the absence or presence of spores, and no treatment exists which will kill them directly, provided they have been in the body for a sufficiently long time. If the above course is followed, experience has so far shown that a cure in the primary and generalisation stages of syphilis is possible, but by no means certain. In the late cases a cure is, for the most part, impossible. Therefore, in the early stages of sj'philis, in my opinion, salvarsan can be used with the idea of curing the disease, and in some of the late stages with the idea of abolishing the STOiptoms onl}'. There is no doubt that many patients who have shown recurrent symptoms become spontaneously cured ; even in a chronic condition like degenerative myelitis, it is highly probable that a spontaneous cure occurs in about 20 per cent, or more of all cases. Nearly every case which 1 have treated by several injections of salvarsan and one or more years' treatment with mercury has, up to the present, remained free of symptoms, and some have been under observation for four years from the time treatment was begun. A majority of the cases has, however, later given positive Wassermann reactions, and a peculiarity about most of them has been that the reaction appeared paradoxical, i.e., one week or one month it was positive, while the next week or month it was negative again. The cause of this paradox is far from clear, but, nevertheless, its occurrence should be a stimulus to make us probe the rationale of the Wassermann reaction down to the very bottom, to see if we are justified in always regarding a positive reaction as necessarily indicative of active s}"philis. It is noteworthy that of two individuals, in exactly the same stage of disease, with the same lesions, one may give a negative reaction after four injections, while in the other, six or more may be required before a negative reaction is obtained. Again, a permanent negative reaction is most easily obtained when the treatment is continuous, that is when the injections of salvarsan follow closely upon one another, and when mercury is given afterwards for a year or more. For instance, early H 112 THE BIOLOGY, CLINICAL ASPECT ANB TREATMENT OF SYPfflLIS. cases of sj^hilis, which had received one or two iujections of salvarsan several months back, have required nearly the same number, given continuously, as presumably would have been required, had those previous injections not been given. Therefore it is important, if a course is going to be started, that it should be persevered with, until the desired effect is obtained. ' As my views have altered considerably since the time when I was prompted to do the research work, of which the above is the outcome, I now never gauge my treatment by the Wassermann reaction. I give the patient the maximum amount of treatment which I have learnt by experience is necessary for those cases, in which a cure by treatment is contemplated ; while the other patients I treat symptomatically. The reader will have seen that the result of treatment upon the Wassermann reaction is extremely paradoxical, and therefore I refer him, when he has the treatment of a case under consideration, to Chapter XXIX. CHAPTER XII. THE CUTIREACTION. Since v. Pirquet demonstrated that the diagnosis of tuberculosis might be assisted by the reaction produced by an intracutaneous injection of tuberculin, several observers have tried to find a similar test for syphilis. At that time the SpirocJiaefa pallida could not be grown in culture, consequently tissue extracts, which contained this organism, were used. Tedeschi^ was the first to use the cuti- and ophthalmoreaction in cases of syphilis. He employed an aqueous extract of chancres, which had been passed through a Berkefeld filter. Tedeschi obtained positive results in animals which had been inoculated with syphilis, but he appears to have made no control vaccinations on man. Meirowsky,' about a year later, used an extract of syphilitic liver, with satis- factory results, but he found in his experiments that tuberculous patients also gave a positive reaction. Ciufio^ repeated Meirowsky's work, but came to the conclusion that the reaction was not specific. In 1910, Nicolas, Favre, Gautier, and Charlet* made a glycerin extract of foetal syphihtic liver, to which they gave the name of " syphihn," and, according to their reports, the results were very satisfactory, but subsequent workers failed to confirm them. When it became known that the antigen in the Wassermaun reaction was non-specific, and that its place could be taken by normal tissue extracts and chemical substances, several observers conducted experiments with the extract of a guinea-pig's heart, with lecithin, sodium glycocholate, etc., but all were with negative results. After Noguchi^ had succeeded in culturing the Spirochaela pallida, he prepared an extract of the growth and named it "' luetin." Luetin, mixed with an equal quantity of saline, is injected into the skin — 0'035 c.c. luetin and 0'035 c.c. sahne. Noguchi distinguishes three reactions : («) the papular ; (b) the pustular ; (c) the torpid. The papular form is most commonly seen in generalised syphilis ; h2 114 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SVPHILIS. the pustular form is seen most often in the late recurrent, and in congenital cases. The torpid form is the rarest, and is recognised by the fact that the reaction does not appear until a few days after the test has been applied. Noguchi found that in untreated cases, in both the primary and the generalisa- tion stages, the luetin reaction was usually negative, while in the latent stage, and in other stages in which treatment had been given, the reaction was generally positive. In cases of degenerative encephalitis and degenerative myelitis, only 50 per cent, gave a positive reaction. Other American observers® ' * who repeated Noguchi's work, obtained similar results. Noguchi very kindly sent me some material, which I tried on several cases. At the same time as I was using luetin, I was also experimenting with the cutireaction obtained with various specimens of gonococcal vaccines.' In early cases of syphilis, as in acute cases of gonorrhoea, whether the gono- coccus was limited to the urethra or had already become s)-stemic, the cutireaction was generally negative. In late cases of syphilis, and in late cases of gonorrhoea, especially when there was a metastatic complication, the reaction was ahnost invariably positive, and often very markedly so. It not only varied in intensity, but also in the time which elapsed, between giving the injection and the onset of the reaction. If a test for diagnosis is required at all, it is most necessary in the early stages of the disease, when cutireactions are usually negative ; therefore, as a means of helping the practitioner to diagnose a sore, the luetin reaction must not be relied upon. With luetin, as with the gonococcal vaccines, the reaction depends not only upon the strain used, but largely upon the experience of the operator, as what is considered a positive reaction, varies with almost every observer. It is important to note that a positive cutireaction only signifies th^t the patient has had the disease, not necessarily that he still has it. Furthermore, the luetin cutireaction is not absolutely specific, as I have been able to get positive reactions in patients who have never had syphilis, 3 cases in 25 controls, and I have been able to produce a positive reaction in cases of syphilis, with substances other than luetin, namely, with certain hpoid-adsorption complexes with globulin. Boas and Ditlevsen^" in a recent article, also found that positive reactions were to be obtained in non-syphilitic cases, as many as 15 in 124. In the latent and recurrent stages of sj^hilis, although the luetin reaction is not more often positive than the Wassermann reaction, cases are to be met THE CUTIREACTION. 115 with, in which the former is positive and the latter negative, and vice versa. It has been suggested that, in these two stages, both tests should be applied, but this is unnecessary, as such cases are very seldom sources of infection ; a clinical diagnosis is more valuable than both, and a positive reaction with either is no certain criterion that the disease is active, and therefore requires treatment. A peculiar phenomenon has been noted by Miiller and Stein^i, and Klausnei'i^, that occasionally a case of late recurrent syphilis, with a negative Wassermann reaction and a positive cutireaction, gave a positive Wassermann reaction after the cutaneous test had been applied. Owing to the difficulty experienced in cultivating the Spirochaeta ■pallida, the attention of a few observers has been directed back to the tissue extracts ; and now the lung, from cases of Pneumonia alba, is the organ used. Fischer,^'* who was the first to use lung tissue, prepared his extract in the following way : — Pieces of lung were finely broken up with powdered glass, and then mixed with an equal quantity of shghtly alkaline saline solution. The mixture was then centrifuged, and the fluid obtained was heated for half an hour at 60'' C. To keep the fluid sterile carbolic acid was added. The control solution was made in a similar way with healthy lung tissue. Of each, -^-4^ c.c. was injected intracutaneously. Fischer himself obtained negative results, but Klausner,i'- who repeated his work on a much larger scale, found that positive results were the rule, in recurrent syphilis and congenital syphilis. In 1,200 control cases, the reaction was always negative. In primary and generalised syphilis, the reaction was also usually negative, as it also was in cases of degenerative myelitis and encephalitis and arterial syphilis. Pallidin is the name which has been given to this lung extract, and it can be obtained from Merck, of Darmstadt. It would not be out of place now to discuss, in a few words, the rationale or modus operandi of this reaction. I do not think it is necessary to mention all the views which have been expressed, as practically each one has entailed the necessity of coining a new word, which is meaningless. So far as syphilis is concerned, two important points come to light, one being that the cutireaction is only of value in the late cases of syphilis, the other being that occasionally a negative Wassermann reaction is converted into a positive reaction. The histological examination of lesions produced by the intradermal injections of syphilitic extracts, also throws considerable light upon the rationale of the cuti- reaction. 116 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. There is, first of all, a dilatation of the vessels and Ipnphatics, and a prohfera- tion of their endothehal cells. These endotheUal cells give rise to ljTiiphoc}i:es, which in turn develop into plasma cells. Others become giant cells. The lymphocytes and plasma cells form the protective substance of the host, and this protective substance is a specific hpoid-globulin, and also happens to be the reagin of the Wassermann reaction. If the host has been forming this protective substance for two, three, or more years, there comes a time when its formation becomes continuous, in spite of the fact that all the parasites have been vanquished. Any extra call upon this pro- tective substance will stimulate the production of this specific hpoid-globuUn. The reply to the stimulus will vary, according to the stage at which it is appHed. Let me further explain this point. The production of hpoid-globuhn, as stated above, becomes continuous, but always in an increasing ratio, and the increasing ratio is greater in the lipoid than in the globulin portion of the molecule. If there is to be an ever-increasing amount of lipoid-globuhn formed, there must of necessity be a corresponding increase of cells formed, to produce it. Should the parasitic Upoid-globuhn be introduced into the host, as is the case when the syphilitic extract is injected intracutaneously, the production on the part of the host of a lipoid-globulin which has the same stereo-chemical molecular configuration as that of the parasitic lipoid-globulin, will vary according to the stage of productive mechanism in which the host is. If the productive mechanism of the host is at or near its zenith, it will follow that any extra call upon it will meet with the greatest response. This means that the greatest number of endothehal cells, lymphocytes and plasma cells will be formed. The reaction will be very marked. The greater the reaction, the more likehhood there will be of the vessels being occluded. Occlusion of vessels means loss of blood supply to that area of sldn supplied by them. Therefore, the greater the reaction, the more the lesion will resemble a gmnma. Syphilitic cutireactions simulate syphihtic lesions. The lesion of a mild reaction resembles a papule ; the lesion of a severe reaction resembles a gumma. No lesion can resemble a chancre, because such a lesion can only be produced when the host does not elaborate the specific lipoid-protein, and, when the host does not manufacture this substance, a positive cutireaction cannot be obtained. Broadly speaking, no negative reaction is of value, therefore onh^ a final word need be said about the positiye cutireaction. As the host persists in manufacturing the specific lipoid-globulin substance, in spite of the fact that there are no organisms to Icill, it will follow that when the homologous parasitic lipoid-globulin is injected, a reaction will result, but this does THE CCTIREACTIOX. 117 not mean that the patient is suffering from s}-j)hilis ; it means only that the pro- babihty exists that he has had the disease. Although tuberculin does not, as a rule, give a cutireaction in cases of syphilis, it is an odd fact that the inflammation produced by an injection of tuberculin, in a syphilitic case, is very much increased, if an injection of pallidin is given afterwards, and vice versa. This interesting observation has been made by several workers (Klausner,^- Kammerer,^* Nogirchi,^ Meirowsky'-), but each has put his own interpretation upon it. The simplest explanation appears to me to be the following : — The tubercle bacillus, and hence tuberculin, have their own specific lipoid- globuhn, and the host upon which they are implanted elaborates a hpc.^d-globulin which has the same stereo-chemical molecular configuration as that of the parasite. The specificity of the lipoid-globnlin does not he in the lipoid-globuhn, as such, but in the polypeptide molecules upon which it is built up. The same applies to the specific s^'philitic lipoid-globulin. The different physical molecular configurations of these groundwork stones (polypeptides), upon which other stones are laid, until the house (lipoid-globulin) is complete, must be very slight, and in many cases no doubt man}' of the stones are identical. Supposing then that some of the gi'oundwork molecules in the syphilitic lipoid-globulin were the same as those in the tubercular hpoid-globulin, an injection of the one would increase the reaction of the other, if it had been previously injected, and vice versa. Although every parasite elicits the production by the host of a specific lipoid- globuhn, the manner in which these specific lipoid-globnlins are built up is in some cases partially identical. Hence, when a crude measure like the intracutaneous injection is adopted, or when we have a still cruder method in the Wassermann reaction, for testing for these specific proteins, it will follow that slightly positive results will occur in other conditions, so we niay call them group reactions. An instance of a group reaction in the cuti-test is seen in the above ; and in the Wassermann reaction we have the positive results given by malaria, sleeping sickness, yaws, and leprosy. , If a few injections of a syphilitic extract are given to a patient who has not had syphilis, time allowed to elapse, and then another injection is given, a positive reaction will be obtained. This has long been known to be the case with tubercuhn. Such a reaction is called an anaphylactic reaction. From what has been stated in this chapter, the rationale of this phenomenon should be quite clear. 118 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. Several injections of a syphilitic extract lead to the formation of an homologous lipoid-globuhn. Provided neither too short nor too long an interval is allowed to elapse, a further injection will give rise to a reaction, owing to the fact that the memory of the formation of the specific Hpoid-globulin remains, with the result that an increased production of the protective substance is brought forward in response to the stimulus. > Tedeschi (1908), '• Gaz. degli Osped.," xxix, 620. 2 Meirowsky (1911), Xeisser'.s " Beitriige zijr Path. u. Ther. der Syphilis." 3 Ciuflfo (1909), " Gaz. degU Osped," xxx, 81.3. * Nicolas, Favre, Gautier et Charlet (1910), " Lyon Med.," cxiv, 621. 5 Noguchi (1911), ".Journ. of Exper. Med.," xiii, 43, 7S, 217. ' Robinson (1912), "Journ. of Cutan. Dis.," xxx, 410. ' Fox (1912), "Journ. of Cutan. Dis.," xxx, 465. 8 Wolfsohn (1912), " BuU. of the Johns Hopkins Hosp.," xxiii, 223. » McDonagh and Klein (1913), " Journ. of Path, and Bact.," xvii, 599. '" Boas u. Ditlev.sen (1913), " Archiv. fiir Derm. u. Syph.," cxvi, 853. " MuUer u. Stein (1913), " Wien. med. Woch.," Ixiii, 2419, 2614. '2 Klausner (1914), " Archiv. f. Derm. u. Syph.," cxs, 444. " Fischer u. Klausner (1913), " Wien. klin. Woch.," xxvi, 49. " Kiimmerer (1912), " Munch, med. Woch.," lix, 1534. CHAPTER XIII. THE BIOLOGY OF THE VARIOUS STAGES OF SYPHILIS. The Primary Stage. After a patient has exposed himself to infection, one or more spores gain access to the skin, in which they develop. When sufficient cycles, which comprise the life history of the Leucoojtozoon si/pJulidis, have been completed, the patient develops a sore. As the host cannot immediatelj^ form protective bodies, there is no limit to the number of sores which may be present, the number depending upon the different points of entrance of the organism. In, roughly, 30 per cent, of cases of syphilis, there is more than one primary sore, the most I have ever seen being eighteen. When the spore has entered the body, it seeks out a connective-tissue cell, or an endothelial cell, to the protoplasm of which it gains access. Therefore, the connective-tissue cell, and the endothelial cell, are the first cells to be attacked in sj-philis, consequently the brunt of the attack, and the resistance offered, will affect these cells, with the result that there will be marked multiplication of them. Connective-tissue cells later become fibrous tissue, hence the explanation of the so-called induration of chancres. The induration is purely relative, since a sore may appear before the connective-tissue cells have had time to form fibrous tissue, or a sore may develop in loose tissue, in which, if fibrous tis.sue did form, it would be scarcely noticed ; or the endothelial cell may be the main cell attacked, in which case there is practically no proliferation of the fixed connective-tissue cells. Furthermore, in those cases in which only the asexual stage is perpetuated, the endothelial cells are the cells most involved, hence the type of sore formed is never indurated. As a sore may appear before there is any induration, it follows that the in- cubation period of syphilis must vary somewhat, as it does — from eight days to six weeks, or more. As the connective-tissue cells and the endothelial cells are first 120 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. attacked, there will be no great call upon leucocytes, and as, in my opinion, phagocytosis plays no part at all in protozoal infections, there will be no pus and no necrosis. Therefore, if a sore occurs, it will be an erosion, and not an ulcer. Occasionally a chancre is to be met with, in which the surface epithelium never breaks. In the sore formed by the asexual development of the Leucocytozoon syphilidis, owing to the manner in which the endothelial cell is attacked, and its consequent multiplication, vessels become occluded. This occlusion results in necrosis of the skin above, hence such a primary sore, is an ulcer from the start. As a primary sore most usually affects regions which are swarming with saprophytic organisms, it may easily become infected or even phagedaenic ; then, instead of a simple erosion, there may be a big ulcer. If the saprophytic organisms attack the sore early enough, and if they are particularly active, they may succeed in annihilating the leucocytozoon. This explains why some phagedaenic sores are not followed later b)' further evidences of syphilis. In any case, the onset of phagedaena alters the sequence of the disease, usually by delaying the outbreak of the rash, sore throat, etc. In this observation I see the indication for removing a primary sore, when possible, or for cauterising those that cannot be so handled. In comparing the primary sore of human syphilis with that of experimental syphihs, one is at once struck by the great tendency to ulcerate exhibited by the latter. Moreover, the experimental sore is always clinically the same, while the sore of human syphihs may show numerous clinical varieties. A human chancre is generally an erosion and not an ulceration (the asexual sore excepted) ; the experimental sore is always an ulceration. From this simple chnical difference between ordinary and experimental syphilis, and from the hght which has already been thrown upon the causative agent of the disease, it may be assumed that, as the lesions of experimental syphihs never vary, only one portion of the life-cycle of the specific organism develops. Since spirochaetae are found in greater abundance in experimental chancres than in ordinary chancres, and since the long angulated forms are frequently to be met with, it is possible that only the extracellular development of the male body occurs. The spirochaetae obtained from experimental chancres are tj'pical of those grown in culture, and those I have found in the brain, from cases of degenerative encephalitis. Therefore, it will now be seen that my earlier remark — " What is happening in the test animal's body may be no more than is taking place in a culture tube " — is possibly near the truth. In rabbits, after the primary sore has THE BIOLOGY OF THE VARIOUS STAGES OF SYPHILIS. 121 existed for a little time, the inguinal Ipuphatic glands become enlarged, and the virus becomes generalised in the system. According to Graetz and Delbanco it is extremely rare for any histological changes to be found in the inguinal lymphatic glands, and often spirochaetae cannot be demonstrated. To prove that the virus is undoubtedly harbouring in them, it was found necessary to inoculate another animal with part of the lymphatic gland. Comparing this with human syphihs, again great difEerences arise. Broadly speaking, the smaller the lymphatic gland, the more marked are the histological changes found therein. Many of the small lymphatic glands which I have examined, are crowded with giant cells and small areas of necrosis, exactly resembling a tuberculous lymphatic gland. The cells in the small lymphatic glands are mainly endothelial cells, a few lymphocytes may be found, and only a very small number of plasma cells, showing that the resistance of the host is feeble, and that its last line of support has been attacked. To understand the full significance of this remark, the reader must be referred to Chapter XLVI. The large glands also show marked changes, but, instead of consisting mainly of endothelial cells, they are crammed with plasma cells. It is not difficult to find spirochaetae in the inguinal glands removed from human syphilis. Tissue, which when inoculated into animals gives rise to lesions from which spirochaetae can be obtained, need not necessarily contain spirochaetae, etc. Therefore, when the organisms are found in the fresh lesion, it is no proof that the tissue which gave rise to that lesion harboured spirochaetae. All that can be said is, that the tissue in question contained spores, which were capable of giving rise to spirochaetae when inoculated. As I have frequently been able to demonstrate, spores of the Leucocytozoon syphilidis do not give rise to inflammation, and therefore the histological structure of any tissue in which they are present may remain unaltered. The phase which causes the greatest histological change is that of the SpirocJiaeta pallida, the adult male form. It must be noted how frequently animals which have been inoculated with syphilitic material, fail to develop even an initial lesion. It is doubtful whether a single human being would escape under similar circumstances. The quantity of material that is usually required to infect the animal should also be taken into consideration ; it would be equivalent to giving a hmnan being a few ounces of the infective material. Therefore, it is not surprising that an infection arises, or rather what is taken for an infection. I have recently discovered, that in some of the human ulcerative chancres, the spirochaetae develop extra cellularly (Plate 31). 122 the biology, clinical aspect and treatment of syphilis. Other Stages. At a varying interval after the sore, a lymphangitis and enlargement of the lymphatic glands occur, and this is part of the host's protective machine, and is for the purpose of elaborating lymphocytes to attack the infection. The enlarge- ment of tlie lymphatic glands bears no ratio to the severity of the disease. On the contrary, it bears a ratio to the protective capacity of the host ; hence big glands are not the best to choose, in which to hunt for the organisms ; it is in the small glands that most are to be found. Glands should be looked upon as the base on the field of operation, and there- fore should not be removed, as has of late been advised. Another point in favour of my view, that phagedaena kills the syphihtic organism, is the fact that most phagedaenic chancres are not accompanied by either a lymphangitis or by an enlargement of the nearest chain of lymphatic glands ; oddly enough, not even the secondary infection causes them to become enlarged. The reason of this is, that when a chancre becomes phagedaenic, the secondary infection is not a staphylococcic or streptococcic infection, but an infection due to the fusiform bacillus and the Gram negative spirochaeta, which live in symbiosis. The glandular enlargement following this infection is minimal. From the nearest chain of lymphatic glands, the organisms spread along the lymphatics, until other chains, and, ultimately, all the lymphatic glands in the body, are infected. While the lymphatic extension is proceeding, the organisms are also pervading every nook and crevice in the body by means of the blood- stream. In this way, the generalisation symptoms arise. The symptoms will eventually disappear without treatment, but their dis- appearance is hastened by the administration of mercury, which works slowly, or of salvarsan, which works almost instantaneously. The action of treatment is primarily to destroy the spirochaetae, whiclj are mainly responsible for the symptoms. The other phases are destroyed secondarily and indirectly. As the spirochaetae are mainly responsible for the lesions, the protective mechanism of the host will be especially directed against these bodies, but their death does not mean that the spores are destroyed. If no treatment is given, or if mercury alone is prescribed, the spirochaetae will vanish for a time. The spores, as they seek fresh hunting-ground, will spread peripherally, so that when symptoms recur, the lesions will be in the form of circles or segments of circles. When no symptoms are visible, the patient is said to be in the latent stage, and when symptoms reappear again, he is said to be in the recurrent stage. THE BIOLOGY OF THE VARIOUS STAGES OF SYPHILIS. 123 If salvarsan is prescribed, tlie spirochaetae are destroyed at once ; the spores are crippled temporarily in situ, so that when they start their life-cycle again, it will take place in the same positions ; hence the reason why recurrences after salvarsan simulate the lesions for which salvarsan was given. The early lesions of syphilis are more infectious than the recurrent ones. Therefore, insufficient use of salvarsan, or the failure to supplement its administra- tion with mercury, may do more harm than good, in that the infectious period may be thereby lengthened. I have seen ten cases in which the wife was infected by her husband, who had been told that he was cured after he had had two injections of salvarsan. In view of what has been stated, and for reasons, which will be given later, I feel that I am justified in advising, as has been my practice for over three years, several injections of salvarsan, given as close upon one another as possible, to be followed by at least one year's treatment with mercury. The longer the spores are present in any one spot, the more chronic inflam- matory changes will the local vessels exhibit. Hence, should a lesion occur, it will lead to still further trouble, even to obliterative endarteritis, which will result in necrosis of the skin over the area fed by the affected artery and the formation of a gumma. A gumma occurs mechanically, and the necrosis is not due directly to the specific organisms. In the necrosis, saprophytic organisms flourish, and they at once kill the leucocytozoon, with the result that the secretion therefrom is, to all intents and purposes, non-infectious. The specific organism lives in the tissue surrounding the necrosis. As the endothelial cell is frequently the cell upon which the Leucocytozoon syphilidis is parasitic it will be readily understood why vascular lesions are so common in syphilis. The biology of syphilis in women will be considered in another chapter, and likewise the biology of syphilis of the central nervous system. CHAPTER XIV. THE CLINICAL ASPECT OF THE SYPHILITIC CUTANEOUS LESIONS. A writteu description of the cutaneous .syphilitic lesions may give a little help in diagnosing them, when seen. It must, however, be remembered that, the only way in which anyone can obtain a good clinical knowledge of the skin manifestations, is by careful study of as many cases as possible. This especially applies to the chancre. Everyone is agreed that, if syphilis is to be lessened, diagnosis of the initial lesion at the earliest possible moment is essential. I feel very strongly that the best diagnosis is a clinical, and not a bacteriological one. Therefore, it behoves the whole medical profession to make themselves au fait with the clinical methods of diagnosing early sj'philis, and to see that the future generation is thoroughly taught such methods. Chancre. A primary sore may occm- on any part of the body, but, for sake of convenience, primary sores may be divided into genital and extragenital sores. In most countries the syphilitic infection is genital in origin, but in some districts, where the people are very poor, uncleanly, and many live together in one room, the infection is more often extragenital. In certain parts of South-Eastern Europe, the ratio between extragenital and genital sores may be as high as twenty to one. Four main points are usually sought for in diagnosing a sore. The sore must be single, it must be indm-ated, it must not appear for from four to six weeks after connection, and the l}Tnphatic glands in the groin must be enlarged and hard. Let us take each of these points in turn, and see how far they are of value in assisting one to make a diagnosis in a difficult case. In about 30 per cent, of cases of syphilis, there is more than one primary sore, when the infection is a genital one. When extragenital, the sore is almost invariably single. A soft sore, which appears in the minds of most to be the only sore, which has to be dis- tinguished from a primary sore, is also sometimes single, especially if it be seen early, or is of the " elevatum " type. Plate 25. — Papulo-erosive Chancre. It should be noted that the lesion is sharply circumscribed, perfectly regular in outline, that it is raised above the surrounding tissue, that there is very little loss of surface, and that there is not a trace of circumferential inflammation. The patient had two similar sores on the opposite side. Spirochaetae can always be found in this type of sore and the micro- scopic appearance of the lesion is characteristic. There is a marked hyper- plasia of the connective-tissue cells ; the walls of the vessels are thickened, and the endothelial cells are increased in number. There are few leucocytes, and those present are nearly all plasma cells ; the others are lymphocytes, but there are no polymorphonuclear leucocytes. The section is crowded with all the phases of the Leucorytozoon syphilidis. This is the type of sore which gives rise to the severest cases of syphilis. Facing p. 124. M'lv (it as I'vir.y cases ;is p-. aaoKAHO avieoaia-CMcraA*! — .5S aTAal i(;rtu9ho(} J)oiIiTj2uiojiiv '{tqir.ris ai noiaoE arii Itsd) hoJoii 'xl bluoti^. i\ modi isiii ,'Ji/8Bit gntbrtijonua orii ovoffs bagiBi at Ji iBilt .oriildijo ni ibIu^'h Ix>iifi9i9irau9iio lo ooBTt « Joa Bi onari* JbiII fans .eaahua io eeof oliiil yiav si .sbig oJieoqqo oxfJ no aaioB lefiniie oiii bmi Inoiiaq otlT .norj/imrruiftrii -oioiin orit biiB o'loa lo oq\(t airiJ ni btrool ad 8v«'wl6 hbo 9BlojBi(ooiiq8 -loqvil bojfiBfn B ai r>i3dT .oi JaiiatooiBrio ai noia^I edi 16 oonBij>o(£qB yiqb'w ' .bangdolrit oib afoaaav orij lo sIIbv/ oHJ ; alloa on«aii-9vidoonnoo oriJ lo Biwulq .aoiijoooijol nai me 9i8riT noclmon ni fasajsoiofii 9tb alleo [filodjobns odi bn^ .aai'^ooriqmvf otb eiedlo 9dl ; alloa BoiaBlq Ifu i^hean 9i£ .Jn989Tq 98od* bn* hsbffoio ai noi}o9a 9dT .aot^ooouol iBelai/nndqioflr^roq on oib m'sdi iiid ' oioa lo oqyt adi si aidT .?»V>'iSW(\^?. «oos<>\^ior>»9A adt loBoaedq od) il« dJiW' .ailidq'ja lo Sfiaeo if/jnyoa ndi ot fwli Kf)/i The process may stop at any one of the stages just mentioned. A primary sore may never be more than a papule. Most primary sores are simple erosions, but many primary sores are markedly indurated before any ulceration occurs. With the exception of the sore that becomes secondarily infected, there is no increase of polymorphonuclear leucocytes, because phagocytosis plays no part in the destruction of the syphilitic parasite, hence there is no pus, and the necrosis which occurs is a mechanical necrosis, and is not due to the presence of several polymorphonuclear leucocj'tes which cause necrosis owing to their proteolytic action. Therefore, the necrosis of a syphilitic sore, not secondarily infected, is a dry necrosis. Plate 26. — Papulo-eeosive Chancre on the Skin of the Penis. I'l.A Facing p. 126. ^VAifi HUT to Kia?! -anT vio aaoKAHO aviP.oaa-ojaiA? — .ii yiii^iiri.l ,11 /(hi[iilJi»( 11-vin [r(I tt'il xh -/.I fifiif(i(n)| .'VKFccvKi irll 1o isni')F)>fi vKili'.niiii/iRrij-nori .9108 uuaus. ■ '.SSl !< 890ijboiq 3'/;B7/tj) yhean li oooqeiq sdi }o qil srit no fnuooo 9108 yiBraiiq a itoriV/ si ifsiifv*' jhii)^ «i"'j iabiiq^ sife'io yfoSfW'dfli} 16 jem^bgo TiotBtnaiBftni-non « . ,. ; . riii' ', ''.. . . /.go j*aijM{ edJ ni Ji/o Jdgtfoid Uevf . bluov/ 9i9dJ JedJ ni«ti80 ifldfiioro* si li ,9ioa rto8 fi naad b&d aioe ad* 11 bfrTO'w aieooirflq io noiJibnc) « Jjidi boB ,T7(yrm\ '0O7i ni enoa e need STcd .riiilnatol ad J to r.rnihoo vnorsmmgHrri otooB sdl oi gfii-wo bsoofxnq naad avfid aoi^aatai srnsgoAnf « asi/tttimoaotr ^«{.B«l(li|{o|dw fluded ii kCl .tia79 vFirigila .basisi otb aagba adi Jadi brie awq dttvf baisvoo Jon -non a 'jfno iiid .noitamniBBni gnibni/onua on ai 9iadT .baniunabnit Jon .baJaiubni ion saw aioa adT .nbJaaiol orit lo cniaboo Y.^oJernausftni -BiJxa, .baniatdo ad yam aaJaadaoiiqe yasiti aioa io aq'^i ardl moi^l ina-iaftih otiup ai Jr io -{gofajaid adT .bnooi 9d ol oala aia annol inIuUa) doum ai iioiJatJfitni icIoUaa oriT .aianeda oviaoia-oIi/qBq adJ io Jerii moil al[90 ouaaiJ-avilaaiiiioo io v^IxFiBtn gnijaianoa io bsaJani hria bsAiKin aioin •odqioflrjfoq bna BalYooriqtirfl io vliaoia qo abam ai ii ,all90 amealq bna aaodJ yllaioaqaa .faaaaaioni au; adoo auaaii-aviJonnnoo adT .aaiYooauaf laalai/n tailwamoa .baidqoitiaqi^d ofn ysdi iu; ai airiX , , ■ 1.1'. 7;ii;uiiiq 'jilt mcil a/tiairiBg-io ari,} to noianoJza Joaiib b y.c' asai'ifi rioiri// isrfito ofiburi tnoitBq oHT .(r/rrftnrrinjrii ai 9'io?. yiiunhq odJ 9suo nixll til njisqqfi o* ,al*Ji(i9§ ariJ oJ baeitKOoI ,de«T Mi tol FjSobii «i .)i bnjs ,8i[i(lqY,8 lo angie ^' 3 on tbr tTU;;k osponds "■- ^Vn^' .881 .i\ ^itno'^ ifVX, ""*** _ -,>' ^f^^^ Plate 32. SYPHILIS OF THE SKIN. 139 The commonest recuiTent lesions are not so regular as the two just mentioned ; either the whole circle is made up of distinct papules or only a segment of it is apparent. g % Not infrequently, the original papule itself recurs, as, often in the middle of the circular lesions a papule is seen. © It can be easily understood that, as the papules in the circumference of the circle mark the limit of extension of the organisms from the centre, some of the organisms may have remained half way, for instance. This will result in papules being found in the recurrent lesion along any part of any radius of the circle. Q-Q--- THREE PAPULES IN' THE RADII OP THE CIRCLE. ^ o <^ Many circular lesions may occur close together, and the tout ensemble may look something like a maze ; b\it, if carefully studied, the circular arrangement of each individual lesion can be easily made out. As the original papules may undergo certain transformations, so also may the recurrent papules. Some maj- be larger than others; in some, necrosis may occur, with the result that a scab develops. On removal of the scab, if the lesion is an early one, a small ulcer may be met with underneath, but, most frequently, the ulcer beneath has scarred, and the floor is covered with well formed epithelium. This latter condition is rather characteristic of syphilis. Another almost pathognomonic feature of the scabbed recurrent papule is, that when the scab is removed, the healed floor is uneven — divided into several loculi — and each of these loculi is separated by a tiny bridge of normal skin. Presumably each loculus has been a distinct le.sion, but, when each ulcerated, 140 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. a common scab formed for all. These loculated scarred lesions are frequently to be seen on the face, in the naso-facial and oro-facial grooves. Especialh^ when they occur in the region of the mouth, almost certainly one or more lesions will be met with, one pole of which will be touching the mucous membrane of the lower lip. One is frequently called upon to differentiate the facial scars which have resulted from Lupus vulgaris and from sj'philis. The tuberculous scar is, as a rule, irregular in outline, sharply circumscribed, and only very slightly depressed below the surface of the surrounding skin. It is, moreover, even and shiny on the surface, and not infrequently infiltrated with telangiectases, especially if the lesion has been treated with X-rays. The syphilitic scar, on the other hand, is not one flat scar, but an area made up of several little ones. Each little scar is deeply depressed, not shiny, and usualh' quite white. If the organisms, instead of spreading from a papule here and a papule there, spread from those papules covering one large area of the skin ; should they in time develop their life-cycles, the lesion formed will be either a very large circle, or a segment of a very large circle. This is the so-called serpiginous syphilide. Characteristic of the serpiginous syphilide is the red-purple discoloura- tion of the skin in the circle. The last recurrent skin lesion to be described is the gumma, and the way in which a gumma is formed is, in my opinion, the following : — The distribution of the blood supply in the skin is not unlike that in the liver, i.e., the skin is divided into roughly circular areas about the size of a shilling. There is a venous ring, so to speak, in the circumference of each circle, and, when congested, it gives rise to circular purple patches with a white centre, to which the name of (livido) is given. In the centre of each circular area an artery runs, and it gives off branches as radii. It is along this central artery that the organisms reach the skin, and it is in the walls of vessels that the organisms develop. Should the recurrent papule ^e of a more pronounced character than those just described, i.e., should the development of the organisms be on a larger scale, there will be a corresponding increase of connective- tissue cells. As these will be formed in the walls of the central artery, they may be sufficient to occlude its lumen. Occlusion of the lumen would result in the loss of blood supply to the circular area affected, consequently the skin corresponding to this area would necrose, an ulcer would be formed, or, in other words, a gumma. In support of the view just enunciated, are the pathognomonic signs that, however many gummata form in a certain area of skin, each will remain separate, they will not coalesce, and each will be approximately the same size, and the scar resulting from the ulceration will have the same diameter as the ulcer had. A SYPHILIS OF THE SKIN. 141 point of extreme diagnostic importance, and one that should always be borne in mind, is the fact that the Leucoajtozoon syphilidis is not a pus-producing organism, therefore the lesions resulting from its development have, as a rule, no circum- ferential signs of inflammation. It sometimes happens that the recurrent rash is generalised, and indistinguish- able from the first eruption. Such a rash may or may not be preceded by a sore indistinguishable from a chancre. The chancre-like sore may either appear on the same site as the original sore, or elsewhere. If the recurrent rash is generalised and is not preceded by a chancre-like sore, it means that, when the organisms first reached the skin either the treatment or the host's resistance, or both, were sufficiently powerful to prevent the organisms from spreading peripherally, hence when they became active again, they did so in the original areas in which their further progress was stopped. Since the salvarsan era, such recurrences are not uncommonly seen, but before the advent of this drug they were distinctly rare. 1 had one remarkable case before " 606 " was in use, which might be recorded here. Case 13. — A man aged 54considted me, complaining of a rash and a sore throat. The rash was a typical maculo-papular syphilide, and its distribution was widespread. There were multiple lesions in the mouth, which were mucous papules. Every lesion was discrete, there was no attempt at the formation of circles, there was no general enlargement of the lymphatic glands, and the patient had not recently had a sore. This patient had contracted syphilis twenty-three years previously, and beyond the early symptoms, which simulated those of which he now complained, he had always been in the best of health, and had never had a recurrence. Originally the patient was treated for about three years with mercury internally. A recurrent rash preceded by a sore is a case of auto-reinfection. The rationale of the phenomena just mentioned is simple. When mercury was the only anti-syphilitic drug in use, owing to its slow action, in most cases the organisms were not vanquished until the host had become accustomed to form antibodies, and to produce them without necessarily a stimulus to do so. If the check on the antibody production occurred early, i.e., before the production became a habit, it is analogous to saying that the patient's immunity against syphilis approaches nullity. In such a condition, the spores can wake up again, when they would give rise to symptoms indistinguishable from those they gave rise to when their development was checked. Since salvarsan has come in, owing to its rapid action, it often happens that the antibody production is checked, or, in other words, the patient's immunity is lessened, hence the more frequent occurrence of a recurrent generalised eruption. 142 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. The earlier the antibody production is checked, the less the resistance of the patient against the disease. Therefore, the initial recurrent lesion will sinudate the lesion first developed by a patient, who has never had syphilis before, and this is a chancre. Immunity against a disease, besides being variable in difTerent indi-\aduals, is largely dependent upon the severity of the infection, and the specificity of the treatment. AVhat it readily comes to is this, that a ratio exists between the existen.ce of immunity and the length of time during which antibody production is maintained. Before closing this chapter, a few more words might be said with advantage, regarding the differential diagnosis of syphilitic rashes from rashes of other origin, which may be confounded with them. Mention has already been made of varicella and lupus, but before mentioning other diseases, certain toxic er\i;hemata must be considered, as there is a causal relationship between some well known types and syphilis. Syphilis may cause typical Erythema nodosum and Erythema multiforme, but as to whether it ever causes purpura, I cannot be sure. The two types of toxic erythemata just mentioned, are indistinguishable from those types produced by other causes, and they invariably occur early in the generalisation stase, indeed, sometimes before the true sy|)hilitic rash makes its appearance. The other skin diseases, which are apt to be confused with syphilis, are Pityriasis rosea, scabies, psoriasis. Erythema induratmn, fungus diseases, such as sporotrichosis and blastomycosis, certain drug eruptions, especially the one caused bv iodides, leprosy, and various rare tuberculides. Pityriasis Rosea. — This rash is, generally speaking, limited to the vest area, it covers this area in a few days after the appearance of the initial patch, which is sometimes called the herald patch, and is scaly almost from the commencement. The lesions are bigger than syphilitic lesions, they are not so papular, those on the back run in the direction of the ribs, a point which often raises confusion with syphilis, but no trouble should ever arise in differentiating the two diseases, if it is borne in mind that a syphilitic lesion does not scale until it retrogresses, while a lesion of Pityriasis rosea is scaly from the beginning. A lesion of Pityriasis rosea is red in the circumference, yellow in the centre, the scales are most evident at the junction of these boundaries, and the scales have their loose ends inwards. When a svphilitic lesion scales, the scales form in the centi-e, they are more apparent and not so sebaceous as those just described, and moreover they are more adherent. Scabies. — A very favourite localisation for scabies lesions is on the penis. SYPHILIS OF THE SKIN. 143 where they form papules, which at first sight might suggest syphiUs. AVhen examined, the papules are found not to be infiltrated, and burrows, and even the acarus itself may be found. Itching, and finding similar lesions elsewhere, namely, on the buttocks, wrists, and in between the fingers, clinches the diagnosis. Psoriasis. — From a naked-eye examination of the lesions, it may in some cases be absolutely impossible to distinguish between psoriasis and syphilis. In such cases one has to rely upon history, and to note whether the scales when removed reveal bleeding points, a phenomenon which is typical of psoriasis only. Many patients with psoriasis have either had the complaint for years, or have had recuiTences of it, and often another member of the family is subject to the disease. A squamo-papular syphilide resembling psoriasis, is a recurrent syphilide, therefore every lesion should be thoroughly examined to see if any of them are circular or gyrate in form, because if so they are certainly syphilitic. An examination of the scalp should always be undertaken, since psoriasis very commonly affects the scalp, while a squamo-papular syphilide does so rarely. Psoriasis may affect the penis only, and so may lichen planus, in which case the lesions are usually on the glans. The type of Lichen planus which affects the glans penis is the circinate form, but, from its smallness and its perfect regular outline, it ought never to be mistaken for syphilis. Erythema induratum. — This condition is a tuberculide and practically affects only girls between the ages of 15 and 24. The lesions usually affect both legs and are situated on the posterior aspects. The initial lesion is a red patch, this becomes a purple coloured papule, and later the centre breaks down to form a deep crateriform ulcer. The only sj'philitic lesion it could possibly be confounded with would be a gumma, but, as I have already stated, a gumma is an ulcer the size of which exactly corresponds to the area affected, hence the term crateriform could never be applied to it. Sporotrichosis, blastomycosis, and oriental Sore can only satisfactorily be diagnosed by demonstrating the specific organism, either in culture, film, or section, made from the lesion in question. An iodide rash is most likely to be confused with a papulo-pustular syphilide, which is an early syphilitic eruption, hence other signs and symptoms of the disease will generally be found on a further examination. An iodide rash disappears very quickly on suspension of the drug. Difficult tuberculides are best diagnosed by the way they react to tuberculin. If every reader will bear in mind the few points mentioned in this chapter, and then confirm them on clinical material, I think he will soon agree with me in stating that, of all skin diseases, the various syphilitic eruptions are the easiest to diagnose. K CHAPTER XV. SYPHILIS OF THE LYMPHO- AND HAEMOPOETIC SYSTEMS. The organisms from the site of infection soon reach the local lymphatics, and spread along them into the nearest chain of lymphatic glands. The lymphangitis may be marked enough to cause occlusion of the vessel, when a hard cord may be felt running along the dorsum of the penis. The lymphangitis may be more marked in some areas than in others, along its course, which on palpation may feel like a chain of beads. One bulging only may be present, or several. Lymphatics, other than those running along the dorsum of the penis, may be affected in the same way. If the lymphangitis is widespread, oedema of the whole skin of the penis may result. Oedema of the skin of the penis is most marked when the sore is in the corona. The sore may often be hidden, because the foreskin cannot be drawn back, but a hidden chancre can always be diagnosed, if it be remembered that such an oedema is non-inflammatory, i.e., not red and painful, as it is in soft sore and gonococcal infections. During the stage of the generahsation of the virus, all the lymphatic glands become impHcated, but the set which is always most enlarged is that draining the site of the primary sore. This point will often enable one to locaHse a sore, ^which has escaped notice during the first examination. Owing to the richness of the lymphatic vessels draining the mucous membrane of the mouth, any sore in this region is always accompanied by an enormous enlargement of the glands in the neck. As lymphatics cross the middle line of the body, the enlargement of the glands on the opposite side to that on which the sore is situated may be greatest. Syphihtic lymphatic glands are hard and discrete, or enlarged, matted together and soft. The degree of enlargement varies enormously in the different cases. As a rule, it may be said that, the greater the enlargement, the better the protective capacity of the host against the parasite, and vice versa. SYPHILIS OF THE LYMPHO- AND HAEMOPOETIC SYSTEMS. 145 It must always be remembered that cocci usually accompany the syphilitic parasites along the lymphatics into the glands, with the result that they may at any time multiply and cause acute inflammation. Acute inflammation causes the lymphatic glands to become glued together, and one or more of them may suppurate, and simulate the bubo so common in the soft sore infection. Generally speaking, the only glands which suppurate, in syphilis, are those draining the site of the initial lesion, and the glands iu the neck. The reason why the glands in the neck not infrequently suppurate is, because of the lymphangitis which results from the early mucous membrane lesions in the mouth, and as the mouth is exposed to the air, and always crowded with pus-producing organisms, some of these find easy entrance into the lymphatic glands, in which they can cause suppuration. Suppuration in these lymphatic glands, although most common during the acute stage of the disease, may commence long after all the syphihtic symptoms have vanished. The lymphatic glands may also be the seat of recurrent syphihtic lesions, and gummata not infrequently afi'ect the cervical set. The diffuse papular syphilitic eruption which is so commonly seen on the penis, in the neighbourhood of the primary sore, and is usually well marked before any signs of a rash have occurred elsewhere, doubtless arises from a spread of the organisms, from the site of infection, along the lymphatics. Late syphilitic lymphangitis is very rare, but, having had a case under my care, a report of it here would not be out of place. Case 14. — A man now aged 46 contracted syphihs in 1882. His first recurrence was a papular syphihde of the right pahu, in 1890. The next recurrence was a ser- piginous syphihde on the left half of the scrotum, and another on the gluteal region on the same side, in 1900. A year later, the scrotum first on the affected side, and in time as a whole, began to enlarge. On examination, 1911, the syphilides had disappeared, the scrotum was 28| inches in circumference, and was somewhat eczematous on the surface. The swelhng appeared to be in the skin, which was hard, barely oedematous, and retained its rugose appearance. The testicles could not be felt. The patient had also chronic superficial glossitis. As a result of thirteen intramuscular injections of grey oil, the circumference of the scrotum was reduced to 13i inches, the skin became softer, the swelhng of the penis disappeared, and the testicles, which appeared normal, could be felt underneath. I saw this patient again, two years later, and his scrotum was then nearly normal in size. Syphilis as a direct cause of elephantiasis, a name which coidd be easily given to the condition just described, is, as I have already stated, exceedingly rare, but k2 14:6 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. the elepliantiasic condition following gummata and such deep-seated mischief as periostitis, is not uncommon. The direct cause, in the former, is a secondary infection ; and in the latter, mechanical obstruction. In the case just reported, the swelhng of the scrotum started some time after the serpiginous syphihde had disappeared, and therefore could not be secondary thereto. There was no iilceration, therefore a coccal infection was unable to play a part. A neglected chapter, in the chnical story of syphilis, is phlebitis. Veins are infected with the organism of syphiUs much more frequently than is supposed to be the case. In my experience, the veins most often affected are those of the upper and lower extremities, especially those of the latter. Syphihtic phlebitis of both arms, or, more commonly, of only one, causes congestion in the fingers. The congestion may come and go, with the result that the diagnosis of Kaynaud's disease is usually made. When the legs are affected, and again it is usually only one leg that is involved, it is nearly always the internal saphenous vein that is thrombosed. As the condition is typical of the infection which caused it, and as the descriptions of it are so scanty, it may be well to describe two typical cases, which I have had under my care. Case 15. — A woman had a sore in July, the eruption commenced in September, when treatment was started. In December, patient complained of severe pain on the inner side of the thigh. There was nothing to be seen, but, on palpation, one could feel, in the line of the internal saphenous vein, about l-J inches above the knee, a hard, tender, spindle-shaped swelhng, roughly 1 inch in length. As time went on, this swelhng came gradually nearer to the surface, and finally ulcerated. Papules developed along the course of the vein, both above and below the ulcer. " Nodules " of phlebitis were also found in both legs, and some of them had come to the surface and ulcerated. * Cose 16. — A man aged 36, no history of syphihs, sought advice for acute pain and swelhng of his right leg. He had several attacks of this pain and swelhng, and occasionally the whole foot became quite blue. No diagnosis was at this time made. While these periodic swellings of the leg were taking place, the patient on two occasions had a pulmonary embolus, and on each occasion very nearly lost his life. The patient frequently complained of very bad headaches, and often felt sick and giddy. The next step in the case was the appearance of very painful red nodules in the skin. These nodules were much longer than they were broad, they were surrounded by inflammation, and they commenced in the internal saphenous vein and gradually descended along all its branches, until the toes were SYPHILIS OF THE LYxMPHO- AND HAEMOPOETIC SYSTEMS. 147 reached. Under appropriate anti-sypliilitic treatment the patient made a good recovery. Venous lesions may occasionally be the first signs of the generalisation of the virus, and they are therefore jDrobably toxic in origin. Such lesions may give rise to symptoms and signs which closely simulate two well known clinical conditions : (a) Erythema nodosum ; (6) Erythema multiforme. Neither of these can be distinguished from the same chnical condition, produced by other causes. Erythema nodosum syphilitica simulates exactly the chnical condition which so frequently accompanies rheumatic fever, and it occurs in the same situation, namely, on the anterior surfaces of both legs. The same applies to Erythema multiforme syphilitica, which affects most commonly the dorsimi of the hands. Since the leucocytozoon pervades every nook and crevice in the body, by means of the blood stream, and since the organism has a predilection for the walls of vessels, in which to carry out its life-cycle, it is not to be wondered at that syphilitic arterial lesions are common. Any lesion in the wall of an artery is liable to lead to an endarteritis, which is certain to occlude the vessel, if it be small, hence the blood supply to the area fed by this vessel will be cut off. There are some arteries which are more frequently involved than others. The arteries which make up the circle of Willis are those, an affection of which gives rise to symptoms, often within a few months of the time of infection. The commonest cerebral arterial lesion is one which gives rise to a hemiplegia. The hemiplegia is usually unilateral. An early syphihtic monoplegia is very rare. Later in the course of the disease, the anterior artery of the cord becomes involved, and gives rise to myelitis. Later still, the affected arteries undergo a lipoid degeneration, with the result that the vessel gives way, an aneurysm may be formed, and the patient dies of haemorrhage. The cerebral vessels, again, are those most commonly affected, and the arch of the aorta is a frequent victim. The main feature diflterentiating syphilitic arteritis from other forms of arteritis, is the marked localisation of the trouble. The whole of the arch of the aorta may be diseased, and yet the descending and abdominal aorta may be natural. Syphilitic aortitis is markedly different from that form met with in general arterio- sclerosis resulting from other causes. Lipoid degeneration is a pathognomonic feature of syphilitic aortitis, hence the calcareous plates, so commonly seen in the other forms, are absent. Any disease of the aorta naturally causes an increased blood pressure and an accompanying general arteriosclerosis, therefore a typical case of syphilitic aortitis 148 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. may be met with, in which the other vessels may exhibit the changes commonly seen in ordinary arteriosclerosis. Late syphilitic lesions are characterised by the lipoid degeneration undergone by the cells in the afEected area. The lipoid formed by these cells is of the nature of a protective substance, and it is largely responsible for the strong positive Wasser- mann reactions to be met with in these arterial cases. This lipoid material fixes itself on to the globulin molecules, and, in so doing, robs these molecules of some of the ions which are attached to them. The salts most easily displaced are the calcium salts, hence the explanation of the absence of the calcareous plates in S3'philitic aortitis. Andrewes^ has done some very interesting and important work in this connection. He incinerated several diseased aortae, estimated the calcimn in the ash, and found that the calcimn content of syphilitic aortae was far and away below that of aortae diseased from other causes. In some cases of syphilitic aortitis, Andrewes also estimated the calcium content of the aorta away from the syphilitic lesion, and found that not infrequently the calcium content was very much raised. This work of Andrewes proves that the syphilitic process is quite localised, and that the vessels elsewhere may show the signs of ordinary arteriosclerosis. Aneurysm need not necessarily be a late syphilitic lesion, as I have seen two cases of popHteal aneurysm, of which one occurred four years, and the other five years after infection. I remember another case in which a bilateral popliteal aneurysm occurred seven years after infection, and I have notes of a case of an aneurysm of the arch of the aorta, in a congenital sjrphilitic girl aged 15. Syphilis of the heart, in the early stages, doubtless occurs more often than is thought to be the case, but unfortunately it cannot be diagnosed with certainty. The early sj-phihtic lesion of the heart is a diffuse myocarditis. As a rule, no enlargement can be ascertained, and in two well marked cases — which I had imder care — the only symptoms and signs which the patients had, were cardiac embarrass- ment and a quick pulse. By cardiac embarrassment, I mean difiiculty in breathing on stair climbing or on any exei-tion, and pronounced sweating. Sternal pain is not an uncommon symptom ; pain on palpation of the cardiac area is also experienced, and occasionally an accentuation of the systolic sound over both the aortic and puhnonary orifices can be easily detected. In a few cases, the area of cardiac dullness is found to be enlarged. No case can be diagnosed correctly until treatment has been prescribed, and any alteration of symptoms has been noted. Late syphiUtic lesions of the heart are locahsed lesions, therefore the sjmiptoms will vary according to the site affected. SYPHILIS OF THE LYJIPHO- AND HAKMOPOETIC SYSTEMS. 149 A gumma of the heart may exist, and heal without ever giving rise to symptoms, but if the gumma is situated in His's bundle, which is not an uncommon site, symptoms arise which are almost pathognomonic, and to which the name of heart- block is given. A lesion of the bundle of His will naturally cause an alteration in the way the impulse travels along the cardiac muscle fibres, and this alteration in most cases can only be detected by an electro-cardiographic tracing. Should the lesion be severe enough to cause spiiptoms, the patient will seek advice for periodic attacks of giddiness, with maybe temporary loss of consciousness. Stoke-Adams symptoms may occasionally be met with, and usually the pulse rate is slow. A slow pulse, i.e., between .30 and 50 in a young subject, should always make the observer suspect a syphilitic cardiac lesion. A physiological brachycardia is extremely rare, the best known instance is that of Napoleon who was always said to have had a normal pulse rate of 40. A syphihtic myocarditis of the left ventricle may give rise to symptoms of cardiac asthma, but, since asthma is so frequently reheved by potassium iodide, it is extremely difficult to make a correct diagnosis. It should not be forgotten that the cardiac sympathetic nerves are not at all infrequently involved, in cases of degenerative myelitis, and, if the symptoms produced are at all severe, the physician's attention may be drawn to the heart only, with the result that the true nature of the trouble is overlooked. To cite a case. Case 17. — A man, aged 37, who had contracted syphilis eight years pre\aously, came to me complaining of attacks of shortness of breath, giddiness, and a feeling as if he were going to faint. He had previously suffered from very bad attacks of coughing, for which a throat specialist had snipped off a piece of his uvula. The patient still had attacks of coughing, and he often felt very sick. On careful examination, one could plainly see that it was a typical case of degenerative myelitis, as many of the other cardinal symptoms were present. As time went on, the sickness developed into typical gastric crises, and the cardiac condition became very much worse. The patient would suddenly swoon away, and become quite unconscious ; his complexion would become blue, and then ashen grey, and for a short interval his pulse could not be felt. Anti-syphilitic treatment aggravated the cardiac crises very much indeed. The relationship between Raynaud's disease and sj^^hilis has always excited a great deal of discussion, consequently opinions vary on the point. I have absolutely no doubt that Raynaud's phenomena can occur in congenital syphilis, and be due to the syphilis. Its occasional association with haemoglobinuria, not to 150 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. mention those cases in which the Wasseriiiann reaction is positive, is quite sufficient evidence, since spasmodic haemoglobinuria is almost invariably due to syphilis. When Raynaud's phenomena are said to occur in adults, more otten than not, they are not the true phenomena of what is called Raynaud's disease. Some of the cases in which recurrent local asphyxia of the fingers, and maybe of the toes occurs, are really cases of syphilitic phlebitis. Syphilis may be a predisposing cause of Raynaud's disease in the adult, just as any other protozoal disease may be.- ^ We have now to discuss the blood changes which usually occur in sj'philis. The true blood changes affect only the leucocytes, since it is only in those cases in which syphilis has caused an anaemia, that changes are to be found in the red blood corpuscles, and then the changes are typical of ordinary secondary anaemia. Syphilitic anaemia, owing to the use of salvarsan, is not now often met with, and, in many of those cases in which it did occur, it was often aggravated by, if not actually caused by the mercurial treatment. Hence the reason for stating that changes in the red blood corpuscles, such as are to be sometimes met with in syphilis, are generally only secondary in nature, and not changes actually pro- duced by the syphilitic organism itself. The changes in the leucocytes are very interesting and very important. In early syphilis, the total number of leucocytes is increased. Before treatment is commenced, the relative increase of the polymorphonuclear leucocytes is greater than that of the lymphocytes ; a ratio between the two exists, and it is dependent upon the severity or lightness of the case. In the severe cases, the relative increase of the neutrophile leucocytes is very much greater than that of the lymphocytes — indeed, the total number of the lymphocytes may be diminished. In light cases, the percentage of lymphocytes may approximate to the number given by the poly- morphonuclears, and may even exceed it. Treatment very quickly diminishes the percentage of the neutrophiles, and increases the percentage of the lymphocytes. Salvarsan is much more powerful in this respect than mercury. The lymphocyte count may approximate, in early cases of syphilis, to 60 per cent. Occasionally a small rise in the eosinophiles is to be met with, but there appears to be no relationship between the eosinophile count and the kind of case. According to Hazen,* from whose pioneer work in this field most of these details are taken, there is no alteration in the large mononuclears or basophiles. Curiously enough, the total increase of leucocytes is greater in the negro, and the relative lymphocyte count is higher also, than in the white man. In severe cases, the lymphocyte count is low in comparison with the lymphocyte count in the mild cases, and, in those cases which are going to do well under SYPHILIS OF THE LYMPHO- AND HAEMOPOETIC SYSTEMS. ] 51 treatment, the lymphocyte count becomes, as a rule, very much higher than in those cases which are not going to do well. Hence, from a lymphocyte chart, a prognosis can be made. Mercury administered to normal men causes a rise in the absolute and relative lymphocyte count, but a slight fall in the total leucocyte count ; therefore the main decrease is in the relative neutrophile count. In the second and third years after treatment, the total leucocyte count is only slightly raised, and the main increase affects the lymphocytes. In the late stages of the disease, the same picture is to be found, and, in cases in which treatment is prescribed, the absolute and relative lymphocyte count increases. As a rule, after the second year, whether the patient is under treatment or not, there is no increase in the eosinophile count. Another interesting point which Hazen brings out, is that males show a slightly greater increase in the total count than do females, and that females show a higher l3^mphocyte count than do males. No relationship exists between the lymphocyte count and the degree of enlargement of the lymphatic glands, a point which supports my view that the lymphocytes manufactured in the lymphatic glands remain in the glands, and that those which reach the circulation emanate from the bone-marrow {vide Chapter XLVI). From these few remarks on the blood picture to be met with in syphilis, the reader will at once observe how important the lymphocytes are, and how relatively unimportant are the polymorphonuclear leucocytes, a point which clearly shows that phagocytosis does not play a great part in bringing about the destruction of the syphilitic parasite. Probably one of the reasons why syphilis is not such a severe disease in women as it is in men, is due to the higher lymphocytosis in the former — after all, it is from the lymphocytes that the protective substances of the host originate. The reagin in the Wassermann reaction comes from the lympho- cytes. Considering how chronic a disease syphilis is, and what a call it makes upon the lymphocytes of the host it attacks, it is not to be wondered at that the manufacture of the lymphocytes becomes abnormal, and that various kinds of lymphocytomata arise, although the syphilitic parasite may have been driven out of the system. A full exposition of this part of the subject will be found in Chapter XLVI. Here it may simply be stated that syphilis is sometimes the cause of both leucaemic and aleucaemic lymphocytomata, and very occasionally of pernicious anaemia. ' Andrewes (1914), " Local Government Board : Report of the Medical Officer." - Parkes Weber (1909), " Trans. Med. Soc. Lond.," sxxii, 370. » Osier (1900), "John Hopkins Hosp. Bull.," xi, 41. * Hazen (1913), " Journ. Cut. Dis.," sxxi, 618. CHAPTER XVI. SYPHILIS OF THE MALE GENITO-URINARY TRACT. Kidneys. In most cases of syphilis, during the acute stage, protein can be demonstrated in the urine. Hitherto this protein has always been considered to be albumin, with the result that the kidneys were considered to be affected, and the patient was said to have nephritis. The protein in the urine is usually increased when mercury is given, hence it was assumed that mercury had an injurious action upon the kidneys. If the protein content of the urine appeared to be at all high, salvarsan was said to be contraindicated. Although there may be an increase of albumin in the urine in early syphilis, the main protein increase in the pronounced cases is globulin or lipoid-globulin, and the albumin content is usually negligible. Jlercury increases this globulin excretion. SalVarsan at first increases it, but afterwards very quickly reduces it, till no protein is demonstrable. The globulin, or lipoid-globulin, comes from the blood, and not from the kidney cells. It is excreted through the glomeruli. Therefore, the presence of protein in the urine does not necessarily mean that the patient is suffering from nephritis. Its temporary increase after mercury, is due to the fact that mercury stimulates the cells to form protective substances, which circulate in the serum as lipoid-globulins, and so more is likely to be excreted. Hence, protein in the urine does not signify that mercury has an injurious action upon the kidneys. This temporary increase and rapid decrease, after salvarsan, is due to the fact that the first action of salvarsan is to increase the production of lipoid-globulin, and then to break it up. Hence salvarsan is not contraindicated in these cases. The kidney cells are undamaged, as no blood or casts are to be found in the urine. The following method of examining the urine is the best : — If there is any protein at all, a drop or two of a saturated solution of salicyl- sulphonic acid, added to the urine, will cause a precipitate. If the precipitate is SYPHILIS OF THE MALE GENITO-URIXARY TRACT. 153 abundant and flocculent, the chances are that the protein is mainly globulin or lipoid-globulin. If the urine contains globulin or lipoid-globulin, a piecipitate will be formed when a few drops of a 5 per cent, solution of potassium ferrocyanide are added, after the urine has been acidified with a drop or two of a 30 per cent, solution of acetic acid. All the globulin, or lipoid-globulin, can be precipitated with a saturated solution of ammonium sulphate. The urine can then be filtered, and the albumin estimated by precipitation with magnesium sulphate. IVIicro- scopic examination of the urine should be made, and if there are refractile colloidal particles, the urine contains lipoid-globulin. In my opinion, true early syphilitic nephritis is very rare. To my knowledge, I have seen only one severe case. The patient was thin and emaciated. He complained of pain in both kidney regions, he had frequency of micturition, and there were casts, blood, and albumin in the urine, but only a trace of globulin. Globulinuria may also occur in late syphilis, alone or with p.seudo-chylous ascites. More lipoid is attached to the globulin in these cases, than is the case in early syphilis. Therefore, the colloidal particles are larger, and display greater optical activity. A trace of globulin may be found in those weird but rare cases of progressive late sjrphilitic nephritis. The nephritis starts without the patient's knowledge, and may progress for years, causing no symptoms, until blood is noticed in the urine If the urine be carefully examined in these cases, it will be found that the main protein increase is albumin, and blood cells and casts are nearly always to be seen. These cases do only fairly well under treatment, and they have to be treated generally like ordinary cases of nephritis, as regards diet, &c. If allowed to progress, these cases of parenchjTnatous nephritis or large white kidney begin to exhibit marked interstitial changes. The connective-tissue con- tracts, causes degeneration of the kidney cells, and the end is an irregularly shaped contracted kidney. I should mention here that salvarsan is badly borne by these patients, and mercury should be used with caution, and its administration regulated by frequent examinations of the urine. Iodides are indicated more than any other drug. Chronic interstitial nephritis may be caused by sj'philis, but it is usually only one of the sjniiptoms of a generalised arteriosclerosis. Amyloid disease may supervene upon some of the acute cases, but this com- plication is more often written about than seen. Bladder. It is only recently that attention has been paid to syphilis of the bladder, but, in the short time, a number of cases have been collected. 15i THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. Naturally, the symptoms will not differ from those produced by other factors which cause cystitis. lu the stage of generalisation of the virus, mucous papules may occur, but they seldom give rise to symptoms. There may be a slight frequency of micturition, and an excess of a mucinoid substance in the urine. This mucinoid substance quickly becomes precipitated as clouds, when the urine is allowed to stand. It is soluble in acetic acid, and it reduces Fehling's solution. It is found in most cases of cystitis, whatever be the origin of the inflammation. In the late stages of syphilis, gummatous ulceration and papillomatous growths have been described.^ ^ ■^ * WTienever ulceration of the bladder is diagnosed by a cystoscopic examination, syphilis should alw-ays be considered, since the progress is so good, if syphilis is the cause, as the cases respond at once to treatment. Testicles. Early syphilitic epidid}Tnitis is not at all an uncommon symptom of the disease. The epididymitis may be unilateral or bilateral, and may be well marked before the rash has even made its appearance. In every case I have seen, it has been only the caput major that has been affected. The feel alone of the epididymis will suggest s}^hilis at once. The affected pole in syphilis feels uneven, as a bunch of grapes would feel through a soft bag. In the other infections which cause epididy- mitis, the organ is evenly enlarged, and feels more or less smooth and hard on the .surface. I had one case in which the epididjTiiis became adherent to skin, broke through, and produced a condition to which the name of hernia testis is sometimes given. In the late stages of the disease, the commonest lesion is a gumma of the testis, but occasionally a ginnma may be limited to the epididymis, in which case the caput minor, or body, is the portion most frequent)}' affected. A short time ago I saw a case of a man, aged 45, who never remembered having had syphilis, and who came up for advice for pain in his " testicle." The caput minor was enlarged, hard, and slightly tender, and the whole of the vas deferens was markedly thickened. Had the patient been younger and delicate looldng, no one would have hesitated in diagnosing the condition as tubercular epididpuitis. However, the fact that the condition cleared up under anti-syphilitic treatment, clearly showed that the affection was syphilitic. Hydrocele may result from any injury to the epididjauis or testis, and is not specially prone to occur in syphilitic affections of these organs. ' Levy Bing et Durvoux (191.3), " Annales des Malad. Veii6r.," i, 242. ' Asch (1911), " Zeitschrf. f. Urologie," v, 504. = Pereschiwldn (1911), " Zeitschrf. f. Urologie," v, 732. ' Dreyer (1913), " Dermat. Zeitschrf.," xx, 477, 591. CHAPTER XVII. SYPHILIS OF THE EYES AND EARS. The commonest early syphilitic eye symjitom is iritis. Syphilitic iritis does not materially difier from iritis produced by other causes, but it has frequently to be distinguished from gonococcal, or the so-called rheumatic iritis. As a rule, syphilitic iritis is not so acute as the gonococcal form, but when one is confronted with a case of iritis, this difEerence is of little value. It should be remembered that syphilitic iritis is a symptom of early syphilis. Gonococcal iritis is more prone to develop during a recurrent attack of gonorrhoea than during the initial infection. Gonococcal iritis may arise mouths after the patient has ceased to think of a discharge, i.e., during the latent stage of the disease. Gonococcal iritis is often accompanied by gonococcal rheumatism, arthritis and neuritis. Gonococcal iritis is recurrent, or even periodical, in one or other eye. Once a patient has had gono- coccal iritis, he is always prone to develop it again, although there may be no exacerbation of gonococcal symptoms elsewhere. Syphilitic iritis may affect both eyes, and, as a rule, they are affected simultaneovisly, and it practically never recurs. Syphilitic iritis disappears like magic under salvarsau, while gonococcal iritis is improved only by vaccines. As gonococcal iritis is usually more acute than syphilitic iritis, and is less amen- able to treatment, it will follow that synechiae are more liable to be found in the former than in the latter infection. True gummata of the iris and ciliary body may occur, but they are very rare. I have seen one case of syphilitic dacryo-cystitis, but it is probable that the initial site of the lesion was in the periosteum of the lachrymal bone, and this brought about a narrowing of the nasal duct and sac, owing to the swelling which had been caused. Choroiditis is, on the other hand, a common symptom of late syphilis. Almost invariably the condition is bilateral, but one eye may be worse than the other ; and, as a rule, the symptoms are only subjective, with the results that the patient does not seek advice until the condition is far advanced. 156 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. The patient complains of seeing large floating specks, if asked to look at parallel straight lines they appear curved, and the patient may have noticed dark spots in his visual field. The vitreous is usually crowded with opacities which often blurr the patient's vision. If the case comes under observation during the acute stage, treatment will be of great benefit ; but in many cases the progress is very insidious, and even the most drastic form of treatment cannot stop it. Nevertheless, treatment must be persisted in, as I have had cases in which the lesion appears to have been brought to a standstill. Naturally, the scars left by the disseminated patches cannot be altered by treatment. Interstitial keratitis is a very common symptom in congenital syphilis, and, oddly enough, it may not show itself until the patient has become an adult. I once saw a case of congenital syphilis, in which the patient developed a most acute bilateral interstitial keratitis, at the age of 36. Many textbooks state that inter- stitial keratitis is never seen in acquired syphilis. I have certainl}* had three cases under my care, and in all of them there were other signs of a recentlj^ acquired infection, and only one eye was affected. Syphilitic retinitis is usually associated with, and secondary to, choroiditis. Isolated syphilitic retinitis is very rare. I have seen only one case, and that was in a patient who also had a sj-philitic myelitis. In spite of the most vigorous treatment, he sufiered from haemorrhages into his vitreous at periodical intervals. The right eye was the eye always affected, and, oddly enough, in all the cases which have been described, the lesion has been unilateral. The first haemorrhage occurred a little more than a year after infection. As the case is of somewhat unusual interest a fuller report would not be out of place. Case 18. — August, 1910. — Primary sore. Commenced treatment at once. February, 1911. — Complete transverse myelitis, which ended in partial recovery after three injections of salvarsan, mercurial inunctions, and potassium iodide, October, 1911. — Syphilitic retinitis, haemorrhage into the right eye. Patient then had six intravenous injections of salvarsan and mercurial inunctions. April, 1912. — Gumma on calf of left leg, for which patient was treated with mercurial injections and iodides internally. August, 1912.— Haemorrhage into right eye. September, 1912. — Haemorrhage into right eye. November, 1912. — Haemorrhage into right eye. Patient then had seven intra- venous injections of salvarsan, and one year's mercurial treatment. December, 1913.— Haemorrhage into right eye. March, 1914.— Haemorrhage into right eye. SYPHILIS OF THE EYES AND EARS. 157 November, 1914. — Haemorrhage into right eye. The Wasseriuanu reaction has been negative, in spite of the recurrent haemorrhages, for the last two years. Syphilitic optic neuritis is not a very uncommon symptom in early syphilis, and, like most early syphilitic lesions of the eye, it is usually unilateral. Optic neuritis in syphilis has come into great prominence lately, owing to the fact that blindness resulted from the use of some of the earlier arsenical preparations. There is no doubt that cranial nerve lesions did increase in frequency when salvarsan first came into use, but we have since learnt that that was due to the fact that salvarsan was not supplemented by mercury, or to the fact that not enough salvarsan had been given. If a case of optic neuritis is recognised early, adequate treatment with salvarsan and mercury will quickly cure it. When the body is infected with syphilis, the organisms invade every part of it, and, as I have shown in Chapter XXIII, meningeal and nervous lesions are prevented from arising, owing to the antibodies circulating in the systemic part. Should the production of these antibodies be checked — as occurs when salvarsan is given, but not in that quantity which will sterilise the meninges — it allows the organisms to develop in the meninges. If they develop around nerves which have to pass through bony canals, it will follow that the pressure caused by the meningitis will inflame the nerve, and so lead to its atrophy. Atoxyl amblyopia is due to a direct degeneration of the optic nerve itself, and is not secondary to a meningitis. Salvarsan does not cause blindness. I have given several thousands of injections, and I have seen only one case of optic neiuitis follow its use. This was in the early days, when it was customary to give only one injection. The case improved under fmther administration of mercury and iodides. I have seen three cases of optic neuritis in early syphilis, in patients who had never received any treatment. In one case the eye became quite blind before anything could be done, and it had subsequently to be removed. Late syphilitic optic neuritis is usually bilateral, and is due to some intra- cranial mischief. Ophthalmoplegia, or multiple ocular paralyses, may be complete or partial, and may affect one or both eyes. If the external muscles are affected, the term Ophthalmoplegia externa is used, in contradistinction to paralysis of all the intra- ocular muscles — Ophthalnioj)legia interna. Of all the causes of the various forms of ophthalmoplegia, syphilis is probably the most frequent. The paralysis may be either sudden or gradual. If sudden, and if the patient is over 50, the paralysis, which, as a rule, affects one muscle only, is due to an arteriosclerotic lesion of syphilitic origin, and the chances are that, sooner or later, the patient will succumb to a hemiplegia. If gradual, one muscle 158 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. may be at first affected, but in most cases, sooner or later, other muscles become involved, and degenerative myelitis generally ensues. Ophthalmoplegia interna, although a common symptom in degenerative myelitis, and indeed it may be the first symptom, may never be followed by other nervous manifestations. In most textbooks, the reader will find it stated that pin-point pupils, which react to neither light nor to accommodation, always signify that a widespread degenerative lesion will ensue later ; while the occurrence of late syphilitic nerve lesions, such as those just mentioned, following upon paralysis of the external muscles, is barely mentioned. Provided pin-point pupils (the reflexes of which have disappeared) are the only signs which the patient has, the chances are that further degenerative changes in the central nervous system will not set in. I have been able to collect eleven such cases. In three, the patients had had iridoplegia for over 30 years, and in seven in which I did a lumbar puncture, the cerebro-spinal fluid was normal. Nearly every case of degenerative external ophthalmoplegia which I have seen has since developed further degenerative changes of the nervous system. The following case is a typical example : — • Case 19. — A patient contracted syphilis in 1904, and he was treated for it for three years with mercury internally. In 1910, patient complained of double vision. He had ptosis of the left eye and paralysis of the external rectus. Under treatment, the eye symptoms disappeared. Two years later the classical symptoms of degenerative myelitis supervened. The following is also an instructive case : — Case 20. — Five years ago, patient had an attack of double vision, which got well of its own accord. Three years ago the double vision recurred, and the patient had very severe attacks of vomiting. The patient was unaware that he had ever had syphilis. I thought the stomach pains were gastric crises, but the patient had no other symptoms of degenerative myelitis. Under the most \'igorous anti-syphilitic treat- ment the stomach symptoms vanished, but the ophthalmoplegia extended, until the patient had almost complete bilateral ophthalmoplegia and ptosis. The gastric crises returned, and one by one the other symptoms of degenerative myelitis began to reveal themselves. Ears. In earlj' syphilis, deafness is a not infrequent symptom. If the deafness is bilateral, and the patient has a bad throat, it will almost certainly be due to mucous papules in the Eustachian tubes. If unilateral, the deafness will almost certainly be due to nerve trouble. The nerve trouble is primarily a meningitis, and is SYPHILIS OF THE EYES AND EARS. 159 analogous to that described in connection with the optic nerve. The trunk of the eighth nerve may be afiected, or only its cochlear or vestibular branches, or both. Syphilitic disease of this cranial nerve is more often bilateral than is the case in any of the other cranial nerves. If the cochlear branch alone is affected, the patient complains of deafness, which may come on suddenly, but more often gradually. Its course may be short, or the deafness may get worse so slowly that the patient's attention is scarcely drawn to it. When the vestibular nerve is involved, the patient complains of tinnitus, giddiness and vomiting ; the vomiting is irrespective of food, and is usually worst on getting up in the morning, owing to the change of posture causing a disturbance in the semicircular canals. In the early stage, nystagmus is present. The following case is typical of a lesion of the trunk of the auditory nerve : — Case 21. — L. M., female, aged 35, came to the hospital with psoriasiform syphilides on her legs. Two years before, the patient contracted syphilis, and was treated for eight weeks with inunctions in the General Hospital, Yarmouth, where she developed double iritis. Two months after leaving hospital, condylomata appeared around the anus and between the toes. Since then the patient had not been treated. It was noticed that she did not seem to hear very well, and, on inquiry, she stated that she had been deaf in the right ear for six months. The deafness had come on gradually, and was slowly getting worse, and, at the same time as it commenced, noises in the ear were experienced, and the patient was much troubled with attacks of giddiness, which prevented her from going out. The patient always had the feeling as if she were going to fall forwards, and she actually did so on two occasions. The giddiness and vomiting were always worst on getting up in the morning, and the latter occurred during the day, quite irrespective of food. These symptoms, except the giddiness, were increasing in severity. When I fii'st saw her, she had slight nystagmus, which later disappeared. Examination of the ears was kindly undertaken for me by Mr. S. E. Scott. The left external meatus showed old stenosis, but there was no defect of hearing on this side, and electrical reactions were normal. There was a marked reaction to the caloric test in one minute at 115° F., the patient falling to the right. On the right side hearing was diminished ; no artificial Rhomberg's sign or nystagmus was produced by syringing for three minutes with water at 118° F.; the electrical reactions of the vestibular nerve were sluggish, but had not quite disappeared. All pointed to a neuritis of the trunk of the eighth nerve on the right side, most probably of syphilitic origin. This case is instructive, since the patient had never had " 606 " ; would not have complained of her nerve condition had her attention not been drawn to it, and had never connected it with her disease. Under mercurial 160 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. injections, all s}Tnptoms referable to the vestibular branch cleared up, but the deafness remains much about the same, and, like so many of these cases, is much less one day than another. I also saw a man who became gradually deaf in one ear, four months after the appearance of the sore, and who had had no treatment at all. His deafness almost completely disappeared three months after two intravenous injections of salvarsan and eight intramuscular injections of grey oil. The cochlear branch is not infrequently implicated alone — much more commonly so than the vestibular. Apart from a neuritis of the eighth and second cranial nerves, of which the former is more frequent than the latter, the other cranial nerves are involved in the following order of frequency : seventh, third, fourth, fifth and sixth. I have seen three cases of facial palsy, in which the nerve affection was almost the first symptom of the generalisation of the virus. All recovered completely after salvarsan and mercury. When a neuritis of a cranial nerve sets in after " 606," in 96 per cent, of cases it does so within the first four months ; the cases are almost invariably in the generalisation stage, the Wassermann reaction is generally negative — that is to say, if the lesion has occurred after treatment, when its onset is usually later in the disease — and the patients have usually had only one injection. This marked similarity, as regards onset and occurrence, finds its explanation, if we consider the frequency of neuritis in sj'philis before the days of " 606." So slight, so gx-adual in onset and progression, may sjTiiptoms of a neuritis of the cranial nerves be, that the patient does not connect them with his disease, and consequently does not draw his doctor's attention to them. By astute observers they have been noticed and described, but, beyond this, cranial nerve lesions in syphilis have not received the recognition due to them. Their occurrence after " 606 " made syphilologists examine their casejs more thoroughly before treatment, with the astonishing result that the frequency of such lesions was nearly as great as that of those reported to be due to salvarsan. They noticed further that these nerve afl'ections were not uncommon early in the generalisation stage, setting in within a year of infection, that they were more often unilateral than bilateral, and were just as common in patients who had not had any mercury as in those who had, although it has more than once been stated that they were more common after the use of soluble preparations than they were after the insoluble salts of mercury. These facts show that nerve lesions are syphilitic manifestations, and that their occurrence after " 606 " signifies inadequate treatment, and that they are, in short, neuro-recurrences. SYPHILIS OF THE EYES AND EARS. 161 While on the subject of syphilis of the cranial nerves, I should like to mention an ear symptom which commonly occurs when the facial nerve is affected. The patient complains of odd noises in his head, on the side affected, and he likens them to vibrations. This is due to paresis of the nerve supplying the stapedius muscle. I have had four cases of unilateral facial paralysis. All set in suddenly, from six to twelve weeks after the sore was first noticed, and in two the stapedial nerve was affected. The vibrations complained of were not incessant, but came on in attacks, which gi-adually lessened as the patient got better, but in both cases the patients had reminders, even two years later. Late syphilitic deafness is usually bilateral, although one ear may be affected before the other. The deafness is usually progressive, and, in my experience, treatment usually makes it worse. Meniere's symptom complex — deafness, giddiness, tinnitus and vomiting — although an uncommon sequence of syphilis, is met with occasionally as a late syphilitic manifestation ; but opinions differ as to whether treatment improves the condition or not, as it is by no means easy to be sure whether syphilis is the cause, even if the patient has had the disease. l2 CHAPTER XVIII. SYPHILIS OF THE MOUTH AND THROAT. A chancre may occur anywhere, but there is one type of chancre to which special reference should be made, because of the way in which it simulates a large spored ringworm lesion. It is called the hypertrophic chancre, and it may be situated at the corners of the mouth or on the lips, where the skin and mucous membrane join. The differential diagnosis is simple, if it always be remembered that chancres in the oral region are always accompanied by very marked enlarge- ment of the lymphatic glands. The so-called mucous patches are nothing more nor less than syphilitic papules. A patient who has had syphilis, especially if he has been treated with mercury internally, is very liable to develop attacks of Herpes oris and aphthous ulcers. Fear of a recurrence of symptoms usually accompanies each outbreak, and as these ulcers are so frequently confounded with mucous papules, it would be well to draw atten- tion to their differentiation. Mucous papules, like all syphilitic lesions, are non- inflammatory — that is to say, a mucous papule is well circumscribed, and has no inflammatory ring surrounding it. A mucous papule is white and raised above the surface. Herpes starts as a crop of vesicles, which quickly become small ulcers. Often the vesicular stage is not observed. Each lesion has a yellow base which is depressed beneath the surface, and each lesion is surrounded by a marked inflam- matory ring. An aphthous ulcer has exactly the same appearance as the ulcerative stage of the herpetic lesion, and it is highly probable that the two terms are only different names for the same condition. The ulcers are painful ; the mucous papules are painless. The former may appear in 24 hours ; the latter do not appear for several days. Therefore, there should never be any difficulty in differentiating between the two conditions. A very common site for an aphthous ulcer is the space posterior to the last tooth on either side of the lower jaw. When this heals, the surface has a white irregular appearance, which suggests leucoplakia. Smiilar white patches are frequently seen in the cheeks, and indeed on any part of the mucous membrane in the mouth, in patients who have taken mercury internally. ■ SYPHILIS OF THE MOUTH AND THROAT. 163 Leucoplakia is regarded by many as being pathognomonic of syphilis. Leuco- plakia is merely an attempt of the mucous membrane to form a stratum corneum, as it will always try to do, whatever be the nature of the irritant. Leucoplakia of the tongue is common in syphilis, and is usually met with in those cases which have received no treatment, and in those which have been treated with mercury internally. Smoking will cause leucoplakia in a non-syphOitic subject, .so will psoriasis, Lichen planus, etc. Leucoplakia may be followed later by carcinoma, but it is not the leucoplakia which predisposes the organ to imdergo the cancerous change ; it is merely the persistence of the irritant which primarily led to the production of the leucoplakia. Leucoplakia is a manifestation of the protective mechanism of the cells, against the agent which is irritating them. If the epithelial cells persist indefinitely in undergoing changes of a protective nature, the cells will ultimately become parasitic upon the host which gave rise to them — i.e., they will become cancerous, but that does not mean to say that the leucoplakia is the cause of the cancer, an opinion which is very widely held. A leucoplakic tongue may remain as innocent as a normal tongue, or may quickly become cancerous. Which of these results will supervene, will depend, not upon the degree of the leucoplakia, but upon the nature of the irritant which gave rise to the leucoplakia. The changes which the tongue undergoes in syphilis are both interesting and important, owing to the frequency with which the}' end in cancer. The changes about to be described, broadly speaking, are only to be seen iu those cases of syphilis which are not treated at all, and in those which are treated with mercury internally. Absence of treatment does not prevent the tongue from becoming infected directly with the organisms of syphilis. Oral administration of mercury frequently causes indigestion, and indigestion is liable to cause inflammation in any part of the mouth, especially in the tongue. Other factors also come into play, namely, bad teeth, smoking, tobacco chewing, alcohol, etc., all these are liable to increase or to keep up any inflammatory changes which have been initiated by syphilis. The first change to be noted is a swelling of the base of the tongue, and this frequently leads to the patient seeing the circumvallate papillae, for the first time in his life. After recovering from the shock, he runs up to his doctor for advice as to what to do for the sores or spots at the back of his tongue. This swelling soon extends to the anterior part of the tongue, when the tongue appears to be too big 164 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. for the mouth, and its edges clearly show the irregularity caused by the pressure of the teeth. Swelling indicates parenchymatous inflammation. If the inflammation persists, fibrous tissue formation is the result. Fibrous tissue contracts, and hence the tongue becomes smaller than it normally was. Fibrous tissue contraction indicates loss of blood supply to surface, hence the papillae vanish, the dorsum of the tongue takes on a smooth, glazed, shiny appear- ance, and then the epithelium begins to protect itself by forming horny tissue. The inflammation may not be evenly marked all over the tongue. In some places it may be worse than in others, hence the tongue may be atrophic in some parts and hypertrophic in others. This irregularity leads to fissure formation, and as fissures occur where the fibrous tissue is densest and the blood supply is poorest, it can be easily understood how readily ulceration, and even cancer may arise. AVarts are very liable to occur in the atrophic areas, and the risk of these becoming malignant is great. Cauterisation will stimulate their malignant ten- dencies, therefore, on no condition whatever should caustics ever be applied to a tongue, or indeed to any other mucous membrane. The warts should be locally excised. There is no necessity to remove half the tongue, as, in these atrophic tongues which became malignant, the process is so slow and localised, and it practically never gives rise to a metastasis. When an ulcer becomes malignant, it is a different question. Removal of half or the whole of the tongue and the lymphatic glands is usually the most expedient course to adopt. Tonsil. A primary sore may have its seat in the tonsil, when it invariably gives rise to a difficulty in diagnosis. A primary sore has to be distinguished from a well-marked case of follicular tonsillitis, a gumma of the tonsil, and from Vincent's angina. Over and over again, these four conditions have been confused with one another, although the differential diagnosis between them should never present any difficvdties. A chancre is often a superficial lesion, circumscribed, and not surrounded by an inflammatory area. On the other hand, a chancre, owing to secondary infection, is more often a deep ulcer, and then the area surrounding it is naturally very much inflamed. Whether the chancre of the tonsil is secondarily infected or not, the enlargement of the lymphatic glands is always very much more marked than is the case with follicular tonsillitis. Follicular tonsillitis is very painful, a chancre of the tonsil is not. Follicular tonsillitis is ushered in with fever, rigor, etc., and, SYPHILIS OF THE MOUTH AND THROAT. 165 throughout its course, the patieut feels very ill, and almost invariably small areas of folliculitis will be observed on the opposite tonsil. A chancre of the tonsil begins insidiously : the patient does not feel ill, and the act of swallowing usually causes nothing more than a mere feeling of slight discomfort. A gumma causes more destruction of tissue, for its size, than a chancre, and it is unaccompanied by an enlargement of the lymphatic glands. Vincent's angina is usually mistaken for a chancre, or more often for a gumma. The course of Vincent's angina should suffice to distinguish it from any other condition. The patient suddenly feels very ill, the temperature shoots up, and the patient may have a rigor ; in two or three days there is a deep ulcer in the tonsil^ extreme pain on swallowing, and only a very slight enlargement of one or two lymphatic glands. The rapidity with which the ulcer develops is the pathognomonic sign of Vincent's angina, and a point which absolutely excludes syphilis, is an affection of the opposite tonsil. A film made from a case of Vincent's angina will also quickly settle the diagnosis, since the condition is caused by two organisms which live in symbiosis, namely an irregularly coiled Gram negative spirochaeta and a Gram positive fusiform bacillus. Syphilitic periostitis and its sequelae are so absolutely pathognomonic of syphilis, that only a passing word is necessary. Syphilitic periostitis of the hard palate often leads to ulceration and perfora- tion of the bone, and it is not at all an uncommon symptom in both acquired and congenital syphilis. In acquired syphilis, so far as the nose is concerned, a perichondritis is more common than a periostitis, and this almost invariably results in a perforation of the nasal septum. CHAPTER XIX. SYPHILIS OF THE BRONCHI AND LUNGS. A syphilitic bronchial catarrh is not very uncommon, but it is more frequently seen as a recurrent syphilitic manifestation than as an early symptom of the disease. The chronic ulcerative syphilitic bronchitis may occur alone, but it is more often associated with a similar condition in the trachea, larynx or pharynx. This late syphilitic bronchitis, as a rule, affects only one or other of the chief bronchi, and the most usual situation for the ulcers is in the neighbourhood of the bifurcation. The ulceration causes a thickening and raising up of the mucous membrane, and these two changes together give rise to violent fits of coughing, and, at the end of a fit, there may be a haemorrhage. No signs are to be found in the lungs. An X-ray examination of the chest gives no clue to the condition, and the diagnosis is rendered extraordinarily difficult. I have seen only one case, and the symptoms were coughing and haemorrhage. The patient first of all comjjlained of a peculiar feeling in the throat, which led to slight attacks of coughing. Later, these attacks became more frequent and lasted longer, until ultimately every attack resulted in a severe haemorrhage. Repeatedly the patient would experience difficulties in breathing, and his complexion would assume the colour associated with venous congestion. , Anti-syphilitic treatment stopped the symptoms at once, but, in the course of two years, the patient had three very severe relapses, which were checked imme- diately by further treatment. Ultimately the ulcers doubtless scarred over, as the patient has been free of any trouble for over two years. Considering the severity of the haemorrhage in this case, the ulcers must have developed backwards, and eroded a small bronchial vessel. Cases have been reported in which the scarring resulting from the healed ulcers has given rise to stenosis. Purulent mediastinitis and lobar pneumonia may also be the end of a case of gummatous bronchitis. Symptoms of an ulcerative bronchitis may be produced by a syphilitic process, starting in the bronchial SYPHILIS OF THE BRONCHI AND LUNGS. 167 lymphatic glands, which become adherent to the bronchi, and may even ulcerate through. Lungs. Syphilitic aii'ection of the lungs is, in my opinion, commoner than is thought to be the case, but unfortunately its diagnosis is fraught with great difficulties, owing to the lesions being well nigh indistinguishable from those produced by tuberculosis. Therefore, no trustworthy evidence as to its frequency is to be obtained. There is still a great difference of opinion as to the influence of s3-philis on the incidence of tuberculosis of the lungs, and vice versa. I think there can be no doubt that individuals whose resistance against tuber- culosis is lowered are more prone to develop this disease, if they also suffer from syphilis. In support of this view may be mentioned the not infrequent occurrence of tuberculous adenopathy in congenital syphilitics, and the very high incidence of pulmonar}- tubercidosis in the black races, in those individuals who have syphilis. If a patient has tuberculosis and S3'philis, the latter disease aggravates the former, but the former appears to have no influence upon the course run by the latter. Treatment of syphilis has its usual effect on the disease, whether tubercle is present or not, but it is seldom that the tuberculosis is much influenced by it, indeed mercury and iodide may make the tuberculosis worse. From this it would appear that there is little ground for assuming that a lesion could be caused by an association of tubercle and syphilis. In recent years, one has not infrequently heard the diagnosis made, that a certain orchitis or an arthritis is due to a combination of syphilis and tubercle. Such a diagnosis shows that the observer does not know whether it is tubercle or syphilis, and, to save himself from making a mistake, he says the lesion is due to a combination of the two diseases. When the differential diagnosis of a lesion between tubercle or s3-philis arises, it can be taken for certain that the lesion is due to either one, but never to a com- bination of both. As the changes produced in the lung by tubercle and syphilis are much alike, it is often impossible to differentiate between them. Broadly speaking, the area affected by syphilis is greater than that affected by tubercle, and the sjTnptoms produced are relatively greater in tubercle than in syphilis. Syphilis affects the middle and lower lobes more often than the upper lobe ; but a true syphilitic apical lesion may be met with. So far I have had three cases under my care. One of these used to get periodically very severe attacks of 168 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. haemoptysis, but tuberculosis could easily be excluded, because the patient always felt ^yell, he never looked ill, he never lost weight, and anti-syphilitic treatment benefited him. Syphilitic lesions are more bronchiectatic than tubercidar ones, hence one of the best diagnostic means is the X-rays. Salvarsan has a rapid action upon sj^hilitic lung lesions, therefore, if there is any difference in the X-ray picture before and after treatment, one can be practically certain that the condition was sj^ohilitic. As is well known, pulmonary tuberculosis is frequently preceded by pleurisy. This is not the case in syphilis — not that syphilis does not affect the pleura, but, in practically all cases of syphilitic pleuritis, the pleuritis is only part of a wide- spread pulmonary affection. The following is a good case of pulmonary sj'philis which I had under my care : — Case 22. — Patient, a man now aged 47, contracted syphilis 10 years ago, and, 10 months ago, began to be troubled with a cough. The cough was dry and hard ; it was not worse at any one time of the day, and there was no expectoration. Friction sounds were discernible almost all over the lung area, and those who examined him, said that there were changes in the lung which were undoubtedly due to tubercle. The patient went away, did what he was told, and became much worse. Seven mouths later I saw him. He looked as if he had fever, but was not emaciated, and I learned that he had lost no weight ; he had never had an haemo- ptysis, and there was no expectoration. Friction sounds could be heard over both lungs, and on the left side were signs of both thickened pleura and patches of consolidation. There was no family history of tubercle ; the patient had spent his life in British East Africa, where tubercle amongst the white population is almost unknown. He looked too well to have such widespread tuberculous lung symptoms, and, as there had never been any expectoration or loss of weight, I considered the trouble must be due to syphilis. After the first injection of neo-salvarsan, the cough vanished, and, by the time the fourth had been given, practically all the physical signs had disappeared, except for some impaired resonance over left lung behind. CHAPTER XX. SYPHILIS OF THE BONES AND JOINTS. In discussing syphilis of the bones, lesions of the periosteum are, of course, included, and for the sake of making the description of the subject easier, the lesions of the periosteum vrill not be, as they usually are, considered separately from those of the bones. Although perhaps as much attention has been paid to syphilis of the bones as to that of any of the other organs, none of us knows for certain whether, in the majority of the cases which we call periostitis, the disease really started in the periosteum, or in the bone itself. Many observers hold to-day that there is no such thing as primary syphilitic periostitis. Others are of the opinion that syphilitic disease of the bones always begins in the periosteum, and that those severe cases of osteitis and osteomyelitis, which were much more often seen years ago than they are now, were due to the mercury which had been prescribed for the disease. There is no doubt at all that the injudicious use of mercury, which was practised only a comparative^ short time back, was partly responsible for a large amount of bone trouble. This planted the seeds of suspicion, which have blossomed forth into that mistrust of mercury which is possessed by so many lay people to-day. The view that was, and is still held, is that mercury caused bone trouble by collecting tn Joco; but animal experiments, and the fact that those who work in quicksilver mines, are no more prone to bone diseases than those who follow other trades, all militate against current opinion. The fact that the patient has syphilis is an important factor. Secondary anaemia in syphilis is common ; mercury often aggravates this secondary anaemia. Fatty degeneration is a frequent result of syphilitic inflammation. Fatty degeneration causes a diminution of calcium, so does the prolonged and injudicious use of mercury. Therefore, although one may still hold the view that mercury was the cause of many of the fine specimens of bone diseases which adorn our museums, it must be said that it was not entirely responsible. 170 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. The periosteum is continuous with the interstitial tissue which interlaces the parenchyma of the bone. The organism of syphilis develops in the interstitial tissue, and not in the parenchyma. Therefore, it will at once be seen that syphilitic osteitis cannot be separated from syphilitic periostitis. It may be said, with a great degree of certainty, that a syphilitic periostitis cannot occur without an osteitis, and vice versa. Therefore, instead of making two divisions, it appears to me to be wiser to talk about syphilitic osteoperiostitis, as the signs and symptoms produced by the two are identical. Syphilitic Osteoperiostitis. Any bone in the body may be affected. Of the long bones, the tibia, humerus, ribs, and clavicle are the most commonly involved, and of the flat bones the nasal, frontal and parietal. There is a great difference in the course run between syphilitic osteoperiostitis of the flat, and of the long bones. In the case of the long bones, the process is generally dry throughout, i.e., there is no liquefaction of tissue, and no pus formation. Therefore the process is one which can scarcely be called gummatous. The skin over the bones often is not even inflamed. Such a process invariably ends in new bone formation, and this corresponds in size with the area affected. The new bone formed is very hard, may be eburnated, usually smooth on the surface, always sharply circumscribed, and is, as a rule, surrounded by a groove. Should the case be one of true gummatous osteoperiostitis, there will be destruction of bone, of the nature of a rarifying osteitis, in the region affected , but around, and in between the gummatous areas, osteo- phytic growths are always to be found. In gummatous osteoperiostitis, the overlying tissues are inflamed, oedematous and there is often marked ulceration of the skin. Many of the ulcers are fistulae, which reach down to the bone. Osteoperiostitis of the flat bones is, aln\ost in- variably, of a gummatous nature. The patient frequentl}^ seeks advice for swellings of the forehead and scalp. These swellings may or may not be inflamed ; they usiially fluctuate, and the diagnosis of lipomata, sebaceous cysts, or cold abscesses, is usually made. On incising them, extremely little pus comes away, and as such a procedure may allow coccogenic bacteria to gain entrance, an acute osteomyelitis of the diploe may result, therefore, on no condition whatever, should an exploratory incision be made. Only quite recently there was a death at the Lock Hospital from a pyogenic infection, which had supervened upon a gummatous osteomyelitis of the diploe. The dura mater was covered with pus. SYPHILIS OF THE BONES AND JOINTS. 171 There is always a destruction of bone in these cases, and it may remain limited to the outer plate, or it may reach right through to the dura mater, which practically always remains intact. In by far the greater percentage of cases, the osteoperiostitis affects the externa plate and the pericranium, but neither the internal plate nor the periosteum. An hypertrophy of bone, and the formation of osteophytic growths, is prac- tically never seen in the skull bone lesions. The reason why osteoperiostitis of the long bones runs a different course from that of the flat bones depends upon blood supply. The arterial blood supply to the scalp is extraordinarily rich, hence gumma forma- tion and the spread of the process is therefore favourable, and, finally, arterial blood can cause bone atrophy. Inflammation of the extremities, where the arterial blood supply is not so good, favours venous congestion, and venous congestion is a potent factor in the causation of bone hypertrophy. Syphilitic osteoperiostitis, such as that just described, may occur as early as a few months after infection, or may not occur for several years. Early gummatous osteoperiostitis affects the fiat bones more frequently than the long bones. In the case of the nasal bones, it is highly probable that the initial trouble arises in the submucous tissue, and involves the periosteum and bone later, since it practically never happens that the skin surface of the bones, or the skin itself, becomes attacked. During the stage of the generalisation of the virus, there may be an inflamma- tion of the periosteum of the long bones, and this often causes severe pain ; but, as a rule, nothing is to be seen or felt. Even in the later stages of syphilis, when no swelling can be seen, a commencing osteoperiostitis may be accompanied with such violent pain as to lead one, if in a hurry, to make a diagnosis of neuritis. Local tenderness on pressure and the distribution of the pain soon suggest the seat of the trouble. However severe bone pain may be, it very quickly responds to treatment, while the pain of neuritis is often temporarily aggravated. Another pitfall for the unwary is the diagnosis of a syphilitic osteoperiostitis as a sarcoma. Quite recently I have had three such cases. On two, an exploratory incision was made, and the third was advised to have an operation, but refused. The mistake has even lead to the removal of limbs. Syphilis does not only affect the bone and periosteum, it may also affect the medulla. As a rule, from a clinical examination only, 'a syphilitic osteomyelitis cannot be diagnosed from a syphilitic osteoperiostitis. In a large number of cases, when one is in a position to examine the bone, it is found in a condition of panosteitis, i.e., the periosteum, the bone itself, and the medulla are all affected. 172 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. Some of those cases with chronic oedema, ulceration, and fistula formation of one leg, are really cases of syphilitic osteomyelitis, or better to say, panosteitis. Only an X-ray photograph can indicate, during life, whether the medulla is involved or not. If the medulla is affected, the inflammation is of the gummatous type, with the result that the medullary surface of the true bone shows marked signs of rarefying osteitis. The abscess formation, so common in tubercle, is not met with in syphilis. One of the best ways of distinguishing a syphilitic osteomyelitis from a tubercular one, is to remember that lipoid or fatty degenera- tion is a typical feature of a syphilitic process, when there is destruction of tissue. Consequently, a fresh or a well prepared specunen of osteomyelitis looks yellow and full of fat, while a tubercular osteomyelitis has a white or more waxy appearance. Cases of spontaneous fracture have been recorded, following syphilitic osteo- myelitis. Syphilitic bone lesions show rather clearly the influence which irritation or continued trauma has upon their origin. The clavicles are most prone to develop osteoperiostitis at the place where the braces touch the skin. Shoemakers are liable to osteoperiostitis of the sternum, and it is highly probable that the reason why the tibiae are so commonly affected, is because of their prominent position, and because of the fact that the anterior surface is not guarded by muscle. Syphilitic Arthritis. From simple inflammation of a joint, up to its complete destruction or ankylosis, the various clinical t\^es met with may be caused by syphilis, and are, per se, indistinguishable from the same conditions produced by other causes. The inflammation may commence in the synovial membrane, in the capsule, or in the articular surfaces of the bones. Slight inflammation of the synovial membrane and capsule may produce no other sign or symptom than pain. ^ When the inflammation commences in the synovial membrane, as a rule fluid is excreted into the joint, and there is one clinical condition which is sometimes caused by s}^hilis, in which, w-ithout warning or pain, the joint suddenly and very quickly becomes distended with fluid. The condition is called Hydrops articuli, and the knee joint is ahnost invariably the joint affected. In some of these cases, the fluid disappears as quickly as it came, and then is liable to recur without any provocation. In those cases in which the inflammation is very acute, and in which one or more joints are affected, the patient usually looks extremely ill, emaciated, and anaemic. There is always marked wasting of the muscles above and below the affected joint, To mv mind it is very odd that patients with a s}'philitic arthritis, and still more so SYPHILIS OF THE BONES AND JOINTS. 173 is it the case with a gonococcal arthritis, should generally look so desperately ill and lose so much weight. I can neither give a good reason, nor can I find one in the literature. It is absolutely impossible to difierentiate between a syphilitic and a gonococcal arthritis. If the patient has a discharge, and signs of an old prostatitis can be detected by a rectal examination, the diagnosis is often obvious ; but, not infrequently, a patient may have a severe gonococcal polyarthritis, after all signs of gonorrhoea have disappeared from his urinary tract. A monoarticular gonococcal arthritis frequently ends in an Arthritis deformans. A syphilitic arthritis does not do so. There is still much division in opinion as to whether syphilis can be a cause of Arthritis deformans. Personally, I think it is very doubtful, and in every case of Arthritis deformans which I have seen in syphilitics, the patients had all had gonorrhoea and gonococcal arthritis, which, in my opinion, was the cause of the Arthritis deformans. I recently had two cases of Arthritis deformans affecting both hip joints. Both these cases had had gonorrhoea and syphilis, and in both the Wasser- mann reaction was positive. In the one case, the process was early in both joints, therefore some improvement could be expected from treatment. Salvarsan, mercury and iodides had no influence whatever. The patient began to improve, only when gonococcal vaccines had been administered. In the other case, one hip showed all the classical signs of advanced Arthritis deformans, while the process in the other had only just commenced. Here, again, benefit resulted from gonococcal vaccines, and not from anti-syphilitic treatment. That familiar condition, so commonly seen in tubercular patients, to which the name of Tumor albus has been given, may also be met with as a late manifestation of syphilis, and, from an examination of the joint alone, the two diseases cannot be differentiated. This fact has led some clinicians (who cannot make a mistake), to diagnose many cases of Tumor albus as a mixture of tubercle and syphilis. In all these very difficult cases, the best means of arriving at a correct diagnosis is to give an injection of salvarsan. The treatment test is far superior to any other, as I have frequently seen patients with symptoms which might not be svphilitic give a positive Wassermann reaction, when the lesions were really due to causes other than syphilis. It should always be remembered, that a patient who has had syphilis is just as prone to contract other diseases as a patient who has not been so infected. Syphilitic lesions of bursae and tendons are more or less curiosities, and, as they have no distinguishing features, it does not appear necessary to discuss them further. CHAPTER XXI. SYPHILIS OF THE ABDOiHNAL YISCEEA. Oue of the least studied chapters of syphihs, is that deaUug with syphiUs of the abdominal viscera. This omission is largely due to the fact that the correct diagnosis is not made, until the patient has reached the post-mortem room. Many other cases escape detection, because they recover from an abdominal section which has been performed for an inoperable maUguant growth. Oesophagus and Stomach. S}^hilis of the oesophagus is undoubtedly very rare, and the only case I have seen was in a health3'-looking young woman, who was operated upon for a supposed carcinoma of the cardiac end of the stomach. The operation revealed a diffuse induration of the cardiac ends of the oesophagus and stomach, and the abdominal wound was closed, with the idea that the lesion was cancerous. The patient was given some potassimn iodide, and from that time onward made an uninterrupted recovery. Cases have been described of syphihtic stenosis of the oesophagus. Syphihs of the stomach is a great deal more common than is generally supposed. A catarrh in the generalisation stage can sometimes be ascertained, if every patient be thoroughly examined. The diagnosis is admittedly difficult, owing to the fact that anaemia may be primarily responsible for the indigestion, h^'peracidity, sickness and loss of appetite ; these being the main symptoms complained of. If mercury has been given internally, it is impossible to say how far it is responsible for the gastric trouble. In the later stages of syphihs, the disease may produce a diffuse infiltration of the walls of the stomach. I have seen such a case which recovered under anti- syphihtic treatment, after the diagnois of sarcoma had been made at an abdominal section. The infiltration may affect the pylorus ; indeed, it is frequently limited to this portion of the stomach. Case 23. — A medical man, aged 36, came to me for some injections of salvarsan. SYPHILIS OF THE ABDOMINAL VISCERA. 175 because he had syphilis. He informed me that he had a sweUiug over the pyloric end of the stomach, and it was quite distinct upon palpation, and had aroused the suspicion of carcinoma in the minds of some of the surgeons whom he had con- sulted. He had been strongly advised to have a gastro-jejunostomy performed, but, knowing that he had had syphilis, he thought he would try salvarsan first. After a few injections, the swelling completely disappeared. Since then I have seen three other cases of a swelling in the pyloric region, in young and apparently healthy individuals, in all of whom the symptoms and swelUng vanished under salvarsan. It is extremely probable that many of the cures, in young middle-aged persons, which have resulted from short circuiting, are not due to the operation, but to the spontaneous disappearance of the lesion, as some of the late symptoms of syphilis are occasionally wont to do. SyphiUs may also cause ulceration of the stomach ; there may be a single ulcer, or several. Such cases, again, are not, as a rule, diagnosed until after death, when it is seen that the syphilitic ulcer is different from the usual type of gastric ulcer. A syphihtic ulcer is sharply circumscribed. There is no surrounding inflamma- tion, it is never terraced, and, as a rule, the edge is raised and thick. As a rule, syphilitic ulcers of the stomach heal and leave a scar ; the scar causes contraction, and usually the patient suffers from chronic indigestion. In most cases of gastric ulcer, syphilis should be borne in mind, because, if syphihs is the cause, the cases recover rapidly under appropriate treatment. Haemorrhage is not a common sviuptom, for the simple reason that the ulcer is usually a necrosis of that area which was fed by a vessel which had become occluded by inflammation. Perforation practically never occurs, as the outer portion of the wall and the peritoneum remain unaffected. A great deal of work on the chemical analysis of the gastric contents in cases of syphihs of the stomach still remains to be done. My experience in this direction is very limited, but, from the few examinations which have been made, a typical feature seems to be the decrease in the hydrochloric acid content. Hausmann,^ who has made a special study of syphilis of the abdominal organs, mentions the following points in the differential diagnosis between syphilis and other diseases of the stomach : — (1) A normal or increased HCl-content excludes gxunma of the stomach, gummatous ulceration, syphilitic hyperplasia, and shrunken stomach. (2) Nocturnal gastric pains, with anacidity, is in favoiu- of syphilis of the stomach, or of a syphilitic retroperitoneal tumour, but it does not exclude ordinary pyloric stenosis. M 176 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. (3) Characteristic symptoms of gastric ulcer, associated with anacidity, favours the diagnosis of gmumatous ulcer. (4) A palpable pyloric swelling, with anacidity and absence of the symptoms of stenosis, and a negative blood test in the stomach secretion and in the faeces, points to there being a diffuse gummatous infiltration of the pylorus. (5) In all cases of shrunken stomach, the diagnosis of sypjiihs must be seriously borne in mind. In every case in which pains in the stomach are complained of, the possibility of these pains being the gastric crises of degenerative myelitis should always be considered. I know of four patients who have had a gastro-jejunostomy performed, when their symptoms were really those of degenerative myelitis ; one of these was operated upon twice, and I have been fortunate enough to save three others from suffering a similar fate. Syphilis of the Intestines. In the acute stage of syphilis, there may be a catarrh of the duodenum, which is nearly always associated with a catarrh of the bile ducts, without and within the liver, the result being that the patient becomes jaundiced. Doubtless a catarrh of the rest of the intestinal tract occurs, but its diagnosis would be a matter of extreme difficulty. The Condylomata lata which one so •commonly sees around the anus may extend up the anal canal, but, as a rule, they give rise to no symptoms unless they ulcerate, and then give rise to a stricture, a sequela which is very rare. Syphihs of the intestines is more common in the congenital than in the acquired form, hence, in acquired syphilis, one would expect to find the intestines affected in the late stages, which is the case. The commonest syphilitic lesion of the gut is a diffuse syphihtic infiltration of the wall. Occasionally the infiltration is localised and annular, and then it quickly gives rise to narrowing of the liunen, and to stenosis. Such cases, when operated upon, are almost invariably regarded as carcinomata. If the stenosis is of long standing, naturally the mucous membrane ulcerates, but in all these cases of syphilitic infiltration of the gut wall the mucous membrane is intact, and only becomes secondarily involved. The diffuse form is usually diagnosed as sarcoma. Syphihs may affect the tissue subjacent to the peritoneum. The peritoneum becomes secondarily involved, and adhesions are formed between the affected area and the surrounding structures. I have seen a case of this sort, involving the under surface of the liver, the duodenum, and the pancreas. I also have notes of another case, in which the pyloric end of the stomach was bound down to the viscera around by adhesions. SYPHILIS OF THE ABDOMINAL VISCERA. 177 This is probably the pathology of the so-called syphihtic stricture of the rectum. Sj'philitic stricture of the rectum is much more common in women than in men, and, in some cases, the whole jielvis seems to be filled with a dense mass of infiltrated tissue. It is the contraction of this tissue which leads to the narrowing of the lumen of the bowel, and here again any ulceration of the raucous membrane is the result, and not the cause. Gummatous ulceration of the bowel is never diagnosed except post-mortem, i.e., when it affects any part of the bowel other than the rectum. The gumniata are almost invariably multiple. They are sharply circum- scribed, have raised edges, and practically no surrounding inflammation. They do not, as a rule, affect the Peyer's patches, and they often heal spontaneously. Gummatous ulceration of the rectum may lead to stricture, and an important point to remember in these cases is, that if the rectal stricture is due to gummatous ulceration, i.e., if it is a primary lesion of the mucous membrane, the chances are that there are gummata higher up in the gut. If there are gummata higher up in the gut, there may also be a stricture higher up. Unfortunately, these cases do not give rise to symptoms until the syphilitic lesion has healed, and its place has been taken by contracting fibrous tissue, therefore surgical interference is usually called for. Syphilis of the Liver. Cholangitis is the connnonest early syphilitic lesion of the liver, and it is extraordinary how very early in the disease the jaundice may be very severe. Not a moment should be lost in giving neo-salvarsan in these cases. In the early days of " 606," when jaundice was not a very uncommon sequence of its administration, syphilitic jaundice was regarded as a contraindication to its employment, but now it is, correctly, a strong indication. Acute yellow atrophy of the liver, though due more often to other conditions, is sometimes caused by syphilis in its early stages, and even such a fatal condition as this may be saved, if neo-salvarsan is used energetically, and as quickly as possible after the onset. The late syphilitic lesions of the liver are very easy to understand, if it be remembered that the disease begins in the connective tissue, either between the acini or between the cells themselves. The interstitial or indurative hepatitis may be diffuse or locahsed. If localised, it may be single or multiple. The diffuse form gives rise to a hypertrophic cirrhosis, which cannot be distinguished from a similar condition produced by other causes. As the fibrous m2 178 THE BIOLOGY, CLINICAL ASPECT A?JD TREATMENT OF SYPHILIS. tissue contracts, the blood supply to the parenchyma cells will be diminished, and therefore many of the latter will degenerate. The liver gets smaller and smaller — the so-called atrophic cirrhosis. The localised form varies enormously in size. Usually the parenchyma cells completely degenerate, and the lesion becomes a giimma. This is also the pathology of the multiple localised lesions. Those lesions on the surface, owing to the contraction of the fibrous tissue, often have a marked depression in their centre. It sometimes happens that only one lobe is affected. Say, for sake of argument, that it is the left, then the right lobe will hypertrophy — a compensatory hyper- trophy. Since the right lobe is more easily palpated than the left, a mistake may easily be made in diagnosing a compensatory hj'pertrophic right lobe as hj'pertrophic cirrhosis. Most cases of sj-philis of the liver run a symptomless course, and are not diagnosed until after death, a circumstance which gives the clinician the idea that S3^hilis of the liver is rarer than it really is. If Glisson's capsule is affected, and there is a marked perihepatitis, pain is a very common symptom. The pain is independent of taking food, and it is increased on deep breathing and coughing. Pain is a good sign, as it shows that the perihepatitis is acute, and therefore much is to be expected from treatment. Vomiting is a common symptom, but possibly the most important symptom is intermittent fever. This intermittent fever is often the only spiiptom which the patient develops and for which he seeks advice, so that many clinicians have described a condition to which they have given the name of tertiary syphilitic fever. ^ I had one case which had been diagnosed for months as malaria. Tvphoid fever, mahgnant endocarditis, febrile cholelithiasis, pulmonary tuberculosis (as the spitting up of blood sometimes occurs), and lymphadenoma may easily be mistaken for late syphihtic fever. I had another interesting case, in which the febrile attacks were accompanied by haemoglobinuria. Late syphilitic fever is best diagnosed by the rapidity with which it disappears under anti-syphilitic treatment. Ascites is not a commbn comphcation of syphihtic cirrhosis. Alimentary galactosuria is, according to Bauer,^ a frequent sign of syphilitic hepatitis ; and so also is urobilinuria, and the occurrence of both of these points to damage of the parenchyma cells. SYPHILIS OF THE ABDOMINAL VISCERA. 179 In practically all the cases of tertiary syphilitic fever, the spleen is enlarged as well as the liver, and one of the distinguishing features between syphilitic cirrhosis and alcoholic cirrhosis is that, in the former, there is more often an enlargement of the spleen than ascites, while in the latter, the reverse is the case. Syphilis of the Pancreas. What has been stated re the interstitial nature of the syphilitic process in the liver, applies also to the pancreas. In most cases of syphilitic disease of the pancreas, it is only the head of the organ which is involved. Syphilitic pancreatitis usually leads to the formation of adhesions which involve all the neighbouring structures, so the clinical picture is often a varied one. The following is a good example of a case of syphilitic disease of the head of the pancreas : — Case 2i. — Patient was a medical man, aged 35, who contracted syphilis three years before onset of present trouble. Treatment had been more or less con- tinuous ; the notes are best given as he wrote them out for me. " In January, 1910, I first commenced to experience attacks of pain in the epigastriinn. The early attacks took the form of a didl ache across the epigastrium, commencing about midday after having been at work for two or three hours. Pain would gradually become worse, till I was forced to lie down, which would almost immediately relieve me of further pain. Minor attacks of this pain were very frequent, and on a few occasions severe attacks were experienced, which necessitated my lying up for a week. The pain was always of a dull, aching character, never localised, but indefinite and extending across the epigastrium. It was seldom accompanied by any other symptoms, except occasionally by a mild nausea and a peculiar chilly feehng. " The attacks were in no way connected with food. During January, February, and March, 1911, the attacks became so bad that in April I left for home. The attacks occurred daily, and were now almost invariably associated with nausea. In May, jaundice developed which lasted three weeks, and diagnosis was then made of catarrhal inflanimation of gall-bladder and duodenum. X-rays showed nothing abnormal. Pains continued throughout June and July, when I consulted Mr. , who diagnosed duodenal ulcer. " In July I was obliged to return to duty, but, as trouble persisted, I came home again in November, 1911, and was operated upon January, 1912, by Mr. . No ulcer of the stomach or duodenum was found, and appendix appeared normal. Gall-bladder was attached to all surrounding structures by adhesions, 180 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. and there was a typical chronic pancreatitis, which had previously been suggested as a result of Cammidge's tests. Following the operation, I remained free of sj-mptoms till March, 1912, when they all returned, and three months later they were worse than they had ever been before." In September, 1912, I saw the f)atient, and, as the Wassermann reaction was positive, I gave several injections of neo-salvarsan, and followed up the treatment with mercury and iodides. After the first injection the symptoms vanished, and patient has been perfectly well since. Intermittent glycosuria may be the only symptom of a syphihtic affection of the pancreas, but it must be remembered that not every case of syphilitic glycosuria is of pancreatic origin ; for instance, it may be a symptom of an intracranial lesion. A thorough examination of the faeces and urine is necessary in all cases of suspected implication of the pancreas. Syphilis of the Spleen. An enlargement of the spleen in congenital syphilis is a very well-known fact, but that the spleen is often enlarged in early sj'philis, few have noted. The spleen is nothing more nor less than a huge lymphatic gland. A general enlargement of the lymphatic glands is one of the commonest and earUest signs of syphilis, therefore, if one thinks, it would be only too reasonable to expect a hyperplasia of the spleen in the early stage. Syphilitic splenitis, in conjunction with syphilitic hepatititis, has already been referred to, and the part that syphilis plays in the enlargement of the .spleen, in cases of lymphocytomata, will be more fully dealt witli in Chapter XLVI. Although Banti himself was against the view that syphihs played a part in the aetiology of the disease which goes by his name (splenitis, anaemia, cirrhosis of the liver, and ascites), there can be no doubt now that syphilis is sometimes the cause. Syphilis of the Peritoneum, etc. Retroperitoneal and mesenterial swelhngs may sometimes be of syphilitic origin, and the site of the trouble is usually in the lymphatic glands. The swelling may sometimes reach an enormous size. An analogous condition occurs in the mediastinum, and a glandular swelhng in this situation is usually mistaken for an aneurysm. There is an extremely interesting condition which is sometimes met with in syphilis, in which the patient has a pseudo-chylous ascites. SYPHILIS OF THE ABDOMINAL VISCERA. 181 Though not a true syphilitic disease of the peritoneum, it may occur in cases in which no trouble of an abdominal organ can be traced, although it is usually secondary to a lesion of an abdominal viscus. The chemical and physical properties of the fluid from cases of chylous and pseudo-chylous ascites, have been so ably worked out by Mackenzie Wallis and Scholberg,* ^ that anyone who is interested in this subject should refer to them. ' Hausmann (1913), " Die Luet. Erkrankungen dcr Bauchorgane." C. Marhold. Halle a. S. 2 Parkes Weber (1907), " Lancet," i, 728. ' Bauer (1910), " Lues unci innere Medizin." * .Mackenzie Wallis and Scholberg (1910), " The Quarterly .Journ. of Med.,"' iii, 301. * Mackenzie Wallis and Scholberg (1911), "The Quarterly Journ. of Med.," iv, 1.53. CHAPTER XXII. EXAMINATION OF THE CEREBROSPINAL FLUID. For drawing off the cerebro-spinal fluid, I prefer Barker's needle to any other. The patient i.s made to lie on his left side, on a hard conch for preference, so as to avoid a spinal curve. The knees should be well drawn up, the left arm and shoulder pulled down, and the head and neck bent towards the knees. The observer should B.arker's Luml.iar Puncture Needles. then see that the back is straight, i.e., that the two halves of the pelvis are lying in the same perpendicular. The highest point of the right iliac crest is ascertained, and then the intra- vertebral space found, which lies to the sacral side of a line drawn across the back from this point. The best intra vertebral space is the one between the fourth and lifth lumbar vertebrae, and it is not in the same position in everybody. It is scarcely ever on the line from the highest point of the iliac crest, but almost invariably just to the sacral side, or well to the sacral side of it. After an injection of a local anaesthetic (0'5 per cent, novocain), the forefinger of the left hand is placed on the spine of the fourth lumbar vertebra, and the needle is inserted in the middle line by the side of the finger. The needle is then directed EXAMINATION OF THE CEREBRO-SPINAL FLUID. 183 horizontally imvards, until the canal has been reached. If the point of the needle impinges on bone, it should be withdrawn, and another direction tried. An experienced observer knows by the feel when he has pierced the dura mater. If the needle has entered the canal too low down, the patient experiences a sharp pain down one of his legs. Occasionally the dura mater becomes attached to the cord higher up in some individuals than in others, so it is always wise to pierce the skin near the spine of the fourth lumbar vertebra. Personally, I think it is easier to insert the needle in the middle line than half an inch below, the point that is usually advised. However careful or expert one may be, difficulties in tajjping the theca may be met with, and the operation is similar in this respect to venepuncture. Men who have had a very wide experience of giving intravenous injections know ordy too well that they may be baffled now and again. If the cerebro-spinal fluid is being withdrawn for testing purposes, and a drop of blood comes through the needle, the needle should be withdrawn and the operation postponed for a week or two. A collodion dressing is all that is required after the needle has been withdrawn. A syphilologist may be called upon to tap the theca for three purposes: (1) for testing ; (2) for relie^^ng pressure ; (.3) for injection. If the fluid is only being withdrawn for testing purposes, as little should be taken as possible, becau.se, even if the quantity is made up by injecting saline, excruciating headaches, which persist from one to seven daj's, cannot always be avoided. Headaches are certainly less frequent if saline is injected, and they appear to be less frequent in those cases in which the central nervous system has already been attacked. If the patient is kept in bed after a lumbar puncture, and the head is allowed to rest on a lower plane than the feet, headaches are rare ; but since lumbar puncture has become more or less a routine, I always perform the operation in my room, and let the patient return home afterwards. I usually arrange to do the operation in the evening, and send the patient straight home to bed, with the request to raise the foot of the bed. If lumbar puncture is done to relieve pressure, the patient is certain to be in bed, and the quantity drawn off does not matter ; 30 to 40 c.c. can be withdrawn comfortably. When an operation for pressure has to be performed, the case is almost invariably one of pachymeningitis, for which salvarsan has been given. Salvarsan causes reactionary inflammation; reactionary inflammation in an already thickened dura- mater may be just sufficient to cause compression. In the case of pach^mieningitis, 184 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. the symptoms of compressiou, i.e., loss of consciousness, etc., usually set in between 48 and 72 hours after the second or third intravenous injection of salvarsan. Lumbar puncture may relieve these cases at once. Since the reactionary inflam- mation is largely due to a vascular dilatation, injections of adrenalin are very useful. Although a recurrence of the compression, after subsequent injections of salvarsan, is not likely to occur, a subcutaneous injection of adrenalin will certainly minimise the chance, and it may be administered prior to the injection, should the observer require more self-confidence. Pachymeningitis is a late symptom of syphilis ; but symptoms of compression, which usually start like Jacksonian epilepsy, may occur after salvarsan in early syphilis. The attack generally sets in about 48 hours after the second injection, and is due to a haemorrhagic encephalitis. This form of haemorrhagic encephalitis is a reactionary inflammation of the vessels in the cortex of the brain, which have been affected by syphilis. A lumbar puncture in such a case is valueless, so is trephining, the only remedy of any use being adrenalin. When the theca has been tapped for injection purposes, it is usually for the injection of salvarsanised serum, and will therefore be described in the chapter dealing with treatment (Chapter XXIX). The first thing one notes in doing a lumbar puncture is the pressure at which the fluid flows through the needle. Not too nuich reliance should be placed upon pressure, since it varies in normal individuals. It is usually raised in syphilitic diseases of the central nervous system, and is often markedly raised in patients whose nervous system has not been involved, but who have had a series of intravenous injections of salvarsan. AVhen the fluid has been collected, its colour is then noted. Normal cerebro spinal fluid is clear, like water. Blood. Blood in the cerebro-spinal fluid may come either from the skin and vessels, and may get into the lumbar puncture needle before the dura has been penetrated, or blood may appear as a result of some severe nervous lesion. The differentiation is simple, since in the former case all the blood is deposited on centrifugiug, whilst in the latter, a yellowish or brownish tinge of the cerebro- spinal fluid remains behind, and gives both the spectroscopic and benzidin tests for blood. Nonne ^ - reports a case where blood occurred in a patient with syphilitic meningo-encephalitis, but the presence of blood is not diagnostic of a sjrphilitic EXAMINATION OF THE CEREBRO- SPINAL FLUID. 185 condition, since it may be found in any case of acute meningo-encephalitis or Pachy- meningitis liaemorrliagica. In some cases of old standing active syphilitic cerebro-spinal meningitis, I have not infrequently, when looking into the column of fluid from above, noticed a faint yellowish tinge. Cells. The cells are next counted, and this can be managed with an ordinary Thoma- Zeiss haemocytometer, but the best method is that known as the Fuchs-RosenthaP counting method. The Fuchs-Rosenthal counting chamber is 16 mm. square and 0"2 mm. deep, hence it differs from the ordinary Thoma-Zeiss blood-counting chamber, in that the latter is only 1 mm. square and ' 1 mm. deep. The resulting count with the latter gives the number of cells in yV c.mm. of blood ; while the former gives the number of cells in -V~ c.mm. This obviously reduces the errors in counting. The fluid must be examined as soon as possible after withdrawal, as the cell content suffers through standing. The fluid should also be well shaken, so as to produce an even distribution of the cells. The cells can be examined unstained or stained ; if the latter, then the best stain to use is the following : — Methyl violet 0.5 gnu. Glacial acetic acid ... ... ... ... 0-50 „ Distilled water 24-45 c.c. Unfortunately, this stain requires to be freshly prepared, as fungi quickly develop in it. The cells which may be found in the cerebro-spinal fluid are : (1) poly- morphonuclear leucocj-tes ; (2) lymphocytes ; (.3) plasma cells ; (4) embryo lymphocytes ; (5) endothelial cells. The eight cells per cubic millimetre which may be found in normal cerebro- spinal fluid are mostly all Ipnphocytes. Polymorphonuclear leucocytes are found most abundantl)' in such conditions as meningococcal meningitis, etc., and, if they occur in syphilitic infections, they either indicate that there is a secondary infection or that the lesion is a meningeal one. Lymphocytes are the cells most connnonly found in syphilis, and as many as 1,000 or more per cubic millimetre may be present. The presence of a lymphocyto.sis is not diagno.stic of the nervous lesion being syphilitic, nor can it alone serve to distinguish accurately a meningeal from an ameningeal nerve lesion. 186 THK BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. Broadly speaking, the higher the lymphocytosis, the greater the chance that the lesion is meningeal. Plasma cells and embryo Ijnnphocytes are occasionally to be foimd in syphilitic degenerative lesions. Endothelial cells are often to be found in syphilitic meningeal lesions. As already stated, from a cytological diagnosis alone, syphilis must not be diagnosed, unless a thorough clinical examination has excluded all other causes. From a cytological examination alone, it is almost impossible to differentiate a degenerative from a meningeal lesion ; but weighed in the balance with other points, a cell count is a very helpful factor in the differentiation of the two conditions. A h'mphocytosis may occur very early in syphilis, even before a positive Wasser- mann reaction in the blood is obtained. The fact that there is no lymphoc3'tosis in the cerebro-spinal fluid does not exclude latent syphilis, because I have had cases in the latent stage of the disease which had a normal cerebro-spinal fluid, but which developed a degenerative encephalitis later. A case of degenerative encephalitis during the remission period, and a case of quiescent or cured degenerative myelitis may have a normal cerebro-spinal fluid. In many cases of isolated Argyll-Robertson pupils, the cerebro-spinal fluid may be normal. This is an important point, since it is considered that a patient with Argyll-Robertson pupils, or pupils in which the accommodation reflex has vanished as well, is sure to develop a degenerative condition later. Within the last few years I have had eleven cases of pin point pupils, which reacted to neither light nor to accommodation, which had been present for years, in seven of which the cerebro-spinal fluid was normal. None of the eleven have, to my knowledge, developed a widespread degenerative lesion. I do not think therefore, if a patient has an isolated pupil symptom and no pathological changes in his cerebro-spinal fluid, that there is any necessity to put him under treatment. In many cases of pure arterial lesions, such as hemiplegia and paraplegia, the cerebro-spinal fluid is normal. The interesting question which now arises is. What is the origin of the cells that one finds in the cerebro-spinal fluid ? At present there are two opinions : (1) That they come from the blood-vessels ; (2) that they come from the meninges. The fact that more cells are to be found in meningeal than in arterial lesions, the fact that they are to be found in very early cases of syphilis when it is known that the meninges are infected, the fact that they may be absent in such conditions as hemiplegia and paraplegia, form sufficient proof for assuming that most of the EXAMINATION OF THE CEREBRO-SPINAL FLUID. 187 cells, at auy rate, originate from the meninges. In severe meningeal lesions, endo- thelial cells may be met with, and it is in endothelial cells that lymphocytes have origin. Therefore, instead of saying that lymphocytes in the cerebro- spinal fluid come from the meninges, it would be more correct to say that most of them originate from the endothelial cells of the lymphatics situated in the meninges. The reason why plasma cells and embryo lymphocytes are more frequently to be found in the late parenchymatous syphilitic lesions than in the earlier meningeal lesions, is doubtless due to the fact that the protective capacity of the host is strained to a greater action in the former. The protective ferment action of a lymphocyte is increased in the cell to which it gives rise, viz., the plasma cell, hence the presence of the plasma cell. The call upon the lymphocyte would be greater, or better to say, more concentrated, therefore the answer would be not so much an increase in the number of lymphocytes , but a greater call upon their progenitors, viz., the embryo lymphocytes, hence the explanation of their presence. These cells probably originate from the lymphatics of the nerve tissue. The influence of treatment is more marked upon the pleocytosis than upon the protein content, or upon the Wassermann reaction. Intravenous injections of salvarsan, and even vigorous treatment with mercurial inunctions, may cause a lymphocytosis to disappear, that is, provided the lesion is a meningeal one. The lymphocytosis in ameningeal lesions may diminish, as the result of treatment, especially after the intrathecal injections of salvarsanised serum, but in most cases, it ultimately returns, and in no case is the proportionate disappearance of the cells so great as it is in the meningeal lesions. Protein. The next important step is to examine the protein content. Neither an excess of albumin nor of globulin, alone proves that the lesion under question is syphilitic. The globulin can be detected by an opalescent ring which forms at the point of contact, when a saturated solution of ammonium sulphate is added to the cerebro- spinal fluid. This ring should appear within three minutes. When the ring has appeared, the tube can be shaken, when the whole contents become opaque. This constitutes Nomie-Apelt's* reaction, phase 1. If all the globulin is precipitated by ammonium sulphate and separated oflt, the fluid left will, if albumin is present, give a ring with nitric acid — Heller's test. This constitutes phase 2. The globulin is also precipitated by distilled water, partly because the electrolytes which are attached to it are separated ofl'. If a single drop of a con- centrated solution of sodium chloride is added, the opalescence caused by the distilled 188 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. water disappears. The globulin also gives a precipitate with acetic acid and potassium ferrocyanide. Noguchis^ test. — This test depends upon the precipitation of globulin which occurs when butyric acid is added to the cerebro-spinal fluid, and it is carried out as follows : — To 0"1 c.c. of cerebro-spinal fluid, add 0"5 c.c. of a 10 per cent, solution of butyric acid in physiological salt solution ; boil this for a short time, and quickly add a quantity of a normal solution of sodium hydroxide equal to the amount of the cerebro-spinal fluid used. Then the mixture is boiled again for a few seconds. An increase of protein is characterised by the appearance of a granular or flocculent precipitate. If the amount of protein is very small, or, in other words, normal, the precipitate does not appear until after standing for two hours. Lange's method.^ — This is also called the CtoMsoI reaction. Globulin has the power of adsorbing, and thereby precipitating gold, when the metal is in a colloidal condition. The protein possesses this action only so long as its electrolytes are still attached to it, hence, when this test is used, it must be carried out as soon as possible after the cerebro-spinal fluid has been withdrawn. The degree of j)re- cipitation of the colloidal gold will natural!}' alter the colour of the fluid in which it was suspended, and the more globulin there is, the more gold there will be preci- pitated, hence the reaction is gauged by the colour of the solution. The colloidal gold suspension is prepared as follows : — In a 1000 c.c. flat- bottom flask of best Jena glass place 500 c.c. of distilled water, which has been freshly prepared in vacuo {vide Chapter XXVIII.). Add to the water 5 c.c. of a 2 per cent, solution of potassium carbonate, and almost immediately afterwards add^5 c.c. of a 1 per cent, solution of gold chloride. The gold chloride must be chemically pm-e, and it must be dissolved in protein free distilled water. Then boil the contents of the flask quickly, just until bubbles appear, remove the flame from the flask, add 3 '75 c.c. of a 1 per cent, solution of formaldehyde, and shake well until the fluid becomes a deep cherry red. On standing, the solution should become absolutely clear and a deep red. It keeps fairly well, but it is wiser to use only freshly prepared solutions. The reagent may be called the Goldsol indicator. In order to perform the test, obtain a test-tube rack holding ten test tubes. Into each tube, with the exception of the first, put 1 c.c. of a 0'4 per cent, solution of sodium chloride. In tube No. 1 place 1'8 c.c. of the salt solution and 0'2 c.c. of the cerebro-spinal fluid, mix and remove 1 c.c. of the fluid. Place this in tube No. 2, and continue the procedure until each tube receives a gradually weaker dilution of cerebro-spinal fluid. Now add to each tube 5 c.c. of the Goldsol indicator, and mix well. Let the tubes stand for twenty-four hours at room EXAMINATION OF THE CEREBRO-SPINAL FLUID. 189 temperature, and then examine them. A clear sohition indicates a positive reaction. The gradation of colours is from an absolutely colourless to a red fluid. Kaplan's method.' — In a test tube 1 cm. wide and 8 cm. long, is placed 0'5 c.c. of cerebro-spinal fluid. It is twice heated up to boiling, then three drops of a 5 per cent, solution of butyric acid in normal saline are added, followed immediately by 0'5 c.c. of a saturated solution of ammonium sidphate, and the fluid set aside for twenty minutes. In adding the ammonium sulphate solution, care must be taken to allow it to flow under the solution and not to mix with the fluid above it. After about, twenty minutes, a protein excess manifests itself, in the form of a thick granular ring. "WTien no granular ring forms, the fluid may be regarded as normal. Every fluid that shows tiie ring is further tested as to the intensity of the excess. For this purpose, four other tubes receive each O'l, 0'2, 0'3, and 0'4 c.c. of cerebro-spinal fluid respectively, and each in turn is brought up to the 0'5 c.c. mark with distilled water. The same procedure is then followed as for the first tube. The quantity of protein matter permitting a ring to appear in the tube containing only O'l c.c. of spinal flitid is designated as O'l excess, and marks the greatest degree of increase. Zaloziecki^ recommends the Pandy reaction, which he performs as follows : — From 80 to 100 c.c. of acidum carbolicum liquefactum purissimum are brought up to 1 litre with distilled water. The mixture is shaken thoroughly and placed in an incubator for a few hours. After complete clarification at room temperature, which requires several days, the clear supernatant fluid is removed and used as the reagent. A drop of the cerebro-spinal fluid is permitted to trickle down the side of a watch-glassful of the reagent. A mild reaction is characterised by the appear- ance of a cloudiness in the liquid ; a strong reaction shows a white precipitate. This reaction is chiefly produced by globulin, but may also be obtained with albumin. In cerebro-spinal syphilis, degenerative myelitis, and degenerative encephalitis, both the albumin and globxdin are increased, but, in the different conditions, the ratio between the two varies. In cerebro-spinal syphilis, the albumin is increased more than is the case in degenerative myelitis and degenerative encephalitis. Therefore a meningeal lesion can easily be distinguished from an ameningeal lesion, if the globulin is separated off and the albumin is tested quantitatively with nitric acid. According to Bisgaard', phase 2 is practically never present in degenerative encephalitis or degenerative myelitis, if the cerebro-spinal fluid is diluted more than 1 in 20 ; but in cases of meningitis, whether of meningococcal, tubercular, or syphilitic origin, phase 2 may be positive up to a dilution of 1 in 200. Oddly enough, very little attention has been paid to the albumin content of the 190 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. cerebro-spiiial fluid, coiisequeutl)^ I should like to make a few observations of my own. Whenever the pressure is increased, there always appears to be an excess of albumin. Intravenous injections of salvarsan raise the albumin content con- siderably. Occasionally a cerebro-spinal fluid which gave a ring with ammonium sulphate will, after the first (and much less frequently after the second) intrasjiinal injection of salvarsanised serum, fail to give this test, but in such instances the albumin content is usually raised. After the third injection, the globulin test becomes positive again, and the albumin content duninishes. I cannot help thinking that there is a very close connection existing between albumin and globulin — indeed, that albumin is a precursor of globulin, as it is practically impossible to draw a hard and fast line between the two, and to tell where albumin ends and globulin begins. From the several examinations I have made, I am sure that there may be a trace of globulin in normal cerebro-spinal fluid. When the central nervous system first becomes infected in syphilis, the albumin content increases, then the globulin increases, and, as time goes on, the more the globulin increases, the less the albumin increases, until in some of the late and very severe cases, the albumin content may be below the normal. Without first precipitating the globulin, the albumin content can by experience be gauged fairly accurately, by a naked eye examination of the precipitate caused by the addition of a drop or two of a saturated solution of salicyl-sulphonic acid. Naturally, such a test is valueless, when the globulin content is raised. If the precipitate caused by salicyl-sulphonic acid is compared side by side with that caused by the addition of one or two drops of a 5 per cent, solution of potassium ferrocyanide, to which one or two drops of a 30 per cent, solution of acetic acid have previously been added, a very vahiable test is obtained. The addition of acetic acid and potassium ferrocyanide precipitates mainly the globulin, and is an exceedingly delicate test. Normal cerebro-spinal fluid becomes opaque with salicyl-sulphonic acid, and less opaque with acetic acid and potassium ferrocyanide, but the dift'erence is slight. As the albumin is increased, the opacity of the s^alicyl- sulphonic acid tube increases, while the acetic acid and potassium ferrocyanide tube remains about the same ; anyhow, the difference between the two becomes very marked. If the opacity in the salicyl-sulphonic acid tube becomes a flocculent or a heavy precipitate, it is tolerably certain that the globulin is increased, and that it will give a ring with ammonium sulphate. If the acetic acid and potassium ferrocyanide tube is left, it gradually assumes a Berlin blue colour, owing to the reduction that has taken place. The rapidity with which this Berlin blue colour appears, varies, but it always appears more quickly, the more globulin that is present. I have not yet fully EXAMIXATION OF THE CEREBRO-SPIXAL FLUID. 191 worked out the significance of the reducing action of the cerebro-spinal fluid, but it is a point which might prove of vahie. One would first have to determine whether the increase of the reducing action was due to an increase of the normal reducing substance, in the cerebro-spinal fluid, or to an increase of the globulin, which we know has a strong reducing action. The more lipoid that is attached to the globulin, the greater its reducing action, hence the reason whj' the reducing action is more marked in degenerative than in non-degenerative lesions. Two tests for estimating the reducing action, are, the intensity of the blue colour, and the rapidity with which it is produced by the addition of a drop or two of an alcoholic solution of alkali blue which has been decolourised with potassium hydrate ; the intensity and rate of production of colour, when a piece of gold chloride paper is left in the fluid. The reducing action may also be tested for with Fehling's reagent. The reader will be aware that, a few lines back, I drew attention to the fact that the globulin test might fail, after the first or second injection of salvarsanised serum. By the unwary, this is assumed as showing that one or two injections have cured the patient. Not only ma}^ the globulin disappear, but the Wassermann reaction may become negative. Exactly the same thing may happen with the serum from a late case of syphilis (vide Chapter XI). The decrease in globulin and the negative Wassermann reaction is smiply due to the fact, that the existing lipoid-globulin particles become hydrolysed, when salvarsan or salvarsanised serum is first given. This is the explanation of the so-called negative phase. Improvement only follows when the negative phase has passed off, and this is due to the destruction of the old lipoid-globulin particles, and to the formation of new ones. It is, moreover, an indication for further treatment, not for a stoppage of the same. The excess of protein in the cerebro-spinal fluid probably comes from three sources : (1) leucocytes ; (2) epithelial cells of the choroid plexus ; (.3) nerve cells. The reason why more globulin is found in degenerative lesions, is doubtless due to the fact that some of the lymphocytes have formed plasma cells, the proto- plasm of which is richer in globulin, because the cells of the choroid plexus and nerve cells are more involved, and both are rich in lipoid-globulin adsorption com- plexes. From what has been said, one would expect to find, in some of the degenerative cases, that the globulin in the cerebro-spinal fluid existed in the form of lipoid-globulin, which happens to be the case, and what has just been called globulin in degenerative lesions is probably more often lipoid-globulin, than pure serum-globulin. Here again there is no clear line of demarcation between the two. The larger the amount of lipoid which is attached to the globulin, the stronger N 192 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. is the oxydase reaction of the cerebro-spinal fluid. Now, the oxydase reaction is practically always present in ameningeal lesions, and not in meningeal lesions, which is strong proof of my assumption, that lipoid-globulins are more abundant in the cerebro-spinal fluid from cases of degenerative encephalitis, than from cases of cerebro-spinal meningitis. According to Bisgaard,* the total nitrogen in normal cerebro-spinal fluid varies from O'OIO to 0"025 per cent., while in degenerative encephalitis it varies from 0'0144 to 0"0345 per cent. Cases of Tumor cerebri, Abscessus cerebri, and juvenile degenerative encephalitis show the same nitrogen content as ordinary degenerative encephalitis. The same may be said of degenerative myelitis and disseminated sclerosis. Lues cerebri, on the other hand, shows a higher N-value. Acute meningitis, of whatever origin, shows the highest N-value, as the following three cases from Bisgaard's® table prove : — Lues cerebro-spinalis . . . . . . . . . . " 0582 per cent. Streptococcal meningitis .. .. .. .. 0'2260 ,, Tubercular meningitis . . . . . . . . . . 0' 1164 ,, The acuter the meningitis, the higher the N-value, and the greater the ratio of the albumin to the globulin ; therefore, the chief excess of the N comes from the albumin, and not from the globulin. During the agony of death, and for some time after, Bisgaard found that the N-value of the cerebro-spinal fluid was very much increased, but that the excess was mainly non-protein nitrogen. The Wassermann reaction is enormously increased in the cerebro-spinal fluid just before death and for some time afterwards — in fact, a positive reaction may be obtained with a fluid which was, during life, normal. The lipoids are very much increased in the cerebro-spinal fluid under the above conditions. As I have shown that a ratio exists between the amount of lipoid ^-idiich is attached to the globulin and the strength of the Wassermann reaction, it is highly probable that this non-protein nitrogen conies from nitrogen containing phosphatids which displace the NH, groups of the protein molecule, and thereby cause a positive Wassermann reaction. Therefore some relationship exists between the N-value and the Wassermann reaction. This interesting part of my work is discussed more fully, in the chapter dealing with the Wassermann reaction (Chapter X). The influence of treatment upon the protein content of the cerebro-spinal fluid is variable. Broadly speaking, in meningeal lesions, when salvarsan is given EXAMINATION OF THE CEREBRO-SPINAL FLUID. 19:3 intravenously and intrathecally, the pathological excess may be made to disappear. In ameningeal lesions, although treatment may cause a diminution in the amount of globulin, it practically never results in causing its entire removal. At present, no great importance attaches to the fact that, in syphilitic lesions of the central nervous system, the pressure of the cerebro-spinal fluid is often raised. The only other test which need be considered is the AVassermann reaction. Wassermann Reaction. A\Tiile the Wassermann reaction mil tell you that the condition under question is certainly syphilitic, and no other test will do this, it will not help alone in differentiating the various syphilitic lesions. Hence the reason why, when the cerebro-spinal fluid is examined, several tests are used. As a matter of fact, in practically every case, all we want to know is whether the condition is syphilitic or not, and this can only be answered by the Wassermann reaction. As to whether the condition is a degenerative one or not, can practically only be settled in difficult cases by the action of treatment. An important point to remember is, that a Wassennann reaction in the cerebro-spinal fluid should never be returned as negative, until the fluid has been used in the strength of 1,000 percent, {i.e., 1 c.c. instead of 1/lOth c.c. of a 1 in 10 dilution). Since the complement fixing capacity of the cerebro-spinal fluid is practically nil, a 1,000 per cent, strength can be used without risk. Wassermann^" has recently shown that the reagin, i.e., the reacting substance of the cerebro-spinal fluid, comes from the Ipnphocytcs. This can be only partly true, since treatment may cause the lymphocytosis to vanish, and yet the positive Wassermann reaction will remain so. Again, the Wassermann reaction is most positive in parenchymatous lesions, while the Ipnphocytosis is greatest in the meningeal lesions. The Wassermann reaction may be increased post-mortem, without there being a corresponding increase in the number of lymphocytes. The Wassermann reaction is increased when the nitrogen-containing phos- phatids are increased ; when there is the greatest change in the cells of the choroid plexus, which are rich in N-containing phosphatids ; when there is the greatest destruction of Nissl's granules, which contain N-containing phosphatids. Therefore, although the reagin does partly come from the lymphoc3rtes, it also comes from the choroid plexus and nerve cells. The reagin in the blood cannot get into the cerebro-spinal fluid, but the reverse can happen, as the following case shows : — Case 25. — A patient consulted me once a year for three years. On these three n2 194 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. occasions, I coiild find no signs of syphilis, and the Wassermann reaction was invariably negative. A few months after the last visit, symptoms of degenerative encephalitis set in. The diagnosis was confirmed by an examination of the cerebro- spinal fluid, and at the same time the AVassermann reaction in the blood was strongly positive. Since then, I have been able to confirm this point in otber cases, and it may occur in any degenerative lesion, but it is more likely to occur in degenerative encephalitis than in degenerative myelitis. It would be as well now to discuss the value of the cerebro-spinal fluid finding, compared with the clinical condition, because an examination of the cerebro-spinal fluid will assist in differentiating a meningeal from an ameningeal lesion, or a degenerative from a non-degenerative lesion. The clinical conditions will be mentioned in the order in which they appear in the table in Chapter XXIII. Brain. Meningeal. Pachymeningitis and Leptomeningitis. — Protein excess, but the excess is mainlj- albumin, although -the globulin is increased as well. The cell count is high, and mainly consists of lymphocji^es, polymorj)honuclear leucocytes, and endothelial cells. The Wassermann reaction is present in the high percentage solutions only. The Wassermann reaction in the blood is not infrequently negative. Meningo-encephalitis. — Protein excess, but the excess is mainly globulin, although the albumin is increased as well. The ratio between the albumin and globulin will depend upon how meningeal or how encephalitic the process is. The cell count is not so high as the process becomes more encephalitic, but the ratio between the lymphocytes and polymorphonuclear leucocytes is altered, owing to the fact that the excess of the former is maintained, while the latter are diminished. The absence of endothelial cells points to an involvement of nerve tissue. The Wassermann reaction is positive in weaker dilutions of the cerebro-spinal fluid, and the same ratio does not exist between the negativity of the blood and the positivity of the cerebro-spinal fluid. In other words, when nerve tissue becomes involved, the positive Wassermann reaction in the blood tends to reappear. Degenerative encephalitis. — Protein excess, but of the globulin only ; the albumin may be diminished. The globulin maj- be a lipoid-globulin, hence the oxydase reaction is often present. The oxydase reaction (amino-acidases) can be tested by adding solutions of the amino-acids to the cerebro-spinal fluid, incubating over EXAMINATION OF THE CEREBRO-SPINAL FLUID. 195 night, and noting the changes in colour, next morning. The cell content is increased, but not to a marked degree, the cells are mainly lymphocytes, but plasma cells and embryo lymphocytes may be met with. The Wassermann reaction is, as a rule, positive in all dilutions, and the Wassermann reaction of the blood, too, is almost invariably positive. Ameningeal. Pure arterial lesions, without involvement of nerve substance. — The cerebro- spinal fluid is generally normal. Arterial lesions, ivith involvement of nerve substance. — If the nerve substance is involved mechanically, as happens in a haemorrhage from a late arterio-sclerotic lesion, the cerebro-spinal fluid is, as a rule, normal. In most cases of gummata, the pathological changes are what one might call borderline changes, i.e., the cell count may be 12 or 15 per c.mm., doubt exists as to whether there is a protein excess or not. The Wassermann reaction in the blood is generally positive, and it may or may not be positive in the cerebro-spinal fluid. It often happens that the cerebro-spinal fluid is normal, in cases of Gumma cerebri. In cases of degenerative encephalitis, at first there may be practically no changes ; then occurs a protein excess which is mainly globulin. The cell count is never high ; often it does not exceed 25 cells per c.mm., and then consists almost invariably of lymphocytes only. The oxydase reaction is generally negative, and so may the Wassermann reaction be. Even in advanced cases, the Wassermann reaction may only be positive when high percentage solutions are used. In the blood, the Wassermann reaction is often negative, at any rate in the early stage of the trouble. The pathological changes may easily disappear under intrathecal injections of salvarsanised serum, in spite of which the patient rapidly becomes demented and dies. In the other form of degenerative encephalitis, the pathological changes are not readily influenced by intrathecal injections, although the clinical condition may improve. Therefore, an examination of the cerebro-spinal fluid ^"ill often help one to differentiate a degenerative encephalitis of meningeal origin from a case of ameningeal origin. Cord. What I have said about the brain, applies equally well to the cord, therefore recapitulation is unnecessary, but there are one or two differences which require special mention. 196 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. In cases of degenerative n\yelitis of meningeal origin, the oxydase reaction is not present so often as it is in cases of degenerative encephalitis, and it is never very marked, when it is present. Furthermore, this form of degenerative myelitis has not the same influence in causing a positive Wassermann reaction in the blood as its intracranial cogener has, and, speaking generally, the Wassermann reaction is not so often positive in the cerebro-spinal fluid. A^'hen a more or less normal cerebro-spinal fluid is found in a case of degenerative encephalitis or myelitis, the observer nmst always ask himself, whether he is dealing with a patient in the quiescent stage, in the former ; or with a patient whose process has undergone a spontaneous cure, in the latter. Spontaneous cure of degenerative encephalitis probably does not exist, while spontaneous cure of degenerative myelitis occurs in quite a high percentage of cases, and this is doubtless one of the reasons, why so many observers state that the Wassermann reaction is not so constantly positive in the cerebro-spinal fluid, in cases of degenerative myelitis, as it is in cases of degenerative encephalitis. Spontaneous cure of degenerative m^^elitis is usually overlooked, for the simple reason that the clinical signs and symptoms of the lesion persist — it is forgotten for the time being that nerve tissue does not regenerate ; therefore once damaged, always damaged. An extremely interesting and useful point, which a pathological examination of the cerebro-spinal fluid reveals, is the persistence of a positive Wassermann reaction, in spite of the most drastic and prolonged treatment. In such cases, one can tell that the patient has a degenerative lesion of meningeal origin. It does not mean that there are actually organisms present, or that the disease is progressive, or even active. This persistent Wassermann reaction may be due to the chemical products which emanate from the disintegration of nerve cell, and fibres, or it may be due to that continued production of anti- bodies, to which the cells give rise, in spite of the fact that there are no more organisms to attack. This persistent production of antibodies is very commonly seen in the systemic portion, and it accounts for the Wassermann-fast reactions which may be obtained in patients, who are in the best of health and show no symptoms. Kaplan's' goldsol curves will materially assist one in making a diagnosis of a degenerative lesion. The colour of the gold solution, as has already been mentioned, is a deep red, and as it is absolutely necessary that it should be of no other colour, it is a very good plan to control it. The best way to control the colour is as follows : — In an ordinary |-inch test tube place 15 c.c. of a decinormal sodium hydroxide solution; add 0'2 c.c. of a 0'5 jier cent, solution of Congo red and EXAMINATION OF THE CEREBRO-SPINAL FLUID. 197 0'3 c.c. of a 1 per cent, solution of alizarin. The intensity and nuance of the colour in the test-tube, as viewed by transmitted light, correspond exactly with the depth and colour of the indicator in the flask, viewed in a similar way. Kaplan sets up a set of 9 to 12 tubes containing dilutions of cerebro-spinal fluid from 1 : 10 to 1 : 2560. The goldsol is placed in each tube, and is permitted to remain at room temperature over night. The next morning, some tubes will show definite colour changes, which he designates as follows : — Complete precipitation, Huid colourless The slightest tinge of steel-grey Deeper grey to blue A reddish-blue or bluish-red ... A red colour slightly different from the original colour No change in colour 4 3 2 1 The numbers are arranged from 5 down to ; the dilutions are arranged from left to right, beginning with the 1 : 10 tube : — 3 2 1 o o o o o o 00 o 0-1 r-< L., and reflexes of R. < L. C.S.F. before treatment. Pressure not raised. Lymphocytes 14 per c.mm. Ring and opacity with ammonium sulphate. Dense opacity with salicyl-sulphonic acid. Marked turbidity with acetic acid and potassium ferrocyanide. Goldsol reaction positive. C.S.F. tested ten days after second intravenous injection of neo-salvarsan. Pressure enormously raised. Lymphocytosis 130 per c.mm. Fainter ring and opacity with ammonium sulphate. Dense precipitate with salicyl-sulphonic acid. Goldsol reaction negative. Salvarsan had temporarily destroyed the specific lipoid-globulin, and the formation of the new lipoid-globulin was being preceded by a tremendous increase of the albumin. Case 36. — Treatment begun before patient reached generalised stage. C.S.F. examined one week after the seventh intravenous injection of " 914." Pressure not raised. No lymphocytosis. No ring or opacity with ammonium sulphate. Fairly dense opacity with salicyl-sulphonic acid. Goldsol reaction negative. In this case, slight increase of albumin due to the salvarsan. Summary. — That syphilitic invasion of the central nervous S3'stem occurs during the generalisation stage, and any lesions which appear later, date from this invasion. The administration of treatment will often provoke pathological changes in the cerebro-spinal fluid, but, before the changes are considered to be pathological. • THE BIOLOGY OF SYPHILIS OF THE NERVOUS SYSTEM. 207 it must be remembered that salvarsan has the action of raising the ]iressure, increasing the albumin and the globulin, and slightly raising the cell count in a normal individual. The duration of this action of salvarsan has yet to be determined. (b) The Paths and Sites of Infection of the Syphilitic Lesions of the Central Nervous System. The apparently slow onset of nervous lesions appears to have induced the belief that the infection would probably originate by passage along the nerves or their lymphatics, and not b}' way of the blood stream. A good deal of experimental work has been carried out, with a view to determine which of these paths is taken by the organism, in its journey to the nervous system. While realising that the nervous path is a possible channel of infection, I believe that enough attention has not been devoted to the possibility of infection by means of the general systemic circulation, and I propose to advance reasons for this opinion. I have gradually reached the view, namely, that the infection of the central nervous system is usually, if not always, haematogenous in origin. Before, however, putting forward my own point of view, the experimental work dealing with infection by a neurogenic channel will be considered. The route of infection of the central nervous system has been worked at experimentally by Weygandt and Jakob. ^ These observers injected syphilitic material into rabbits, using both the testicular and intravenous routes. They found that 50 per cent, of the animals showed changes in the central nervous system, and that these changes were the same, whichever route was adopted. The lesions fomid can be classified under three main headings, in order of frequency, viz. : (1) leptomeningitis of the brain and cord ; (2) inflammatory changes in the perineural sheaths of nerve roots as they left the cord ; and (3) inflammatory changes in the connective tissue coverings of the peripheral nerves. In all these lesions, the blood-vessels showed inflammatory changes, and were surrounded with lymphocytes and plasma cells. Some blood-vessels in this con- dition were also to be seen, in the brain and cord. In a few cases, the vessels in the brain cortex showed marked inflammatory changes ; and scattered areas of cellular infiltration occurred in the nerve substance, and a marked proliferation of glial cells, without any changes in the pia-arachnoid. In a minority of these cases, the areas of cellular infiltration in the nerve substance showed considerable resemblance to gummata. o 208 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. The two points in Weygandt and Jakob's work that are most striking are: (1) that although inflammatory changes were to be found in the perineural sheaths of nerves, it was around the blood-vessels in the connective tissue that they were most marked ; and (2) that the lesions of the central nervous system were the same, whether they were from a testicular or an intravenous infection. In England, owing to the work of Orr and Rows,- many neurologists believe that an important path, along which infection is carried to the nervous system, is the lymphatic system of the peripheral nerves. It should be stated first, that Orr and Rows did not work vnth. syphilis, and only presumed what might occm- in this disease, from the knowledge they had gained in watching the paths along which toxines spread, from injected staphylococcic material in rabbits. Orr and Rows concluded from these observations : — (1) That the lesion in the spinal cord always corresponded with the nerve supply of the infective focus. (2) That the degeneration of the intramedullarj- portion of the spinal roots commenced at the point where the neurilemma sheath was lost. (3) That the posterior root entry zone was always most affected. (4) That, as examination of the extramedullary portion of the nerves yielded a negative result, it seemed correct to assume that toxines could, in certain cases, ascend along the perineural lymphatics, ^vithout producing parenchymatous changes in the nerves. In their experimental work, they placed a celloidin capsule containing a broth culture of Staphylococcus albus in contact with the nerve, and found that inflam- matory phenomena could be traced upwards to the posterior root ganglion, and beyond it, into the spinal roots. Orr and Rows infection by the haematogenous route also produced change;, which allowed them to separate, by histological means, a haematogenous from a lymphogenous lesion. In lymphogenous infection they found : — (1) Inflammatory reaction of the cells of the fixed connective tissue. (2) Proliferation of the cells of the adventitial sheath of the veins aM capil- laries. (3) The appearance of scavenger cells where the myelin was disintegrated. (4) Nerve cell degeneration and neuronophagic phenomena. In haematogenous infection they found : — (1) The most highly developed structure — the nerve cell — suffering least of all. (2) A primary degeneration of the myelin sheath around the margin of the cord, and on either side of the postero-median septum. (3) That the in3-elin degeneration was greatest in the upper part of the cord. THE BIOLOGY OF SYPHILIS OF THE NERVOUS SYSTEM. 209 (4) Marked oedema of the cord. (5) The vessel walls showing hyalin degeneration, and containing thrombi of the same nature. From these observations, Orr and Rows offer the opinion that tabes dorsalis and general paralysis of the insane are lymphogenous infections, and they state that the distribution of the former, and the histological characters of both, are similar to those produced by infection of the lymph stream of nerves. The points raised by these investigations may now be considered in somewhat greater detail. Orr and Rows state : — (1) That the lesion in the spinal cord always corresponded with the nerve supply of the infective focus. It may, however, be pointed out, that we do not find that digital or cephalic chancres are more prone to be followed by degenerative encephalitis or degenerative myelitis of the cer\4cal region than are genital chancres. (2) They found that the degeneration of the intramedullary portion of the spinal roots commenced at the point where the neurilemma sheath was lost. This part is, however, frequently not affected in degenerative myelitis, but it would be affected, were the mode of infection an ascending one, by means of a nerve root. (3) That the posterior root entry zone was always most affected. In degenera- tive myelitis, however, this part may not be affected at all. (4) That as examination of the extramedullary portion of the nerves yielded a negative result, it seemed correct to assume that toxines could, in certain cases, ascend along the perineural lymphatics without producing parenchymatous changes in the nerves. In syphilis of the nervous system, we are dealing with live organisms, not with their toxines. Although highly improbable that a leptomeningitis ma)' result in this way, it is theoretically possible. It appears to me, that Orr and Rows observations are hardly in accordance with established clinical facts, and that it would be an error to lay too much stress upon them. Further, I have been unable to distinguish any differences which could be attributed to variation of route, in a large number of cases of degenerative ence- phalitis which I have examined histological!}', and I am not inclined to believe that the routes, whether haematogenous or lymphogenous, can be differentiated. On the other hand, it is possible to distinguish whether the infection occurred primarih' in the meninges, or in the brain substance. If the brain from a case of degenerative encephalitis be examined, pro- vided the meninges still show signs of inflammation, vessels will be seen running 02 210 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. into the brain substance from the pia mater, and it is mostly in the wails of these vessels that the phases of the leucocytozoon are to be found (Plate 12 (1) ). The main exception to the above rule is, that the Spirochaeta pallida does not necessarily follow the route taken by the vessels ; it may wander and be found anywhere. In most cases of degenerative encephalitis, acute or chronic inflammatory changes are to be found in the pia-arachnoid. In early cases, the inflammation in the leptomeninx may be acute, and acute inflammatory changes are to be found in the superficial part of the grey matter. In both situations, one finds the phases of the leucocytozoon (Plate 33 (1) ), but in only the latter are the spirochaetae to be found. In late cases, the acute inflammation has reached the white matter, in which the phases of the leucocytozoon can also be demonstrated. In some cases of degenerative encephalitis, on the other hand, no meningeal changes are to be found. In these cases the process begins in the brain substance itself. Probably, in the majority of the cases of syphilis, the organisms get into the meninges by means of the blood-vessels. They may give rise to no symptoms ; their spread may not even be noticed, but, when they later give rise to symptoms, degenerative myelitis or encephalitis is the result. My reasons for thinking that these two degenerative affections arise in probably the greater majority of the cases, the smaller minority being ameningeal in origin, by a direct extension of the organisms from the meninges, are the following : — The meninges of the brain are most closely attached to the brain substance over the cortex, and, in cases of degenerative encephalitis, the blood-vessels run directly from the meninges into the nerve tissue. In all cases of degenerative encephalitis, the morbid changes are limited practically to the cortex, and, the earlier the case, the nearer to the surface are the histological changes to be found ; while in late cases, only the superficial jjart of the cortex may show the results of inflammation, the recent areas being deeply situated. In the case of the cord, the blood-vessels run from the meninges along the septum posticum, into the posterior columns. Hence the ease Mith which the organisms in the meninges can invade the cord and produce degenerative "myelitis, which, in nearly all cases, is a lesion of the posterior part of the cord. Early syphilitic lesions of the cord usually affect the anterior part, and the myelitis which results is, in my opinion, an endarteritic lesion, analogous to that endarteritic lesion of the brain which causes hemiplegia, itself a frequent early symptom of syphilis. The anterior surface of the cord corresponds to the base of the brain : the blood supply to both comes from the same source. There is no anterior meningeal ligament along which organisms can spread ; the main blood-vessel is free. Plate 33. A section through the pia- arachnoid covtring the cerebral cortex from a case of degenerative encephalitis. The pha.se of the leucocytozoon depicted, is a female gametocyte, containing one blepharopla.st. Schematic repre&ehtation of the various phases' of the Leucocytozoon siiphihdis. / mi' STAGE 'Q f § Wi A £" 'W" ..'^ ^ (^ •^ h I Facinj p. aid. Platb 33. '.y, in T.be m ■- i. .■ .-voiuiis, the org .Li'»*9iq3|yno03iO*>^oo3iref aril lo 'jKcdq oilT .8i*iifirfq<»yo3 aviJeiojisgabiio i^ntb KoosoS\j»r \ ASEXUAL STAGE ^^\ © © > ©•'@ 1/ •6 ~®-— 0- Plate 33. THE BIOLOGY OF SYPHILIS OF THE NERVOUS SYSTEM. 211 Therefore, one might imagine a lesion of the anterior part of the cord to be of the nature of an endarteritis. The early endarteritic lesions of syphilis are peculiarly localised, and they are due to the direct local action of the organism, which starts its life-cycle in the coats of the vessel, a point I have been able to follow. As the cycle may start in one part, and not necessarily in the whole circumference of the vessel, the unipolar changes to be met with are accounted for. In time, the organism may spread beyond the vessel into the nerve substance, and, if it did so in the anterior part of the cord, it would immediately cause nerve degeneration. This is probably the pathology of those late anterior horn lesions which are occasionally to be met with in syphilis. Lateral column lesions are also be to met with, although very rarely, in spite of the close connection this part of the cord has with the meninges, through the ligamerita denticulata. The reason is that there is no direct blood supply between the two at this point. Direct extension of the organisms into the central nervous system, by way of the peripheral nerve trunks, most probably never occurs, for the simple reason that lesions of nerves, along which the organisms have spread, give rise to symptoms early in the disease. Moreover, peripheral syphilitic nerve lesions affect both motor and sensory nerves. Again, a posterior column lesion frequently exists, without a corresponding lesion in the posterior root ganglion, and I am unaware that syphilitic root neuritis is followed by degenerative myelitis (tabes). Finally, early cranial nerve lesions, which arise at the time when almost every nook and crevice in the body is being infested with organisms, are undoubtedly secondary to inflammation of the meninges surrounding them. The nerves most commonly affected are the second, eighth and seventh, all nerves which have to go through small bony foramina. Therefore, any increase in the bulk of the meninges would make the foramina smaller still, and the nerves would degenerate by the increased pressure produced thereby. To prove that these early cranial nerve lesions are primarily meningeal in origin, one only has to examine the cerebro-spinal fluid, when often as many as 600 cells per c.mm. are to be found. Furthermore, the administration of adequate treatment, provided it is prescribed early enough, completely and quickly cures the lesion, which would certainly not be the case if the infection were primarily in the nerve. One of the chief reasons observers give to explain the occurrence of degenerative myelitis, from a spread of the organisms along the posterior root sheaths, is that the Spirochaeta pallida has been found in sections of a chancre in the nerves of the skin. 212 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. In my opinion, such an occurrence is a coincidence, since the Spirochaeta pallida, owing to its motility, can be found in any tissue. Since the Spirochaeta pallida is not the direct cause of syphilis, its extension along the lymphatic sheaths of the posterior root nerves would not give rise to degenerative myelitis. For symptoms of syphilis to occur, the whole of the life-cycle of the j^rotozoon nnist take place in loco, therefore the spores and the other phases must be present in the brain and spinal cord in cases of degenerative encephalitis and myelitis. I have examined brains from ten cases of degenerative encephalitis, and in nine of them I have found the phases of the leucocytozoon, which mostly occurred in the walls of the blood-vessels, while the Spirochaeta pallida had no particular distribution. There are two points to which I would like to refer, before discussing the subject in hand from other points of \'iew. One is that many cases of degenerative encephalitis die, not from a fresh outbreak of symptoms, or from a fresh development of the spirochaetae, but from a haemorrhagic encephalitis caused by the pneumotoxine, and possibly by other toxines as well. The other point is, that syphilitic affections of nerve tissue may be dependent upon primary venous lesions. The role played by phlebitis in the causation of lesions other than those that can be observed under the skin, is, one might say, quite unknown. A great deal of work is required in this direction, as veins are commonly afEected in syphilis, and syphilitic phlebitis exhibits phenomena which I have not observed in any other disease. A most interesting point which now crops up is, why should degenerative encephahtis and myelitis — two parenchymatous lesions — be, broadly speaking, incurable, while meningeal syphilis is curable ? To my mind, the whole difference depends upon the number of organisms which develop extramurally, i.e., away from the walls of blood-vessels, and over how much nerve matter tlieir development spreads. In the severest cases of degenerative encephalitis all the phases of the leuco- cytozoon can be found scattered about in the nerve substance away from the blood- vessels, while in the early cases, and probabl_y in meningeal syphilis, and in meningo-encephalitis and myelitis they are only found in the walls of the blood- vessels. Moreover, the development of the spirochaetae is very much more pro- nounced in the degenerative lesions, especially is this the case in degenerative encephalitis. They develop more or less independently of the other phases ; they wander away from blood vessels and Ij^mphatics, flourish at the expense of the nerve cells, and cannot be reached by drugs, however given. There is sufficient clinical evidence alone, in favour of an haematogeneous THE BIOLOGY OF SYPHILIS OF THE NERVOUS SYSTEM. 213 origin of syphilitic nervous lesions, without having recourse to experimental work. Hemiplegia and transverse myelitis are true vascular lesions, so are those cases of hacmorrhagic encephalitis occurring either before or after salvarsan. If we ask ourselves what becomes of these early nervous lesions, we shall see that new light will be thrown upon the pathology of the late degenerative encephalitis and myelitis. It must be remembered that there are many cases which are on the verge of developing any one of the above-mentioned vascular lesions, and that the develop- ment is prevented by timely treatment. There must also be many cases in which the spores are present in the vessels, and in those positions in which, should they develop, any one of the above lesions would be produced ; but these cases develop only in later years, when the symptoms are somewhat different. Let us take, first of all, that group of cases in which there have been early vascular nervous lesions, and see what becomes of them. Most recover from the symptoms, provided the treatment is sufficient, early prescribed, and sufficiently drastic. If, on the other hand, the treatment is not prescribed early enough after the onset of the symptoms, and is not sufficiently powerful to kill all the organisms, there is a tendency for the organisms to spread peripherally, just as they do in the skin ; and, should they develop later, it will be in nerve tissue proper, and it will not be merely limited to a blood-vessel, consequently nerve degeneration will follow. Amongst my notes I have two cases of degenerative encephalitis, in which the patients some years previously had had a hemiplegia. One case of degenerative encephalitis had had aphasia and other symptoms of an encephalitis, twelve years before the onset of the degenerative lesion. Two cases of degenerative myelitis which had followed a transverse myelitis, and three cases of degenerative myelitis, which began with a peroneal palsy. Macnamara* pubhshed an interesting case of syphilis with Landry's syndrome, with later development of degenerative m3'elitis. Think of the number of cases there must be, then, of degenerative encephalitis and myelitis which have arisen without any previous symptoms of a vascular lesion. The same thing happens in the skin. The patient's first rash may be a recurrent syphilide or a gumma. An early hemiplegia usually results from a thrombosis of the middle cerebral artery, or one of its branches, in the sylvian fissure. If the organisms radiate from these branches, they will ultimately reach the teraporo-sphenoidal lobe. It is not at all uncommon to find in cases of degenerative encephalitis, that the part of the brain most affected is the temporo-sphenoidal lobe, another point in favour of the haematogeneous origin of the syphilitic nervous lesions. 214 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. There is another important point in favour of the haematogeneous route, nnd it should be brought forward. The Leucocytozoon syphilidis is carried all over the body by the blood stream, and the spores, as they develop in either endothelial cells or connective-tissue cells, first of all remain in the blood-vessel, in which they develop. The more pronounced their development, the greater will be the area over which the bodies that ultimately arise from them will spread. The area covered by the spread mil also naturally depend upon the motility of the phases, i.e., the more motile the phase, the greater the area it will encroach upon. The most motile part of the Leucocytozoon sypJiilidis is the male. Now the male phase can develop extracellularly, and is the main cause of the symptoms. The extracellular development will take place onlj' provided the pabulum on which it is growing is suitable. Nerve tissue, owing to its richness in hpoid- globulins, is just the medium for the extracellular development of the male phase, consequently spirochaetae are to be found in abundance in certain positions in degenerative encephalitis, and naturally they will have no special locahsation. To make this part of our subject a little clearer, an analogy will be drawn between what happens in the skin and in the nervous system. In early generalised syphilis, the cortex of the brain may be affected by lesions which are primarily vascular in origin, analogous to the common cutaneous lesions. Later in the disease, one knows that the cutaneous lesion, instead of being a small lesion like a papule, is a large lesion, which is often made up of several papules, as a serpiginous syphilide, for instance. The recurrent cutaneous lesions are in circles, or in cycloid forms, owing to the peripheral spread of the organisms from the original papule which preceded the recurrent lesion. A similar state of affairs can also occur in the central nervous system. If they occur in the cortex of the brain, and if the organisms do not develop outside of the vessels, and if the spirochaetae do not multiply extracellularly, the lesion will be one of encephalitis, and non-degenerative. Such cases usually develop symptoms about the fourth year after infection, and are usually diagnosed as cerebral syphihs. If the symptoms occur later, we are often in a position of being unable to differentiate the condition from initial degenerative encephahtis, which differs from ordinary encephalitis only in that the organisms develop outside the vessels, and that the spirochaetae multiply extracellularly. On two occasions I have treated, by intrathecal injections of salvarsanised serum, cases which have been diagnosed by well-known nem-ologists and by myself as degenerative encephahtis, and they recovered completeh', showing that our original diagnosis was incorrect. Should a condition analogous to an orbicular or serpiginous syphihde occur in THE BIOLOGY OF SYrHILIS OF THE XER\ OUS SYSTEM. 215 the cord, if about the fourth year, it is diagnosed correctly as spinal sypliiiis, or better, non-degenerative myelitis ; if it occurs later, then it may so closely simulate degenerative myelitis that the two cannot be difEerentiated. I remember well a case which had all the symptoms of degenerative myelitis, viz., Ai-gyll-Robertson pupils, lightning pains, ataxia, bladder trouble, and loss of erections, symptoms which entirely disappeared after two intravenous injections of " 606." The injections were given over four years ago, and the patient so far has had no recm'rence. Naturally, cases which are neither wholly degenerative nor wholly non- degenerative are to be met with, and, as already mentioned, non-degenerative lesions may ultimately become degenerative. The syphilitic organism may, early in the disease, affect the main vessel whose branches go to the skin, and so cause endarteritis, which may result in an aneurysm. I once had a case of popliteal aneurysm which occurred three years after the infection, and, six months later, a popliteal aneurysm formed on the opposite side. The main trunk, which sends branches to the cortex, may frequently be involved very early in the disease, and may give rise to hemiplegia, which may also be bilateral, as in the above case. In later years, any part of the artery, from the trunk to a terminal branch in the skin, may be the focus where the leucocytozoon starts its life-cycle again. Owing to the time the organism has been in the host, and the efforts which the host has made to overcome it, the damage wrought by the organism will be more localised, but on a relatively greater scale, and the resistance offered by the host will bear a ratio thereto, with the result that the blood supply to that area will be cut off, the tissue will necrose, and the result ^dll be what we know as a gumma. The same state of affairs may occur in the basilar artery, or in any of its branches, right up to a terminal branch in the cortex. A gumma may occur, and more than one, if more than one branch is affected, and that in any part of the brain substance. An exactly analogous condition may occur in the cord, and this would appear to be an explanation of many phenomena which have hitherto remained obscure. The analogy between nerve and cutaneous lesions now ceases, although we have other conditions in the former which require explanation. The brain and cord are surrounded by meninges. The skin has no external covering, and as the meninges are infected when the leucocytozoon becomes generalised, and as in some places they are in juxtaposition to the nerve matter, it will at once be seen that, theoretically, a spread of the organisms from the former into the latter may take place. The organisms reach the meninges via the blood 216 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. stream ; therefore, should they ultimately invade nerve tissue, the lesion resulting will be of haematogeneous and not of lymphogeneous origin. From the foregoing it would be justifiable to classify syphilitic diseases of the nervous system into two classes : (a) meningeal ; {b) ameningeal, and here a list is appended. Beaix. Meningeal Ameningeal I ! I Dura Piaarachnoid Puie arteiial I i . .. I .. Pachymeningitis Leptomeningitis Endarteritis (hemiplegia) Gumma Gumma Meningo-encephalitis Degenerative encephalitis (G.P.I.) Arteiial with involvement of nerve substance I Encephalitis Gumma Degenerative encephalitis (G.PI.) Cord. Meningeal Pure End (par; Ameningeal Du :'hym ra iuingitis nma . Piaarachnoid 1 Leptomeningitis Gumma -myelitis 1 arterial 1 irteiitis iplegia) Arterial wit of nerve h ini subs -olveinent tance. GllE My jlitis Gui Qiua Degenerative myelitis (tabes) Meningo 1 Atrophic muscular Latei'al sclerosis Degenerative myelitis (tabes) paralyses Degen myelitis ;rative (tabes) i' By adopting the above nomenclature, such terms as parasyphiUs and metaluetic lesions of the central nervous system could be discarded. The term parenchymatous lesion would not be required, as it only means a lesion of nerve substance, and does not denote whether the lesion was primarilv nervous or primarily meningeal. Although the table separates the brain from the cord, it must be remembered that clinically there is no separation, and that many case.«, originally degenerative myelitis, may end in degenerative encephaUtis. Summary. — An analogy exists between the infection of the skin and the THE BIOLOGY OF SYPHILIS OF THE NERVOUS SYSTEM. 217 infection of the nervous system, and again between the brain and the cord lesions. The skin infection is an haematogenous one, and so is the infection of the nervous system. The organisms may develop outside the vessels, and produce degenerative lesions, such lesions being ameniugeal. In most cases, the organisms reach the nerve tissue by an exten.sion from the meninges, and they get into the posterior part of the cord more readily than into the anterior part, because of the septum posticum, which conveys the blood vessels into the posterior part of the cord. Pure arterial lesions affect the anterior part of the cord and are analogous to those arterial lesions, which affect the base of the brain. In other words, transverse myelitis is analogous to hemiplegia, and degenerative myelitis of the posterior part of the cord to degenerative encephalitis of the cortex of the brain. Degenerative lesions may also occur in any part of the cord or brain, and are due to the phases of the Leucocytozoon sypMlidis spreading perijsherally from the vessel in which they developed, and to the fact that, if the spread is in grey matter, the spirochaetae develop very rapidly extracellularly, and cause marked local destruction of the nerve cells. (c.) Influence of Treatment upon the Incidence of Syphilitic Nervous Affections. Curiously enough, the influence of treatment upon the incidence of syphilitic nervous afiections has never heretofore been considered. A more important chapter in syphilis than this, does not, in my opinion, exist. I trust it will not be long before the profession at large takes the matter into very careful consideration, as I have no doubt myself but that nervous symptoms are very rapidly on the increase, and, as this view is a rather disquieting one, it would be as well to go as fully as possible into this question. Two facts must first of all be borne in mind : one is, that the organisms reach the nervous system at about the same time as the so-called secondary rash appears, and that all future trouble dates from this invasion. The other is, that such an invasion occurs in at least 70 per cent, of all cases. As, to all intents and purposes, there is no communication between the blood and the cerebro-spinal fluid, the body, for sake of argument, may be divided into — (a) the systemic portion ; (b) the nervous portion. In the blood, or, rather, in the serum, the natural protective substances of the host circulate. These natural protective substances are lipoid-globulins, and have their origin in lymphocytes, which are again mainly manufactured in the lymphatic glands. Broadly speaking, there is no limit to the production of these protective substances. 218 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. Although the blood from the systemic portion circulates in the nervous portion, the individual cells of the latter are not bathed with it in the same way as is the case in the former. When there is a nervous lesion, the protective substances circulating in the blood do not enter the cerebro-spinal fluid, in which circulates the main supply of protective substances to nerve tissue. Protective substances can enter the blood only from the cerebro-spinal fluid, and the cerebro-spinal fluid is the fluid supply, so to speak, of nervous tissue. The reagin which circulates in the cerebro-spinal fluid can enter the blood stream, and this is the partial explana- tion of the positive Wassermann reaction which is obtained in the blood, in cases of degenerative encephalitis and degenerative myelitis. Hence, if there is a lesion of nerve tissue proper — i.e., apart from the meninges — the main supply of protective substances reaches it vid the cerebro-spinal fluid. Those circulating in the blood are nevertheless useful. The protective substances in the cerebro-spinal fluid come mainly from the epithelial cells of the choroid plexuses, the supply of which bears no relative proportion to that from the lymphatic glands ; and partly the}^ come from the lymphocytes, which constitute the lympho- cytosis, and these in their turn come from the lymphatic vessels of the meninges and nerve tissue. Not all cases of syphilis show symptoms during the stage of the generalisation of the virus, but most do so. This is perfectly true of the majority of the 70 per cent, of cases in which the generalisation has reached the nervous system. If every physician will from henceforth examine very carefully the nervous system of all his cases of early syphilis, he will be surprised at the very high per- centage which show symptoms. The symptoms are slight, but unmistakable, and are usually of this nature : — Inequality of pupils, irregularit}' of the pupil reflexes, disturbances in the cranial nerves, altered elbow and radial reflexes, unequal abdominal and cremaster reflexes, exaggerated knee-jerks on one or both sides, faint alterations in cutaneous sensations, etc. With and without treatment, the rule is for all the early symptoms of'syphUis to disappear spontaneously. Treatment naturally aids their disappearance, as it increases the production and efficacy of the protective substances, or, as they may be called for short, antibodies. Owing to the comparative weakness of the protective substances in the cerebro- spinal fluid, the host is partly dependent upon those circulating in his blood, to overthrow the organisms in his central nervous system. As substances cannot reach the cerebro-spinal fluid vid the blood stream, it will be easily understood that treatment given by the mouth, skin, muscle, or vein THE BIOLOGY OF SYPHILIS OF THE NERVOUS SYSTEM. 219 is only going to reach the nervous tissue in infinitesimal doses. Therefore, the steriUsation of the systemic portion will be achieved long before that of the nervous portion. If the systemic portion is sterilised early in the disease, the production of antibodies is checked, hence an important supply to the nervous part is cut off, at a time when it is most needed. The result is, that the organisms may get the upper hand, and may give rise to serious symptoms. From what has just been stated, it will be readily seen what a close connection there is between treatment and the occurrence of nervous lesions. For the sake of clearness, treatment may be divided into three heads, and every patient will be regarded as a possible candidate for a nervous affection. 1. Treatment by mercury alone. Sterilisation of the systenr by mercury only is a long process, hence it will be a matter of years before the supply of systemic antibodies to the nervous part is cut off. The supply to the nervous part may prevent the spores of the Leuco- cytozoon syphilidis from developing into their gametal forms, but it will not prevent them from extending. The spores ■will extend from the meninges into the cord and brain. Should the supply of antibodies be cut off when the spores have reached thi cord and brain, the spores mil develop in situ, and will cause degenerative myelitis and degenerative encephalitis. The more thorough and the more drastic the mercurial treatment is, the quicker and more perfect the stoppage of the supply of antibodies to the nervous system vnW be, therefore the greater likelihood of degenerative myelitis and encephalitis arising, and the more meningeal in charactt'^' tlie early symptoms will be. As I have frequently stated, it is not the untreated cases which are more liable to develop a degenerative affection ; it is those which have been well treated with mercury. In more than 75 per cent, of the cases of nerve degeneration of which I have notes, the mercurial treatment has been severer than either Fournier or Hutchinson would have advised in their time. 2. Spasmodic or inadequate treatment by salvarsan, supplemented or not with mercury. Although, one, two, or three injections of salvarsan will not, strictly speaking, sterilise the system, the sterilisation being only pro tempore, they will stop the manuiacture of antibodies. The spores may be still in the meninges, or may be on the point of entering the nerve tissue, hence the symptoms will be mainly meningeal. In the majority of cases, these symptoms are so slight that, unless an exhaustive exanrination be made, nothing is detected. Since I have made it the rule to run over the nervous system in every syphilitic 220 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. patient, and to test the cerebro-spinal fluid of everj^ ease in which my examination leads me to suspect some mischief, I have been surprised by the enormous number of cases which have marked evidence of imphcation of the nervous system. Time is 3'et too young to say what the future of these cases will be. 3. Several injections of salvarsan, given as closely after one another as possible, and followed by mercury for two years. Such a treatment is usually able not only to sterilise the systemic part, but to sterilise the nervous part as well. If, on the other hand, the sterilisation of the latter is not complete, the check on the production of antibodies has been so quick and sudden, that the spores will develop rapidly and early. Early development of the spores means that it will take place in the meninges. Rapid development signifies that the symptoms will be severe, and therefore noticeable. Consequently, these cases are purely meningeal, easily diagnosed, and, being meningeal, can be cured (\\ith reserve) by further drastic treatment. These views are not hypothetical, but \'iews which I have been forced to hold from my clinical experience of several hundreds of cases. There are several other factors which come into play in the causation of nervous lesions, such as the resistance of the host, the protective power of the cerebro-spinal fluid, the \nrulence of the infection, and the inter^^al which is allowed to elapse between the commencement of the generalisation of the virus and the inauguration of the treatment. Also, it must not be forgotten that spontaneous cure plays a great part in syphilitic nervous affections. To make the subject still clearer, a brief discussion of these various points will not be out of place. The resistance of the host plays an important role in this respect. The reader has doubtless often heard the remark made, that, in many cases of degenerative encephalitis and myelitis, either no history of s}'philis could be obtained, or that the primary stage and stage of the generalisation were slight. The remark is perfectly true, and its explanation is, in my opinion, the following : — When such a patient is infected, the generalisation of the virus tal^s place, but symptoms do not appear, owing to the patient's natural protective power being above the normal. As time goes on, this naturally high protective power will succeed in annihilating all the organisms in the systemic portion, with the result that the formation of antibodies will be checked. The organisms have meanwhile been resting in the nervous portion, where they do not come under the influence of this naturally increased protective power to the same extent, consequently they have sufficient life in them to spread. A peripheral spread of the organisms in the nervous portion, always means a spread THE BIOLOGY OF SYPHILIS OF THE NERVOUS SYSTEM. 221 into nerve tissue proper, and, the further the spread into nerve tissue, the less the influence the natural protective capacity of the host has upon them. Deduct from this the power systemic antibodies would have, as by this time they will have ceased to exist, and there is very little to check a widespread and active development of the organisms. The cerebro-spinal fluid is not itself strong enough to vanquish the organisms, as, by this time, one has to counterbalance its action with the wonderful medium nerve cells form, for the organisms to develop upon, hence de- generative encephalitis and m3'elitis result. Here I shoidd like to point out a very important clinical observation. A patient who, during the latent stage, gives a persistently positive Wassermann reaction of the blood, stands little chance of getting a degenerative nerve lesion ; while a patient, who during this stage gives a persistently negative Wassermann reaction, is far more likely to develop a degenerative nerve lesion. Therefore, I have for some time made the rule not to treat a patient who persistently gives a positive Wassermann reaction during the latent stage, i.e., provided his previous treatment has been adequate, because I regard such a reaction as an indication of his protective capacity, which I am only likely to damage by treatment. On the other hand, I do not treat the opposite case until I have satisfied myself that a persistently negatiVe Wassermann reaction does not indicate that the patient is cured. A cure can be best ascertained by giving a provocative injection of salvarsan, or, better, by testing the cerebro-spinal fluid. Cases which have very bad symptoms, dm'ing the generalisation stage, are very prone to develop acute meningo-encephalitis and myelitis. Severe symptoms in the systemic portion call forth an abundance of antibodies, and the greater the call upon antibodies the more persistent their production, and not only that, the production continues in spite of the destruction of the organisms. Severe symptoms in the nervous portion call forth an abundance of antibodies, which raise the protective capacity of the cerebro-spinal fluid. The result is, that once the active organisms — i.e., those which cause the symptoms in hand — are vanquished, the spores are unable to spread, owing to the powerful protective bodies circulating in both the blood and in the cerebro-spinal fluid, consequently degenerative encephalitis and myelitis do not follow. From what has already been stated, the reader can easily argue out for himself the influence which the interval, allowed to elapse between the commencement of the generalisation of the virus and the inauguration of the treatment, has upon the incidence of syphilitic nervous manifestations. Broadly speaking, the earlier treatment is commenced in the generalisation 222 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. stage, the greater the likelihood of the nervous lesions being meningeal in character, and therefore being earlier in appearing. The later treatment is commenced, the greater the likelihood of the nervous lesions being degenerative, and therefore being later in appearing. Naturally, the kind of treatment, the kind of case, and all the other points which have been discussed will exert their influence in each individual case. Spontaneous cure is a factor always to be reckoned with, although it is one which does not lend itself to discussion. Spontaneous cure naturally depends upon the protective capacity of the antibodies which circulate in the blood stream and in the cerebro-spinal fluid, hence one would expect spontaneous cure most readily to follow true cases of meningitis This we know clinically to be the case. It is a well-known fact that many cases of degenerative myelitis are spontaneously cured, but it has not previously been pointed out, that it is in the meningeal form that a spontaneous cure is most likely to occur. The same with degenerative encephalitis. It is in the degenerative meningo- encephalitis that periods of quiescence are most common, while, in the ameningeal form, death frequently terminates the fii'st attack. The reason is obvious. In the meningeal lesions, the organisms are not living upon a particularly luxuriant medium, and they are more open to attack from the protective bodies, both in the blood and in the cerebro-spinal fluid. In the ameningeal lesions, the organisms are living upon a particularly luxuriant medium, and they are only open to attack from the protective bodies in the cerebro-spinal fluid. The moral of this nervous discussion is clearly that no treatment, however perfect it may be, which is begun only after the commencement of the generalisation of the Leucocijtozoon syfhilidis, is an absolute guarantee of a cure. For a cure to be guaranteed, the treatment must be prescribed before the organisms have reached the nervous part. This necessitates an early diagnosis of the primary lesion, and brings me to say once more, that patients should be urged to come up for trsatment sooner than they are now accustomed to do, that there should be sufficient men scattered about the United Kingdom who know what a sore is, when they see one ; as the reader w^ have learnt ere this, that a bacteriological examination of a sore is not quite so satisfactory as it is frequently stated to be. As the clinical condition of haemorrhagic encephalitis has come into prominence since salvarsan has been in use, and is largely dependent upon this drug, it should now be considered. In some early cases of s}'3)hilis, no skin lesions are to be seen, until salvarsan THE BIOLOGY OF SYPHILIS OF THE NERVOUS SYSTEM. 223 has been given, when either diffuse boiled-lobster-coloui-like blotches occur, or small areas of redness, simulating a pronounced roseola. Such lesions disappear rapidly, and a histological examination of them shows nothing more than an unusual dilatation of the vessels. No cellular infiltration is to be found, and often the section appears to be normal. In the brain, an exactly analogous condition is to be found, in the so-called haemorrhagic encephalitis. Now, haemorrhagic encephalitis has received special significance of late, because it has occurred somewhat frequently, and usually ^nth fatal results, after the administration of salvarsan. Haemorrhagic encephalitis may occur as a syphilitic symptom, and may end fatally, before any treatment has been prescribed. I have had such a case, and, histo- logically, all that I could find were dilated vessels in the cortex, small haemorrhages from them, without there being any very marked cellular infiltration around them. The pons showed the greatest changes. Therefore the condition may occur independently of salvarsan. The erythema on the skin may also follow mercury when it is first given, therefore the erythema need not necessarily be due to salvarsan. The fatal cases of haemorrhagic encephalitis following salvarsan have always occurred in syphilitic patients, most commonly after the second injection had been given — usually on the third day — and in patients who were in the early generalisation stage of syphilis. I had one case, soon after salvarsan first came into use. Case 37. — A man, aged 23, consulted me for syphilis which he had contracted three months previously. His symptoms, upon examination, consisted of a maculo- papular rash, and iritis of the left eye. No organic disease in the \'iscera was discernible, and there was no albmnin in the urine. After the second intravenous injection of " 006," which was given eight days after the first, the patient complained of headache. Suddenly, during the evening of the third day, he had an epileptic fit of Jacksonian type. He soon went into the condition of Status epilepticus, in which he died a few hours later. Neither after the first nor the second injection was there any albumin in the urine. Post-mortem, the only macroscopic change to be noticed was an arachnoid cyst over the right rolandic area. Microscopic examination showed that the meningitis was of some years duration, and that there was no recent inflammation, although syphilis had been contracted only three months previouslv. The nerve cells of the cortex underneath the cyst' had undergone marked plasmolysis. Their shape was altered, and no NissFs granules were discernible. Elsewhere the vessels of the cortex appeared to be dilated ; there was no extrusion of blood, and there was no perivascular cellular infiltration. p 224 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. There can be no doubt but that this was a case of haemorrhagic encephahtis, which started as an epileptic fit of Jacksonian type, o\^-ing to the old arachnoid cyst, which proved an area of minor resistentiae. The arachnoid cyst was probably due to an accident which the patient had had years before, but no history was obtainable upon this point. The patient was always morose, and none of his relations or friends knew much about him. There are degrees of haemorrhagic encephalitis, because, in some cases, no macroscopic or microscopic changes are to be found in the cerebral cortex. In some cases, merely a dilatation of the vessels is all that is to be seen ; in some, the dilatation of the vessels is very severe, with the result that they are sur- rounded by extravasated blood, and in one case I examined, which occurred independently of salvarsan, there was in addition some perivascular cellular infiltration. In another case, the perivascular cellular infiltration was very marked. As to the direct cause of the condition, difierent opinions prevail. The fact that it occurs most commonly after the second injection of salvarsan, early in the generalisation stage of syphilis, suggests the following to my mind : — Early in the generalisation stage, the body has not yet become accustomed either to the s\T)hiUtic organisms, or to the toxines which would naturallv result upon their destruction. The patient can probably stand the first toxic dose he gets, but succumbs to the second, which acts as an anaphylotoxine. The anaphylotoxine paralyses the vasoconstrictors. Hence the dilatation of the vessels, extravasation of blood, and oedema of the brain. Why should the symptoms not arise until the third day ? If a drug is given intravenously, we know that it reaches the skin more quickly, and in greater quantities than it reaches the cortex of the brain. The erythema, following salvarsan, sets in often twenty-four hours or more after the injection has been given. If the drug readies the brain more slowly, and in smaller quantities, it would take more than twenty-fom' hours for the anaphylotoxine to be formed — possibly seventy-two hours, i.e., the third day. It is undoubtedly on the third day, 'that the reactionary inflammation surrounding intracranial lesions is most marked. I had a patient with syphilitic pachymeningitis, who became unconscious on the third day after the second injection, due to the reactionary inflammation having raised the intracranial pressure so as to cause compression. Lumbar puncture was followed by immediate rehef. Ehrlich^ is of the opinion that the condition is partly due to the toxic action THE BIOLOGY OF SYPHILIS OF THE NERVOUS SYSTEM. 225 of an oxidation product of salvarsan, namely, paramiuophenylarsenoxide, and that symptoms do not appear until the third day, which is the time required for the oxidation product to be formed. The following facts, to my mind, rather point against Ehrlich's conception, since haemorrhagic encephalitis may occur independently of treatment, because it is analogous to the cutaneous erythema which may follo^\ mercury, because it is commoner after salvarsan than after neo-salvarsan, while the latter oxydises very much more quickly than the former. It is not quite such an active spirillocide, hence the amount of anaphylotoxine formed, following the use of neo-salvarsan, would be less than that formed from the use of salvarsan. The formation of paraminophenylarsenoxide is favoured by all forces which cause a delay in salvarsan excretion, such as an overdose, or presence of kidney disease. Under these conditions, larger quantities of salvarsan than usual may remain behind in the body, and succumb later to oxidation, forming the dangerous oxide. These are extra explanations which Ehrlich brings forward in favour of his hypothesis. Many of the cases which have been reported have not had overdoses, and in many there was no kidney disease. If the question of kidney disease came in, it is difficult to see why Encephalitis haemorrhagica does not occur in the cases of late syphilitic nervous diseases, when the kidney is sometimes diseased, when the nervous tissue is far below par, and when several injections of salvarsan are given. Under these circumstances, haemorrhagic encephalitis does not occur, because the patient is immune to the toxine formed from the death of the organisms, some of which doubtless have been killed daily for months or years. In lesions, where there are myriads of spLrochaetae present, such as in some cases of degenerative encephalitis, their destruction leads to such a big dose of toxine that the patient quickly succumbs. Another interesting point which now crops up, is the question as to whether the kidney is diseased — because of syphilis — in the early generalisation stage of the disease. The occurrence of protein in the urine in early sj'philis is no proof that the kidney is diseased. In many cases, the so-called albuminuria in generalised syphilis is not due to albumin. It may be due to globulin, or to a lipoid-globulin, which is merely excreted through the kidneys from the blood, because the serum can hold no more. Ehrlich further considers that a third factor comes into play, namely, the insufficient quantities of adrenalin in the blood, as would occur in Addison's disease. p2 226 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. So far as we know, the suprarenals are not afiected by syphilis in the early stages of the disease, therefore it is unhkely that this factor plays a great role. There is no doubt, as Mihan * ^ has ingeniouslv shown, that tbe administration of adrenalin will often combat unpleasant symptoms following salvarsan, such as blue- red swelling of the face, lips, dyspnoea, etc., severe diarrhoea, and suppression of urine. Milian, by means of energetic adrenalin treatment, saved an otherwise hopeless case of Encephalitis haemorrhagica in which, after the second salvarsan injection, the deepest coma ensued. Adrenalin doubtless overcomes the vasodilation effect of the anaphylotoxine, and this is probably its action in these cases. There seems no justification for assuming that these vasodilatator phenomena arise because there is less adrenahn circulating in the blood at the time. There is some deeper reason for haemorrhagic encephalitis than its mere occurrence after salvarsan. Haemorrhagic encephalitis is a syphilitic lesion, and it may occur in any stage of syphilis, although it is extremely rare after the third year following the infection. The earlier the case, the more truly haemorrhagic the lesion is, but, as a rule, if the condition occurs independently of treatment, the dilated vessels are generally surroimded by a l}anphoc3rtic, and, in some cases, by a mixed lymphocytic and plasma-celled infiltration. I have had one case occurring after salvarsan, in which there was no perivascular cellular infiltration ; two cases, which occurred independently of treatment, in which there was a marked perivascular infiltration ; and one case which occurred seven years after infection. This last case is one of the most interesting I have ever seen, as it throws considerable light upon many points, which I am attempting to emphasise in the chapters on s}^hilis of the nervous system. Case 38. — The patient, a man, aged 32, contracted syphihs seven years pre- viously, and he was treated with mercury internally for about three years. One year before I saw him he had complained of severe pains in his legs, bladder trouble developed, and the patient became slightly ataxic. In this condition he "svas seen by two physicians, who diagnosed the condition as tabes. He was then given two intramuscular injections of salvarsan, with the result that his symptoms practically vanished. A few months after the salvarsan had been prescribed, the patient developed very bad headaches, he lost his memory, he took a very long time to answer questions, and became very quiet, apathetic, but not irritable. Three days after definite sjonptoms of cerebral trouble had manifested themselves, the patient became comatose, and a week later he died, in spite of every effort made to save him. THE BIOLOGY OF SYPHILIS OF THE NERVOUS SYSTEM. 227 Post-mortem, the meninges and cortex of the brain were markedly inflamed, histologically, one fomid a dilatation of the cortical vessels, with a pronounced lymphocytic and plasma-celled infiltration surrounding them ; here and there there had been extravasations of blood. The changes were well marked in the pons, into which there had also been several haemorrhages, but, in every area in which a haemorrhage had taken place, there was a pronounced cellular infiltration. The interesting points about this case are, first, that the nervous symptoms were primarily spinal ; these cleared up, and then the patient died with cerebral symptoms. Secondly, the cerebral symptoms did not develop until treatment had been prescribed. Similar symptoms to the above, only very much milder, although the patient may become actually comatose, are not at all uncommon after treatment, in cases of encephalitis and meningo-encephalitis. As a rule, the coma develops on the third day after the second injection of salvarsan. Active continuance of the treatment cures the patient, but it failed to do so in the case just described, because the condition had occurred some time after the treatment had been given, and was therefore more due to the disease itself than to the treatment ; and it also failed because the active treatment was not prescribed soon enough. This case fully proves the statement made some pages back, that unless the treatment of a nervous lesion be drastic, it is better not to prescribe salvarsan or neo-salvarsan at all. /SMmmary.— Treatment has a very decided influence upon the outbreak of nervous symptoms. The development of the organisms in the central nervous system is kept in check, both by the cerebro-spinal fluid and bj^ the antibodies which circulate in the blood stream. Treatment exerts its influence by checking the production of systemic bodies, and thus deprives the central nervous system of one of its protective arms. The more quickly the systemic antibodies are destroyed the earlier the onset of nervous symptoms, and vice versa ; i.e., provided the treatment is first prescribed in the generalisation stage. The earlier the onset of nervous symptoms, the more meningeal, and the later their onset, the more degenerative in character they will be. Hence, the more drastic the early treat- ment is, the better the prognosis, should nervous symptoms arise, since meningeal lesions are easier to cure than degenerative ones. Moreover, early drastic treat- ment destroys all the organisms in the walls of the blood vessels, with the result that ameningeal nervous lesions will be rare. To avoid the onset of any nervous symptoms at all, treatment must be pre- scribed before the patient enters the generalisation stage. Haemorrhagic encephalititis, occurring in syphilis, is always primarily due to 228 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. the disease, but its onset may be influenced by treatment, and may be produced by the spirochaetal toxine. The condition is never due to saJvarsan. {(!) Other Factors Which Play a role in the Causation of Syphilitic Nervous Lesions. Having described how syphihs attacks the nervous system, it might be as well to see it there are any other factors, which come into play in its causation. Although no actual statistics exist as to the prevalence of acquired nerve syphilis, I do not think one would be far wrong in saying that about 10 per cent, of patients who contract sj-philis, develop a marked central nervous system lesion. Although, personally, I think the percentage is on the increase, which is contrary to the view generally held, I feel still more certain that in a few more years the percentages will be greater still, owing to the indiscriminate and inadequate manner in which the new arsenic preparations have been prescribed. We are now certain that, in at least 60 per cent, of cases of syphilis, the organisms reach the nervous system, i.e., including the meninges, very early in the stage of the generalisation of the virus. In fact, it may be possible to obtain a lymphocytosis in the cerebro-spinal fluid before the Wassermann reaction in the blood is positive. If in as many as 60 per cent, of cases the organisms reach the nervous system, why do only so few develop symptoms later ? The local protective power of the host, the antibodies circulating in the blood system, the amount of treatment, and the time at which it is begun, are all factors which influence the destruction of the organism. Do those organisms which remain, and give rise to symptoms, do so because they have a special neurotropic action, or because the patient has a neuropathic disposition ? Affirmative e\'idence for both suggestions has frequently been brought forward. In favour of the neurotropic action of the organism is the fact, that cases have been described in which two or more individuals — not blood relations — have been infected Irom the same source, and have developed a degenerative lesion later. In favour of the neuropathic disposition is the fact, that degenerative ence- phalitis is most likely to affect those whose brains have been severely taxed by worry, etc., and also individuals who have had their resistance lowered by alcohol, which acts as a poison, especially upon the brain cortex. Difierent poisons which have a neurotropic action, the area involved is very seldom the same. THE BIOLOGY OF SYPHILIS OF THE NERVOUS SYSTEM. 229 The diphtheria toxiji3 has a predilection for certain nerves ; tubercle and alcohol seldom affect the cord. Ergot favours the posterior columns. Lead picks out special peripheral nerves, such as the nuisculospiral, and, oddly enough, that musculospiral belonging to the arm which does the most work is most frequently affected, a neuropathic phenomenon. Although the biology of s3'philitic central nervous system lesions can be explained on other lines, it would appear at present, that the neurotropic action of the organism and the neuropathic disposition of the individual played some role. Taking all the evidence we have, we ought to be able to throw more light upon the nature of the syphilitic lesions affecting the central nervous system. If there was anything in the neurotropic action of a certain strain of the specific organism, many more cases would have been described. Think of the thousands of cases of degenerative myelitis and encephalitis there have been, so that the few described, as pointing to a neurotropic action of the organism, may safely be regarded as coincidences. Weygandt and Jakob^ proved experimentally that, if they infected rabbits with a neurotropic strain of organism, that is, a strain that had already produced nervous symptoms, no more developed nervous lesions than rabbits which had been infected with a non-neurotropic strain. The neuropathic disposition is merely another expression of the locus minor resistentiae. Against the neurotropic action and neuropathic disposition, is the fact that parasyphilitic affections of the nervous system are rare, and in many cases unknown, in spite of the fact that syphilis is very common in Turkey, Persia, Egypt, Algiers, Abyssinia, China, and in certain parts of Africa, where often more than 70 per cent, of the natives have syphilis. Moreover, the natives who have contracted the disease have been infected by white men, many of whom develop a degenerative lesion later. The reason why these natives do not suffer from late nervous lesions is, in my opinion, due to the fact that they are so badly treated that a period seldom arises in which the antibodies in the systemic part are absent, therefore, what organisms there are in the nervous part are kept at bay. It will be seen readily, from what I have stated, how much the development of the organisms in the nervous s^'stem is influenced bj' treatment. Since most patients are not treated until the leucocytozoon has reached the nervous system, if the treatment is quick and sivre, should nervous symptoms arise, they will be those of pure meningeal syphilis ; if the treatment is slow but sure, should symptoms arise, they will be degenerative ones. If the treatment is bad, then nervous symptoms will be less likely to arise. By slow and sm-e treatment, I would mean treatment with one or two injections 230 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. of salvarsan, and mercurial injections given intermittently for two or three years. By the bad treatment, I would mean treatment by pills only. Since the treatment has been passing from the bad into the slow and sure, there has been a steady increase in the so-called parasyphilitic affections. This has been proved to me, apart from my own personal experience, by a letter sent by Professor Wimmer, of Copenhagen, in which he clearly indicates that the percentage of cases with nervous lesions is gradually going up, year by year ; and by several talks with Mr. Shillitoe, who, from his notes of cases of syphilis which have been through his and his father's hands during the last fifty years, is sure that many more patients are developing degenerative lesions than used to do so. When we come to discuss the selective influence of different organisms for different nerve paths, we immediately run against an impenetrable wall, since absolutely nothing is known about it at present. "Who can answer, why should the virus of anterior poliomyelitis pick out for preference those nerve cells situated in the anterior horns ? So far as syphilis is concerned, I can see no evidence for assuming that the leucocytozoon has any selective action, and the reason why posterior column lesions should be so much more common than anterior horn lesions, can, I think, be readily explained on anatomical grounds. Late lesions of the brain need not necessarily be those of degenerative ence- phalitis — gummata, for instance, may occur. The reason why, in the one case, it is degenerative encephalitis, and in the other a gumma, is explained by Mackintosh and Fildes' on the hy3)ersensitiveness theory. As already stated, the cause of hypersensitiveness is not known, and, moreover, why degenerative encephalitis or a gumma should arise, can be easily explained on anatomical grounds, and by the manner in which the organism develops ; whether it develops in the walls of the vessels or outside them. 1 Weygandt u. Jakob (1914), " Dermat. Wochensclirf." Festschrift, 150. ° Orr and Rows (1914), " Proc. Roy. Soc. of Med." vii, (Psych. Sect.), 21. , 3 Erhlich (1914), " Brit. Med. Journ." i, 1044. •• MiHan (1913), " Bull, de !a Soo. Franc, de Derm, et de Syph.," xxiv, 272. "■ Ibid. (1914), ., „ „ „ XXV, 231. « Macnamara (1913), " Lancet," ii, 385. ' Mackintosh and Fildes (1914). " Brain," xxxvii, 141, CHAPTER XXIV. THE CLINICAL ASPECT OF SYPHILIS OF THE NERVOUS SYSTEM. It is not my intention to describe in full the symptoms of the syphilitic nervous lesions, because the reader could be better informed by consulting a textbook on nervous diseases. All I propose to do, is to draw attention to the chief signs and symptoms of each of the lesions mentioned in the table in Chapter XXIII, with which a syphilologist is most likely to be confronted. Before dealing with the central nervous system, a few words must be said about syphilis of the peripheral nerves. Syphilitic neuritis may be single or multiple. The lesion, when one nerve is affected, is usually to be found in its distal part, while, in those cases in which more than one nerve is involved, the lesion or lesions are either in the plexus itself, or the case is one of a root neuritis. The so-called syphilitic polyneuritis, which is only met ^vith in the generalisation stage, is a peripheral neuritis, and is probably due partly to the presence of the organisms themselves in the endo- and perineurium, and partly to the toxines which are elaborated by the death of the spirochaetae in situ. That the neuritis is most probably partly a toxic neuritis, is proved by the fact that, in nearly all cases of syphilitic polyneuritis, the patient has had mercurial treatment. Because of this fact, it has been frequently maintained that the poly- neuritis under discussion was a neuritis due to mercurial poisoning. This is certainly not the case, because if mercury is pushed in such a case, or salvarsan is prescribed, all the symptoms disappear. The most common nerve to be affected, when the neuritis is single, excluding the cranial nerves, is the sciatic nerve, but it must be remembered that neuritis of the sciatic nerve is not infrequently secondary to a syphilitic lesion in the neigh- bourhood. It may be secondary to a gumma in a muscle, or to a periostitis of the ischium. It depends upon the position of the inflammation, whether the motor part is more involved than the sensory part, or vice versa. Treatment in these cases should be begun as quickly as possible, so as to prevent 232 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. the fibrous tissue contraction from causing degeneration of some of the nerve fibres. If fibrous tissue contraction and degeneration have set in before treatment is prescribed, it may be a matter of weeks before the patient is relieved, and even after drastic salvarsan treatment, pains may still persist. In all cases of peripheral neuritis not of syphilitic origin, the administration of salvarsan is bound to aggravate the symptoms in increasing ratio, as the number of the injections is raised ; hence this form of aggravation can be differentiated from that of reactionary inflam- mation, which only follows the first two, or, at most, three injections. In s;^'philitic neuritis of the sciatic nerve, the sensory fibres are more often affected than the motor fibres. If the neuritis is mainly a motor neuritis, the chances are that the inflammation is in the sciatic plexus, and if only one motor nerve is affected, and it is most often the peroneal, it is to be feared that the lesion may be central. The brachial plexus is, in my experience, the plexus most frequently affected, and the side I have seen involved has always been the right. It is characteristic for a syphilitic plexus neuritis to be unilateral. When the condition is bilateral, it is almost certain that the patient has a root nem-itis, or, in other words, a cer^acal pachymeningitis. In the cases of brachial neuritis which I have seen, the motor disturbance has always been greater than the sensory disturbance, while, in two cases of root neuritis I have had under my care, the sensory signs were more pronounced than the motor signs. In both of my cases of root neuritis, the cerebro-spinal fluid was markedly pathological, and indicated a meningitis : while in one of my cases of brachial neuritis, the cerebro-spinal fluid was normal. In both the cases of root neuritis referred to, the upper extremities were much more involved than the lower ones. Both plexus neuritis and root neuritis do excellently under treatment with salvarsan, but in the case of the latter, if a cure is to be hoped for, several intrathecal injections of salvarsanised serum have to be given. Poll/neuritis syphilitica is most commonly to be met with in the generalisation stage, while the other forms just described generally occur round about the fourth year and later, seldom earlier. We now have to consider neuritis of the cranial nerves, but lesions of the cranial nerves, which occur in syphilis, should be discussed from a different standpoint. The lesions may be di%-ided into two classes : {a) secondary ; {b) primary. Lesions of Secondary Origin. Xeuro-recurrences come under this heading, but they are fully discussed else- where {vide Chapter XXVIII). The lesions which have not so far been mentioned THE CLINICAL ASPECT OF SYPHILIS OF THE NERVOUS SYSTEM. 233 are those which occur in syphilitic basal meningitis (leptomeningitis). The following cases are good examples : — Basal Meningitis. Case 39. — A man, aged 40 years, developed syphilis eleven years previously, but as he had no other symptoms but the sore, he only took mercury internally for six months. In 1908, gummata developed in the skin, and some of the cranial nerves became involved. Some improvement was obtained, after several injections of soamin, and potassium iodide internally. In January, 1910, he had diplopia, and was much troubled with headache and vomiting. In March, 1910, he first noticed weakness of the right side of the face, and was treated with mercury and iodide, with only temporary improvement. When seen on September 12th of the same year, the condition was as follows : — " There is an internal strabismus with diplopia, due to paralj^sis of the right external rectus and weakness of the left external rectus. The movements of the eye dependent on the third nerve are good. The pupils react well, and the vision is good. There is some swelling of both optic disks. There is paralysis of the right side of the face, and both motor and sensory portions of the right fifth nerve are involved. There is deafness on the right side, but the tuning-fork is audible when placed in contact with the mastoid. There is some unsteadiness in gait, but this would seem to be dependent on the diplopia. Rhomberg's sign is absent, and there is no weakness of the limbs. The knee-jerks are active and equal : the plantar reflex cannot be obtained, and the abdominal reflexes are difficult to elicit, but they are equal. The articulation is somewhat nasal, but no weakness of the palate can be detected, although there is some difiiculty in deglutition. The movements of the tongue are good. It seems probable that there is a circumscribed syphilitic meningitis at the base of the brain, involving the right fifth, sixth, and seventh cranial nerves, and probably also the right eighth and ninth, and the left sixth to a lesser degree. There is no evidence of any affection of the p}T:amidal tracts. '' An intramuscular injection of 0'.5 grm. of " 606 " was given. The patient was very ill for a few days, but on the third day the temperature returned to normal, and he declared that his hearing had improved. Within a week he could walk without a stick, all the affected nerves had regained some of their power, the improvement in the sixth and seventh being very striking. The injection was given on Sep- tember 12th, and on September 28th the following letter was received from Mr. Hare under whose care the patient then came : — " Optic neuritis is still present, but the patient says his visual power has improved daily, especially during the last four or five days. The third, fourth, fifth, sixth, and seventh nerves all show signs of improvement in fimction, but I cannot find any increase of hearing on the right side, though the patient says there 234 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. is. Swallowing, respiration, and heart's action all improved. To-day the heart beat was perfectly regular at 78, whereas I have often found marked irregularity both as regards rate and strength." Another letter, dated October 12th, states that the optic neimtis has almost gone, the eyesight greatly improved, and that the patient can walk 100 yards without staggering. The hearing has also greatly improved. In this last case, although there was no return of symptoms, the patient had an idea that a further injection would possibly aid in completely getting rid of those that remained ; consequently a second was given, with dire results. Soon after the injection he became cyanosed, and had great difficulty in breathing ; this as well as another similar attack passed oft', but they were followed on the third day by another, which proved fatal. This case is exceedingly instructive, because, in all intracranial afiections, this difficulty in breathing is not uncommon, especially after an intramuscular injection. The dyspnoea is undoubtedly due to a further raising of the intracranial pressure, caused by reactionary inflammation around the diseased focus, which inhibits the respiratory centre. Should such a thing occur, either a lumbar puncture should be resorted to, or the skull should be opened. In any case, adrenalin injections should be given. Cerebrospinal Meningitis. — It is impossible to say where cerebral sj'philis ends and cerebro-spinal syphilis begins, since the meninges, vessels, etc., of the brain and spinal cord are continuous ; and, although a case may have symptoms only of cerebral syphilis, post-mortem examination may reveal changes in the meninges of the cord, and ince versa. For instance, a man came up complaining of headaches, insomnia, and double vision, five years after infection. He had lately become so depressed and irritable, that he was on the point of giving up his work in the city. The double vision, due to paresis of one third nerve, was accompanied by paresis of the facial on the same side. Both would be present for a few weeks, then disappear, to become evident again later. Pupils unequal, R. > L. Right reflexes gone, left weak, disks normal. Patellar reflexes gone. Wassermann reaction in blood negative, but in cerebro-spinal fluid positive, positive lymphocytosis, and phase I. Mercurial in- unctions soon stopped the double vision, but, no sooner had the patient finished a course, than the paresis again appeared. In October, 1910, patient had an intramuscular injection of " 606 " during an attack of facial paralysis and double vision, which disappeared within a few days, the headaches and insomnia, vanished, and the patient felt no longer depressed or unable to work. Both the pupil and patellar reflexes reappeared. THE CLINICAL ASPECT OF SYPHILIS OF THE NERVOUS SYSTEM. 235 Case 40.— A married woman, aged 47, whose infection occurred probably twenty- four years ago, and who, after her second marriage, had five consecutive miscarriages. Nervous symptoms began in 1901, when the left arm and leg were noticed to drag, and there was giddiness, with disturbance of vision — in the patient's words, " things went suddenly black." She was admitted into the Great Northern Hospital for seven weeks. Four years later, she complained of partial paralysis of the left arm and leg, cramps in both legs, double vision, and loss of memory for minor events. This time she was admitted into King's College Hospital for sixteen weeks, and left much better. A year later, she was re-admitted for eleven weeks, because she had occasional attacks of imconsciousness, during which she squinted. Dui'ing the past year, there were further attacks of faintness and giddiness, which have been very much worse for the past three months. Three weeks ago, she dropped down unconscious in the street ; since then she has complained of continual dizziness and headache, and a marked tendency to fall to the right side when walking. On admission she had double optic neuritis ; the right pupil was smaller than the left, but both reacted to light and accommodation. There was paralysis of both external recti, paresis of the lower half of the left side of the face, and deafness on the right side. The patient could not hear a watch held within an inch of the ear, nor when it was placed on the temporal bone ; the tongue was protruded to the right, the other cranial nerves were normal. Muscular power and sensation in the arms was good and equal, tendon reflexes increased, there was inco-ordination. In the legs, muscular power and sensation were good and equal on both sides. Knee- jerks present and equal, no clonus, plantars brisk and flexor, co-ordination impaired ; other systems normal. On October 24th patient had an injection of " 606." On October 26th the paralysis of the external recti had completely disappeared, and there was less headache ; inco-ordination was less, the hearing on the right side had improved to the extent of hearing a watch held within one inch of the ear. The paresis of the lower half of the left side of the face, and the protrusion of the tongue to the left were still present. By November 8th, the facial paralysis had almost dis- appeared, the tongue was protruded in the middle line, and when the patient walked about the ward it was noticed that there was no tendency to fall to either side. When she left, on November 16th, one would not have known that there had been anything the matter with her. Mr. Etherington Smith examined the case on January 24th, and kindly sent me the following note : — " Her improvement has been maintained, and she has now no symptoms at all ; the optic neuritis has gone, leaving, of course, post-neuritic changes, and the 236 THE BI0L0C4y, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. vessels are markedly degenerate. She lias slight facial weakness on the left side, but all the other paralyses are gone. The left pupil reacts fairly well, the right is small and does not, which is probably due to old posterior synechiae. She now does all her ordinary work." Instead of the process spreading anteriorly, as it usually does, it may spread posteriorly, and involve the last cranial nerves, but fortunately syphilitic bulbar paralysis is rare. Another fairly common secondary lesion is one which gives rise to a sudden diplopia. The nerve most frequentlj^ affected is the third nerve, and the paralysis is due to a thrombosis of one of the arterial supplies to that nerve. The double vision comes on instantaneously. Often the patient wakes up in the morning to find the defect. Frequently the paralysis is preceded by head- ache. In almost every case, only one branch of the oculomotor nerve is involved. The patient is generally over 50 years of age, and the condition clears up under appropriate treatment, but it is, one might say, invariably the signal for a more extensive thrombosis at a later date. Within the last four years, I have seen three cases. In all the cases, the patients died T\'ithin three years from hemiplegia, with extensive haemorrhage. Lesions of Primary Origin. These are natm'ally lesions which commence in the nerves themselves or in their nuclei, hence they are degenerative in nature. Curiously enough, it is nearly always the eye nerves that are affected. Primary optic atrophy is the example of the second cranial nerve. Primary optic atrophy is always bilateral, but the sight in one eye is usually better than that in the other. In most cases, it is a matter of years before the patient becomes bhnd, and even then the blindness may not be absolute. The condition is almost always accompanied by a degenerative myelitis, but there are one or two rather interesting points about the ty|)e of the myelitis. The signs and symptoms of the degenerative myelitis are not, as' a rule, pronounced ; indeed, they may be missed, unless the patient is examined carefully. As a rule the knee-jerks are gone, and the patient may have a slight ataxia, but lightning pains are generally absent. Another very interesting point, is that in some cases the signs and symptoms of the degenerative myelitis vanish when the optic atrophy appears. I may say that I have never seen a case of optic atrophy accompanied by a very pronounced or severe degenerative myelitis. Statements have been made that, if treatment is sufficiently early prescribed, the course of the atrophy will be checked, but it must be remembered that, in many THE CLINICAL ASPECT OF SYPHILIS OF THE NERVOUS SYSTEM. 237 cases, the normal course is slow, eo that it would be an extremely difl&cult matter to say whether treatment had influenced the course or not. Nevertheless, treatment is going to do no harm. Salvarsan will not aggravate the condition, therefore every patient should be given the chance, and treated vigorously. The other nerves commonly affected are the sixth, the third, and the fourth. The diplopia following a lesion of any one of these cranial nerves is, usually, of slow origin. Individuals on the rightside of forty-five are those most commonly affected, and although the double vision may disappear under treatment, the chances are that the patient will develop degenerative myelitis, and more rarely encephalitis later. The course run by the cases varies enormously, but the follo'wing is what most usually happens. The patient complains of double \nsion. On examination, the external rectus is found to be paralysed on one side. Under treatment the paralysis disappears, or it may remain permanently. If the paralysis does disappear, it usually recurs later, when the lesion becomes more extensive and a part of the third nerve usually becomes involved. In time, in spite of treatment, all the eye muscles become affected, and the patient ultimately develops bilateral ophthalmoplegia. The trochlear nerve may be affected first, or the oculomotor nerve ; or ptosis may be the first indication that a cranial nerve is affected. Unless treatment is started early, and even in spite of treatment, atrophy of the affected nerve may quickly result. As a rule, when the case recurs, the paralysis does not disappear under treatment. The paralysis of the eye muscles generally precedes the degenerative myelitis, and often when the paralysis recurs, signs and symptoms of the myelitic condition begin. As in the case of optic atrophy, the degenerative myelitis which follows is not usually severe ; it is of the meningeal type, and whether it is only a coincidence or not I cannot say, but, in every case I have seen in which the paralysis has caused ptosis and affected many eye muscles, the patient has always had gastric crises. The knee- jerks have been absent, the patients have not been ataxic ; as a rule the patients have had areas of numbness, and every one has lost his sexual power. We will now pass on to the syphilitic lesions of the brain, and discuss them in the order in which they appear in the table in Chapter XXIII. Meningeal. Pachymeningitis. — A syphilitic inflammation of the dura may be either generalised or localised. Generalised pachymeningitis is one of the commonest symptoms of early syphilis, and is probably one of the causes of the headaches which are so frequently complained of in the generalisation stage. Chronic diffuse 238 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. pachymeningitis is a common cause of persistent headache in the later stages of syphilis — indeed, syphilis should be seriously considered in every patient over forty who complains of continual headache. It must also be remembered that pure arterial lesions are also a common cause of headaches in patients over forty, and it is highly probable that a diiJuse vascular lesion is the other cause of headaches in early syphilis. The generalised forms of pure pachymeningitis do not give rise to any other symptoms, and do not cause optic neuritis. The headaches may be situated anywhere, but as a rule they are worst over the vertex and at the occiput ; in fact, they are ofteia localised to one of these two areas. The pain does not tend to shift about, and not infrequently a tender spot is to be felt when palpating the head. The patient usually knows where it is, as he has frequent cause to touch it when combing and brushing his hair. Generalised pachymeningitis responds almost instantaneously to anti- syphilitic treatment, but the form occurring in late syphilis is very apt to recur, though never ^dth the same severity as before the initial treatment was prescribed. As to whether headaches are produced by meningeal or vascular lesions, the cerebro-spinal fluid must be examined before a differential diagnosis can be made. The locaUsed pachymeningitis is the Pachymeningitis gummosa, symptoms of which are indistinguishable from those of cerebral tumour. An examination of the cerebro-spinal fluid and watching the effect of treatment are the only means of making a differential diagnosis. Leptomeningitis. — A diffuse syphilitic inflammation of the dura is most common on the vertex, while a diffuse syphilitic inflammation of the arachnoid and pia is most common on the base. Leptomeningitis does not cause headaches. As a rvile, it does not give rise to symptoms till late in the disease, when an affection of certain cranial nerves calls one's attention to it, and it frequently causes optic nem'itis. Meningo-encepJuilitis. — The diagnosis of meningo-encephalitis is not a difficult matter, but it is important to ascertain, as soon as possible, whether the lesion is a degenerative one or not. , The meningo-encephalitis may be diffuse or localised. If diffuse, besides the headaches of which all patients complain, the chief symptom is a progressive dementia. The patient is apathetic. He takes no interest in his work, and his memory deteriorates ; but there is neither the exaltation nor the depression, which are characteristic of the degenerative type. Other symptoms are that the patient becomes slovenly in his habits, and all his movements are slow, and bis reactionary period is lengthened. The pupil anomalies are an exceedingly important and frequent symptom. THE CLINICAL ASPECT OF SYPHILIS OF THE NERVOUS SYSTEM. 239 The pupils maj^ be equal, dilated, but tlieir reflexes sluggish. On the other hand, they may be unequal, and the reflexes may be absent only on the one side. It is because of the pupil anomalies that a diagnosis of degenerative encephalitis is frequently made. If the reflexes of the affected pupil are absolutely lost before treatment is commenced, it may generally be presumed that the patient has a degenerative lesion. In a degenerative lesion, tremors are more constant and marked than in a non-degenerative lesion. To make absolutely certain as to whether one is dealing with an ordinary case of meningo-encephalitis, or with a degenerative one, the only way is to watch the effects of treatment upon the pupils. If the reflexes return, the case belongs to the former category, if they do not return, then the case is a degenerative one. It must be remembered that a degenerative meningo-encephalitis may begin as an ordinary case of meningo-encephalitis. The age of the patient, the time of onset of the symptoms after the infection, and an examination of the cerebro-spinal fluid, are points which will weigh in a properly adjusted balance, and cause either the scale which represents the degenerative form, or the other to fall. Localised meningo-encephalitis is very seldom degenerative, therefore the difficulty of mistaking the two does not arise. Jacksonian epileiDsy is a common symptom of this localised form. Monoparalyses and hemiparalysis may be met with. The patient may have attacks of unilateral or localised paraesthesias, usually accompanied by dizziness. Cortical speech disturbances and hemianopsia are other symptoms which may be encountered. When optic neuritis is met with in meningo-encephalitis, the chances are in favour of the lesion being basal and not cortical, therefore, in all cases in which optic neuritis occurs, a thorough examination of the cranial nerves should be instituted, as an affection of any one of these practically clinches the diagnosis of a basal meningo-encephalitis. a form of encephalitis which is practically never followed by the degenerative form. Treatment of ordinary meningo-encephalitis is always followed by excellent results, and, if the treatment is thorough, the tendency to recur is small. Ameningeal. Endarteritis. — Endarteritis may be an early or a late symptom of syphilis. In the early stage, hemiplegia is the commonest lesion, and the course of the case is nearly always of this fashion. The patient complains of bad headaches, which he may have had for some days, or only for a day or two. With the exception of the headache, which may even in some cases be absent, the patient goes to bed feeling perfectly well, and wakes up in the morning, to find himself paralysed down one Q 240 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. side. If treatment is commenced at once, the patient so far recovers that an expert would fail on examination to discover that the patient had ever had hemi- plegia. If treatment is delayed, restoration is never complete, and there is great risk of contractures, etc., supervening. The great difference between early and late hemiplegia is that, in the latter, there is always haemorrhage, which ultimately kills the patient, if not during the first attack, during a subsequent one, and the hemiplegia is often preceded either weeks, months, or years by a small endarteritic lesion elsewhere, such as, for instance, an ocular palsy. Haemorrhagic ejicephalitis and gumma have already been described, and need no repetition (tJw/e Chapter XXIII. ). Degenerative Encephalitis. — As has been already seen, degenerative encephalitis may be of meningeal or of ameningeal origin. The prognosis of the meningeal form, so far as relapses or periods of quiescence are concerned, is better than in the ameningeal form, for reasons already explained. Treatment in both forms is very unsatisfactory, and, in the ameningeal form, usually results in hastening the end. The following case is instructive. Ca.se 41. — A man, aged 39, contracted syphilis in 1896. He had several primary sores, and the usual symptoms of the generalisation stage. He was treated with mercurial inunctions for six months, and then developed a right-sided hemiplegia. The mercurial inunctions were continued, in spite of the hemiplegia, with the result that, in three days, the patient could talk again, and in a few more days the power in the arm and leg returned. Mercurial treatment was continued for over three years. The patient consulted me in Julj^ 1914, because he felt so fearfully depressed. The depression bordered almost on suicidal mania. The pupils were unequal, E. > L. The left pupil did not react to light, but it did to accommodation, while the right pupil reacted to both. All the reflexes were exaggerated, and the patient had tremors. It should be said that the depression had set in, only three months before I saw him. > Examination of the cerebro-spinal fluid: Pressure not raised. Lymphocytes, 12 per c.mm. Phase I feebly positive. Wassermann reaction positive in 1,000 per cent, only If any case appeared amenable to treatment, this one certainly did, so I gave eight intraspinal injections of salvarsanised serum, the number required to render the cerebro-spinal fluid absolutely normal. The patient appeared to improve somewhat, and the reflexes in the left pupil were undoubtedly brisker than they were to start with, but the faint reaction to light only lasted for a few days. A fortnight later THE CLINICAL ASPECT OF SYPHILIS OF THE NERVOUS SYSTEM. 241 the patient suddenly entered the exaltation stage ; a week later he became violent, he then gradually became more and more demented, and had to be interned in an asylum. I was able to get the cerebro-spinal fluid absolutely normal, and yet the case went more and more downhill. From other similar experiences, I have decided not to prescribe anti-syphilitic treatment in cases of degenerative encephalitis, especially if they are of ameningeal origin. A very interesting point, and one which, to my mind, throws considerable light upon the explanation of the Argjdl-Robertson pupil, is the fact that pupil anomalies are less frequent in cases of degenerative encephalitis than in cases of degenerative myelitis. Since, moreover, pupil anomalies are to be met with in cases of degenera- tive encephalitis, there nmst be some regulating factor of the pupil in the cerebral cortex. Cord. Me7iingeal. Pachij- and Leptomeningitis. — Owing to the fact that the spinal cord itself does not occupy the whole of the spinal space, symptoms of a spinal meningitis are not usually pronounced enough to cause the patient to seek advice. Furthermore, a spinal meningitis is most often a combined meningitis, and even if one gets a true pachymeningitis or a true leptomeningitis, it is not a very simple matter to difEerentiate them, therefore the two forms will be considered together. It is said that the meninges of the spinal cord are much less frequently affected than the meninges of the brain. This is certainly not true, although it is a fact that cranial meningitis is much more frequently met with than spinal meningitis, for the simple reason that an inflammation of the meninges of the brain always gives rise to symptoms, while inflammation of the meninges of the cord only gives rise to symptoms when the inflammation is particularly severe. Although, for sake of convenience, a line is drawn between cranial and spinal meningitis, the reader must never forget that a combined cerebro-spinal meningitis is more common than either a pure cranial, or a pure spinal lesion. In cerebral meningitis, the meninges covering the cortex are more frequently involved than those covering the base. In the case of the cord, this is even still more marked, as, in the majority of cases, it is the posterior surface that is affected. The symptoms are pains in the neck, between the shoulder blades, and down the back. Paraesthesias of the extremities, especially of the legs, are commonly to be met with. A tender spot may be elicited on tapping the vertebral column. The 242 THE BIOLOGY. CLINICAL ASPECT AND TREATMENT OF SYPHILIS. tendon and skin reflexes are usually increased. Symmetrical analgesia, or a distui'bance in the temperature and touch senses, often occur as early symptoms. If the symptoms are severer than those described, either the meningitis has caused a root neuritis or a myelitis. Meningo-myelitis. — This is the form of spinal cord syphilis which is most frequently encountered, as the symptoms caused compel the patient to seek advice. The symptoms are either exaggerated forms of those above described, or they may be only slight. On this latter account, it is by no means always an easy matter to distinguish between a spinal meningitis and a meningo-myelitis. In undoubted cases of meningo-myelitis, the tendon reflexes are, at any rate at first, usuall}' increased, but the skin reflexes are as often diminished as they are increased. Babinski's and Oppenheim's phenomena are usually present, but they may be ascertainable on one side only. A weakness of the bladder and sexual functions are common symptoms. The symptoms of meningo-myelitis vary, according to the part of the cord affected. Those already described are typical of an affection of the dorsal region, the part of the cord which is most frequently involved. Should the meningo- myelitis be most marked in the lumbar region, the bladder and sexual symptoms come more to the fore, and, as a rule, all the reflexes are absent. If, on the other hand, the inflammation is most pronounced in the cervical tegion, the reflexes of the upper extremities are altered, and the varied cutaneous sensations are to be found in the arms. Owing to the close connection between the cervical and sympathetic nei-ves in this region, pupil anomalies are to be met with, and also other signs of an affection of the sj^mpathetic system. The pupil on the affected side is smaller than the one on the opposite side. The eyeball may appear more .sunken, and alterations of blood supply and sweat secretion of the face, on the ^affected side, may be very noticeable symptoms. If meningo-myelitis were a distinct disease, it would not be difficult to diagnose it, but as it is in most cases accompanied by meningo-encephalitis, and as the symptoms of the latter usually both precede and are severer, or, better td say, more noticeable than those of the former, the diagnosis is complicated. This is, no doubt, the reason why the term cerebro-spinal syphilis was given to the combined condition. Meningo-myelitis differs in no way from meningo-encephalitis, that is to sa}% ^;he case may run an extremely acute course, and may kill the patient. On the other 'hand, it may advance verj' slowly, and with the exception of the very acute cases, if treatment is prescribed early enough, and is sufficiently drastic, the condition may ibe cured. If he disease has progressed fai- before treatment is prescribed, naturally. THE CLINICAL ASPECT OF SYPHILIS OF THE NERVOUS SYSTEM. 243 secondary degeneration will ensue, and the case will become one of degenerative myelitis. Just as it may be difficult to differentiate the degenerative from th& non-degenerative form of meningo-encephalitis, so may the differential diagnosis of the two forms of meningo-myelitis be by no means an easy matter. Hence the reason why we meet with the term " pseudo-tabes " in literature. As both the degenerative and the non-degenerative types of meningo-myelitis frequently exist together, one cannot tell to what extent the lesion is degenerative until thorough treatment has been given. Since treatment can do no harm in any form of meningo-m5'elitis, provided it is not stopped too soon, every doubtful case should, at least, be given the chance of being improved thereby. Ameningeal. Paraplegia. — Like hemiplegia, paraplegia occurs in early syphilis. The patient often wakes up to find his legs paralysed, and the paralysis is frecpiently preceded by acute pains down the lower extremities. Occasionally the course is slower, or a transient paralysis is all that occurs, or only one leg is paralysed. When only one leg is paralysed, the other may follow suit at a later date. If treatment is prescribed early, no trace of the lesion is left behind. It is frequently stated that the condition is liable to recur. I have seen many cases of syphilitic paraplegia, but have only notes of a single case in w'hich the condition recurred, four years after the first attack. Transverse myelitis is the term usually applied to the lesion, but it must be remembered that there is not in every case an involvement of nerve substance. Besides the paralysis, the other symptoms are, loss of sensation, increased tendon reflexes, or abolished tendon reflexes. If the lesion is located in the lumbar cord, paralysis of the sphincters of the bladder and rectum, and oedema of the lower extremities, and decubitus are sometimes to be met with. The advent of transverse myelitis may sometimes be anticipated, before the condition actually occurs, as the prodromal symptoms may be quite pronounced. If treatment is begun then, the onset of paralysis may be thwarted. The prodromal symptoms can be divided into sensory, motor, and sphincteric disturbances. The sensory symptoms consist in paraesthesias and radiating pains down the lower extremities. Sensitiveness to movements of the trunk is very characteristic, and is a point upon which Charcot always laid emphasis. The motor symptoms consist in twitchings of the toes, feet or legs, with, maybe, transient palsies thereof. Paralysis of the sphincters may be preceded, as Williamson has pointed out, by retention. 244 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. Arterial Lesions with involvement of the Nerve Substance. — The myelitis may be haemorrhagic in character, analogous to haemorrhagic encephalitis, and, like the condition just mentioned, it generally has a fatal termination. I have only had one case of this form of myelitis, and, in spite of commencing treatment at once with salvarsan, mercurial inunctions, and potassium iodide internally, the patient died. Naturally, there are stages of haemorrhagic myelitis, as there are stages of haemorrhagic encephalitis. By this I mean that some cases are foudroyant and haemorrhagic only. Others, again, are less acute, and death does not take place so quickly.' Post-mortem, instead of finding dilated vessels with extramural haemorrhages, there is a marked lymphocytic infiltration — lymphocytic myelitis. In those cases of myelitis where the involvement of the nerve substance is less sudden and the area is less, varied conditions may be met with, such as localised muscular paralyses, the syphilitic form of Landry's paralysis, lateral sclerosis, gumma, and degenerative myelitis (tabes) itself. Degenerative myelitis usually begins de novo, or it may be preceded by a localised muscular paralysis, or even by the sj'philitic form of Landry's paralysis. Instead of one muscle being paralysed, several muscles may be paralysed, with the result that a true syphilitic anterior poliomyelitis may be met. Degenerative Myelitis. — The name most frequently given to this condition is tabes or locomotor ataxy. Since, broadly speaking, hardly any two cases of tabes are exactly alike, since the antitheses to the so-called classical signs may frequently be met with, since the origin is not always the same, and, finally, since patients have such a wholesome dread of the condition, it appears to me to be wiser to drojj the terms tabes and locomotor ataxy, and to supplant them by the general term — degenerative myelitis. Degenerative myelitis may be of meningeal or ameningeal origin, and, in those cases in which it is possible to differentiate, it should be done, because the prognosis is better, and treatment ma}^ be expected to be more efficacious, in the meningeal than in the ameningeal form. It may be impossible to differentiate the two types, and often one has to watch the effects of treatment, before being able to do so. A close attention to the follo-R-ing points will assist the observer to know with which type he is dealing. The onset of symptoms is slower, and the progress of the disease is much more insidious in the meningeal form. As a rule, the meningeal form begins sooner after the infection than does the ameningeal form. The patient loses weight more quickly, and appears to be more generallj' affected, in the ameningeal form. Trae Argyll- Robertson pupils, i.e., pupils which are of the same size, and react to accom- modation and not to light, are a more common symptom in the meningeal form. THE CLINICAL ASPECT OF SYPHILIS OF THE NERVOUS SYSTEM. 245 In the other form, the pupils are often irregular, and the reflexes may be only sluggish to light and sluggish to accommodation, and, as a rule, the reflexes are diminished on one side more than on the other. In the meningeal form, lightning pains are more pronounced, the knee-jerks are always absent, and ataxia is generally an early symptom. In the ameningeal form the pains may be absent, the knee-jerks may be present and even exaggerated, ataxia may not be met with until late, and, as a rule, the altered cutaneous and tendon sensations are more marked. Trophic disturbances are more frequently met with — anyhow as earlj^ signs of the disease — in the meningeal form, while paralyses are commoner in the ameningeal form. In the former, the Wassermann reaction in the blood is less frequently positive than it is in the latter. The cause of this is probably due to the fact that the ameningeal form is caused by a primary disease of the blood-vessels in the cord itself, because the lesion is sometimes really only a symptom of a general arterio- sclerosis, and because aortic disease more frequently accompanies this form, for, in most cases of syphilitic aortitis, the AVassermann reaction of the blood is positive. An examination of the cerebro-spinal fluid helps one in differentiating the two types of myelitis, but it must be remembered that spontaneous cure of the meningeal form is not a very uncommon sequence of events, hence, if such a case is met with, the cerebro-spinal fluid may be normal. The pressure is more often raised in the meningeal form, the lymphocytosis is more marked, and consists of lymphocytes and endothelial cells onlj*. The ratio between the amount of albumin and globulin is not so great, the increase of globidin is not so marked, and the Wassermann reaction, when tested quantitatively, is not so positive. In both conditions there is an increase of globulin, but there is a greater increase of albumin and a lesser increase of globulin in the meningeal, than in the ameningeal type, therefore the difference between the two is less marked in the former. When attempting to differentiate the two forms, every pomt must be taken into account, and the diagnosis must not rest on one or two only, since the stage of the disease, its severity and localisation — i.e., as to whether the process is mainly cervical or mainly lumbar — are strong influencing factors. I do not want to mention all the symptoms of degenerative myelitis, as they are legion, and can be better studied elsewhere ; but I will mention those which the reader is most likely to come across, and for which there is a probable explanation. Mention will be made of the Argyll-Robertson pupil first, because the opinions as to its origin are much at variance. The most probable explanation of this phenomenon, to my mind, is that it is due to an affection of the cervical sympathetic. The pupillo-dilator fibres arise from the first, second, and third dorsal nerves. They pass upwards, in the ascending branch of the superior cervical 246 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. ganglion, and thence to the Gasserian ganghoii, reaching the eyeball through the first division of the fifth and the long ciliary nerves. The proof of this is forthcoming, in the fact that the fibres which travel along the first division of the fifth travel along the nasal nerve. Now, as many observers are aware, the tactile sensation in the skin over the nose is, in a very large percentage of eases, very considerably lessened. Again, this pupil phenomenon is more constant in the meningeal form of degenerative myelitis — in fact, sympathetic nerve lesions are in general more common in this form, probably owing to the implication of the nerve roots being easier in a primarily meningeal infection. It is possible that a lesion of the sympathetic nervous system is primarily responsible for laryngeal and gastric crises, and also for those unpleasant cases in which the pulse slows down and finally stops for a brief interval of time, and the patient becomes almost unconscious, and turns a very bad colour. I had one case in which these cardiac symptoms were most distressing, and no anti-specific treat- ment could be administered, as it always aggravated the attacks. This same patient had very severe gastric crises. Concerning the other symptoms to be mentioned, it must be borne in mind that almost any one may occur alone, often for some years, that almost any one may precede or succeed the other symptoms, and that almost any one may persist, in spite of the fact that spontaneous cure has resulted. One of the most common symptonas of degenerative myelitis is pain. The pains may be of the nature of crises, or lightning pains down the extremities, usually down the legs. The abdominal pains are very apt to be mistaken for biliary or renal colic, or some intestinal trouble. I have had three patients who had had gastro-jejiinostomy performed, and one of the patients had been operated upon twice ; therefore, in all acute abdominal conditions, the surgeon should exclude degenerative myeUtis before undertaking an operation. The lightning pains in the extremities are apt to be mistaken for rheumatism or neuritis, but the following are points, the remembrance of which should minimise the observer's risk of making an error : — ' If the lightning pains are in the arm, they are usually limited to the region of the ulnar distribution ; and the skin over this area, even if there are no pains, is very often insensitive. If the lightning pains are in the lower limbs, they are usually most marked below the knee. They are often limited to the heels, ankles, or toes, and are very liable to affect one spot at one time, and another spot at another. Reduced tactile sensation is very marked in the skin of the feet and ankles, but it tends to become normal again as the knees are reached. THE CLINICAL ASPECT OF SYPHILIS OF THE NERVOUS SYSTEM 247 Pains are due to the degeneration of those fibres which connect the posterior nerves with the cord. As I have already stated, when dealing with peripheral neuritis, provided the degeneration of sensory nerves has progressed to a certain extent, pains will persist, in spite of the fact that the cause of the degeneration has vanished. Analgesia is by no means limited to the areas above mentioned. The loss of sensibility to pain, in the skin of the nose, is a very common symptom, and the analgesia of the skin of the chest, the upper margin of the zone lying at the level of the second rib in front, is practically speaking a constant sign. Although the loss of the knee-jerk is a very common symptom, it must not be forgotten that, in some cases, they are not only present, but they may be even exaggerated. The loss of the knee-jerk depends on degeneration of those fibres, or their collaterals, which pass to the motor cells in the ventral horns of the spinal cord, hence it will be understood why the loss of the knee-jerk is more common in the meningeal than in the ameningeal form of degenerative myelitis. The explanation of the converse is equally clear. If the lesion commences in the anterior part of the cord, the knee-jerks will be exaggerated, and only when the posterior columns are reached will the reflexes vanish. Rhomberg's sign is due to the degeneration of certain fibres in the posterior and lateral columns, and therefore again is most marked in the meningeal form — indeed, in some cases of ameningeal degenerative myelitis, not only is Rhomberg's sign absent, but the patient is not ataxic. The ataxic gait is supposed to be due to a certain set of nerve fibres which terminate in Clarke's column, which is indirectly connected with the cerebellum, and part of the brain, which is well known to exercise a constant controlhng and co-ordinating influence on volitional movements, and especially on those which maintain equilibrium. Another very common symptom of degenerative myelitis is a diminution or complete loss of all sexual desire. Other less constant symptoms are insensibility of the tendons, Charcot's joint, perforating ulcers, whitlows, and spontaneous fracture of the patella or os calcis, ■ and bladder disturbances. Of these, the first is not infrequently a very striking sign, and it is an easy one to elicit. The tendo Achillis, when pressed hard, is pain- less. The same phenomenon may be experienced ■with the biceps tendon at the bend of the elbow ; but, as in most cases of degenerative myelitis, the signs and symptoms of the upper extremities are not so pronounced as those of the lower, for the simple reason that the lesion is usually below the cervical enlargement of the cord. Insensibility of the tendo Achillis generally goes by the name of Abadie's sign. CHAPTER XXV. SYPHILIS IN WOMEN. Syphilis in women may be looked upon as the greatest curse of the disease, since a woman who has once conceived a syphilitic infant may infect, in utero, all her subsequent offspring, although the father of the latter may be a different husband who has never suffered from the disease. To make matters worse, conceptional syphilis is not recognised until the infant has been seen to settle the diagnosis, owing to the fact that many mothers show no evidence of the disease until after the child-bearing period is over, as the following two cases illustrate : — • Case 42. — Mrs. A. B., aged 46 j^ears, came up to hospital in March, 1910, complaining of a rash on her right arm. The rash had appeared about Christmas, 1909, and, some short time before, she had had some sore places on the right leg. The lesion on the arm was a gumma, and the right leg was covered with the scars of gummatous ulceration. This patient was 21 years old when she married, and neither before her marriage nor since, until the date above-mentioned, had she ever experienced the slightest evidence of syphilis. She had had four miscarriages ; eleven children were born, two of whom were still living — the results of the second and fourth pregnancies. All the other children had died within six months after birth, as the result of syphilis. Her last pregnancy had been a miscarriage, immediately after which she developed a bad leg ; this period also corresponded with the change of life. The patient had giVen a strong positive Wassermann reaction. Her second pregnancy resulted in the birth of a son, who had given a negative Wassermann reaction, as had also his wife and child. The fourth pregnancy resulted in the birth of a daughter, who had also given a negative Wassermann reaction. Neither child had shown the least taint of the disease. Case 43. — L. B., aged 47 years, had come up to hospital complaining of sores, on the calf of the right leg, which were typical gummata. As in the preceding case, the ulcers had appeared just after the " change of life." The patient had been SYPHIIJS IX WOMEN. 249 pregnant nine times : the eliildren had mostly been premature. Some liad been born alive, others born dead, but not one had lived for more than three weeks. Since 1910 I have seen numerous similar cases, in all of whom I was able to obtain a positive Wassermann reaction, provided the child-bearing period was over. This led me to rely upon, and to do the test, in every case in which a syphilitic infant had been born, when, to my surprise, I found that many cases of women who were giving birth to syphilitic children themselves gave a negative Wasser- mann reaction. A rough rule can be formulated, viz., that if a woman contracts syphilis after she has conceived, the Wassermann reaction will be positive, because the disease becomes generalised, and behaves in the ordinary way ; that if a woman contracts syphilis at the time of conception, the Wassermann reaction may be negative, because the disease, even if it do become generalised then, does not give rise to symptoms until some later date. Herein we have the explanation why such patients only develop manifestations after the child-bearing period is over, and why it so frequently happens that the first and last pregnancies result disastrously, while one or more healthy children may be born in the middle. It is interesting to inquire into the rationale of conceptional syphilis. The germ must, in the first instance, be conveyed by the semen. But does the germ, which travels with the embryo along the Fallopian tube into the uterus, develop after a time into the gamete forms described by me, which I regard as responsible for the s}-mptoms, at the expense of the embryo — with, maybe, its death — leave some of the sporozoites behind after its expulsion, to be already there to develop at the expense of the next embryo ? Or, does the mother become infected directly, but the symptoms are prevented from recurring, owing to the formation of some chemical substance, possibly in the form of a lipoid-globulin compound from the embryo, which prevents the gametes from being developed ? When the question was discussed after the Spirochaeta pallida had been discovered, when the Spirochaeta pallida was held to be responsible for everj'thing syphilitic, only confusion resulted. If my discovery of the Leucocytozoon syphilidis be accepted, and the views accepted that the sporozoite is the infective agent, and that the gametes are responsible for the symptoms, the alternative need not appear in the above illustration, as both in part may turn out to be correct. It may be considered that the sporozoites, themselves onlv potentially harmful, travel in the semen, reach the uterus with the embryo along the Fallopian tube, and find themselves in both the maternal and foetal portions of the embryo. Those 250 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. in the foetal portion, after a period of some weeks, develop into gametes, which may or may not kill the embryo. Those in the maternal portion find themselves unable to develop, owing to a chemical substance, from the chorionic cells, which circulates in the mother's blood but not in the foetal, and so they remain dormant for a tune. Herein lies the solution of the phenomenon that a mother may give birth to a severe syphilitic infant, without herself even giving so much as a positive Wassermann reaction. The theory above put forward will also explain why a woman who has once given birth to a syphilitic child is always liable to do so again, although the father of her later children may be another husband, who has himself never suffered from the disease. Hence the necessity for treating such a case throughout the whole period of each succeeding pregnancy. There is no necessity to refer to the lengthy discussion relating to the greater frequency of maternal over paternal infection, or vice versa. A father may be the cause of his first infant contracting the disease ; the mother, ipso facto, becomes likewise affected ; her future children may be by another and a healthy man, but they may all be syphilitics. Therefore, maternal syphilis must obviously be more important and more frequent than paternal sj^philis. The only reliable information as to the national loss by ante-natal syphilis is the oft-culled figures of Hochsinger.^ ^ This observer, since 1869, had been able to keep under observation 134 women who showed no signs of syphilis, but had given birth to syphilitic children. These women had given birth 569 times, 253 of the children being born dead, i.e., 44*4 per cent. ; and 316 were born alive. Of those born alive 263 were syphilitic, and 53 were without a taint. Of the 263, 55 died before the fourth year, i.e., over 20 per cent. These figures are so appalling, that it is of the utmost importance for every medical man to have particular regard for the welfare of syphilitic women, in seeing that they are properly treated. ' Keference must now be made to what we have called Colles' law, although Colles originally stated merely that syphilitic children did not infect their mothers. Colles neither enlarged upon this nor attempted to give a reason for the phenomenon. It is perfectly true that syphilitic children cannot infect their mothers, the reason being that the mothers are invariably syphilitic themselves, in spite of the fact that they may never have had symptoms nor have given even a positive Wassermann reaction. Colles' observation goes strongly to support my view SYPHILIS IN WOMEN. 251 of there being jjhases in the life history of the organism of syphilis other than the Spirochaeta pallida. The observation, moreover, shows that no deductions can be made from a negative Wassermann reaction, where women are concerned. Profeta's law states that a healthy child boru of a syphilitic mother is immune against syphilis, but loses its immunity at puberty. Apparently healthy children may be born of syphilitic mothers but yet be syphilitic, although they may never show signs or symptoms of the disease. On the other hand, absolutely healthy children may be born of syphilitic mothers, but they are not immune against the disease. This possibility should especially be borne in mind to-day, when it is almost always possible — by thoroughly treating a syphilitic mother throughout the whole of her pregnancy — to render the child non-syphilitic at birth. Under such conditions, the mother should never be allowed to suckle the child, because in some cases the mother is not cured by the treatment, and the infective agent can pass through in the milk. While CoUes' law still holds good, Profeta's law does not. The Primary Sore. Many of the points about to be mentioned have already appeared in Chapter XIV., but as the clinical diagnosis of the initial lesion is the most important part of the struggle against the whole disease, recapitulation is pardonable. A chancre may occur in any part of the \'ulva, vagina or cervix uteri. It always begins as a tiny papule, which in time becomes eroded on the surface. No value should be attached to history. Asking a patient how soon after connection a sore appeared is often useless, because not infrequently a woman does not know that she has even got a sore. The good old rule that multiple sores are soft sores, single ones syphilitic, has led many astray. A single sore on the genitals is usually syphilitic, but not invariably. Induration, when present, is positive, but its absence does not negative syphilis. Many of the multiple primary sores on the external genitals of women never are indurated. Of the greatest value in differential diagnosis is the appearance. A syphilitic sore is sharply circumscribed, not irregular or undermined at the edge. The erosion is either on a level with the surrounding skin or raised above it. The surface is often dry, especially when on the labium majus ; it has a shiny appearance, bleeds easily on friction, and does not discharge freely. There is none of that surrounding inflammation which is so typical of soft sores and of other infective sores, because the organisms of the latter are pus-producing 252 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. organisms, while the Leucocytozoon syphilidis is not. This is also the reason why the inflammatory sores are undermined, ragged-edged, and depressed in the centre beneath the circumference — ulcers, in contradistinction to erosions — and an ulcer covered with pus, which discharges freely. Clinical Types op Chancres. 1. Erosive chancre. — This is the most typical of all chancres. It is found most commonly on the labia. There is often a corresponding sore on the opposite side. It varies in size from that of a threepenny to that of a shilling piece, or it may be bigger. It is red, has a shiny surface, the erosion is flush with the surface, and the circumference is sharply circumscribed and regular. Induration is usually present, but a common symptom is the non-inflammatory hard oedema of the labium on which the sore is situated. The oedema is due to syphilitic lymphangitis. 2. Papido-piistular chancre. — This chancre is almost invariably single, and practically only found on the true skin. •3. Ecthymatoiis chancre. — This chancre is also most frequently found on the skin. It is usually single, sharply circumscribed, raised and crusted on the surface. With this chancre there is often some inflammation of the surrounding tissues, owing to the fact that it is a chancre which has become secondarily infected. 4. Ulcerative chancre. — This may be a sequela of any chancre which becomes secondarily infected. A phagedaenic chancre is a further stage of this variety. 5. Pseudo-membranous chancre. — These chancres are usuall)'^ multiple, they are about the size of a threepenny piece, they have a yellow base, which may be flush with the surface or raised above it, and there may be a red inflammatory ring surrounding each lesion. These chancres are usually slightly indurated. At first sight, the chancres look like soft sores, but they can be easily distin- guished . Although the former have a yellow base, no pus comes away from them. They are regular in outline, unlike soft sores. And, again, soft sores always tend to advance in one direction, while healing is taking place at the opposite pole. Further- more, the surrounding inflammatory zone is much more apparent in the soft sore lesions. 6. Hypertrophic chancre. — This type of chancre is uncommon, but may some- times be met with on the labia majora. It is, almost invariably, single, and it closely resembles the hypertrophic large spore ringworm seen on the hairy parts of the face. 7. Lenticular chancre. — These chancres are invariably multiple. They vary in SYPHILIS IN WOMEN. 253 diameter from 1-5 millimetres; they are circular, regular in outline, and are merely abrasions. 8. The furrowed chancre. — This chancre may be single or multiple. It is never indurated, and at first sight looks not unlike a soft sore. It is sharply circumscribed and circular. There is no surrounding inflammation ; there is little loss of surface, but the base of the chancre is yellow and very uneven, not unlike a ploughed field. There are several other types of chancre which are merely transitions of the above, and naturally the characters of a chancre may alter, according to the position in which it is situated. For instance, an erosive chancre occurring on either side of a fold may be deeply fissured in the centre. Then the mixed chancre has to be considered, i.e., when a patient is infected at the same time with the bacillus of soft sore and with the organism of syphilis. Owing to the short incubation period of the former, and the long incubation period of the latter, a soft sore may appear long before the papule of the syphilitic erosion has begun to develop. In the case of a mixed infection, the soft sore may not heal, and so it may gradually develop into a chancre, so that, in every case of a soft sore infection, the patient should be kept under observation for two months at least. Most of the types of chancres above described may occur in the vagina, and on the cervix uteri. In the vagina, they seldom give rise to difficulties in diagnosis, because other venereal infections very rarely attack that tract. Chancres on the cervix are frequently diagnosed wrongly, and then are usually mistaken for erosions, aphthous ulcers, gummata and tuberculous ulcers, and Vlcera mollia. Cervical Chancre. Chancres of the cervix nearly always give rise to an indurative oedema of the whole cervix, often giving it a characteristic dark red-purple colour, as if it were venously congested. Erosions can be distinguished from chancres, because the cervix is soft, and of normal colour ; the erosion is bright red, not as a rule sharply circumscribed. In some areas, it is difficult to say where erosion ends and normal nmcous membrane begins, a feature which is common to traumatic lesions. If an erosion is covered with pus which looks like a membrane, it is easily rubbed off, and this is not the case with a primary sore. The follicular and papillary erosions are too distinctive to be confused with any other condition. In a majority of cases where there is an erosion, there is a discharge or exuda- tion from the cervical canal, and this discharge was possibly primarily responsible for the erosion. 254 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. ApJithous ulcers are soft, multiple, either flush with the surface or only a little depressed beneath it. They have no undermined edges, such as soft sores frequently have. They have a membranous base which cannot be rubbed away, and they are almost invariably surrounded by a narrow inflammatory ring. Gummata are more deeply ulcerated than chancres. Unlike chancres, they tend to spread a little, and, for the degree of ulceration, the surrounding parts are softer and less inflammatory than would be the case if in an ulcerative chancre. Tuberculous ulcers only occur in women who have marked signs of tuberculosis elsewhere. The ulcers are, as a rule, circumscribed, and can generally be diagnosed from other forms of ulceration, because, surrounding the ulcers, tubercles are fre- quently to be seen, and tuberculous ulcers are very painful. Ulcera mollia. — The sores are soft, multiple, undermined, and surrouiided by a red and inflammatory ring. They discharge freel)', and the ulcers quickly spread, but as a rule in one direction only. Syphilitic sores of the external genitalia are frequently mistaken for soft sores. This need not be so, for they can be readily distinguished clinically. Failing clinical differentiation, they may be distinguished pathologically, since the spirochaeta can be found in the former, and Ducrey's streptobacillus, a gram negative organism, in the latter. Syphilitic sores may be confounded with Vulvitis erosiva et gangrenosa, and with the Ulcera pseudo-venerea. A soft sore possesses a feature which is possessed by practically no other ulcer with which we are concerned ; it is auto-inoculable. The Ulcera pseudo-venerea have only very recently been recognised, owing to the work of Lipschiitz.^ Their occurrence should always be borne in mind, since virgins are most frequently aSected, therefore they are not venereal in origin, in the sense that sjrphilis is so. They may occur " over night," and are usually ushered in with fever, rigors and local pains. With or without treatment they tend to disappear quickly. In other cases the onset is not so sudden, and the course of the trouble may last several weeks. ' The ulcers are soft, deep, usually undermined, and the base is covered with pus. Owing to the close resemblance these ulcers bear to soft sores, a bacteriological examination is usually necessary. The organism always found in Ulcera pseudo- venerea is a Gram positive bacillus, occurring either alone or in chains, or in threads like a streptothrix. Its ends are square, and no success has so far been achieved in attempts to cultivate it. Oddly enough, two cases of which I have notes gave a positive Widal's reaction. Lipschiitz also had a similar experience, although none of the cases developed other SYPHILIS IN WOMEN. 255 symptoms of typhoid. A bacteriological examination will also serve to distinguish these ulcers from the Ulcera gmigrenosa, in which the fusiform bacilli and un- evenly coiled spirochaetae are found living in symbiosis — the same organisms which cause Vincent's angina. Generalised Syphilis. The marked difference between the stage of generalisation, as it affects men and women, is the very much larger proportion of the latter which develops Leuco- derma colli. The areas of leucoderma may be discrete or confluent. When confluent, they are frequently arranged in the form of a rosette. These areas occur where macules have been, and, not infrequently, in the centre of the depigmented area, a hyperpigmented spot is to be seen, and it occurs where a papule has succeeded the macule. The condition is more common in brunettes than in blondes, because it is more easily seen. The condition is probably more common in women than in men, owing to the skin being more delicate and not so red in the former, therefore the contrast is more noticeable. Most women exhibit the condition ; it may be limited to the neck and anterior folds of the axillae, or it may occur over the whole body. Treatment does not alter the condition ; it is a chronic one, begins in the early stage of the generalisation of the virus, and only tends to disappear in course of time, which is often a matter of years, usually from one to four years. Syphilis of the Generative Organs. Unfortunatel)'^, this branch of syphilis is still more or less veiled in obscurity. A few stray cases of syphilis of the uterus, Fallopian tubes, and ovaries have been described, but no light has been thrown upon them, so far as their differential diagnosis and pathology is concerned. Recently, some observers have attempted to gauge the relative frequency of syphilis as the cause of chronic metritis, by the Wassermann reaction. In the first place, the percentage of positive results obtained was too great to allow much unportance to be attached to them ; and, in the second place, because the reaction is positive, it does not necessarily follow that the menorrhagia and metrorrhagia of which the patient is complaining are significant of a syphilitic metritis. Such symptoms are common in women who have had children, but have never suffered from a venereal disease. They are extremely common in women who have had gonorrhoea, and it is absolutely impossible, from either a clinical or a pathological examination, to R 256 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. diagnose a gonococcal from a syphilitic metritis. That sji^hilitic metritis cannot be very common, is seen from the fact that, if a series of cases with symptoms of chronic metritis giving positive Wassermann reactions be treated with salvarsan and mercury, in only a small minority do the symptoms vanish. Wasseemann Reaction. Broadly speaking, a positive Wassermann reaction has greater significance, and a negative reaction less significance, in women than in men, owing to the com- plicating factor of pregnancy in the former. Assuming that all women are prospective mothers, a positive reaction must always be interpreted as meaning that children born of that parent are liable to be syphilitic. A positive reaction does not necessarily mean that the woman has active sj^philis, but a woman need not have active syphilis, to bear syphilitic children. During the child-bearing period, a woman giving a positive AVassermann reaction must, through each and every pregnancy, be thoroughly treated, in spite of later changes in the reaction. After the child-bearing period is over, a positive Wassermann reaction can mean no more than that the patient has had syphilis, therefore there is no indica- tion for treatment, unless, upon a thorough examination, an)' active signs of the disease are to be found. As a negative Wassermann reaction may be obtained in a woman who has active syphilis, during the child-bearing period, it can be seen at once that a negative reaction is of no value. Some of these cases can be made to give a positive reaction after a provocative injection of salvarsan, but such a test may fail, therefore a negative reaction, obtained with the blood withdrawn 48 hours and the fifth day after the injection, means nothing. It is very seldom necessary to do a Wasser- mann reaction during the period when a woman is capable of bearing a child, owing to the frequency of conceptional syphilis, and to the negative reaction which may accompany it. Clinical experience will generally suffice. If a prospective father is known to have had syphilis, he should, regardless of giving a negative Wassermann reaction, receive seven injections of neo-salvarsan, with five to seven days' interval between successive injections. He should also receive mercury for two years, given in the form of eight weekly intramuscular injections of grey oil, with two months allowed to elapse between each course. Iodides should be given for the first three weeks of each two months" interval. SYPHILIS IN WOMEN. 257 Marriage may be allowed after the salvarsan, but the wife should not be allowed to become pregnant until the end of the second year. If the parties concerned are married, and the husband develops s)Tnptoms of syphilis, and should his wife not be already syphilitic, and should she be desirous of having more children, then the husband should be treated as in the previous case and the two-year limit enforced. If to a married couple a syphilitic child has already been born, it would be better for the father to undergo the same treatment as above. It would be essential for the mother to do so, and, moreover, throughout each succeeding pregnancy treat- ment should be prescribed. If the rule is carried out — to treat such a woman during the whole time she ■ is pregnant^ — it would not be necessary to enforce the two-year limit upon her. The fact that a child is born healthy, does not prove that it is not syphilitic, because symptoms may not develop for weeks, months, or even years. It must also be remembered that such a child may give a negative Wassermann reaction. Even if a syphilitic child develops no symptoms, as a rule a negative Wassermann reaction obtained soon after birth, usually becomes positive about the sixth month. Owing to the consequences resulting from a positive reaction obtained in a woman during the child-bearing period, the reader cannot be too carefully warned against accepting any result, unless it has been obtained by the original method. The modifications of the Wassermann reaction are very liable to give non-specific reactions. If the original technique be employed, any result obtained with a cholesterolised antigen should be discarded. In my opinion, the only justifiable variation is to use the sera active. Difference Between Syphilis in Men and Women. It is a well-known fact that syphilis in women is not nearly such a serious disease — i.e., so far as the individual herself is concerned— as it is in men. There is no difference in the nature and severity of the primary lesions in the two sexes. The early manifestations of the generalisation stage are also much the same, but the later manifestations are very much milder in women than in men. Recurrences are fewer and milder in the female sex, and arterial lesions are, comparatively speaking, rare. Gummata, on the other hand, may be equally frequent and severe in both sexes. There is no doubt that, in women who are bearing children, the symptoms of syphilis are even milder still. From the facts just brought forward, one is tempted to conclude that the serum of women contains more natural protective substances e2 258 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. than the serum of men does, and that these protective substances are still further increased during pregnancy. Owing to the fact that the incidence of gummata in both sexes is about equal, and since gummata as a rule do not break out until after the ages of 45 to 50 have been reached, it would appear that women lose their increase of natural protective substances after the menopause. The protective substance against syphilis, as well as against any other infection, microbic or otherwise {vide placenta), is the lipoid-globulin of the serum ; but, in each infection, this lipoid-globulin has a specific stereo-chemical molecular con- figuration, and there appears to be no limit to the range of the specificity. The specificity does not lie in the lipoid-globulin as lipoid-globulin, but in the foundation upon which the lipoid-globulin is built up. Lipoid-globulin may be likened to a house which is built of bricks. The house is always the same, but the bricks with which it is built vary. These bricks are the amino-acids, polypeptides, etc., which go to build up the lipoid-globulin, which is the house. Specificity is caused by the variation in the bricks. We know that the range of specificity is unlimited ; therefore the variation in the bricks is not so much the alteration of one brick, as a change in the combination of several. This being the case, it is possible for different infections to produce partly similar combinations of the groups which go to make up the lipoid-globulin molecules. The combination may be the .same up to a point, and then the last brick or two may make all the difference. If this be the case, it may so happen that some of the groups which go to make the syphilitic lipoid-globulin, are also the same as some of those which go to make up the lipoid-globulin of the sera of women. In other words, there is a common combination of the groups which constitute the lipoid-globulin of syphilitic sera and the sera of women up to the menopause, and that the similarity becomes the closer in women who are pregnant. That this is not pure theory, is proved by the fact that the sera of syphilitic non-pregnant women give a positive Abderhalden's reaction with placental extract. Abderhalden's reaction is, in my opinion, a physical reaction which depends upon the adsorption of particles posses.sing homologous stereo-chemical molecular configurations. When such an adsorption occurs, the molecules are precipitated, and, when dialysed, they break up. The hydrolysis results in an increase of dialysable amino-acids, which give the positive ninhydrin reaction. Sera of sj^^hilitic non-pregnant women behave, then, in the same way as the sera of pregnant women. Placental extract contains the analytic products of placental protein ; these products represent some of the bricks. For adsorption to take place between placental extract and the sera of both SYPHILIS IN WOMEN. 259 preguaut women and syphilitic non-pregnant women, the stereo-chemical molecular configuration of the placental extract must have its homologues in the sera. This proves that some of the bricks which are responsible for the specificity of the sera of pregnant women, towards placental extract, are likewise responsible for the specificity to be met with in a syphilitic serum. Therefore, the reason why syphilis is a less severe disease in women, is probably owing to the fact that sexual differences render the sera of women more like syphilitic sera. 1 Hochsinger (1910), " Wien klin. Woch.," xsiii, 8S1, 9.32. ^ HoclLsinger (1898), '' Studien iiber die hereditiire Syphilis." Leipzig. ' Lipschutz (1913), '■ Archiv. f. Derm. ii. Syph.," cxiv, 363. CHAPTER XXVI. CONGENITAL SYPHILIS. Before opening this chapter, I should like to warn the reader, that when he is deahng with a case of congenital sj^hihs, the possibihty of the infection being acquired after birth, should always be borne in niind, since a syphilitic infection of an infant is an easy matter, and many cases of acquired syphilis, are labelled as congenital syphilis. I have in mind two cases of supposed congenital syphilis, which I have recently seen. In the one, the primary sore was on the heel ; and in the other, on the occiput. Syphilitic infection causes abortion, miscarriage, or still-birth ; or the birth, before or at full time, of a live child showing signs of the disease, either at birth, or at some subsequent period. Congenital syphilis resembles the acquired form, the chief difference being, that it is a general infection from the beginning, while the acquired variety com- mences with a local lesion or chancre. It is a very much more serious form of the disease than is the acquired form. In the former, the tissues affected are un- developed, and therefore fall a more easy prey to the poison, the mortality being high, while death, as the result of acquired syphihs, is the exception. In the severer form, death takes place in litem, and the macerated fcetus is expelled two or three weeks later. A history of such an abortion occurring in each successive pregnancy is characteristic of syphilis, but habitual abortion of a non-macerated fcetus,'within the first four months of pregnancy, is not proof (or evidence) of syphilis. Frequently, after a series of abortions, a seven or eight months' child is born alive. Premature labours likewise not uncommonly run in succession, until, finally, a full-term, and possibly non-syphilitic, child is born. It is not at all uncommon to find the first few and the last few pregnancies disastrous, one or two healthy children being born in between. Many syj)hilitic children, though born alive, die a few hours or a few days after birth, section usually showing marked syphilitic changes in the internal organs. CONGENITAL SYPHILIS. 261 Such children come into the world thin and niarasmic, with dry, kx and wrinkled skin, an old and haggard facial expression, and a weak and scarcely audible voice. Arrest of development may occur at any period of extra-uterine life ; growth is stunted ; there is lateness in dentition, speech, and walking ; frequently there is deficiency of intelligence, and also a delay in the changes of puberty. The degrees to which errors of development, such as hare-lip, cleft-palate, club- foot, Spina bifida, and hydrocephalus, are dependent upon syphilis, must at present remain unsettled, but, in a certain proportion of cases, a definite relationship seems to be suggested. The danger of producing a syphilitic child is greatest during the first year after the contraction of the disease ; is great during the first four years, but is largely influenced by treatment ; it then diminishes. If the parents are properly treated, healthy children can be produced. Although of extremely rare occurrence, cases have been recorded in which the disease was handed down to the third generation, i.e., cases of congenital syphilitics propagating syphilis. I have so far only come across two instances, one of which is worth recording. Case 44. — A woman, aged 37, brought to see me two of her children, sufl'ering from ringworm. The mother had signs of old bilateral interstitial keratitis, fissures at the angles of the mouth, and well-marked Hutchinson's teeth. She had had seven children, no abortions or miscarriages. I examined the seven children, and found that two o]iIy had any symptoms of syphilis, the others were perfectly healthy. These two died later, at the ages of 8 and 9, of degenerative encephalitis, while the other children remain perfectly healthy, but they are said to be extremely backward at school. The mother's Wassermann reaction was positive, the father's was negative ; the two affected children gave a positive reaction, two of the others gave a doubtful reaction, which two years later had become negative, and the other three gave a negative reaction throughout. Symptoms. A child may have manifestations of syphilis in utero, and they may jjass off before birth, for children have been born with synechiae, the sequelae of a previous iritis, also with pigmentation from old skin lesions. Other children may present all the manifestations of the disease at birth. Jlore commonly the infant is born healthy and strong, but develops signs of the disease within three months. Should no signs appear within this time, the child must not be regarded as free, for they may not develop until puberty or later, i.e., late congenital .sjrphilis. 262 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. The later the s_yDij)toms appear after birth, the better the prognosis, so far as life itself is concerned ; for, whereas the early signs are invariably general, the late are local, i.e., affection of bones, or ej'es, etc. So far as the effects of treatment are concerned the prognosis is not so good in late, as it is in early congenital syphilis, as the following very interesting case shows : — Case 45. — A man, aged 36, developed bilateral interstitial keratitis, he had fissm-es around the mouth, and well-marked Hutchinson's teeth. He had seven injections of salvarsan, without any improvement. Mercury was prescribed for one year, and during this time the eye symptoms vanished, but patient became deaf in both ears. In spite of still further treatment, with salvarsan and mercury, patient became stone deaf, and developed arthritis in both his knee joints. Early symptoms are marasmus and a dry and wrinkled skin, with Httle or no subcutaneous fat ; the hair is short and the nails undeveloped, the nasal bridge depressed, the voice weak, and the little patient snuffles and has a peculiar cry. Skin. The skin lesions of congenital syphiUs, like those of the acquired form, consist of macular, papular, and pustular rashes. In both cases, the rash affects the whole body, but, in congenital syphilis, it shows a marked predilection for the palms of the hands and soles of the feet ; so characteristic do some authors regard this, that they state that papules found in these situations can be safely regarded as syphilitic, and that their absence is evidence that an eruption is non-syphiUtic. In spite of the commonly entertained opinion to the contrary, a rash on the buttocks is not absolutely diagnostic of syphilis, being more usually due to the use of dirty napkins ; adjacent surfaces that rub against the buttocks — the backs of the thighs, the calves of the legs, and the heels — are similarly affected. The non-syphilitic erji^hemata are always of a bright red, inflammatory colour, while the rashes of congenital syphilis have a marked brownish tint, and ar6 often very pronounced in the flexures, where, owing to continuous friction, the horny layer is rubbed ofE and the surface eroded. The presence of ulcers does not necessarily indicate s^'phihs, for the erythemata may become ulcerated ; and sometimes deep, punched out iilcers, resembhng gummata, are found — the so-called ecth}nna or vaccinifomi dermatitis. To avoid a wrong diagnosis, one should always bear in mind Kaposi's axiom, that a poly- morphic skin eruption on a baby is diagnostic of congenital syphilis ; for example, the presence of a macular rash on the face or other parts of the body, and of a CONGENITAL SYPHILIS. 263 papular rash on the pahiis and soles, will go far to establish the syphilitic nature of a doubtful rash on the buttocks. Seborrhoeic dermatitis is frequently mistaken for a syphilitic rash, but in the former the scalp is invariably dry and scurfy, and the mother is usually suffering from seborrhoea. A congenital syphilitic roseola is practically unknown. The commonest congenital syphilide consists of macules distributed over the whole body, and well marked on the face and head. On the face, the eruption is not infrequently orbicular. The papular syphilide affects chiefly the genitals, anus, palms of the hands, and soles of the feet, at the same time as the macular syphilide is present on the trunk. The papules may coalesce, and the surface may become scaly or eroded ; the erosions or rhagades occurring at the corners of the mouth leave, after healing, those radial scars so suggestive of congenital syphilis. Linear scars are also found along the lower lip — a point of some importance, since rhagades at the corners may occur after any acute illness. Fissures are not infrequently found beside the nose and around the anus. Peeling of the palms is a iiseful diagnostic sign. Condylomata are found around the anus, and more rarely in the mouth ; they do not usually make their appearance until the child is some months old, often a year or more ; as a rule, the rash has disappeared, and their presence denotes absence or inadequacy of treatment. The pustular syphihde is the Pemphigus syphiliticus Jieonatormn of the older writers ; it is seldom found alone, for it is ahnost invariably accompanied by a maculo-papular rash. The typical papules on the pahns and soles confinn the diagnosis, and serve to distinguish the syphilitic pemphigus from the streptococcal variety of Pemphigus neonatorum. When found alone, however, it is usually limited to the palms and soles. Syphilitic pemphigus is generally present at birth, although it may develop later, but seldom after the first few days. The streptococcal pemphigus always appears after birth, and is really a form of impetigo, impetigo being usually found in some other member of the family ; it does not, as a rule, attack the palms and soles. Further, a child with syphilitic pemphigus is always wasted, and looks to be at death's door, while a child with streptococcal pemphigus looks fat and cheerful. The former disease generally ends fatally, while the latter responds readily to weak antiseptic baths. Gummata are occasionally seen, but do not in any way difEer from the acquired form. Cases have also been described of symmetrical gangrene, with and without haemoglobinuria, occurring in children after 2 vears of age. 264 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. It is still opeii to question, whether the cases of purpura which have been described as occurring in congenital syphilis, usually between the ages of 5 and 10 years, are really specific in nature. The nails are not exempt, and syphilitic onychia is by no means uncommon. The matrix becomes inflamed, and the nail over it loses its gloss and becomes irregular on the surface ; the whole nail is gradually shed, and, unless mercurial treatment is given, the new nail will likewise sufier. The bullae of pemphigus may afEect the matrix, the nail being raised off its bed, and undermined by sero-pus. Diffuse Defluvium capillitii is not uncommon in congenital syphihs. Some children are born without any hair on the head, but such an occurrence is distinctly rare. The lanugo hair often persists longer than usual ; when it disappears, the scalp is left bald or sparsely covered, since, owing to the malnutrition, the new hair does not grow. The alopecia may afEect the eyebrows also. Indeed, thinning of the eyebrows, in an infant a few months old, is very suggestive of syphihs. Teeth. Contrary to current opinion, the primary teeth are occasionally affected. Still recorded a case of the primary central incisors resembling in every particular the so-called Hutchinsonian teeth. The permanent teeth show marked and characteristic changes, especially the incisor teeth of the upper jaw, which are shorter and smaller than normal teeth ; consequently there are gaps between the teeth, and when the mouth is closed the teeth of the upper and lower jaws do not meet ; the edges are not parallel, but conical and wedge-shaped. The free border is thin and crescentic, a central notch being caused by lack of development of the middle tubercle. The lower central incisors not rarely present changes. They may resemble the incisors of thp upper jaw, but more often they are rounded, and, in their upper parts, deficient in enamel, and therefore thin and rough. The canines may occasionally be notched, and the molars are not infrequently dome-shaped, owing to the maldevelopment of their tubercles. Bones. Bone affections in congenital syphilis are usually late signs ; but changes in utero do occur, e.g., gummata resulting in spontaneous fractures. Further, CONGENITAL SYPHILIS. 265 there is a characteristic boue lesion of early syphilis, often found at birth, called by its discoverer — Wegner — Osteo-chondritis sypJdlitica. This is, in the main, an epiphysial disease, which affects the long bones and ribs, and is found in almost every case of congenital syphilis, although it may not be sufficiently pronounced to be diagnosed during life. Post-mortem, it is perhaps the most valuable sign in a doubtful case. It is frequently present at birth, but cannot, as a rule, be diagnosed by external signs, until some months later. It reaches its acme at the age when rickets is common, making a differential diagnosis extremely difficult. The incidence of this condition is as follows : it is most marked in the lower epiphysis of the femur ; next, in the lower epiphyses of the tibia, ulna, and radius, upper epiphyses of the tibia, femur, and fibula ; and least in the lower end of the humerus. The increased growth leads to an enlargement of the epiphysis ; as a sequel, the bone involved may be shortened or lengthened, or the epiphysis may be separated from the diaphysis. The separated epiphysis usually unites again with the shaft, and no permanent disfigurement ensues. Separation of an epiphysis gives rise to a chain of symptoms, to which the term pseudo-paralysis is frequently applied. In such a case, if the afiected limb be raised and dropped, it falls as if paralysed ; spontaneous move- naents are impossible, but muscular action persists ; pressure and movement are painful. According to Schmidt, the pathological changes which result in a separation of the epiphysis are, first, an increase in width of the medulla, in which the cartilage cells disappear and become absorbed by the blood-vessels and the medullary tissue ; and, subsequently, a growth of granulation tissue between the diaphysis and the epiphysis. It was held that this granulation tissue originated from the bone marrow of the diaphysis, but Schmidt showed it to be a richly cellular connective tissue, containing an extraordinary number of blood-vessels, which are shut off from the diaphysis, but communicate with the vessels of the perichondrium, from which they originate. In consequence of the syphilitic infection, this connective tissue increases in growth, and takes on the character of granulation tissue. Thereby the canals are widened. In this connective tissue growth, there is an attempt at bone forma- tion, from the cartilage cells included m it. The process increases towards the diaphysis, so that in time the cartilage which should next ossify is completely destroyed, being pushed, so to speak, into the marrow of the diaphysis, to become the prey of the blood-vessels and marrow cells therein ; further, the granulation tissue forms a barrier which prevents ossification of the cartilage cells above ; and, in consequence, separation of the epiphysis follows. 266 THE BI0L0C4Y, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. The most characteristic feature to the naked eye, in a longitudinal section o-f the diseased epiphysis, is the appearance of a yellow line, often zigzag, between the epiphysis and the diaphysis. Besides the changes described above, there is usually some thickening of the periosteum, and osteophytic growths. Osteo-periostitis is a manifestation of late con- genital syphilis, and shows itself in various ways. For instance, in the fingers and toes, the phalanges are enlarged in a spindle-shaped manner, the result of an ossifying periostitis of the shafts — Dactylitis syphilitica. The same condition may also affect long bones, most frequently the tibiae, especially on their anterior surfaces. New bone forms, as the result of the inflam- mation, and either gives rise to a spindle-shaped swelling or to nmltiple swellings • — nodes. Ossifying periostitis or pericranitis affects both the parietal and frontal eminences, causing prominences known as Parrot's nodes, and giving a natiform or " hot-cross-bun " appearance to the calvarium. Syphilitic inflammation, if secondarily infected with septic organisms, may result in necrosis and caries of bones, especially in the case of the hard palate, jaws, nasal bones, and cranium, and may lead to perforation. Perforation of the palate is especially diagnostic of syphilis, in both the acquired and congenital forms. True gummata may affect any of the bones, as in acquired syphilis, but those occurring on the slcuU do not usually pierce the pericranium or the dura mater. Rarefaction of bones — osteo-porosis — may also occur, and may lead to multiple fractures. Parrot described a " gelatinous " atrophy which affects the skull bones, in particular the occipital, giving rise to the softening known as craniotabes. Premature synostosis of the sutures of the skull not infrequently occurs, and is supposed to be a cause of idiocy; or their patency may be abnormally prolonged. Hydrocephalus occurs in congenital syphilis, but is not common. It is usually due to a lepto- and pachymeningitis. Osteo- chondritis syphilitica is an early manifestation, while usually the other bone changes occur much later. ' The bone changes above described are, for the greater part, also met with in rickets. So closely do rickets and congenital syphilis simulate one another, that formerly they were generally believed to be one and the same disease — an opinion held until it was proved that rickety children could acquire syphilis. There is no doubt that congenital S3q)hilis predisposes to rickets, and, although the two diseases are quite distinct, some of the lesions produced by either are indistinguishable during life. As a result of osteo-chondritis, hydrarthrosis may supervene. CONGENITAL SYPHILIS. 267 Occasionally a joint becomes filled with pus ; when this occurs the condition is almost invariably symmetrically bilateral. A chronic, bilateral, painless, symmetrical hydrarthrosis, usually of the large joints, the knees being most commonly affected, is very frequently due to congenital S3rphihs. An arthritis simulating a tubercular joint, with as much wasting of the muscles as is typical of the so-called Tumor albus, may also be met with in con- genital syphilis. It may, moreover, occur at any age. Vascular System. The heart is rarely affected. Both diffuse myocarditis, secondary to an endophlebitis, and periphlebitis or arteritis of the small vessels, and gummata in the heart muscle, have been described. The gummata are small, multiple, and to the naked eye appear as white spots. Changes in the small vessels are all important, since there is no syphilitic manifestation which is not primarily dependent on such changes. In no way do they differ from those occurring in the acquired form, namely, round-celled infiltra- tion of the media and adventitia, Endarteritis obliterans, etc. Veins are not uncommonly affected in congenital syphilis. A marked dilatation of the super- ficial veins is often seen, and there is no doubt that syphiUs is often the cause of varicose veins in children and young adults. Aneurysms may be met with in congenital syphilis. I once saw a case of syphilitic aortic aneurysm in a girl, aged 15, and I have had a case of syphilitic hemiplegia in a boy, aged 8. Mucous Membranes. Catarrh of the mucous membrane of the nose, causing coryza, the so-called " snuffles," is a very frequent manifestation. It may be the first sign, and it is a persistent one. The probability is, that the lesion commences in the submucous tissue. Ulceration and involvement of the underlying periosteum and bone not infrequently occur, causing falling-in of the bridge of the nose, and thus producing the so-called " saddle-nose." Papules, erosions, and ulcers, may also affect the mucous membranes of the lips, cheeks, and tongue, but, with the exception of ulceration of the hard palate and jaw bones, they are more common in acquired than in congenital syphilis. 268 the biology, clinical aspect and treatment of syphilis. Lungs. One or both lungs, either as a whole or in part, may show the characteristic white pneumonia of Virchow. An affected lung is large, and has impressions of the ribs on its surface ; on section, it is white or greyish. The chief changes are a growth and desquamation of the alveolar epithelium, with considerable cellular infiltration and hyperplasia of connective tissue. This is the true " white pneumonia," and is generally said to be incompatible with life. Carpenter reports a case in which death did not occur until the age of 13 months. Still considers that the condition is consistent with much longer life, and that it is the cause of the fibroid disease of one lung which is by no means an uncommon disease in children. A second form, usually described as interstitial pneumonia, is, as its name implies, dependent upon a growth of the interalveolar and interlobular connective tissue, which starts from the vessels and bronchi. Owing to this connective tissue growth, the alveoli become compressed. Such a lung is enlarged, pale, or greyish- red, and hard. The capillaries are often enlarged, and tortuous ; the alveolar epithelium is swollen, and may show desquamation, but more often it assumes a cubical character, the lung alveoli presenting the appearance of glandular spaces. A com- bination of the white pneumonia with interstitial overgrowth is the most common appearance in the lungs of syphilitics. Digestive Tract. The intestinal canal may be the seat of ulcers, which are gummatous in nature, and which occur most commonly in the small intestine. Multiple miliary gummata are also met with in the mucous and muscular coats, from the stomach downwards. Bowel lesions are more common in congenital than in acquired syphilis. Liver. , The liver is very frequently found diseased in children who are born dead. Jaundice and ascites are rare complications. The liver is usually enlarged. The surface is commonly unaltered, except in the contracted hob-nail tjYie of cirrhosis, which is found in later childhood. Hochsinger describes four varieties of hepatic changes : — 1. Diffuse, small, round-celled infiltration of the connective tissue, and involvement of the acini by these cells. The inflammation starts around the small arteries. The macroscopic appearance of the liver is normal. CONGENITAL SYPHILIS. 2G9 2. H3'perplasia of the connective tissue, so that the liver is enlarged, hard in consistence, and yellow or yellow-brown in colour. The commencement is a hyper- plasia of the connective tissue in the adventitia of the vessels. 3. Miliary gummata (flint-like liver), greyish-yellow nodules about the size of a pin's head, are scattered about, in the parench^mia chiefly, but also in the interacinous connective tissue, and especially around branches of the portal vein. 4. True gummata. A rare condition. The most typical hepatic condition found in infants is a combination of the first and second of the varieties described by Hochsinger. The liver may be enlarged and hard, but the surface remains smooth, or very slightly granular ; there is a diffuse pericellular cirrhosis, the newly formed connective tissue being both cellular and vascular. The liver cells are isolated by this newly formed tissue into small groups of one, two, three, or four cells. The Spirochaeta pallida may be demonstrated in considerable numbers, in this form of the disease. In Hochsinger's third variety, there is often marked fibrosis in the neighbour- hood of the gummata. Large gummata — the true gummata of Hochsinger's fourth variety — are less common in the congenital than in the acquired form of the disease. Amyloid degeneration of the connective tissue stroma may occur. Besides the usual forms of Hepatitis interstitialis et gummosa, Schiiffel described a condition peculiar to congenital .syphilis, and he called this Peripyle- jMehitis syphilitica. This is characterised by enlargement of the liver, which is of a brown-green colour, and flabby. Throughout the soft parenchjana, the larger branches of the portal vein can be felt as hard cords, about the thickness of a little finger. Cross-section of a cord shows the lumen of the vein narrowed, the bihary ■ducts and branches of the hepatic artery shut in and constricted by fibrous tissue. The change depends upon an excessive fibrous tissue increase of Glisson's capsule. The disease aSects either of the chief branches of the portal vein, and stops short at the sinus venae porta;. The umbihcal vein is intact. Jaundice, colourless faeces, meteorism, ascites, enlargement of the .spleen, and intestinal haemorrhages are the cUnical symptoms. Pancreas. This organ may be afiected by a chronic interstitial inflammation, leading to enlargement, and also by gummata. 270 the biology, clinical aspect and treatment op syphilis. Kidneys. Interstitial nephritis is the commonest manifestation of this disease, and it is not infrequently associated with amyloid degeneration. True gummata are very rare. SUPEARENALS. Virchow and Barensprung describe the suprarenals as being enlarged, dotted with small, scattered, yellowish-white nodules, and as showing marked fatty changes in the parenchyma. Sj^hilis may also be the cause of some of those cases in which blood cysts are found. Testicles. Gummata are extremely rare, but diffuse interstitial inflammation is not uncommon ; usually occurring, as it does, within the first few months, it is pathognomonic of syphiHs ; the epididpiiis may or may not be affected, and an accompanying hydrocele is rare. In consequence of this connective tissue hyper- plasia, there is a growth and degeneration of the glandular epithelium. Syphilitic affections of the female sexual organs are extremely rare. Besides the usual interstitial changes, which differ in no way from those observed in other organs, Schukowsky reported an interesting case of Metrorrhagia neonatorum, which was caused by an Endarteritis obliterans of the vessels in the fundus uteri. Spleen. Enlargement of the spleen is common in cases of congenital syphihs, and is most obvious when the child is IJ or 2 years old. It is difficult in many of these cases to decide whether syphihs or rickets is the proximate cause of the enlargement. Parrot recognised two forms of enlargement — one resulting from a chronic h}rperaemia due to stasis in the portal circulation, the other due to a true hyperplasia of the connective tissue in the gland and in the capsule. Still reported two cases of gummata of the spleen, but the condition is extremely rare. Thymus. This gland is here mentioned, since an affection of it has been described as being diagnostic of congenital syphilis, namely, Dubois' abscesses. These are single or multiple abscesses, found in the gland substance. There is very little evidence that they are definitely syphilitic. congenital syphilis. 271 Central Nervous System. The severe forms of defective development of the central nervous system are characteristic of congenital syphilis — naturally the infant is either born dead, or it dies a few days after birth. It is not at all uncommon for one cerebral hemisphere to be much smaller than the other, and yet, as far as one can tell, the functional activity of each is the same. A marked asymmetry of the head and face accompanies this deformity. I had such a case quite recently, in a boy, aged 11 ; beyond a high myopia and a positive Wassermann reaction, nothing abnormal could be detected ; and the boy's intelligence and knowledge was very much in advance of his years. Hydrocephalus is sometimes caused by syphilis, and its pathology is not in all cases the same. In some cases, it is highly probable that the condition is due to an early syphilitic arteritis. This has resulted in a pronounced exudation of lymph, which, in accumulating, distends the ventricles and the central canal of the cord. On the other hand, and more frequently, the condition is due to a severe involvement of the meninges. A child may develop hydrocephalus m utero, or not until after birth — if the latter, never later than the first year. In many cases, the condition is associated with nervous symptoms. A localised gumma, or miliary gummata, may affect any part of the brain and cord, and diffuse gummatous pachymeningitis and leptomeningitis is well known. As in acquired syphilis, the brain is more frequently involved than the cord, except in the true degenerative lesions, when the lesion is generally a mixed one. There is no doubt now that congenital syphilis may cause degenerative myelitis, in which the symptoms do not differ from those met with in the adult form. Most congenital syphilitic degenerative lesions do not give rise to symptoms until the child is about eight years old, or older. Degenerative lesions are really lesions of late congenital syphilis, and may not manifest themselves until the patient is over 20 years of age ; hence it is sometimes quite a difficult matter to be sure, when one is dealing with a degenerative nervous lesion in a patient of 25 years of age, whether the case is one of acquired, or of congenital syphilis. According to Halbau and Dydynski, optic atrophy and sphincter (bladder) paralysis are more frequently met with in the congenital form than in the accpiired form of degenerative m3^elitis, while severe ataxia is rare. Most authorities are now agreed that Friedreich's ataxia is never of syphilitic origin. Degenerative encephalitis is not at all infrequently met with in congenital syphilis, and the symptoms do not differ from those met with in the acquired form. s 272 THE BI0L0C4Y, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. As a rule, the patient is over eight years of age. The course of infantile degenerative encephalitis is, on the average, longer than that met with in adults. According to Alzheimer, the average duration is aboiit four and a-half years. In the majority of cases, inferior mental endowment can be dated back to infancy. The course the case runs is usually one of a simple progressive dementia, and the depressive and maniacal states so commonly witnessed in the adult form are very frequently lacking. Actual paralyses are more common in the congenital form, and, as already stated, the case is frequently a mixture of degenerative myelitis and encephalitis. The more thoroughly every congenital syphilitic is examined, the more fre- quently will nervous symptoms be found, and, as is the case in acquired syphilis, the nervous signs and symptoms may be of almost any nature, both meningeal and arterial. Generally speaking, the nervous diseases of congenital syphilis are more often of ameningeal origin, while in acquired syphilis, they are more often of meningeal origin. Although the brain is more frequently involved than the cord, cases of spastic spinal paralysis are undoubtedly met with in congenital syphihs, and sometimes idiocy is associated with the condition. Diminished intelli- gence, even amounting to idiocy, is no doubt often caused by syphilis, but it is almost impossible to state accurately the rdle which syphilis plays, because many of the cases have never had a syphilitic symptom, nor have given a positive Wassermann reaction. Whether the idiocy is due to the syphilis itself, or occurs only because the parents have had syphilis, is not at present known, but of one thing I am quite sure, and that is, that syphilis is far more often blamed in this class of case than it should be. Again, as regards epilepsy in children, the greatest difference of opinion exists as to whether syphilis is a potent cause or not. Sj'philis should always be con- sidered as a possible cause, for the simple reason that most cases of sj'philitic origin do so well under treatment, but, according to my own experience, syphilis is far from being a common cause of the condition. , Other lesions which are occasionally met with, are cranial nerve palsies, which may be of the true degenerative t^^pe or secondary to a basilar meningitis. That isolated pupil phenomenon, to which I particularly called attention in acquired syphilis, ma}' also be met with in congenital syphilis. Mere inequality of pupils should not be invariably diagnosed as sj'jjhilitic, since some healthy people are born with unequal pupils. Almost a characteristic symptom of congenital syphilis, when it occurs, is Diabetes insipidus. The lesion is in the posterior lobe of the pituitary body. congenital syphilis. 273 Eyes. Affections of tlie eyes are extremely common. Changes in the fundus oculi, choroiditis, and iritis may occur soon after birth, or they may be strictly congenital. The patches in the choroid are usually iiTegular in shape and white in colour, with dark, pigmented borders, and they are generally associated with vitreous opacities. Choroiditis may interfere with vision, nystagmus being the first sign which calls attention to the defect. Hutchinson says that iritis most frequently affects females, is most commonly seen at the age of 5 months, and is often bilateral ; that it is not characterised by the inflammatory phenomena which are met with in adult iritis ; and that it quickly leads to occlusion of the pupil, but is extremely amenable to mercurial treatment. The characteristic and diagnostic eye-change, in late syj)hilis, is interstitial keratitis. This usually appears just before puberty, affects one eye first, and then usually becomes bilateral, whether the patient is treated with mercury or not. Opaque areas appear on the deep surface of the cornea, and fine blood-vessels which come from the conjunctiva and sclerotic run on and into its substance. The condition may last for months or years, till sight is almcst lost ; but, however bad the case may be, there is always something to be hoped for from treatment. Mercurial treatment is the best ; salvarsan appears to have no action. Double interstitial keratitis is frequently associated with Hutchinsonian teeth and nodes on the tibiae — the so-called " syphilitic triad." Any of these eye lesions may appear first in adult life. Ears. In infancy, there may be a catarrh of the external auditory meatus and middle ear, but it is in no wise characteristic of syphilis. In the late form, usually after puberty, there occurs an insidious inflammation of the internal ear, and in time this leads to complete loss of hearing. Syphilis is also a cause of deaf- mutism. In late syphilis, all auditory symptoms appear to be uninfluenced by treatment, and in my experience salvarsan seems to aggravate them. Lymphatic Glands. In congenital syphilis, the lymphatic glands may become enlarged, but there is never a general enlargement all over the body, as is the case in acquired syphilis ; one group becomes enlarged, but not from any ascertainable cause. So rarely are the glands affected, that enlargement makes one suspect acquired syphilis. s2 274 the biology, clinical aspect and treatment of syphilis. Diagnosis. The diagnosis of congenital syphilis is made too often. A rash on the buttocks seems to be regarded as diagnostic : it is more often due to a simple erythema than not. A macular rash on the face, and papules on the palms and soles, are, however, pathognomic. It should not be forgotten that " snuffles " is often due to a simple catarrh, and some flattening of the bridge of the nose is characteristic of all infants. Orchitis and pseudo-paralyses are most important signs, syphilis being the only cause in early life. Much weight cannot be laid on enlargement of the liver and spleen. Enlargement of the epiphyses before the first year is diagnostic of syphilis. In a doubtful case, an ophthalmoscopic examina- tion should be made. In later life, Hutchinson's teeth, interstitial keratitis, and periostitis of the tibiae are the most important diagnostic signs. Prognosis. Infants born with manifestations of syphilis, usually die. Death is the rule in cases of pemphigus. In degenerative nervous cases, the termination is almost invariably fatal. Children born healthy, but showing signs in early infancy, if submitted to appropriate treatment for a full period of two or three years, may perhaps escape subsequent manifestations altogether. Children who have late signs, have probably often been free in early life, and consequently have had no treatment. In these cases, the symptoms often remain uninfluenced by treatment, but ultimately heal up of their own accord. The amount of damage done will depend upon the site affected. General Pathology. A point upon which a good deal of stress should be laid, is the appearance of embryonic areas in the organs. ' The syphilitic virus affects an organ before it is mature ; since its action is to increase the formation of fibrous tissue, especially of the vessels, the parenchyma of the organ suffers in nutrition, and cannot mature so quickly as it would other- wise have done ; consequently, at or after birth, it may in parts retain embryonic characters. For instance, the foetal liver has the capacity of manufacturing blood, a function which normally disappears after birth, but which may be retained in congenital syphilis ; and Schridde describes cases showing areas where both red and white corpuscles were found in process of manufacture. CONGENITAL SYPHILIS. -'/O Spirochaetae have been found in every organ, but are most abundant and most frequenth- found in the connective tissue of the medulla of the suprarenals. In the liver, they are especially found in the neighbourhood of the large blood- vessels ; and in the lungs, especially around the vessels in the walls of the alveoli. I have found the phases of the Leucocijtozoon syphUidis in congenital syphilitic liver, lungs, and suprarenals, but, for the examination to be successful, the tissue must be fixed as soon after death as possible. WORKS CONSULTED. Bab. (1907), '' Miinch. med. Woch." liv, 2265. Fournier (1886), "La Syphilis H^reditaire Tardive." Paris. Xonne (1909), " Syph. u. Xervensystem." S. Karger. Berlin. Still (1908), " Congenital SjT^hili.s," in D'Arcy Power and Mvirphys " System of Syphilis." i. Unna u. Jannus (1906 u. 1907), " Dermat. Jahresbericht." ii-iii. Adamson (1907), " The Skin Affect, of Childhood." Oxf. Med. Press. London. Hochsinger (1904), " Studien Uber die hereditare Syphilis." Wien. Hutchinson (1901), " Syphilis." Cassell & Co. London. CHAPTER XXVII. CHEMOTHERAPY AND ITS MODE OF ACTION IN THE CASE OF SYPHILIS. The Chemistry of Salvarsan and the Action to be Expected from its Composition. A few words of general chemical explanation may be offered, before discussing the chemical nature of " salvarsan " and its mode of action. A monovalent element is one which can, under suitable conditions, combine equimolecularly with one element of similar valency, in the proportions of one atom of each. Thus, hydrogen and chlorine are monovalent elements, and they combine to form hydrogen chloride, or hydrochloric acid. Their valencies, or combining capacities, are then satisfied. Di-, tri-, tetra-, and pentavalent elements can combine with two, three, four, and five monovalent elements respectively to satisfy their combining capacities. A trivalent element may combine with one mono- and one divalent element, and so following, for elements of higher valency. Carbon is a tetravalent element, but it differs from other elements in that it can link up with other carbon atoms to form stable compounds. The result of this extraordinary fact, due to electro-chemical inertia, is that there is absolutely no limit to the number of carbon compounds. In benzene, six carbon atoms form a ring. The empirical formula of tenzene is CgHg. The graphical formula is usually wi-itten, after Kelnile : — H I C •"^ H— C C— H II I H— C C— H \// C i H CHEMOTHERAPY AND ITS MODE OF ACTION IN SYPHILIS. 277 For the sake of convenience, this compound is usually represented by a simple hexagon. Arsenic may be either tri- or pentavalent, and it is exceedingly poisonous. The valencies of nitrogen correspond with those of arsenic. Arsenic is an element on the border line between metals and non-metals. Salvarsan is the commercial name given to dioxydiaminoarsenobeuzol. The constitutional formula of this body is ; — As = As n n H.N I I 11 NK. OH OH It will be seen that it contains two oxygen atoms, attached to separate benzene rings ; two amino (NHo) groups, attached to separate benzene rings ; and two arsenic atoms, attached to separate benzene rings. The two benzene rings are linked together by the two arsenic atoms. This body has several interesting properties : — (i) Arsenic is at once metallic and non-metallic in its properties ; here it is trivalent, but it may be pentavalent. (ii) The amino (NH^) group is basic in nature, (iii) The hydrogen in the OH group is acidic in nature. Here, then, we have a body which is at once acidic and basic, or amphoteric, and it also contains an element which is both metallic and non-metallic, and which has a varying valency. The body is insoluble in water, and on this account the hydrochloride of the body was prepared. Its formula is : — As = As C1H.H,N \/ V NH.,.HL'l OH OH The hydrochloride dissolves sparingly in water, but its solution is strongly acid, hence it is not very suitable for intravenous administration. It may be injected intravenously, and is on the whole more potent than the basic solution prepared from it, but it is at the same time more toxic. From the hydrochloride, the sodium salt is prepared, by adding sodium hydrate to the acid solution, and this renders it more soluble in water. Therefore, the drug is generally administered in this form. The formula of the sodium salt is : — As = As 278 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. Comparing this formula with that of the fundamental substance, it will be seen that the two OH groups have been replaced by ONa groups. The OH groups were acidic ; the ONa groups are basic, as are also the NH, groups, so that the compound injected is distinctly basic. A nice point now arises. When the compound is injected, does it remain basic, or does it become amphoteric ? In other words, are the ONa groups replaced by OH groups ? One cannot give a definite reply to this question, because the precise chemical composition of the body fluids is not known. We do, however, know that the blood tends to maintain a definite standard of alkalinity. We know, too, that, if this standard be disturbed, the blood will proceed, with almost inconceivable rapidity, to re-establish its standard. Now, therefore, if an alkaline compound be injected into the body, the blood will at once reduce the alkalinity of that compound. In the case of the sodium compound which we are considering, this can only be done by converting the ONa groups into OH groups, with the formation of neutral sodium salts. That is to say, an alkaline ONa group is converted into an acid OH group, with the formation of a neutral sodium salt, so that the final result is a reduction in the total alkalinity of the compound injected. To what does this lead ? To the highly important fact that now we again have the original base -substance, which is amphoteric, by reason of its possession of basic NHj groups and acidic OH groups. The importance of this fact consists in the point that such an amphoteric compound will be ready to attack either acidic or basic compounds. Reference to the chapter on the chemistry of the Leucocytozoon syphilklis will show proof of the fact, that some phases in the life-cycle of that organism are more basophilic, and that some are more acidophilic than others. It is therefore possible that reaction between these phases and the amphoteric salvarsan plays a r6le in the action of the drug upon the syphilitic organism. It may be objected to this line of argument, that the only active principle in salvarsan is the arsenic, and that the other facts are irrelevant, and this is a view which is very largely held. Let us consider the action of the arsenic. In the fii'st place, the arsenic will exert no action, until it has been freed from the compound. An amphoteric compound will tend to break down when it comes in contact with either a basic or an acidic substance. Therefore, the arsenic will tend to be set free for action in contact with the Leucocytozoon syphilidis ; hence the great activity of the drug against the organism. It is, therefore, fair to conclude that salvarsan is particularly well fitted to apply its arsenic at the most necessary point. In the second place, consider the action of the arsenic. The arsenic is excreted unchanged. That is to say, it is trivalent when injected, and it is also trivalent CHEMOTHERAPY AND ITS MODE OF ACTION IN SYPHILIS. 279 when excreted. To what conclusion does this lead us ? To the conclusion that the arsenic acts as a catalytic agent. In what way can the arsenic act as a catalyst ? In all probability it acts as an oxygen carrier — in other words, as an activator of oxydase ferments. Finally, then, we may state that, from a study of the chemical formula alone, salvarsan might be expected to destroy the Leucocytozoon syphilidis in the following ways : — (i) The basic portion takes up the acidic phases of the organism. (ii) The acidic portion takes up the basic phases of the organism. (iii) The catalytic action of the arsenic, set free in the two above-mentioned reactions, destroys the organism by oxidation. (iv) Salvarsan also is a reducing agent, and it may well exert action in this direction. Neo-Salvarsan. Neo-salvarsan is the commercial name for sodium-dioxydiamino-arsenobenzene- mono-methane-sulphonate, and its formula is : — As OH Salvarsan was the 606th body investigated, and neo-salvar.san was the 914th. It is obtained by the action of formaldehyde sulphoxalate upon " 606." It is rather surprising that 307 preparations were made before neo-salvarsan was tried, for it is well known that the addition of an SO.;H group is a great aid in preparing a soluble body. The base dioxydianunoarsenobenzol was the 592nd preparation tried — salvarsan is the hydrochloride of this base — and it was the 606th preparation tried. Again, it is a matter for some surprise that thirteen preparations were made before the hydrochloride was investigated. One may safely say that ninety-nine chemists out of a hundred would prepare the hydrochloride of a base immediately after preparing the base, and the same percentage would have immediately added an SO3H group, if they wanted to make the body soluble. The marked advantage possessed by " 914" over " 606 " is the greater solubility of the former. When a body is to be injected in solution, the advantage of ready solubility is obvious. Both these bodies have a great affinity for oxygen, and they must, therefore, be kept in an inert gas. 280 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. Now, let us consider the therapeutic action of these two bodies, and let us see if the difference in action can be explained by their differences in chemical constitution. The difference in action of these two drugs is, that " 914 " is less potent than " 606," though the dosis tolerata of the former is greater than that of the latter. The actual weight of arsenic injected is greater in the case of " 914 " than in that of " 606." In the case of salvarsan the arsenic content per cent, is 31 '56, while in neo-salvarsan it is 32 "10. We therefore must conclude that arsenic is not the greatest factor in destroying the organism of syphilis. As = As As = As H,N \y \y \^ ONa ONa OH OH Salvarsau. Neo-salvarsan. NH.CH.,O.SONa The above formulae represent the composition of the compounds, as injected. The arsenic has been already considered. "606" contains two basic ONa groups, and "914" contains two acidic OH groups. "606" contains two basic NHg groups; "914" contains one NHj group and one NH.CHjO.SOH group. This latter is a very important point, for an NHj group very readily attaches to it other complicated groups, whereas the ONa groups are rather stable. The fact that one of the NHj groups in " 914" is already attached to a complicated group, destroys its usefulness. We are, therefore, led to the conclusion that the most important factor in these two compounds is the NHj group. Further evidence, in support of this conclusion, is given by the action of arsenophenylglycine, which will be referred to later. In this compound there are two NH.CHj.COOH groups, and the therapeutic action of the compound compares unfavourably with that of " 600 " and of " 914." It must not be forgotten that both of these compounds were prepared as reagents against the Spirochaeta jxtUida, which is the most basophilic phase o'f the life-cycle of the Leucocytozoon sijfhilidis. In future research it would be well to seek for a compound which would also attack the most acidophilic phase of the leucocytozoon. Earlier Arsenical Compounds. Before salvarsan came into use, three other ring carbon compounds of arsenic were widely used. CHEMOTHERAPY AND ITS MODE OF ACTION IN SYPHILIS. 281 (1) Atoxyl, or monosodiumparaminopbenylarsenate. The composition of this body is shown in the formula — NH., O = iSs — ONa I OH Compare this formula with that of salvarsan, and it will be seen that there are several points of difference : — «. The compound contains only one benzene ring instead of two. /3. The arsenic is pentavalent instead of trivalent. J. The OH sroup is attached to the arsenic atom, and not to the benzene ring. S. The arsenic is in the para position to the NHo group, and not in the meta position. This body is amphoteric, for the OH group is acidic, and the ONa and NHj groups are basic. Atoxyl is unstable, and it exerts a highly toxic action on the optic nerve, hence it was rapidly superseded by — (2) Arsacetin, which is the acetyl compound of the above body. The formula of arsacetin is : — CH3.C0.HN O = As — ONa I OH This body is less toxic and more stable than atoxyl. The addition of an acetyl group (CH;.CO) is a common device in chemistry, when one desires to render a body more stable. Both of these bodies are much more toxic than salvarsan, and they are so because the arsenic is pentavalent. The fact that the acetyl compound is the less toxic, leads to the conclusion that the arsenic does not exert its full toxic action until the compound is broken down. Now, in order that any compound may exert an action on the syphilitic organism, the compound must break down, 282 THE BIOLOGY. CLINICAL ASPECT AND TREATMENT OF SYPHILIS. therefore we must conclude that arsenic should be trivalent in these therapeutic agents. This brings us to — (3) Aisenophenylglycine, which has the formula : — As = As HOOC.CH2.HN NH.OH2COOH Let us note the characteristic points of this compound. ". It has two benzene rings. /3. The arsenic is trivalent. 7. It is a substitution product of acetic acid. 0. The arsenic is in the para position to the nitrogen. £ It contains two acidic hydrogen atoms, the hydrogen atoms in the carboxyl (COOH) groups. ^. It contains two basic hydrogen atoms, the hydrogen atoms attached to the nitrogen atoms. From the last two points it follows that the body is amphoteric, but the basic nature of the body is very feeble, for, not only is one basic hydrogen of each NH3 group substituted, but also a carboxyl acidic group is attached to the substitution body. The advantages which this body possesses over atoxyl are, that the arsenic is trivalent, and that there are two benzene rings. The disadvantage is, that the basic nature of the body is, so to speak, destroyed by the two carboxyl groups. It is, of course, possible that the acetic acid group is broken off in the blood stream, for the blood is faintly alkaline. This would leave a basic NHj group, and the arsenic compound would cease to be amphoteric and would be basic only. Judging the action of these drugs by clinical methods, it would appear that the action is regulated by the constitutional formula of the drug before it is injected, and that, however near to the base a salt may be /!on- verted by the serum, its action is never so powerful as when a similar compound to the converted product is itself injected. French Arsenical Compounds. Several other arsenic comiiounds have been synthesised, since salvarsan and neo-salvarsan have come into wide use. Mouneyrat has prepared two such bodies — " galyl " and " ludyl " — and he considers that they have some advantages over the earlier preparations. CHEMOTHERAPY AND ITS MODE OF ACTION IN SYPHILIS. 283 Galyl is the commercial name for tetroxytetraminotetraphenyldiphosphoric acid, and its constitutional formula is : — (iH I PO HO /^'\^ OH r^NH HiNff^ NH Hn'v/ HO -- -^ -^ OH PO I OH The chief characteristics of this body are that it contains six acidic OH groups and four trivalent arsenic atoms. The four amino (NH) groups are linked up with acidic phospho groups, and so they have lost their basic nature. The three elements — arsenic, phosphorus, and nitrogen — are closely related in chemical characteristics. One would, therefore, naturally expect that the introduction of phosphorus would increase the activity of compounds such as we are considering. It must, however, be noted that the phosphorus here introduced is in an acidic group, and so is in no way comparable with the arsenic or nitrogen. Galyl is dissolved in sodium carbonate solution before injection, and so it is rendered basic. This destruction of any possible amphoterism must of necessity militate against its usefulness. I have, unfortunately, no clinical experience of this drug, but if some accounts are correct, that it is as potent as salvarsan, it would be a point in favour of the importance of the OH groups. This drug shows still further that the arsenic is not the most important group in the compound, since it contains 35'3 per cent, arsenic. Ehrlich's Conception of Chemotherapy. Having given a brief outline of the chemistry of the arsenic compounds, and of their mode of action, as it might be deduced from a comparison of their chemical formulae, Ehrlich's own views on their action must now be given.' ^ oiou Ehrlich's work is based upon the principle that there are, in the protoplasm of the parasites, certain chemical groups which are capable of combining with certain chemical groups of the drug injected. The name given to this affinity is " chemoceptor. " 284 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. The observation was also made that parasites co\ild be rendered immune to drugs. Ehrlich found, as a result of experimentation, that trypanosomes, for instance, could be rendered arsenic-fast. Organisms which have been rendered arsenic-fast are immune to arsenic compounds only, but to this rule there is one exception. This exception requires special mention, as it largely influences the theory of the mode of action of these arsenical compounds. Ehrlich found that certain dyes, such as pjTonin, for instance, were closely related to the arsenoceptor, since parasites which had been rendered immune to pyronin were also immune to the arsenical compounds. So far as the arsenical compounds were concerned, Ehrlich was primarily of the opinion, that the sole receptors between the chemical groups in the protoplasm of the parasites and the drugs used were the arsenic receptors. That other receptors existed, as well, was shown only when it was noted that the action of arsenophenylglycine was not affected by previously working on the parasites with an arsenic derivative of phenyloxyacetic acid and the corresponding thio-compound. The chemical formula of the arsenic compound used was — As = As /\ \J S I I CO2COOH hence it was assumed that acetic acid receptors existed as well. As acetic acid receptors were said to exi.st in the protoplasm of the parasites, it was only logical to suppose that amino-acid receptors would be found there also. Working upon this hj'pothesis, Ehi'lich discovered salvarsan. According to Ehrhch, salvarsan works by means of its arsenic receptors and its orthoaniinophenol receptors. When it was discovered that a certain drug had a fatal action on one kind of parasite and not upon another Idnd, although in both instances a combination occurred between the drug and the bodies of the parasites, some further elaboration of the action of salvarsan was required. Consequently, salvarsan was stated to act in the following way : — The arsenic was considered to be the toxophore group, the benzol ring the carrier, and the amino atoms the haptophore group. Smnming up Ehrhch's %dews as to the mode of action of salvarsan, all that can be really said is, that a union takes place between the drug and the parasite. CHEMOTHERAPY AND ITS MODE OF ACTION IN SYPHILIS. 285 with a destructive action upon the latter. What the nature of the union is, and why the death of the parasite should follow, are not explained. It must not be forgotten that, so far as syphiUs was concerned, Ehrlich was under the imprsssion that the Spiroclmeta ■pallida was the cause, and that the destruction of this organism would result in the cme of the disease. Moreover, most of the experunents were conducted in vitro, and no parallel exists between the mode of action of a certain drug in vitro with its mode of action in corpore. A FuETHEK Elaboration of My Own Views upon the Action of Salvarsan. From the knowledge now to hand upon the cause of syphilis,^ -^ * coupled with the work I have done upon the chemistry of the organism and the rationale of the Wassermann reaction,* I will attempt to explain what the probable action of salvarsan is, and upon what lines chemotherapy would afiord the best results in the future. Before discussing the probable mode of action of the anti-syphilitic drugs, it would be best to pay some attention to the way the body naturally protects itself against the disease. The cell which the host elaborates, to protect itself from the syphilitic organism, is the plasma cell. This cell is also called forth in any chronic inflamma- tion. In all instances, the plasma cell is morphologically the same, but although its gross action may be similar in every instance, it is, nevertheless, specific in each case. To be more exact, one should call the specificity a group specificity, not an individual specificity, since the plasma cells behave in the same manner, as here described, in trypanosomiasis as in syphihs. Take, for example, three plasmomata, one caused by syphilis, another by tuberculosis, and the third by a foreign body. If an injection of salvarsan be given to patients suffering from these three conditions, and sections be then made of all three lesions again, on examination it will be found that only the plasma cells in the case of syphilis have altered. To explain this specificity, we must probe the chemistry and physico-chemistry of the plasma cell. This may be best done by referring to the oxygen positions in the cells as a chain, " the oxygen chain." Each link of this chain will be made up of free oxygen and a ferment, which activates it in varying degrees, according as to whether the first or last link of the chain is being dealt with. The first fink is the red blood corpuscle, which contains free oxygen and a peroxydase : the ferment action is further increased by the iron in the haemoglobin. 286 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. Oxidising enzymes have their action increased by metals ; attention need only be drawn to the extraordinary accelerating action manganese has upon some plant oxydases, in support of this statement. Eed blood corpuscles supply every tissue with oxygen in an active state. The next link in the chain is a ma.st cell, one of the functions of which is to supply the basal cell layer of the epidermis with the active oxygen for the tyrosine- tyrosinase reaction, which results in the production of pigment, and this is one of the protective mechanisms of the body. In support of this statement, reference need only be made to the well recognised increase of mast cells in Urticaria pigmentosa, ephelides, and all known pigmentary affections of the sldn. Another function is, possibly, to supply the next hnk with free active oxygen, namely, the nuclei of the cells of inflammation. The accelerating element in the mast cell is possibly sulphiu-. The next link in the chain is an eosinophile cell, the action of which is probably analogous to that of the mast cell. Between these two cells there is a fundamental difference, which is a difference of reaction. The mast cell granules are basophilic, the eosinophile granules are acidophihc. In some chronic infections, the mast cell predominates ; in others, the eosinophile cell is most to the fore ; both are carriers of oxygen ferments, hence the reaction of the base, as to whether it is acid or alkaline, as I have already suggested, must play an important role in the combating of infections. Nuclei contain free oxygen and a ferment for activating the same, but this ferment is not nearly so strong as the peroxydase in the first tliree Hnks. Iron is the accelerator of the enzyme action in the nuclear link, and possibly phosphorus as well. The oxygen in the nucleus is used by the protoplasm of the cell and of the nucleolus. The last link in the chain is the protoplasmic, which contains oxygen, but no peroxydase. The activator probably comes directly from the nucleus, and indirectly from other cells which contain peroxydases, through the blood serum. The accelerator of the enzyme action is the element contained in the drug which is prescribed against the infection ; in the case of syphilis, arsenic, antimony, and mercury, for instance. The lesions of syphiUs may vanish without treatment, because of the ferment action of the serum, and of the protoplasm of the plasma cells. The protoplasm of plasma cells is rich in lipoid-globuUn, and it is well known that lipoids are carriers of ferments ; therefore, in the protoplasm of plasma cells, and in the serum, the host has the means of overcoming the parasite. Treatment assists the host's resistance, by accelerating the ferments, and therefore treatment destroys the parasites indirectly. I have shown in Chapters X and XL VI that CHEMOTHERAPY AND ITS MODE OF ACTION IN SYPHILIS. 287 the lipoid-globulin circulating in the serum and in the plasma cells is the same. It constitutes the antibody, and its specificity lies in its stereo-chemical molecular configuration. The action of antibody is one of adsorption, a phenomenon which can only take place in the presence of a ferment. The ferment is an oxydase, and is what we commonly call complement. Therefore treatment stimulates the com- plementary action of the antibody, and it also, as I have recently discovered, increases the production of antibody. It is the antibody which destroys the parasite, the ferment is only the activator of its action, which is one of adsorption ; con- sequently the ferment is not specific. When I first worked at this subject, and after I had learnt, from my investigations into the chemistry of the Leucocytozoon syphilidis, that the parasite was made up of a lecithin-globulin envelope, which encased nuclein, and before I had discovered the modus operandi of the Wasser- mann reaction, which gave me the clue to the whole problem, I thought that the ferment itself was specific, and I therefore attempted to find a specific lecithase and a specific protease. Failing in my attempts, and with the additional knowledge that I had gained in the meantime, I came to consider that the ferment was an oxydase. In support of this view, I have been able to collate the following facts : — 1. The granules in the epithehal cells of the choroid plexus give marked oxydase reactions, and, as shown by Pighini,® they are able to synthesise indo- phenol from a mixture of a-uaphthol and dimethylphenylenediamine hydrochloride, the blue colour resulting being dependent upon an oxydase zymotic action. 2. These granules are increased in cases of degenerative encephalitis, which shows that the zymotic action is increased. 3. The cerebro-spinal fluid obtains its active properties from the cells of the choroid plexus. 4. I have been able to prove that the cerebro-spinal fluid from cases of degenerative encephalitis is rich in oxydase ferments (amino-acidases), while normal cerebro-spinal fluid contains none. 5. The cerebro-spinal fluid from cases of degenerative encephalitis and meningo- encephalo-myelitis gives the goldsol reaction, a reaction which is dependent upon the presence of an oxydase. 6. The cerebro-spinal fluid in cases of syphilis of the central nervous system contains an excess of globulin. 7. This globulin is in an adsorption complex with lipoids. 8. Oxydases are frequently carried by lipoids ; therefore, not only is there proof that the cerebro-spinal fluid from cases of syphilis of the central nervous system contains oxydase ferments, but also that the ferments are carried by the lipoid-protein complexes, the adsorptive action of which they accelerate. T 288 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. This view is still further supported by the analogy to the blood serum and plasma cells. Still more convincing is the fact, that I have been able to prove that the granules of the epithehal cells of the choroid plexus, and the tigroid or Nissl's granules to be found in the nerve cells, consist of a lipoid-protein, and behave to reagents similarly to the envelope of nucleoli, the protoplasm of plasma cells, and the envelope of the syphilitic organism. Pighini showed that Nissl's granules also sjmthesised indophenol, especially those around the nucleus, which was to be expected, since the nucleus contains free oxygen and an oxidising ferment. The explanation of the protective mechanism of the serum and the cerebro- spinal fluid, against the syphilitic parasite, by means of adsorption, a process which is dependent upon oxidising ferments, is simple ; in fact, it is its smiplicity which makes one think that it is correct, for the more one considers how the body protects itself, the more convinced one becomes that it is not nearly so elaborate a process as all have been led to believe. After all, why should such an exceedingly complex ferment as a lecithase or protease be manufactured specifically against syphilis ? Supposing another protozoal disease sprang up in our midst to-morrow, the body would be ready to protect itself, and it could not possibly, in the short time at its disposal, manufacture highly complex specific ferments. The actual process of destruction of the organism probably takes place in the following manner : — The host elaborates lymphocytes, these in turn give rise to plasma cells, from the protoplasm of which an oxydase lipoid-globulin is freed into the serum. This oxydase lipoid-globulin has a stereo-chemical molecular configuration homologous to that of the sypliihtic parasite, consequently adsorption between the two takes place, when they come in contact. Adsorption results in precipitation, and finally hydrolysis, hence both the lipoid-globulin molecules of the parasite and of the serum become broken up. As to whether further sjmiptoms of the disease will become manifest, that will depend upon whether the host can manufacture more hpoid-globuhn, befo're the spore can develop and form new male and female bodies. A most interesting point now crops up, namely, why are the spirochaetae destroyed more quickly than the other phases, and why so quickly by salvarsan ? Chemistry showed that the male gamete, or Spirochaeta pallida, had the strongest reducing action of all the phases. In in vivo staining, it showed a marked affinity for methylene red, and it increased the reducing action of the female cell after impregnation. In this reducing action, in my view, lies the solution of the problem as to why CHEMOTHERAPY AND ITS MODE OF ACTION IN SYPHILIS. 289 the male cell, and not the other cells, stains with silver nitrate in Levaditi's method of staining, and as to why the action of salvarsan is more marked upon the male cell. The reducing action is due to an unsaturated fatty acid — a substance in which the male cell is especially rich, for two reasons : (a) because it is the result of an intracellidar development ; (6) because it has a very important function to perform, namely, that of impregnation. In other phases where the metabolism is less active, and the cells are more or less in resting forms, the fatty acids are more hkely to be saturated than unsaturated. The more unsaturated a fatty acid is, in a complex, the more free OH or hydroxyl groups will there be. To these free OH groups, different chemical substances can become attached ; therefore, the Spirochaeta pallida, owing to the fact that it contains more free OH groups, can have its lipoid envelope altered by substances which combine immediately with it. In staining tissue with silver nitrate, in order to get a black colour, two things are necessary : one is that the silver must be taken up ; the other is that it must be reduced in situ. Owing to the free OH groups in the lipoid envelope of the Spirochaeta pallida, the silver is readily taken up, and is reduced by the pyrogallic acid. In the other phases, on the other hand, there are no free OH groups to take up the silver, so they therefore cannot stain black. The action of salvarsan is also probably to be explained in this way. The " 606 " molecule fixes on to the free OH groups, with the result that the arsenic immediately robs the colloidal membrane of oxygen, hence the death of the organism. As there are no free OH groups in the other phases, salvarsan caimot become so readily attached to them. The destruction of the other phases is brought about partly by the direct action of salvarsan, and partly by the adsorptive action of the protoplasm of plasma cells, and the lipoid-globulin (antibody) of the serum, which action the salvarsan stimulates and accelerates. Therefore, the action of salvarsan upon the spirochaetae is wholly a direct one, and upon the other phases partly an indirect one. From the little that has already been said, it will be at once understood why sjrphihs is so hard to cure, for the simple reason that the spore contains little or no lecithin-globulin, and therefore, as a spore, it is only potentially harmful, and so is not touched immediately by the host's antibodies, or by the direct action of salvarsan. If the spore cannot be vanquished before it has entered what may be called its resting stage, all that we can hope to do is to prevent its re-developing. This we do by following up salvarsan with mercury. t2 290 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. The question might now very naturally be asked, if the action of salvarsan is an indirect one, why arsenic should be more active than mercury, since, under ordinary circumstances, the latter is a more powerful anti-syphihtic remedy. In my opinion, both mercury and arsenic act as catalysts, i.e., that they accelerate a reaction going on spontaneously, but more slowly without their assistance. A ratio exists between the intensity of action of a catalyser and the degree of the colloid state in which the catalyser is. In salvarsan, the arsenic is in a colloidal state, hence its action would necessarily be greater than that of any mercurial com- pound which we are in the habit of using. The proof of what has been said can be found, if we compare the action that different manganese compounds have on plant oxydases. Manganese formate, for instance, has nothing like such a powerful accelerating action upon plant oxydases as colloidal manganese hydroxide. The latter is colloidal, and the former is not. In many other synthetic organic arsenical compounds, the arsenic is also in a colloidal state, but the action of the drug is very inferior to that of salvarsan. Therefore this fact at once suggests that salvarsan when injected becomes fixed to the substance which the arsenic is going to accelerate. The proof that this is not pure theory is seen in the following statements : I showed in my work on the Wassermann reaction that complement and antibody were the same substance in one, and that they constituted the lipoid-globulin or the protective substance of the serum. Further, that the action of antibody was to adsorb its antigen, which it did by means of its ferment properties which constitute the complement, and that adsorption resulted in precipitation and final hydrolysis of the bodies adsorbed. Further, that the action of " 606 " is to break down the lipoid-globulin of the serum and that of the plasma cells. Again, that adsorption takes place between the amino and fatty-acid groups. Now, salvarsan has amino-acid groups and OH groups which other organic arsenical compounds have not, hence sufficient proofs can be brought forward to allow the assumption to be made, that salvarsan fixes on to the lipoid-globulin of a syphilitic serum, of the plasma cells in a case of syphilis, and of the syphilitic parasites by nature of its amino and OH groups, hence allowing the arsenic free play as a catalyst. Since the " 606 " molecule enters into adsorption with the lipoid-globulin of a s}qDhilitic serum, and of the plasma cells in a case of syphilis, it will be seen that Ehrlich's statement that the drug is parasito-tropic only and not organo-tropic, cannot hold good. For a drug to be parasito-tropic it must be organo- tropic. There can also be no doubt that amphoterism plays a very great part in the way in which salvarsan acts. I have already suggested that its action is greatest on the CHEMOTHERAPY AND ITS MODE OF ACTION IN SYPHILIS. 291 spirochaetal phase, be3ause the spirochaeta is the most basophilic of all the phases, owing to the fact that it contains an unsaturated fatty-acid group, hence it would be expected that the action of " 606 " was more marked in the late stages of syphilis than in the earl_v ones. This happens to be the case, since the lipoid-globulin of the serum is more readily broken down by " 606 " in the case of a late recurrent syphilide than in the case of generalised syphilis. I have shown in Chapter X. that serum from a late case of syphilis is richer in COOH groups than that from a case of early syphilis. A? the former serum is more readily broken down by salvarsan, and as the spirochaetal phase is the phase most easily destroyed, it is reasonable to assume that there is a ready attachment between salvarsan and the COOH groups of the bodies aforementioned. Amino groups can be fixed by COOH groups, therefore one cannot say for certain, whether the attachment just mentioned is dependent more upon the OH groups, or upon the NH^ groups of the "606." Further research must gauge the imporbance of the OH groups. Suffice it to say at present, that the NH^ groups are probably the most important in the salvarsan molecule. That this is true is seen by the fact, that any alteration in the NH^ groups diminishes the efficiency of the drug. Hence the reason why neo-salvarsan is not so potent as salvarsan ; in spite of the fact that it contains two hydroxyl groups, which are less stable than the ONa groups in salvarsan. In Ehrlich's own work there appear to me to be two points which require very careful consideration. One is that parasites which have been rendered arsenic- fast are also pyronin-fast, and the other is that although salvarsan may be linked on to a parasite, it need not necessarily prove fatal to that parasite. If there is a relationship between arsenical immunity and pyronin immunity it cannot be the arsenic that the parasites become immune to. If the formula of pyronin is studied — CI I () HoN/\^\/\NH., CM 2 it will be noticed that there are two amino groups. Now there are two amino groups in salvarsan, and from what has been already said it would appear to be due to these two amino groups that the drug becomes attached to the syphilitic parasites, the plasma cells, and the lipoid-globulin of a syphilitic serum. 292 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. I have little doubt in my own mind, but that immunity is mainly dependent upon the adsorption between certain amino groups, and the case in point certainly favours such a view. In view of the fact that parasites which are salvarsan-fast are also pyronin- fast, it proves that immunity is not acquired against the arsenic, therefore the parasites cannot be strictly said to be arsenic-fast. So far as future experimental work is concerned, it is a very important fact to have in front of one, namely, that an immunity cannot be produced against a catalyst. The fact that salvarsan can become attached to parasites, and yet not be fatal to them, is an observation in which there is a great deal wrapped up. During the time when I was working at the rationale of the Wassermann reaction, I thought that for adsorption to take place between two molecules, both of which possessed amino groups, it was necessary that they should have homologous stereo- chemical molecular configurations. This idea soon proved to be ■wTong, when fixation occurred of a non-specific antigen, and of an antigen whose amino groups had been converted into methane groups by formalin, respectively with the serum globulin from a case of svphilis. As a result of further experiments, I proved that the complement fixation test, as applied to syphilis, in contradistinction to the true bacterial complement fixation tests, depended not upon the molecules having homologous stereo-chemical molecular configurations, but solely upon their number and size. Application of this to the action of salvarsan, confirms the points just mentioned. The attachment of salvarsan to the syphilitic parasites, to the plasma cells, and to the lipoid-globulin in a case of syphilis, cannot possibly be due to an homologous stereo- chemical molecular configuration between the adsorbed molecules, since for one thing alone, salvarsan is an optically inactive body. The adsorptive capacity as a whole, appears to be greater in the case of a syphilitic serum than in the case of a serum from any bacterial disease, and it appears to be greater, the later the case of syphilis. As the lipoid-globulin from a late case of syphilis is richer in COOH groups than that from an early case of syphilis, it follows that any substance it happens to adsorb will tend to break down the molecules. The first result of breaking down the lipoid-molecules is to increase the area over which they can work, hence the probable reason why late syphilitic lesions disappear more quickly under treatment than do early ones. In my opinion, in the case of syphilis, and in all protozoal diseases, the lipoid-globuhn molecule appears to be bigger, and to have a greater adsorptive capacity than the lipoid-globulin molecules in the serum of bacteria] diseases. CHEMOTHERAPY AND ITS MODE OF ACTION IN SYPHILIS. 293 The bigger the size of the molecule, and ths greater its adsorptive capacity, the more easily will a di'ug like salvarsan be adsorbed, and the more readily the adsorbed compound will break down. WTien the lipoid-globulin first breaks down, the area of its action is widened, hence the catalytic action of the arsenic will have its fullest play. If salvarsan became attached to a small molecule, the adsorbed compound would not break down, at all events, not until much later than it does in the case of syphihs. This would mean that the arsenic would get little chance of acting as a catalyst. Therefore, salvarsan seems to act in protozoal diseases because of the physical state of the lipoid-globulin molecules of the serimi, and it fails to act as a bactericidal agent, because the lipoid-globulin molecules in the sermn of bacterial diseases do not possess the requisite physical properties. Summary. Salvarsan becomes attached to the lipoid-globuhn molecules of the s}'philitic parasite, the plasma cells, and the serum, by N^rtue of its amino groups and of the peculiar physical properties of protozoal lipoid-globulin. It attacks those phases of the Leucocytozoon syphilidis in which reaction is most marked, especially the spirochaetal phase, in virtue of its free hvdroxyl groups. The arsenic acts as a catalyst, that is to say, it accelerates the complementary or oxydase action of the lipoid-globulin (antibody) of the serum, which destroys the parasites by means of adsorption. 1 McDonagh (1913), " Proc. Roy. Soc. Med." (Path. Sec), vi, 83. " McDonagh (1913), " Demiat. Woch.," Ivi, 413. ^ McDonagh and Mackenzie Wallis (1913), " Biochem. Journ.,"' vii, 517. * McDonagh (1914), " Archiv. f. Derm. u. Syph.," cxix, 205. 5 McDonagh (1915), " The Quart. Journ. of Med.," viii. 129. 8 Pighini (1912), "Biochem. Zeitschr.," xlii, 124. ' Ehrlioh u. Bertheim (1907), " Berichte der Deutsch. Chem. Gesellsch.," xl. 3292. 8 Ehrhch u. Bertheim (1908), " Berichte der Deutsch. Chem. Gesellsch.," xli, 931, 1672. 9 Ehriich u. Bertheim (1910), " Berichte der Deutsch. Chem. Gesellsch.," xliii, 924. 1° Ehrhch u. Hata (1910), " Die experimentelle Chemotherapie der Spirillosen." Springer. Berlin. " Ehriich u. Gonder (1913), " Handbuch dor pathog. Mikroorganismen," iii, 337. \\'ORKS CONSULTED. Ehrhch (1912), " Zeitschr. f. Chemother.," i, 1. Moore, Nierenstein and Todd (1907), '" Biochem. Journ.," ii, 300. Wolflf (1908), D.R.P. 213.394. Meister. Lucius u. Briining, D.R.P. 204664. Meister. Lucius u. Briining, D.R.P. 206057. Meister. Lucius u. Briining, U.S. pat. 888321. References (1908), "Chem. Soc. Trans.," p. 93, 1180, 1893, 2144. References (1909), " Chem. Soc. Trans.," p. 95, 1473. CHAPTER XXVIII. TOXIC SYMPTOMS OF SALVARSAN AND NEO-SALVARSAN. Before opening this chapter, the reader must be fully aware that the salvarsan used when the drug first came upon the market, was less potent and toxic than the samples used for experimental purposes. Before the profession was able to obtain salvarsan there were two varieties, " Ideal " and " Hyperideal." Both of these were less soluble than salvarsan, and, although they were more potent and more toxic, it was partly on account of the insolubility that salvarsan superseded the " Ideal " and " Hyperideal." As we all know, salvarsan had not been in use long before neo-salvarsan saw daylight. The reason which prompted the discovery of neo-salvarsan was the desire to obtain an easily soluble and neutral salt, since some of the unpleasant symptoms following the use of salvarsan were undoubtedly to be attributed to an excess of sodium hydrate, which it was necessary to add to neutralise the solution, as salvarsan was an acid salt. Speaking generally, neo-salvarsan is not quite so potent as salvarsan. Relationship Between Toxicity and Potency. In my experience, a direct ratio exists between potency and toxicity, that is to say, that the more potent a special sample of salvarsan is, the more toxic it is. Clinically, one sees this in many instances. To give an example. Case 46. — A patient, a woman aged 36, had on the left breast a primary sore which had healed, but, when she came up for examination, she 'was covered from head to foot with a large papular rash. The papules were of the dense form, a form which, under ordinary circumstances, requires, even under salvarsan, at least a month to disappear, often more. I gave the patient an intravenous injection of neo-salvarsan (0"45 grm.). For three days afterwards the patient ran a temperature of 103° F., felt very ill, complained of pains all over, and was sick. Five days later I gave another injection of neo-salvarsan (0"45 grm.). The patient was ill for nearly a week afterwards, and the symptoms were more pronounced than on the first occasion. Although the rash began to fade on the third day after TOXIC SYMPTOMS OF SALVARSAN AND NEO-SALVARSAN. 295 the first injection, it all of a sudden vanished in twenty-four hours on the fourth day after the second injection, but prior to its disappearance, the patient developed, on the second day after the second injection, a diffuse and very severe toxic erythema. Ten days later, on examining the patient, it would have been difficult to say that she had ever had a syphilitic eruption. I then gave a third injection of neo-salvarsan (0'45 grm.), as I thought the symptoms after the first two were probably due to the endotoxines liberated from the wholesale destruction of the syphilitic parasites. The patient was violently sick and ill, for two days, the temperature was 106° F., and she again developed a toxic erythema. Although she was able to get up on the fifth day, the patient felt very ill and weak for a fortnight. The future course was uneventful. The water used in this case was pure, and other patients were injected on the same days, without showing a single toxic symptom. Before the water question was shown to be so important, I had two cases which developed jaundice after the second injection of salvarsan. One patient was in the early generalisation stage, and the other patient had a recurrent palmar syphilide. These patients were treated in February, 1911. The toxic manifesta- tions were sufficient to lay them both up for nearly three months. Neither would consent to have any mercurial treatment. I have frequently examined them since, and have recently examined their blood and cerebro-spinal fluid, and I have also given them a provocative injection of neo-salvarsan (0'45 grm.), all with negative results. I have, on the other hand, had cases in which severe toxic symptoms do not seem to have had such a beneficial action on the syphilitic lesions. Since I first began to use salvarsan, I have kept a book in which I have noted every evil effect from its use. In many of the earlier cases, the water was, no doubt, to blame, because for the last two years and more I have not seen a toxic symptom of note. The Water Question. Unfortunately there is no drug which has not, at some time or other, given rise to toxic symptoms, so differently constituted is each human frame. Evolution up the animal scale increases this idiosyncrasy towards drugs, the human body being more prone to toxic symptoms, and behaving more inconsistently towards drugs than those of the lower mammalia ; therefore, useful as animal experiments may be, the results cannot be taken as being identical with those obtained in human beings. Salvarsan, used in curative doses on animals, is absolutely non-toxic ; so it is in the majority of human beings, but, since we cannot pick out beforehand those individuals to whom it will be toxic, it is well to bear in mind the toxic symptoms 296 THE BIOLOGY, CLIXICAL ASPECT AND TREATMENT OF SYPHILIS. that may occur. Patients with an idiosyncrasy for arsenic, which is often hereditary, do not exhibit this idiosyncrasy to salvarsan, and it is extremely doubtful whether any one is unduly susceptible to this drug. The feeling of malaise, as that is all that the toxic symptoms amount to nowadays, which sets in after the first two injections in the generalisation stage, may in some cases be due to the action of the drug on the spirochaetae, since, in a few of the more severe cases, the reaction is greater, and this is especially to be noticed when malaria complicates syphilis. When we weve less carefid in the preparation of the distilled water which we used, toxic symptoms were frequent. Wechselmann^ was the first to point this out, and he showed that the reaction was produced by the dead bodies of bacteria and fungi or their toxines, which cj[uickly contaminate distilled water that has been allowed to stand. Since I have used water which has been prepared in the way to be shortly mentioned, my patients have suffered no inconvenience from headache, rigor, pyrexia, or sickness, be it their second or even fifteenth consecutive injection. Further, the toxic symptoms which we have learnt to associate with salvarsan can be produced in animals, by the use of distilled water alone. Dispensers have always had trouble with distilled water, getting precipitates with drugs which should not precipitate. Surgeons have also realised that intravenous injections of saline often gave rise to unpleasant symptoms, but unfortunately most have not had the opportunity of estimating why, owing to the fact that saline injections are not generally used, unless the patient is almost moribund. Wechselmann's discovery is of immense value, as it renders the administration of salvarsan innocuous. Like most people, I was sceptical when I read that the toxic symptoms following salvarsan were due to the distilled water, and I was convinced only after personal trial. It may be said that some of the toxic symptoms are so typical of arsenical poisoning that they cannot be due to the water ; but may not this be exj)lained by saying that the tissues have primarily been damaged by the impure distilled water, and so have fallen an easy prey to the arsenic ? This'seems to me to be most likely, because toxic symptoms due to the distilled water set in about two hours after the injection, while those due to arsenic do not do so until the third day. Moreover, the arsenic ion is not detached, in sufficient quantities, soon enough to give rise to those toxic symptoms which set in immediately after the injection. Again, most of the severe cases have occurred after the second injection, when the immediate efiects of the first one were pronounced. These symptoms set in within a few hours of a second injection, then the next day the patient recovers, to get signs of arsenical poisoning on the third or fourth day. TOXIC SYMPTOMS OF SALVARSAN AND NEO-SALVARSAN. 297 None of these toxic symptoms would, in my opinion, have occurred, had I used redistilled distilled water. The fact that a patient may have a severe reaction after his first injection, and none after his second, clearly shows that the arsenic plays no part, since the same quantity is used in both injections ; it can therefore be only the distilled water that varies. If one patient, of several who are injected on any given day, has a severe reaction, all the rest will have the same ; while if one escapes, all escape. On more than one occasion I have given, on the same day, four injections^two with redistilled distilled water and two with distilled water forty-eight hours old, the tubes of salvarsan all coming from the same packet. The former two had no reaction, while the latter were sick, had rigors, and a rise of temperature. On another occasion, I used half doses of salvarsan with old distilled water, and gave full doses with the redistilled distilled water, the amount of fluid being equal in all (half pint). The patients who had the half dose had a marked reaction, while those who had the full dose had none. Evidence is therefore complete as to the necessity of invariably using specially prepared distilled water, which is best made as follows : — Ordinary tap-water is used ; there is no advantage in using redistilled water. It is boiled vigorously in a hard glass vessel, first at atmospheric pressure, then at reduced pressure, so as to ensure complete freedom from all volatile bodies. The boiled water is then transferred to the hard glass still, which has been carefully sterilised. The distillation is carried out under a pressure of 3 to 3 '25 atmospheres, by which means the boiling point is considerably raised. In order to avoid mechanical transference of any contaminating body, the heat applied must be so regulated that distillation goes on slawly, and a water-trap should be interposed between the still and the receiver. Glass taps must be used for cutting off one vessel from another, and each tap must be carefully ground in with carborundum. The preparation gains in interest from the fact that some care and ingenuity in manipulation is required, for high-pressure steam gives an exceedingly painful scald. The careful sterilisation of all vessels is imperative. Toluene is a useful steri- lising agent. It is conveyed into the cold vessels in a current of steam. The steam and toluene first condense on the cold surface of the vessels, and, as the temperature rises, both are vaporised and swept away, thus ensuring complete sterility. By means of a little ingenuity, the water never comes into contact with air, from the beginning of the distillation proper until it is poured out for making the injection solution.* * Water prepared in this way can be obtained from J. Patterson, 51, Church Street, Stoke Newington, N. 298 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. The water may be kept for several days without deterioration, provided that the vessel be not opened. Before pouring out the water, the mouth of the vessel should be carefully wiped with sterile wool. The reaction, again, is largely influenced by the preparation of the patient beforehand, and bj^ the degree of alkalinity of the fluid injected. This corresponds with the well recognised fact that patients who have been well prepared for anaesthetics suffer less than those who have not. Toxic Manifestations in the Pre-pure Water Days. Before taking the precaution of using water which had been prepared in the above fashion, I encountered the following toxic effects : — (a) A patient in a perfectly healthy condition, developed acute muscular pain in his left pectoralis major muscle, three days after the injection. A fortnight after the first, a second was given, when the pain above described spread to almost every muscle of the body, like influenza. Muscular pain is common after salvarsan, and usually starts in the small of the back, and resembles lumbago. As a ride it lasts only a day or two. It is quite likely that these symptoms are produced by a toxic action on the sensory nerves. Any pain caused by a sj'philitic lesion, such as sciatica for instance, is sure to be aggravated, for the time being, by an injection, and it is very difficult to say whether this is due to a toxic action on the nerve, or to reactionary inflam- mation around it. (b) Cases of Herpes zoster have been described, which suggest a toxic action of the drug on the posterior horn cells ; but far more common are cases of Herpes febrilis, on both the face and genitalia. Herpes genitalis is so common in patients who have had venereal diseases, that whether the occurrence after " 60G " is projiter hoc or post hoc cannot be with certainty established, because we are quite in the dark as to the real nature of the condition. ' I have had four cases of Herpes genitalis breaking out on the site of the chancre, after it had completely healed under salvarsan, and one of them had, at the same time. Herpes febrilis on the lips. On two occasions I have seen Herpes zoster succeed salvarsan, and I have had three cases in which this condition followed mercurial treatment. (c) Case 47. — A patient in perfect health developed a bad headache on the third day after an intravenous injection of salvarsan, an intramuscular one having been given six months previously. He went to bed, became feverish, almost unconscious. TOXIC SYMPTOMS OF SALVARSAN AND NEO-SALVARSAN. 299 talked gibberish, and had widely dilated— not reacting— pupils ; at times he was almost aphasic, but there were no paralyses. A few days later, he was quite normal again, and has remained so. Prior to the attack he had undergone severe mental strain, which, no doubt, was an exciting cause. I think this must be regarded as a result of the toxic influence of salvarsan upon the sensorium primarily injured by the endotoxines in the distilled water, and not as an inflammatory reaction of the meninges, as in a case of incipient pachymeningitis, because the immediate reaction was so severe. (d) The toxicity of salvarsan is greatly increased by the presence of organisnisother than those which it is destined to destroy. For instance, if a patient with influenza be injected, the reaction is violent ; or, if a patient with septic tonsillitis be injected, he may run a temperature for some days, and the tonsillitis may become very much aggravated. Bronchitis has likewise occurred after injection, due to a lighting up of some dormant pathogenic organism. It is possible that some cases of encephalitis may be caused in the same way, and that their onset may be stimulated by the endotoxines in the distilled water. Most important work on the action of bacterial endotoxines, in increasing the toxicity of salvarsan, has recently been undertaken by YakimofE." ^ The first endotoxine experimented with, was that obtained by a twenty-four hours' broth-culture of Bacillus coli communis. The tolerant dose of both this and salvarsan being ascertained, such doses were given intravenously to animals, mixed and separately, at varying intervals, with the residt that a dose of salvarsan which was ordinarily non-toxic, became, on the addition of a harmless close of endotoxine, lethal. Toxicity was, in fact, increased two and a half times. If the animals were infected with protozoa, the toxicity was still further increased. In mice, for instance, slightly infected with trypanosomes, the residt of injecting endotoxine with salvarsan was to increase the toxicity of the latter eight times, and, if markedly infected, sixteen times. The same results were produced by giving the endotoxine intravenously, and the salvarsan subcutaneously. The endo- toxine of Bacillus pyocyaneus increased the toxicity of salvarsan three and a half times, and still higher if the animals had trypanosomiasis. Other bacteria, such as Staphylococcus aureus, Bacillus subtilis, etc., were also found to increase toxicity in varying degrees ; while, on the contrary, Bacillus tetragenus was inert. These experiments suffice to show that Wechselmann's statement, that the reaction following injection is due to endotoxines in the distilled water, stands correct. They also corroborate the view that the reaction depends somewhat upon the number of protozoa present. Another point has struck me about these toxic symptoms, that they have 300 THE BI0L0C4Y, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. occurred only after the second injection, although, in the majority of cases, they were foreshadowed after the first. This is not due to anaphylaxis, as had been thought, but to the second injection of endotoxines in the distilled water still further increasing the toxicitj^ of the salvarsan. (e) True epileptiform attacks have occurred after salvarsan, and are probably dependent upon inherited tendency, for they may occur after any exciting cause ; therefore a patient who has had epileptic fits, definitely not syphilitic in origin, should never receive an injection. I have had two such cases. (/) A case, diagnosed as cerebro-spinal syphilis, died three days after an intra- muscular injection of salvarsan. The patient was extremely ill when the injection was given, and it was only prescribed as a last resource. Post-mortem, he was found to have primary sarcoma of a suprarenal, with secondary deposits in the brain and meninges. The cortical cells in this case also showed changes produced by a toxine, and here again the resisting power of the nerve cells must have been very considerably below par, and, of course, the case ought never to have been injected. (9) On the digestive tract, salvarsan may occasionally act in a toxic manner, and here again the initial reaction is always severe. Two cases had persistent vomiting and rise of temperature for three days, and then they became jaundiced, due to a catarrh of the bile ducts. Both occurred after the second injection, and both had severe initial reactions. Aladow* showed that in dogs which had been operated upon to demonstrate the secretion of the stomach, an injection of salvarsan inhibited both the secretion of gastric juice and bile, and could lead to catarrh of the stomach and biliary system, which, ha\ang once been set up, did not disappear until the arsenic had been eliminated. This shows the extreme importance of not injecting a patient with a disease of either the liver or of the stomach. If a patient has fasted too long, the administration of salvarsan may cause a sudden fall in blood pressure, and may cause the patient to be immediately sick. Patients with severe secondary anaemia, and those who feel very ill, are liable to be sick during or immediately after the injection. Sleeplessness is a very conmion symptom after " 606." The above are the only examples of the evil action of salvarsan which I have experienced, and, in the last case, it should certainly never have been used. Toxic Manifestations in the Post-pure Water Days. The toxic manifestations, which have followed salvarsan and neo salvarsan, since only pure water has been in use, will now be described. TOXIC SYMPTOMS OF SALVARSAN AXD NEQ-SALVARSAN. 301 (a) If the patient lias had merc\irial stomatitis while salvarsan or neo-salvarsan is being used, almost directly after the injection has been given, the patient experiences the most acute pain in his gums. This sets in half to two hours after the injection, and lasts, may be, for several hours. When several injections of neo-salvarsan are given quickly after one another, occasionally it may happen that, after the sixth or seventh injection, the patient complains of electric shocks down the arms and legs, aSecting only the hands and feet, when the limbs are outstretched. Attacks of giddiness sometimes accompany these symptoms. In a few of the cases I have had, the symptoms have not come on for several weeks after the last injection has been given. As a rule, the symptoms last for some time, but ultimately always disappear. The administration of m,ercury afterwards is apt to impede their disappearance, as the symptoms are undoubtedly due to a metallic neuritis. {b) Acne vulgaris and furuncidosis are not at all uncommon after " 606." This is probably owing to the tonic action of the drug, as many patients only have boils when they are in the best of health. But another explanation is equally likely : salvarsan breaks up the lipoid-globulin in the serum — the carrier of all the protective substances — thereby decreasing the resistance to staphylococci. Many cases of gonorrhoea are aggravated by salvarsan, undoubtedly for the same reason, and the explanation just given will account for the relative ease with which patients who have had salvarsan contract other diseases. I have had several cases who have contracted follicular tonsillitis, Vincent's angina, influenza, measles, and scarlet fever, so that the occurrences of these diseases have been more than mere coincidences. (c) Toxic erythemata are rare after salvarsan, but I have had one case which developed tjrpical exfoliative dermatitis. Toxic erv'themata occurring after the first or second injection in the generalisation stage, are doubtless often due to the endotoxines liberated from the death of the sxi^hilitic organisms, and, as a rule, a rash does not appear after the subsequent injections ; consequently there is no harm in repeating them. It is quite easy to distinguish a toxic erythema produced by the drug from one produced by the spirochaetal endotoxine, since the former is a true toxic erythema and always affects the backs of the hands, and is not unlike Erythema multiforme, while the latter is a true reactionary inflammation, conse- quently the rash is merely an aggravation of the already existing syphilitic lesions. The severe toxic erythema due to the arsenic does not generally come on until after the patient has had several injections at frequent intervals. The rash may appear soon after the last injection, or not for weeks, and the palmar h^'perkeratosis not for months. I have seen a case in which exfoliative dermatitis followed the 302 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. first injection of neo-salvarsan, but the drug used was the French substitution product. From the English substitution products, I have seen five cases of exfohative dermatitis, one of which terminated fatally. None of these cases had had more than two injections. (d) An odd point about salvarsan and neo-salvarsan is, that patients who have undergone a course some time ago are very apt to develop toxic symptoms, when an interval is allowed to elapse, and the course is repeated. This is one of the reasons why I prefer to give at one time all the salvarsan the patient is to have. The toxic symptoms are fever, rheumatic and neuritic pains, with headache and vomiting. In some of the cases, the symptoms increase as the number of injections goes up ; but, as a rule, the symptoms are pronounced for the first two injections, and then diminish as the injections increase. Women are more susceptible to " 606 " than men are, but this susceptibility is not increased during the menstrual period, therefore there need be no fear in giving an injection at this time. (e) I have seen four cases in which an ulcer in the mouth appeared after " 606," and in all four it was situated just behind the last molar tooth. (/) In three cases, I have seen small patches of leucoplakia on the lips, tongue, and cheek, caused by salvarsan, but never anything in the way of an approaching malignant lesion, as I have yet to see a case in which the toxic symptoms have not sooner or later disappeared. In two cases, I have seen transverse ridges appear on the nails, and I once had a case in which Alopecia areata appeared to be associated with the administration of neo-salvarsan. ig) I have seen a few rather odd cases, which might with advantage be mentioned. A patient had two intravenous injections of salvarsan, one in each arm, and as the operator had had a difiiculty in getting into the vein, both had been exposed through a small incision. Some weeks later, the patient consulted me about her arms, and where the incisions had been made were large Condylomata lata. It appeared that the wounds never healed by first intention, and, owing to the injury caused, syphilitic lesions had developed locally ; and, owing to the con- tinuous oozing from places which had not healed properly, the papules 'had developed into condylomata. In another case, also in a woman, wherever I punctured a vein, a crop of Lichen planus lesions appeared sometime afterwards. I once had a patient with syphilitic palmar papular hyperkeratosis, the most resistant syphilide to treatment that I know, and he invariably developed a typical syphilitic lesion wherever he injured his hand, and a lesion always resulted in the spot where I pricked his finger for blood. This patient had seventeen injections of salvarsan and thorough mercurial treatment, and yet the papules still persisted in coming out, and his blood was always positive. TOXIC SYMPTOMS OF SALVARSAN AND XEO-SALVARSAN. 303 The patient married, and has already had two children, who are both clinically and serologically sound, in spite of the fact that the father still gives a + + + Wasser- mann reaction. Syphilitic patients, whether in the early or late stages of the disease, may get general enlargement of the lymphatic glands after salvarsan, doubtless due to the production of lymphocytes, which salvarsan stimulates. Patients with peripheral nerve lesions, not of syphilitic origin, and of syphilitic origin if late, often have their symptoms very much aggravated by salvarsan. Peripheral neuritis, such as sciatica, if aggravated, does not very much matter, as the trouble will in time disappear, but when it is the eighth nerve that is affected, irreparable damage may be done. I have had two cases of old syphilitics with nerve deafness become absolutely stone deaf after salvarsan. I have also known of patients over fifty years of age, in whom the deafness was certainly not of syphilitic origin, have their deafness permanently increased by salvarsan. I had a case of congenital syphilitic deafness, in which the ear trouble did not commence until the patient was 32 years of age, and he went stone deaf after the second injection of salvarsan. I have seen so much trouble caused by salvarsan in aural lesions, that unless the lesion is syphilitic and acute, or unless I am compelled to give salvarsan for other reasons, I always avoid using it. {h) Some other interesting cases are the following : — Severe nose bleeding after each injection of salvarsan, in two patients with a high arterial blood pressure. I have had four cases of bad sexual neurasthenia after salvarsan, but, of course, it is very difficult to say whether the salvarsan was in any way the cause, or whether the neurasthenia simply developed because the patient had had syphilis. The reason why I think salvarsan had something to do with it is, that some patients do become very much depressed after " 606," and all the four cases referred to never had any other symptoms except the chancre. Reactionary Inflammation (Herxheimer's Reaction). A phenomenon which now requires mention, is that which is known as Herx- heimer's reaction. Herxheimer's reaction was the term applied to the exacerbation of the generalised rash in early syphilis, which followed the first few inunctions of mercury. Since the advent of " 606," owing to the greater frequency with which the reaction is seen, more attention has been paid to the phenomenon, and we now know that Herxheimer's reaction and the so-called reactionary inflammation — which, by the way, is a far better term — are synonymous. Prior to the salvarsan era, all we knew about Herxheimer's reaction was, that it occurred most frequently when mercurial inunctions were used, rarely when u 304 THK BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. mercurial injections were employed, and never when mercury was administered internally. Practically, the only mercm-ial preparation which caused the reaction with any regularity, when injected intramuscularly, was the salicylate. The reaction generally occurs when salvarsan and neo-salvarsan are used, but it is never so pro- nounced now as when salvarsan was first used. Mercury reaches the lesions more quickly, when prescribed in inunctions than in injections, and the reason why intramuscular injections of the salicylate cause the reaction more frequently than any other preparation, is due to the rapidity with which the salicylate is absorbed. As the reaction is so constant after salvarsan, it shows that this drug is a more powerful spiriUocide than mercury is ; and as the reaction is not so marked with the present day preparations, it shows that their action is not so great as the action of those which were first used. As the interpretation of the reaction is far from clear, it would be as well to consider all the possibilities now. The reaction occurs at the site of the lesion. It is most marked in those lesions which are full of spirochaetae. The more potent the drug is, and the more of it that reaches the lesion, the more pronounced is the reaction. That is all we can learn from clinical experience. If a microscopic examination of a lesion, before and during the inflammatory reaction, is made, other points can be elucidated. The most noticeable features of an inflammatory reaction are, the dilatation of the capillaries, the beginning of the breaking down of the protoplasm of the plasma cells, and the increased acti\'ity of the lymphatic endothelial cells. The sum of these changes is considerably to increase the dimensions of the lesion. We know that more salvarsan is taken up by the syphditic lesion than by the healthy tissue around it, and that the reaction is largely dependent upon the ratio which exists between the severity of the lesion and the amount of salvarsan that reaches it. The chief factor in the inflammatory reaction is the vascidar dilatation, since, as Milian^ showed, it can be prevented by administering adrenalin before the injection of salvarsan is given, and by repeating it afterwards. Moreover, if an inflammatory reaction has begun to appear, its further development maj^ be checked by injecting adrenalin. Adrenalin acts on the sympathetic nervous system as, shall we say, a stimulator. Certain poisons, acting on the sympathetic nervous system, cause paralysis. Stimulation produces constriction, paralysis causes dilatation of the vasomotor fibres of the sympathetic nervous system. TOXIC SYMPTOMS OF SALVARSAN AND NEQ-SALVARSAN. 305 In other words, then, adrenalin, by having an antagonistic action, neutralises the poison which is formed in a syphihtic lesion, when salvarsan is given. This poisonous substance can only come from three sources : (a) the syphilitic organisms ; (6) the host's protective cells ; (c) the drug. It cannot come from the host's protective cells, because the reaction has come and gone, by the time the breaking up of the protoplasm of the plasma cells has reached its acme. It is very unlikely that it comes from the drug, as one would expect it to be more pronounced the longer the drug is prescribed. The inflammatory reaction occurs when mercury is the drug prescribed, most frequently when it is used in the form of inunctions, and then when the salicylate is injected intramuscularly. The mercury in the ointment used is ordinary metallic mercury ; it cannot be split up, and in this form it is innocuous. The salicylate is again a very stable salt and also innocuous. The inflammatory reaction is very marked after sah^arsan, and one might rush to a conclusion, and assume that it is due to the breaking up of this complex molecule, in the process of which a poisonous product. is liberated. Against this view is what has already been said about the mercury, and the fact that no inflam- matory reaction occurs in LicJien flanus papules and psoriasis lesions, which respond to salvarsan before they disappear. The inflammatory reaction is most marked after the second injection of salvarsan. There may be none after the third, although the dose of salvarsan used may be bigger, and the changes wrought in the syphilitic lesion raoie pronounced. The only rational conclusion to come to is, that the inflammatory reaction is due to poisonous products liberated on the death of the sy|Dhilitic organisms. The first two injections of salvarsan do not kill the main supply of the syphilitic organisms, at all events, not before the third injection is given. Furthermore, it is mainly the spirochaetal phase of the Leucocytozoon syphilidis that is killed directly by the salvarsan. As already stated, the reaction is most marked in those cases which are richest in spirochaetae, and in which most of the drug finds entrance. The greater the quantity of drug which finds entrance to the lesion, the greater the number of spirochaetae that are killed. Therefore, the inflammatory reaction is, in my opinion, due to the endotoxin?s which are liberated from the spirochaetae as they are killed. Other evidence in favour of the view just enunciated, is the fact that the spiro- chaetae contain an hydroxyl group in their chemical structure, which the other phases do not. Metals are fixed on to these hydroxyl groups, and with greater ease, the freer they are. The rate of adsorption of the metal will play a rdle, and so will the quantity which can be injected. u2 300 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. The mercuiy used in inunctions is metallic mercury, and therefore can be readily fixed by the hydroxyl groups of the spirochaetae. Mercury salicylate is quickly absorbed, but it must be broken down and the metal set free, before it can act, hence the inflammatory reaction is not so regular when this preparation is used as when inunctions are employed. In salvarsan, relatively enormous quan- tities of the metal arsenic can be administered, simply because it exists in a colloidal state. As soon as the "606" reaches the syphilitic lesion, its complex molecule becomes broken. The arsenic is liberated and gets fixed to the free hydroxyl groups. This is also the reason why the spirochaetal phase stains with silver nitrate, and the other phases do not. When a metal becomes fixed to the hydroxyl groups of the spirochaetae, it not only robs the molecule of some of its oxygen, but also rapidly alters its normal arrangement of ions, hoice the protoplasm of the organism becomes disintegrated, and the parasite is killed. Endotoxines are liberated from the death of all organisms. They all act as poisons, and all appear to paralyse the vasomotor fibres of the sympathetic nervous system, in the area in which they are generated. Dilatation of the vessels results in an erythema, which can be recognised by the naked eye. Erythema in an already inflammatory lesion, will increase the dimensions of that lesion, and the patient's trouble appears for the time being to be aggravated. This is what is known as Herxheimer's, or, better, reactionary inflammation. The syphilitic reactionary inflammation differs from the so-called focal reaction, which one often sees after the administration of a vaccine, for instance. The latter is due to the breaking down of the already existing lipoid-globulin or protective substance, and the ultimate formation of a new product. In the interim, or during the time in which there are no protective substances, the organisms naturally flourish to their heart's content, hence follows an aggravation of the areas which they are inhabiting. It is only old lipoid-globulin which can in this way be broken up — that is, lipoid-globulin especially rich in COOH groups. Now, in the case of any substance having anything like the same stereo-chemical molecular configuration as the pro- tective lipoid-globulin, and a specific vaccine has this, the richer the protective siibstance is in COOH groups, the greater the ease with which the molecules of the vaccine can become attached to it. The molecules become attached by adsorption. Adsorption results in precipitation of the adsorbed substances, and hydi'olysis soon follows. The more vaccine that is used, the more protective substance there is adsorbed ; and the more quickly it is hydrolysed, the more marked the focal reaction. TOXIC SYMPTOMS OF SALVARSAN AND NEO-SALVARSAN. 307 The focal reaction following a vaccine is due then to the temporary inhibition of the host's protective substance, and this allows the organisms to flourish, and to aggravate the condition. Why cannot this theory also serve to explain the syphilitic inflammatory reaction ? The inflammatory reaction is most marked in the early stage of the disease. In the early stage of syphilis, salvarsan does not break up the existing lipoid- globulin, at any rate the first two or three injections do not do so. It is in the late stages of syphilis that the first and second injections of salvarsan break up the lipoid-globulin of the serum, in the stage in which the inflammatory reaction is often absent, and never is very marked. The interval which exists between the breaking down of the old lipoid-globulin by salvarsan and the production of the new lipoid-globulin, is only a matter of a few days at the most. The development of the syphilitic organisms requires many more than a few days, hence a focal reaction can never be caused by their multiplica- tion. Moreover, the spirochaetae — the main cause of the symptoms — are vanquished by the first two injections, in spite of the fact that there has been an inhibition of the host's natural protective substances. Arguing now from the other side. After a vaccine, a focal reaction is most marked in the late, not in the early, stages of the infection. If the protective lipoid-globulin has been recently renewed, a focal reaction does not occur. Further, a vaccine does not directly kill the organisms it is sent to attack, as salvarsan does the spirochaetae. Lastly, bacteria, such as gonococci, can multiply rapidly in twenty-four hours, and hence are easily able to aggravate the symptoms. Neuro-Eecurrences. An inflammatory reaction must not be mistaken for the onset of symptoms which do not make their first appearance until some time has elapsed, after treat- ment has been suspended. This now brings me on to describe the neuro-recurrences, which many observers incorrectly have regarded as a form of inflammatory reaction. Neuro-recurrences are lesions of cranial nerves, especially the eighth and second, and they have occurred with greater frequency since the advent of salvarsan. The lesions are primarily meningeal, and the increase in size of the meninges, due to inflammation, causes pressure upon the nerves as they are going through bony canals. Pressure on a nerve first produces neuritis, and, if continued, atrophy. If the reader has read Chapter XXIIT, he will remember that the body can be 308 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. divided into two parts : {a) systemic ; (b) nervous ; that there is little com- munication between the two ; that the occurrence of lesions in the nervous part depends largely upon the quantity and quality of the antibody circulating in the systemic part, and that a ratio exists between the kind of treatment prescribed and the quantity of the antibody circulating in the systemic part. If the treatment is sufficient to check the production of antibodies, and is only prescribed after the organisms have reached the nervous system, the organisms in the nervous system will be rid of one of their enemies, and will therefore be able to multiply and develop, more or less at their owia free will. The so-called neuro -recurrences arise in this way : they are true syphilitic meningeal lesions, afiecting secondarily certain cranial nerves, and are exactly analogous to other meningeal lesions of the brain and cord, to which I have recently attempted to draw so much attention. Neuro-recurrences occur more frequently after salvarsan than after mercury, but they only occur after the former, if it has been inadequately administered — a tremendous support in favour of my argument that, owing to the inadequate and injudicious manner in which salvarsan is being used in this country, nervous diseases are on the increase. Oddly enough, most observers admit that the cranial nerve lesions have been more common since salvarsan has been in vogue, but yet my statement that nervous diseases are on the increase has, even amongst neurologists, met with the greatest opposition. Perhaps in twenty years' time, when it is too late, everyone will realise that the connection between the onset of nervous lesions and the administration of treatment is a very firm one. Owing to the fact that amaurosis has occurred after the use of atoxyl and arsacetin, there was at first a very strong suspicion that salvarsan might be followed by the same result. There has been but one case in which optic atrophy followed an injection of " 606." A female, aged 22, under the care of Prof. Finger, received on July 6th, 1910, 0'4 grm. of salvarsan in an emulsion, for a malignant form of syphilis of long duration. On October 5th, that is, three months later, she 'com- plained of dimness of vision in both eyes ; the pupils were imequal, and there was early bilateral optic atrophy. It should be mentioned that this patient, throughout the previous year, had been rigorously treated with organic arsenical compounds, having received thirty injections of arsacetin and sixty-nine of " enesol " (salicyl- arsenate of mercury). Other than this instance, there has not been a single case of optic atrophy following salvarsan, due directly to the drug, although the number of injections given must now run well into seven figures. It is a well known fact, that an over-sensitiveness of the eyes to arsenic sometimes occurs after TOXIC SYMPTOMS OF SALVARSAN AND NEO-SALVARSAN. 309 continuous treatment with the organic synthetic compounds, and it has been shown that arsacetin is more liable to produce optic atroph}' in cases which had been previously treated with atoxyl, than in fresh cases, so it is more than likely that tliis single case was determined by the previous arsenic treatment. Lesions of the optic nerve and auditory nerve have occurred after " 606," but they are not toxic manifestations, since they are unilateral, and improve either under a second injection, or under treatment with mercury. These optic and auditory lesions are of the nature of a neuritis. The optic neuritis often starts with conjunctivitis, photophobia, and headache, making objects appear hazy. If the trunk of the eighth nerve is affected, symptoms referable to both of its branches will be manifest. If the cochlear alone is affected, then deafness may come on suddenly, but more often gradually. Its course may be short, or the deafness may so slowly get worse that the patient's attention is scarcely drawn to it. When the vestibular nerve is involved, the patient complains of tinnitus, giddiness, and vomiting ; the vomiting is irrespective of food, and is usually worst on getting up in the morning, owing to the change of posture causing a disturbance in the semicircular canals. In the early stage nystagmus is present. The following case is typical of a lesion of the trunk of the auditory nerve : — Case 21. — L. M., female, aged 35, came to the hospital with a psoriasiform syphilide on her legs. Two years before, the patient contracted syphilis, and was treated for eight weeks with inunctions in the General Hospital, Yarmouth, where she developed double iritis. Two months after leaving hospital, condylomata appeared around the anus and between the toes. Since then the patient had not been treated. It was noticed that she did not seem to hear very well, and on inquiry she stated that she had been deaf in the right ear for six months. The deafness had come on gradually and was slowly getting worse, and, at the same time as it commenced, noises in the ear were experienced and the patient was much troubled with attacks of giddiness, which prevented her from going out. The patient always had the feeling as if she was going to fall forwards, and she actually did so, on two occasions. The giddiness and vomiting were always worse on getting up in the morning, and the latter occurred during the day, quite irrespective of food. These symptoms, except the giddiness, were increasing in severity. ^Vhen I first saw her she had slight nystagmus, which later disappeared. Examination of the ears was kindly undertaken for me by Mr. S. R. Scott. The left external meatus showed old stenosis, but there was no defect of hearing on this side, and electrical reactions were normal. There was a marked reaction to the caloric test in one minute at 115° F., the patient falling to the right. On the right side hearing was diminished ; no artificial Rhomberg's sign or nystagmus 310 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. was produced by syringing for three minutes with water at 118° F. ; the electrical reactions of the vestibular nerve were sluggish, but had not c^uite disappeared. All pointed to a neuritis of the trunk of the eighth nerve on the right side, most probably of syphilitic origin. This case is instructive, since the patient had never had " 606," would not have complained of her nerve condition had her attention not been drawn to it, and had never connected it with her disease. Under mercurial injections all symptoms referable to the vestibular branch cleared up, but the deafness remains much about the same, and, like so many of these cases, is much less on one day than on another. I also saw a man who became gradually deaf in one ear four months after the appearance of the sore, and who had had no treatment at all. His deafness almost completely disappeared, three months after two intravenous injections of salvarsan and eight intramuscular injections of grey oil. The cochlear branch is not infrequently implicated alone, much more commonly so than the vestibular. Apart from a neuritis of the eighth and second cranial nerves, of which the former is more frequent than the latter, the other cranial nerves are involved in the following order of frequency : seventh, third, fourth, fifth, and sixth. When a neuritis of a cranial nerve sets in after " 606," in 96 per cent, of cases, it does so within the first four months. The cases are almost invariably in the early generalisation stage of syphilis, the Wasserniann reaction is generally negative, and the patients have usually had only one injection. This marked similarity as regards onset and occurrence finds its explanation, if we consider the frequency of neuritis in syphilis before the days of " 606." So slight, so gradual in onset and progression, may symptoms of a neuritis of the cranial nerves be, that the patient does not connect them vdth his disease, and consequently does not draw his doctor's attention to them. By astute observers they have been noticed and described, but, beyond this, cranial nerve lesions in sj'philis have not received the recognition due to them. Their occurrence after " 606 " made syphilologists examine their cases more thoroughly before treatment, with the astonishing result, that the frequency of such lesions was nearly as great as that of those reported to be due to salvarsan. They noticed further that these nerve affections were not uncommon in the early generalisation stage, setting in within a year of infection, that they were more often unilateral than bilateral, and were just as common in patients who had not had any mercury as in those who had, although it has more than once been stated, that they were more common after the use of soluble preparations than they were after the insoluble salts of mercury. These facts show that nerve lesions are syphilitic TOXIC SYMPTOMS OF SALVARSAN AND NEO-SALVARSAN. 311 manifestations, and that their occurrence after " 60G " signifies inadequate treat- ment, and that they are, in short, neuro-recurrences. Igersheinier^ showed that atoxyl amblyopia was a simple progressive atrophy of the optic nerve, and that it might occur early or late after treatment. In only two cases was the amblyopia stationary, and did not advance further than a retrobulbar neuritis. Nonne, who had the opportunit}^ of studying the condition post-mortem, found that the chief changes occurred in the nerve fibres themselves, in the neigh- bourhood of the chiasma. The changes were purely parenchymatous. The same changes could be produced artificially in the eyes of rabbits, by means of a local application of atoxyl, and in dogs and cats after subcutaneous injections. In cats, cell-changes were also to be found in the brain and spinal cord, the part most affected being the optic thalamus. Neuro-recurrences are not primary nerve lesions, the nerve is affected mechanic- ally by the lesions in the meninges. If the cerebro-spinal fluid of these cases be examined, the changes found will be those which one associates with meningitis. Deafness due to a nervous lesion must be clearly distinguished from middle- ear deafness, which occurs in the generalisation stage, either from involvement of the mucous membrane of the middle ear itself, or from mucous papules occurring in the mouth and encroaching on the Eustachian tubes. If the statement, that these nerve affections are syphilitic recurrences, is true, one would expect to find that giving two or more doses of salvarsan, with or without mercury, to commence with, would considerably diminish their frequency. Such is the case, and accounts for the absence or the presence of such recurrences in different clinics. In the Easter of 1911, I visited many Continental cities, and found that, in those clinics in which neuro-recurrences were common, it was the custom to give one injection of " 606 " and wait for a recurrence before giving another, while, in those clinics in which they were almost unknown, it was the custom to give two or more injections with short intervals, and to combine the salvarsan treatment with mercury. Neuro-recurrences followed intramuscular more often than intravenous injec- tions, because, owing to the accumulation of arsenic, one was never certain when it was safe to repeat the injection. I have had one case of unilateral optic neuritis within three months of giving one intravenous injection, and it improved under further treatment with mercury and iodides ; also one case of unilateral neuritis of the trunk of the acoustic nerve, within three months of giving one intramuscular injection, and it also improved under a second intravenous injection combined with mercury and potassium iodide. These two cases were in the early stage of syphilis, signs of the primary 312 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. sore still being present. Both cases occurred within the first four months of my experience, and since I have made it the rule to repeat the salvarsan within an interval of a few days, and to combine it witli mercury, I have not had a single case of a cranial neuritis. Since my attention was drawn to these affections of the cranial nerves, I have carefully examined all cases in the generahsation stage which had had no treatment, or only a little mercury. Since October, 1910, I have seen five cases of unilateral optic neuritis, one of which went on to atrophy withiai a few weeks ; nine cases in which the cochlear nerve on one side alone was ajJected ; two, in which the nerve affection was bilateral ; and three in which the trunk of the eighth nerve was affected. I have also had six cases in which the facial nerve on one side was affected, but I have never seen a case in which both the optic and acoustic nerves were involved in the same patient. Such a condition has, however, been described. To sum up, then. Lesions of cranial nerves are syphilitic in origin, and their occurrence after " 606 " is a syphiUtic recurrence, secondary to a meningitis, not due to " 606," but to inadequate treatment. Fatal Cases and Contraindications. Fatal cases have now to be considered. Some fatal cases have occurred through faulty technique, by injecting air or a solid particle into a vein, and, when salvarsan first came in, by making the solution too acid or too alkaline. Other fatal cases have occurred, again, by giving injections to patients who ought never to have been treated, i.e., patients with advanced cirrhosis, cardiac trouble, and nephritis. A too pronounced inflammatory reaction has been the cause of most of the deaths reported, and very special consideration will be given to these. A very few deaths have been due to the drug itself, and I should very much doubt if any of the deaths which have occurred within the last two or three years have really been due to a toxic action of the drug.* That arsenic is found in the body after death is no proof that the death has been produced by arsenical poisoning. In the same way, a man with a wound in his thigh — in which, fost- mortem, the tetanus bacillus has been found — who has been killed by a bullet through the head, has not died of tetanus. The first group of cases need not be considered, as they only arise through pure carelessness. The second group of cases opens up the question of contraindications, so these will be now considered. * Since the war, owing to the substitution products which have been employed, this state- ment does not hold good {vide page 302). TOXIC SYMPTOMS OF SALVARSAN AND NEO-SALVARSAN. 313 To the drug now in use, there are practically no contraindications. Old age does not make one withhold neo-salvarsan, provided the organs are tolerably sound. On two occasions, I have given as many as seven injections of neo-salvarsan to a patient over 70 years of age, without experiencing the slightest bad effects. Naturally a marked organic disease of the liver, heart, or kidneys is a contra- indication, if the lesions of these organs are not sj^hilitic in origin. If they are syphilitic in origin, it will depend upon whether they are early or late lesions of the disease. Cholangitis and early yellow atrophy are not contraindications, but severe gummatous disease of the liver and marked cirrhosis are so. Syphilitic myocarditis is not a contraindication, but gummatous myocarditis and severe valvrdar disease may be. The nephritis of early syphilis should be treated with salvarsan. It is not a true nephritis, and does not prevent the excretion of the arsenic. Tn the true and late syphilitic nephritis, salvarsan should. certainly be withheld. Now comes a very important question. How is one to judge when a late syphilitic lesion is a contraindication, and when it is not ? This can be answered by estimating the effects that a marked inflammatory reaction would have, should the drug be prescribed. There are only four organs in the body which need be considered — liver, heart, kidney, and nervous system. Liver. — The only late lesion in which a reactionary inflammation could do any damage, would be a gumma. Cirrhosis is the result of a syphilitic infection, rather than a sign of an active syphilitic process, and only serves mechanically as a contraindication, as it prevents rapid excretion of the arsenic. If there is only one gumma, and if it is not large enough to have caused much destruction of the hepatic parenchyma, an inflammatory reaction would be innocuous. If, on the other hand, much liver substance had been destroyed, an inflammatory reaction might prove fatal. Therefore, in all cases of gummatous disease of the liver — and this applies equally to the heart and kidneys — it is better thoroughly to treat the case with mercury and iodides, before prescribing " 606." In all cases of acute yellow atrophy, I think salvarsan should be given, because the patient is bound to die if " 606 " is not given, and he may live if it is. The reactionary inflammation may be diminished by prescribing subcutaneous injections of adrenalin. Heart. — ^When the earlier preparations of salvarsan were used, we had to contend with sudden alterations of blood pressure. With the preparations now in use, the alterations of blood pressure are too insignificant to note. Therefore, no arterial lesion, be it even an aneurysm of the aorta, can be considered to be a contra- indication to neo-salvarsan. Early cases of aneurysm are undoubtedly improved 314: THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. by neo-salvarsan, and even in the late cases, relief from the intercostal neuralgia is usually afforded. Myocarditis in the stage of generalisation is not a contra- indication — ^indeed, it is a condition which urgently calls for neo-salvarsan. Gummatous myocarditis, and especially a gumma in the bundle of His, should always be energetically treated with mercury and iodides, before neo-salvarsan is prescribed. In all late cardiac lesions, there is a great probability that one or more of the coronary arteries is diseased. Endarteritis of the coronary arteries also accompanies syphilitic aortic disease, and the slightest reactionary inflammation may be sufficient to render the endarteritis momentarily obliterative. This results in sudden death, and is undoubtedly the cause of some of the cases of sudden death that have followed the use of " 606." Rare as the condition may be, it should be borne in mind. Pathologists should remember, especially those who have to give evidence before a Coroner's Court, that in a case of death which has resulted from an inflammatory reaction, no sign of the_ inflammatory reaction will be found j^ost- mortem. Haemorrhagic encephalitis and obliterative endarteritis of a coronary artery are the commonest causes of death after salvarsan. Both are inflammatory reactions. Post-mortem, in the former case, the cortex of the brain may show no signs of a recent encephalitis, and in the latter case, the endarteritis of the artery in question may have ceased to be obliterative. Arsenic is found in the liver, and the patient has died of arsenical poisoning. I know of at least three instances, in which the verdict given has been one of arsenical poisoning, when the real cause of death was inflammatory reaction produced by the endotoxinss liberated from the bodies of the dead spirochaetae. It really is most important that false verdicts should not be given in a Coroner's Court, as they find their way into the daily papers, and mislead both the medical profession and the public. AATiat a check to patients seeking instant advice these false verdicts have alveadj caused, cannot be appreciated, except by those who are, day in day out, dealing with venereal cases. Kidneys. — The so-called nephritis of earlj syphilis is, in over ninety cases out of a hundred, not a nephritis at all, but merely an excretion, by filtration through the kidneys, of some of the protective lipoid-globulin or of the albumin that precedes the globulin of the serum. Therefore salvarsan is urgently called for. In late cases of syphilis, nephritis secondary to arterial trouble, " 606 " is contra- indicated, not because there is any fear of sudden death occurring, but because the arsenic cannot be properly eliminated. Storing up of the arsenic can only lead to dangerous symptoms, should several injections be given, and as has been my experience, in cases of late syphilitic nephritis, the patients have borne the first two injections so badly, that one would not dream of repeating them. As one TOXIC SYMPTOMS OF SALVARSAN AND NEO-SALVARSAN. 315 alvrays starts with small quantities of the drug, little damage can be caused, as the case is never so bad that elimination is totally impossible. Nervous System. — Inflammatory reaction in the nervous S3^stem is by far the commonest cause of death after salvarsan. Death may occur in early S3'philis or in late syphilis. If in the former, the probability is that it is a case of haemorrhagic encephalitis, if in the latter, a case of degenerative encephalitis. As to how and when haemorrhagic encephalitis arises, the reader must be referred to Chapter XXIII, where the whole matter is discussed in detail. Suffice it here to state that, in all cases of generalised syphilis, in which no treatment has been given, and " 606 " is contemplated, the possibility of setting up a haemorrhagic encephalitis should be borne in mind, because, in every instance, it can be prevented. There are three ways of preventing haemorrhagic encephalitis, and tliese will now be enumerated : — (1) Killing off all the spirochaetae first, with mercury. In other words, use mercury until all the symptoms have vanished, and then begin the " 606." (2) Begin with " 606," or, better, with " 914," in small doses, and repeat them in gradually increasing doses, allowing the shortest possible interval to elapse between each injection. (3) If the treatment is begun with neo-salvarsan, give subcutaneous injections of adrenalin, during the second and third days after the first three injections. I feel myself, that much valuable time is lost by giving mercury first ; and if the patient has noticeable skin lesions, he is naturally most anxious to undergo that form of treatment which will get rid of them most rapidly. Moreover, giving mercury first, increases the toxicity of the arsenical compounds. If one decides to commence the treatment with neo-salvarsan. the risk of haemorrhagic encephalitis arising is nil, if seven to nine injections, beginning with 0'4.5 grm., are injected intravenously every third or fourth day, anyhow for the first five injections. The other injections can be given at weekly intervals, if desired. Adrenalin is an additional safeguard, and if it be prescribed, even when symptoms of haemorrhagic encephalitis have already started, the chances are that the patient will be saved. When " 606 " first came in, I had one death from haemorrhagic encephalitis, but I have never seen a symptom of this condition since. If our knowledge had been as great then as it is now, there is no doubt that this case would have been saved. Case 27. — On the third day after the second injection of " 606," the patient, after having previously complained of bad headache, developed Jacksonian epilepsy, which rapidly developed into Status epilepticus, in which condition the patient died. 316 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. The patient was in the generalisation stage. He had a severe papular rash, and an iritis of the right eye. The first injection of " 606 " {0"6 gnn.) had been given a week previously, without symptoms other than those which followed every injection in those days, when no attention was paid to the purity of the water. The second injection was also 0'6 grm. Posl-mortem, the patient had a subarachnoid cyst over the Kolandic area, on the side opposite to that in which the Jacksonian epilepsy started. This was of old duration, and was probably produced by an accident some years before ; never- theless, it would appear to have been a locus minor resistentiae. A microscopic examination showed a degeneration of the nerve cells around and underneath the cyst, but nothing else. At that time, the nerve degeneration would have been pronounced as being typical of arsenical intoxication. One now knows that it is due to the endotoxine liberated by the dead spirochaetae. In this case, as in all, the vascular dilatation had vanished post-mortem. In cases of haemorrhagic encephalitis, it is useless either to trephine or to do a lumbar puncture. In the late degenerative cases, death is due to a liberation of spirochaetal endotoxine, which does not amount exactly to an inflammatory reaction. Death, as a rule, occurs later than in the early haemorrhagic encephalitis, for reasons which will now be made clear. In degenerative encephalitis (G.P.I.), owing to the pabulum upon which the organisms are nourished, the extracellular development of the male phase of the Leucocytozoon syphilidis is much in evidence, with the result that the lesions are rich in spirochaetae. Owing to the fact that the spirochaetae are not in the walls of the blood-vessels, as in haemorrhagic encephalitis, but are extramurally situated, it will follow that only a few will be killed at a time, as only a trace of the drug will reach the spot in which they are. Under these circumstances, the amount of endotoxine resulting from the death of only a few spirochaetae will be very small in amount, consequently, the inflammatory reaction will never be severe or acute enough to cause damage of its own accord. As the nerve cells in degenerative encephalitis are apt' to be on their last legs, the gradual accumulation of endotoxine, from the gradual process of destruction of the spirochaetae, is just sufficient to knock the cells clean out, and kill the patient. Although death may result in cases of degenerative encephalitis, after the first and after the second injection of salvarsan, it is more usual for death to occur much later, and for the patient to die with symptoms of aggravation of the trouble. Salvarsan and neo-salvarsan cannot be said to cause death directly in cases of degenerative encephalitis, but they certainly do, in the majority of the cases, make TOXIC SYMPTOMS OF SALVARSAN AND NEO-SALVARSAN. 317 the patient very mucb. worse, so that he dies sooner than he would have done if he had been left alone. In the ameningeal form of degenerative encephalitis, death after salvarsan is always due to an aggravation of the symptoms of the disease, but in the meningeal form, death may be sudden, and due to a true inflammatory reaction, because the spirochaetae are more in contact with the vessels, more are killed, and more of the drug can get to them. Although I have never had a sudden death in a case of degenerative encephalitis myself, I have had six cases in which the patient was made very much worse, and died sooner than he otherwise would have done. I know of four other- cases, in which I was personally interested, which came to an untimely end. In two of these the patient committed suicide — one on the third day after the first injection, and the other one week after the second. Oddly enough, both of these cases were in the quiescent period when ' 606 " was prescribed. In one case the man had been "perfectly well " for two years, and in the other case for nine months only. Both had had only one attack before. From the experience I have had, I have now made up my mind to withhold salvarsan and neo-salvarsan in cases of degenerative encephalitis, and I would warn others never to put under treatment a patient who has had an attack, but is now in the quiescent stage. We can now pass on to nervous lesions, which are to be met with between the early haemorrhagic encephalitis and the late degenerative encephalitis. These are cases of either pure intracranial meningitis, or cases in which the nerve tissue underneath has become involved — meningo-encephalitis — but in which the encephalitis is not of the tj^ical degenerative type. It might here be stated, that no cord lesion is an absolute contraindication to " 606," and that the question of salvarsan in these cases will be fully gone into in Chapter XXIX. Inflammatory reaction in a case of widespread pachymeningitis may, owing to the rise of intracranial pressure produced thereby, render the patient uncon- scious. I have had three cases under my own observation. In two, the patient became suddenly unconscious on the third day after the third injection, and in the third, on the same day after the second injection. Lumbar puncture produced immediate relief in one of the cases, and the relief was maintained, while in the other two, the operation made no appreciable difference. In none did the symptoms recur after the subsequent injections, as each patient had six more. I had another case, in which the patient had a severe syphilitic basal meningitis, and he died of asphyxia, produced by a rise of intracranial pressure, due to a severe reactionary 318 THE bioi-oc:y, clinical aspect and treatment of syphilis. inflammation after too large a second injection of " 606," and after too long an interval had been allowed to elapse between the two injections. This death occurred early in 1910, before our knowledge was as complete as it is now. Death would not have occurred, if the patient had received several intravenous injections of neo- salvarsan at short intervals, and if a lumbar puncture had been performed at the moment when signs of a rise of intracranial blood pressure had shown themselves. If an inflammatory reaction occurs in cases of meningo-encephalitis, and the patient gets an aggravation of his symptoms, on no account whatever should treatment be suspended, as the ultimate condition of the patient may be worse than the first. The thing to do, is to push the treatment as quickly as possible, and instead of relying only upon intravenous injections, to give intraspinal injec- tions of salvarsanised serum as well. The following case will show the importance of continuing the treatment : — Case 48. — Patient, a man aged 29, had no history of a sore, but had had a bad throat in 1911, which was diagnosed as sj'philis. The patient was treated with mercury internally until January, 1914, when he developed a rash (? nature). At this time he was also said to have had a left hemiplegia, which came on qiiite suddenly, but the attack had not been preceded by headaches. As far as I could gather from the patient, when I saw him in September, 1914, he completely recovered from the hemiplegia in a few days, and had had no treatment since. On examination, I found that the pupils were unequal R > L. The reflexes of the R. j^upil were not as brisk as those of the L. pupil, and in both eyes the reflexes were diminished. All the other reflexes were very brisk indeed, but not more so on the right side than the left. There was bilateral ankle clonus, and an extensor response on both sides. Sensations were unaltered. Patient answered questions correctly and quickly, and beyond feeling as he called it, "nervous," he had no symptoms to complain of. Examination of the Blood. — Wassermann reaction + +. Examination of the Cerebrospinal Fluid. — Pressure not raised. Fluid clear. Strong positive lymphocytosis. Strong positive Nonne-Apelt reaction. Excess of albumin and globuhn. Wassermann reaction 100 per cent. (1 10 c.c.) + + -f-. Patient was admitted into the Lock Hospital and received two intravenous injections of " 606." On the third day after the second injection, the patient went off his head — ^he talked the most utter nonsense, took his discharge, and found his way home. Two days later, the patient was brought to see me. He stood staring, took several minutes to answer a question, and then could only answer it correctly if it were a simple one, such as asking him his name, age, etc. His reflexes had become brisker than ever. I then gave him another intravenous injection of salvarsan and an intrathecal injection of salvarsanised serum the next day, with the TOXIC SYMPTOMS OF SALVARSAN AND NEO-SALVARSAN. 319 result, that in three days' time the patient was absolutely normal again. Further intrathecal treatment was given. If care is given to the points I have mentioned in this chapter, and if only the purest distilled water is used, the administration of neo-salvarsan is absolutely unaccompanied by the smallest risk. I have given several thousands of injections, and have never experienced any evil effects other than those I have been most careful now to mention, and all the evil effects I have experienced happened before the end of the year 1912. Although, injection for injection, neo-salvarsan is not as potent as salvarsan, I always prefer to use the former, becaiise the inflammatory reaction is never so severe as in the case of the latter, and quite as good results are obtained with neo-salvarsan as with salvarsan, provided sufficient injections are given. As it is now necessary to give several injections, and at the shortest intervals, in the end better results can be obtained with neo-salvarsan than with salvarsan, because not only is the inflammatory reaction sUghter and the observer not frightened away from giving further injections, but the ordinary after-efEects are nothing after neo-salvarsan, and practically never does a patient show an idiosyncrasy to the drug. In the case of salvarsan there is always the additional factor of the sodium hydrate used for neutralising purposes, for it may so often give rise to symptoms which make one hesitate to repeat the injection, or, at the least, compel one to allow a longer interval than is desirable, to elapse between the injections. Before closing this chapter, mention might be made of the question of treating patients with neo-salvarsan as out-patients. There are two alternatives — either that the patient should be kept in after an injection, or allowed to go out at once. If the patient is to be an in-patient, there can be no reason to detain him, other than to have ready access to him should the inflammatory reaction cause symptoms which require urgent treatment. Now, as the symptoms following an inflammatory reaction do not, as a rule, appear till the third day, it will at once be seen how senseless it is to detain a patient for any period shorter than this. Patients who are in the best of health, and in whoni the injection makes no difference, severely resent being detained for three or more days, especially if the process has to be repeated. Patients, moreover, resent going to nursing homes for " 606 " treatment, for obvious reasons. As the reactionary inflammation is, as has already been stated, so slight after neo-salvarsan, if this drug is used, patients can leave immediately and go to their destination, even by train if necessar}'. This has been my practise for three years, and I have never had cause to find fault with it. 320 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. In cases with nervous lesions, in which an inflammatory reaction is to be feared, the patient can be treated as an in-patient for the second and third injec- tions, if thought necessary. ' Wechselmann (1911), " Deutsch. nied. Woch.," xxxvii, 778. - Yakimofi (1911), " Miinoh. med. Woch.," Iviii, 2601. ' Ibid. (1912), lis, 124. * Aladow (1911), " Charkowsky Medizinsky Joiirii.," xi, 5. ° Milian (1914), " Bull, de la Soc. Franc, de Derm, et de Syph.," xxv, 231. ' Igersheimer (1912), " Zeitschr. f Chemotherapie," i, 106. CHAPTER XXIX. THE TREATMENT OF SYPHILIS. ■ ^ For the sake of lucidity, sjq^hilis will be divided into the following stages, and the treatment of each will be considered separately : (a) Stage of the initial lesion ; (b) Stage of the generalisation of the virus ; (c) Recurrent stage ; (d) Latent stage ; (e) Syphilis in women ; (/) Congenital syphilis ; (g) Syphilis of the nervoua system. Primary Sore. Excision of the primary sore should be practised, when possible. When impossible, owing to the site affected, it should be cauterised, or, failing cauterisa- tion, mercurial ointment should be rubbed in, until every trace of the induration has vanished. Induration often prevents sterilisation of the site of the initial lesion, and since salvarsan quickly gives the clue to the host that there is no necessity for a further continuation of the production of antibodies, the host is unaware that it has any spores locked iip in what was the chancre. Should the activity of these spores reawaken, a lesion will be produced, indistinguishable from a primary sore. Should such a sore occur in any position other than in the site of the original chancre, the case is considered to be one of reinfection. Is it not possible that the majority of these cases of so-called reinfection are really cases of auto-reinfection ? If sufficient treatment be given, and if it be prescribed early enough in the disease, to give the host the signal that no further antibodies are required, it does not mean that all the spores have been killed. A few may be hidden in any part of the body. Now, should these develop, owing to the fact that the production of antibodies was so quickly checked, the host wiU behave to these spores as would a fresh host which had never had syphilis, with the result that the lesion will be clinically a chancre, and not a recurrent papule. To give an instance. I had a case, very early in the generalisation stage, which I had treated with salvarsan and mercury. Some months later, the patient came to me with a sore on his chin; clinically, it was a typical x2 322 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OP SYPHILIS. chancre, accompanied by the usual adenitis, etc. I have had another similar case, in which a sore simulating a cliancre appeared on the nape of the neck. Had these two sores appeared on the penis, they might have been mistaken for cases of reinfection. I have seen seven cases with a recurrent sore on the penis, in a different position from the original sore, therefore a chancre redux could be excluded, and five of those I was convinced were cases of auto-reinfection. In reading the literature, I have noticed that the greater number of cases of reinfection occurred some time ago, not recently, i.e., not since the continuous treatment mth salvarsan has been in vogue, a point in favour of the auto-reinfection view. V Before the salvarsan era, -f'had seen three cases^of auto-reinfection, ©ne~of-wnieh: I showed before the Dermatological Section ;i ajid since I have made it a rule to give several injections of salvarsan: at the shortest possible intervals, and to supplement these with thorough courses of mercury ^^ have not seen a single case of auto-reinfection. The question as to the advisability of removing the lymphatic glands draining a primary sore has frequentlj' arisen, and their excision is even practised by some. Those in favour of removal state that it is only necessary to excise the glands which are eidarged. Those cases in which the lymphatic glands are most enlarged are usually those in which the infection is slight, and histological examination reveals the smallest number of parasites. Those cases in which the lymphatic glands are smallest and hardest, are usually those in which the infection is severe, and a histological examina- tion reveals the largest number of parasites. Therefore a ratio exists between the size of the glands and the protective capacity of the host against the disease. Since the lymphatic glands are responsible for some of the protective substances with which the host attacks the parasite, it would appear wiser to leave them alone. Having treated the sore locally, I give' from five to seven intravenous injections of neo-salvarsan, with two, three or four days' interval between each. To be quite sure that the organism has not become generalised, I examine\ the cerebro-spinal fluid, and close the treatment with one year's mercury, given in three courses of eight weekly intramuscular injections of grey oil, allowing two months to intervene between each course, for the first three weeks of which iodides are prescribed internally. ^ Tabulated, the treatment appears as follows : — 1. Local treatment. 2. Intravenous injection of neo-salvarsan, O'iS grm. 3. Four days later, second injection of neo-salvarsan, 0"J:.5 grm. 4. Four days later, third injection of neo-salvarsan, 0'45 grm. 5. Four days later, fourth injection of neo-salvarsan, 0"60 grm. THE TREATMENT OF SYPHILIS. 323 G. Four days later, fifth injection of neo-salvarsan, 0'60 grm. 7. Four days later, sixth injection of neo-salvarsan, 0"60 grm. 8. A week later, seventh injection of neo-salvarsan, 0"75 grm. 9. A week later, an intramuscular injection of grey oil, which should be continued weekly for eight weeks. 10. Iodides for three weeks. 11. No treatment for five weeks. 12. Mercury, iodides, and rest as before, twice repeated. Stage of Generalisation. A good plan is to examine the cerebro-spinal fluid before treatment is com- menced. If the fluid is normal, I^ve seven injections ot neo-salvarsan^ at four to seven days' interval. If the fluid shows pathological changes, -Lgis^B nine to eleven injections ; and if still positive after this, I give as many intrathecal injections of salvarsanised serum as are necessary' to render the fluid normal again. Then six courses of mercurial treatment are prescribed, and spread out over two years, with the iodides as above. Tabulated, the treatment appears as follows : — 1. (2-4) as above. 2. Four days later, fourth injection of neo-salvarsan, 0"4.5 grm. 3. Four days later, fifth injection of neo-salvarsan, 0'4.5 grm. 4. Four days later, sixth injection of neo-salvarsan, 0'60 grm. 5. Four to seven days later, seventh injection of neo-salvarsan, 0"G0 grm. 6. Seven days later, eighth injection of neo-salvarsan, 0'60 grm. 7. Seven days later, ninth injection of neo-salvarsan, 0"75 grm. 8. Seven days later, tenth injection of neo-salvarsan, 0"75 grm. 9. Seven days later, eleventh injection of neo-salvarsan, -90 grm. 10. Mercury, iodides and rest, as above, to be repeated six times. Recurrent Stage. If the recurrence is early, and if the previous treatment has been poor, then the case should be treated as belonging to the stage just described. If, on the other hand, the recurrence is late, and the previous treatment has been good or poor, three facts should be considered before any line of treatment is adopted — site of recurrence, marriage, age of patient. If the site is in or near a vital organ, and if any spread or future recurrence would endanger the life or blight the happiness of the patient, he should receive 324 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. the same treatment as previously mentioned. A man who is going to marry should be treated likewise, but marriage need not necessarily be delayed for two years. If the site is not an important one, and if the patient is not going to marry, and if he is of a certain age, his treatment should be symptomatic, i.e., two to three injections of salvarsan and a course or two of mercury. Latent Stage. Wlien one relied solely upon the Wassermann reaction in this stage, treating those who gave a positive reaction, and leaving those who gave a negative reaction, the course was clear ; but now that I no longer attach the importance to the reaction which I once did, I have had perforce to alter my routine. ( In this stage, I now begin by- examining the cerebro-spinal fluid.'? If tlie cerebro-spinal fluid is normal, however positive the blood may be, -I— do- not -advise any treatment. Naturally, the kind of treatment the patient has had before, and the interval that has elapsed since the infection, are points which have to be taken into consideration. If the cerebro-spinal fluid is positive, whether the blood is positive or negative, i-give as many injections of salvarsanised serum intrathecally? as are necessary to render the fluid normal again, and supplement these by one or two j^ears' treatment with mercurv. Syphilis in Women. Since syphilis in women is the worst of the evils caused by syphilis, I must repeat a few lines that have already appeared in Chapter XXV. Syphilis in women may be looked upon as the greatest curse of the disease, since a woman who has once conceived a syphilitic infant, may infect, in utero, all her subsequent offspring, although the father of the latter may be a different husband, who has never had the disease. To make matters worse, conceptional syphilis is not recognised until the infant has been seen to settle the diagnosis, owing to the fact that many mothers shc\v no evidence of the disease until after the child-bearing period is over, and, as often as not, the Wassermann reaction during this period is negative. A general rule may be formulated, viz., that if a woman contracts syphilis after she has conceived, the Wassermann reaction will be positive, because the disease becomes generalised arjd behaves in the ordinary way ; that if a woman contracts syphilis at the time of conception, the Wassermann reaction will often be negative, because the disease does not become generalised, at any rate not until some later date. »AM^^^'^ THE TREATMENT OP SYPHILIS. 325 Herein we have the explanation why sucli patients develop manifestations only after the child-bearing period is over, and why it so frequently happens that the first and last pregnancies result disastrously, while one or more healthy children may be born in the interim. It is interesting to inquire into the rationale of conceptional syphilis. The germ must, in the first instance, be conveyed by the semen. But does the germ, which is with the embryo in the uterus, develop after a time into the gamete forms described by me — which I regard as responsible for the symptoms — at the expense of the embryo, with, maybe, its death, and leave some of the sporozoites behind after its expulsion, to be already there to develop at the expense of the next embryo? Or, does the mother get infected directly, but the symptoms are prevented from recurring, owing to the formation of some chemical substance, possibly in the form of a lipoid from the embryo, which prevents the gametes from being developed ? When the question was discussed, after the Spirochaeta pallida had been discovered, when the Spirochaeta pallida was held to be responsible for everything syphilitic, only confusion resulted. If my discovery of the Leucocytozoon sy2}hilidis be accepted, and the views accepted that the sporozoite is the infective agent, and that the gametes are responsible for the symptoms, the alternative need not appear in the above illustration, as both, in part, may turn out to be correct. It may be considered that the sporozoites, themselves inert, travel in the semen, reach the uterus, and find themselves in both the maternal and foetal portions of the embryo. Those in the foetal portion, after a period of some weeks, develop into gametes, which may or may not kill the embryo. Those in the maternal portion find themselves unable to develop, owing to a chemical substance, from the chorionic cells, which circidates in the mother's blood, but not in the foetal, and so they remain dormant for a time. Herein lies the solution of the phenomenon that a mother may give birth to an actively syphilitic infant, without herself giving even so much as a positive Wassermann reaction. The theory above put forward, will also explain the fact that a woman who has once given birth to a syphilitic child is always liable to do so again, although the father of her later children may be another husband who has himself never suffered from the disease. Hence the necessity for treating such a case throughout the whole period of each succeeding pregnancy. To women who are syphilitic, I give, as soon after they have conceived as possible, six intravenous injections of neo-salvarsan, and 1 continue the treatment with mercury, till as near the time the child is to be born as can be done. 326 the biology, clinical aspect and treatment of syphilis. Congenital Syphilis. Attempts have been made to limit the use of mercury to those manifestations which correspond to the so-called secondary in the acquired form, and potassium iodide to those simulating the so-called tertiary symptoms. But if the child has s}T3hilitic symptoms of any nature whatever, this is evidence of an active vims ; therefore mercury should be invariably employed. Potassium iodide is undoubtedly useful in the late manifestations, but should never be solely relied up)n. Mercury is best given intermittently, each course being followed by iodides. Iodides, given in this way, aid elimination of the superfluous mercury which has been stored up in the system. Infants are very tolerant of mercury given inter- nally, because they are toothless and consequently run no risk of stomatitis. Treatment should be commenced as soon as the case is diagnosed. Half a grain of grey powder should be given in milk three times a day; if there is any diarrhoea, gr. iii of pulv. cretce. aromat may be added. After nine months of age, the dose should, by gradual increase, be doubled. This treatment should be continued for three years, and then be followed by 5-10 m. of syrupusferri iodidi three times a day, for three weeks. If symptoms have not disappeared before the iodide is started, or if ib is advisable to get the child quickly under the influence of mercury — for instance, in cases of epiphysitis, iritis, etc. — the internal treat- ment should be augmented by inunctions, 10-20 gr. of ung. hydrarg. being nibbed in gently for about an hour every other night, a fresh, site being chosen for each application. The rubbing should be performed either in the early morning or in the evening ; the part is then to be well covered with a flannel binder, and the ointment washed off at the next bath time. Infants are especially liable to dermatitis ; therefore it is important never to allow any of the ointment to get near the groins, where the urine acts as an additional irritating factor. Should dermatitis ensue, inunctions must be stopped and recourse had to injections. AVhile injections are being used, the oral adminis- tration must be stopped. Intramuscular injection into the glutei of a 10 per cent, emulsion of mercury salicylate, in liquid paraffin or almond oil, is the best. The injection, 3 m., shoixld be given twice a week for six weeks, or until symptoms have disappeared ; iodides should then be exhibited. If the child has open sores, nothing is so efficacious as a mercurial bath, containing 20 gr. of the perchloride in 3 gallons, continued daily until the sores have healed. THE TREATMENT OF SYPHILIS. 327 Application of emplastrum cinereum, or wearing next to tlie slcin clotlies impregnated with mercury, is a useful adjunct in treatment, if neither of the above forms can be borne. After the first year, the treatment should be intermittent, i.e., one of the above methods should be em pi 03' ed for six weeks, or until symptoms have dis- appeared, and then followed by iodides. This course should be repeated three times a year, for the ensuing two years. Congenital syphilis, with late manifestations, should be treated, by preference, with inunctions or injections of mercury. We come now to discuss the value of the new arsenic preparations in congenital syphihs. If a child is born with symptoms, the chances are that it will die. Salvarsan, or neo-salvarsan, given intramuscularly, may save it, but, in my experience, this treatment may also hasten the fatal termination ; indeed the risk of its so doing is great. Although giving the mother an intravenous injection of salvarsan, and then allowing her to suckle her child may result in a disappearance of the lesions, and the child may grow up to be a healthy child, provided fiu:ther treat- ment is prescribed, it may also have the opposite effect, and may precipitate the end. The same can be said of giving an infant an intramuscular injection of salvarsanised serum. As a child born with symptoms runs a very great risk of dying, I certainly think the chance may be taken, and one of the latter two methods adopted, as both of them are safer than the first. If a child develops symptoms after birth, unless for exceptional reasons, I do not give salvarsan, as the judicious administration of mercury nearly always produces the result desired, and I am rather inchned to hold the view, that neither the early administration of mercury nor even of salvarsan is going to prevent the patient from developing late symptoms, such as interstitial keratitis, nerve troubles, deafness, etc. It has been my experience, that patients who develop late symptoms, such as those just described, did not have early symptoms, and vice versa, while treatment appeared to play a subordinate role. In cases of late congenital syphilis, I have 'never seen salvarsan do any good, except in gunimata, and these I have frequently seen heal up hke magic, when mercury and iodides would not touch them. I am not at all sure that salvarsan does not aggravate interstitial keratitis. I have treated seventeen cases, without having once noticed the shghtest improvement, and in spite of several injections, in four of the cases the other eye became affected while the patient was under treatment. I am quite sure that it makes congenital sj'philitic deafness worse — in fact, it is just possible that it stimulates its appearance. In cases of so-called Syphilis hereditaria tarda, I have always found mercury 328 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. and iodides to be the best drugs, with the single exception of the cases with gummata of the skin, bones, etc. Intravenous injection of infants under six or seven years of age is no easy task, hence, if salvarsan is to be prescribed, it is best administered intramuscularly. The dose should range from O'OOl grm. to 0"004 grm. per lb. weight. For a child aged seven not more than 0'2 grm. shoiild be given intravenously. If salvarsan is to be used in congenital syphihs, repeated small doses, given intramuscularly, is the best plan to adopt, but the treatment should invariably be supplemented by mercury and iodides, in the same quantities as they would have been prescribed, had the salvarsan not been given. Syphilis of the Nekvous System. Brain. Meningeal. Meningitis. — Early meningeal lesions should be treated in the same manner as described under the generahsation stage, and, after six or seven intravenous injections of neo-salvarsan have been given, the patient should receive as many intrathecal injections of salvarsanised serum as are necessary to render the fluid normal. It must be remembered that salvarsan and neo-salvarsan have an influence upon the constitution of normal cerebro-spinal fluid, hence, when it is stated that intrathecal injections should be given until the cerebro-spinal fluid becomes normal, certain reservations must be made. The cerebro-spinal fluid to be tested, will naturally be that taken when the next injection of the serum is to be administered, hence an intravenous injection of the arsenic salt will always have been given 24 hours previously, and the last intraspinal injection from seven to ten days or more ago. It will follow, therefore, that, in all cases in which injections are being given until the cerebro-spinal fluid becomes normal, treatment will be still exerting its influence upon the constituents of that fluid. I am unable to tell yet for how long such an influence is exerted, but I do know, as I have found out some years ago when gauging the influence of treatment upon the Wassermann reaction of the blood, that even if onh' one or two injections were given, and one or two months were allowed to elapse before the blood was tested, many cases gave a negative reaction, but all recurred later. Therefore, the negative reaction did not signifv that sufficient treatment had been given. The same happens with the cerebro-spinal fluid, and most of the cases recur, if only one or two intraspinal injections are given. This being the case, I made THE TREATMENT OF SYPHILIS. 329 the rule to give as many injections of salvarsan or neo-salvarsan as I found were necessary to produce a negative Wassermann reaction in the blood withdrawn 48 hours after the last injection. By this means, I found how many intravenous injections in the early stages of the disease were required. As approximately the same number was required in most cases in the same stage, I fixed upon the maximum, and have, since early in 1912, given the number above mentioned to every case according to the stage of the disease, with the result that, provided the mercurial treatment has been persisted in, I have had so far very few recurrences. In some of the cases, the Wassermann reaction has become positive again, but I doubt whether that means anything, as in most instances it has been paradoxical, i.e., negative at one examination, positive at the next, or vice versa. Owing to the vagaries of the Wassermann reaction, I have done for some time, and do still, rely upon my clinical experience ; that is to say, I give the treatment already specified to every case alike, and never regnlate it by the reaction. Up to the present, I have not had cause to regret it, and I do not think I am Hkely to have cause for regret. Doubtless many cases receive too much treatment, but that cannot be helped, so long as we have no accurate means of gauging, in each individual case, the exact amount required. At the present moment, I am much in the same position as regards the influence of treatment upon the cerebro-spinal fluid, as I was in 1911-1912, when I was gauging it in the blood. I know that two intraspinal injections are far from being sufiicient to prevent recurrences of meningeal lesions, but I cannot gauge for certain how many are required, because I have not had time enough to watch my cases, and I have not, to my satisfaction, worked out the influence treatment has upon the tests we employ in examining the cerebro-spinal fluid. In the case of the blood, we had only the Wassermann reaction to consider, but in the case of the cerebro- spinal fluid, we have the amount of albumin and globulin, the number of the cells, and the Wassermann reaction to take into account. My rule, which must needs be still sub judice and hable to change, is to give about sis intraspinal injections of salvarsanised serum in early meningeal cases, as I have so far found that this number is usually required to render the fluid " normal," when tested on the day on which the last injection is given. A normal cerebro-spinal fluid after treatment, I regard as one in which the cell count is not more than 12 per c.mm. ; in which there is only a trace of giobuhn, but may be an excess of albumin ; and one in which the Wassermami reaction is negative in 1,000 per cent. Such a result, in a patient who has had no treatment, is certainly suggestive of the presence of a morbid process. If the patient has been treated with salvarsan, it is not at all an unusual result to find. 330 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. Gumma. In any late intracranial lesion, one must always be on guard against reactionary inflammation, when salvarsan is prescribed. In the case of a gumma, and it must be remembered that cerebral gummata are usually multiple, the reactionary inflam- mation following intravenous injections of salvarsan may be very severe, hence, it is a good plan to prescribe a course of 40-60 inunctions of mercury first, then increasing doses of iodides for one month, and then, finally, intravenous injections of salvarsan ma}- be given. Or intraspinal injections of salvarsanised serum may be given from the start, as I have never yet seen these injections produce sufiicient reactionary inflammation to render the patient comatose. Assuming that " 606 " has been given first, if reactionary inflammation is going to be severe enough to make the patient either temporarily mad or unconscious, the symptoms will set in suddenly on the third day, either after the second or the third injection. Reactionary inflammation is less severe after neo-salvarsan than after salvarsan, and it may in most cases be avoided, if not more than two or three days are allowed to intervene between the first three injections of 0"45 grm. The objection to salvarsan is that such big doses at such short intervals cannot be given. If the patient has reactionary inflammation, subcutaneous injections of adrenalin should be prescribed, 1 c.c. of 1 : 1000 solution, every four hours. Four or five injections may be given. A lumbar puncture may be done, but the reUef which follows is often only temporary and slight. The best plan is to give another intravenous injection of neo-salvarsan, and an intraspinal injection of the serum next day. The future course of treatment should be undertaken, as if no reactionary inflammation had occurred. If the patient has a Gumma cerebri, the chances are that, however much treatment be given, an actual cure of the disease will not be obtained. Therefore, it appears to me to be better to treat these cases symptomatically. Let us look back for a moment, and see what happened to the cases of Gumma cerebri, before the salvarsan era. Mercurial inunctions, with large doses of iodide, often succeeded in ridding the patient of his symptoms. Some recurred very quickly, others •went years without a recurrence. When salvarsan first came in, one or two injections were given, with the result that the symptoms vanished quickly, but soon returned. When mercury was prescribed as well, and the number of injections was increased, so far the cases have not recurred. In any case, the treatment we now adopt has not been sufiiciently long in use, to allow us to say that such and such a course should be adopted. THE TREATMENT OF SYPHILIS. 331 Therefore, I can only state what appears to me, at present, to be the best treatment for a case of Gumma cerebri. I give nine intravenous injections of neo-salvarsan, and use some of these for preparing the salvarsanised serum, which I inject intraspinally the day following the intravenous injection. Between each pair of the nine injections, four to seven days are allowed to elapse : — 1. Intravenous injection ; intraspinal next day. 2. Intravenous injection only. 3. Intravenous injection ; intraspinal next day. 4. Intravenous injection only. 5. Intravenous injection only. 6. Intravenous injection only. 7. Intravenous injection ; intraspinal next day. 8. Intravenous injection only. 9. Intravenous injection ; intraspinal next day. After that course is finished, I prescribe mercury and iodides for two years, i.e., six courses, each com'se consisting of eight weekly intramuscular injections of grey oil, three weeks iodides, and five weeks rest. Meningo-encephalitis. Many of the statements made under the preceding heading, apply equally well here, and the treatment is identical. A cure can scarcely be exjjected, but a recurrence may be delayed for several years, and, if the treatment is thorough, as in every case I think it ought to be, the chances are that, if a recurrence occurs, it will not be degenerative, as it may be if the previous treatment has been poor. There is no doubt that spontaneous cure results in many of these cases, and the influence of present-day treatment upon such a termination is a point which requires most careful consideration, as it is Ukely to be a burning question in some years to come. Cases of meningo-encephaUtis, occurring within two years of the infection, usually because sufficient treatment has been prescribed to steriHse the systemic portion of the body only, require very drastic treatment. In these cases, I give nine to fifteen intravenous injections of neo-salvarsan, and an intraspinal injection of salvarsanised serum the day following every alternate intravenous injection, so as to render the cerebro-spinal fluid normal. This treatment is supplemented by mercury and iodides for two years. Cases of meningo-encephalitis, occurring after the period just mentioned, should be treated symptomatically, but nevertheless thoroughly, because the more thorough the treatment, the less the probabihty of 332 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. the recurrence being of a degenerative nature, and vice versa. Such a statement must, in the present imperfect state of our knowledge, be based mainly on theory. Late cases of meningo-encephahtis should be treated in the same way as described under the heading gumma. The chances of severe reactionary inflammation are greater in cases of meningo-encephahtis than they are in Gumma cerebri, but if three injections of neo-salvarsan be given, two of which form the first stage of the intraspinal injection, severe reactionary inflammation can be almost invariably avoided. To show how quickly an intraspinal injection of salvarsanised serum will stop reactionary inflammation, the following case of meningo-encephalitis will form a good example : — Case 49. — Man, aged 29. Infection in 1911. Early in 1914, patient com- plained of bad headaches, which steadily become worse. On two occasions he had a fit. I saw him in July, 1914, and the following is an outhne of what I found. Patient thin, had rapidly lost weight, could not sleep very well, he was apathetic, and slow in answering questions. All the reflexes were exaggerated. The pupils were unequal, and so were the pupillary reflexes. Cerebro-spinal fluid showed marked pathological changes. Patient was given at the hospital three intravenous injections of neo-salvarsan. On the third day after the last injection, the patient became comatose, and all the chnical signs were intensified. I drew oft' 50 c.c. of blood, and injected intra- spinally, the next day, 25 c.c. of serum mixed with the same quantity of sahne, after having drawn off a nearly equivalent amount of cerebro-spinal fluid. The next day, the patient was sitting up and tallcing as if nothing had happened. Further treatment was continued, without any untoward eft'ect. The main change in the cerebro-spinal fluid in these cases of severe reactionary inflammation is, besides the great rise of pressure, the tremendous increase of the albumin content. Degenerative Encephalitis. If the case has obviously been of meningeal origin, treatment may be prescribed more with the idea of lengthening the period of quiescence, since the cases all recur in time, however drastic the treatment may be. Nibbhng treatment does the patient more harm than good, and treatment should never be prescribed during a quiescent period, for fear of precipitating an attack. If it is the patient's first attack, I give six to eight intraspinal injections of salvarsanised serum, at seven to fourteen days' interval between each pair, and mercurv and iodides for a vear. THE TREATMENT OF SYPHILIS. 333 Giving only one or two intravenous injections of neo-salvarsan, or one or two intraspinal injections of salvarsanised serum, has, in my experience, made the patient worse. If it is the patient's second attack, I do not think any anti-syphihtic treatment ought to be given. Cases in which no anti-syphihtic treatment is recommended, should all receive hexamethylene tetramine internally, and if the relatives are anxious that something should be done, injections of nucleinate of soda can be given. Pilcz^ and Wagner v. Jauregg^ advocated, some years ago, tubercuHn injections and large doses of staphylococcic and streptococcic vaccines. The idea was purely empirical, and was due to the observation that had frequently been made, that intercurrent febrile processes sometimes exerted a beneficial effect upon the course of degenerative encephahtis. Both act in virtue of their capacity of producing a rise in temperature, and, since nucleinate of soda is far more powerful in this respect, it has entirely taken the place of tubercuhn and the vaccine of the pyogenic cocci. Ameningeal. In pure arterial lesions without involvement of nerve substance, such as in the early form of hemiplegia, the case should be treated as described under the generaUsa- tion stage, and there is no necessity to examine the cerebro-spinal fluid. It is imperative to treat these cases at once, so as to avoid subsequent con- tractures, etc., resulting from the paralysis. In later cases, such as encephalitis or gumma, the treatment should be the same as that already mentioned for similar lesions of meningeal origin. In cases of ameningeal degenerative encephahtis, anti-syj^hihtic treatment is contra-indicated, even if it is the patient's first attack. Hexamethylene tetramine should be given internally, and intramuscular injections of nucleinate of soda may be given if desired. The most difficult cases to treat are the late cases of hemiplegia. If the patient comes up with premonitory signs, such as an ocular palsy, it is certainly worth while to give him seven or eight intravenous injections of neo-salvarsan — never salvarsan, as " 606 " is apt to cause marked variations in the blood pressure, such as I have not noticed with " 914." Mercury should be given for a year, either in the form of pills or suppositories, and the patient should be more or less under iodides for the remainder of his hfe. The iodides .can be prescribed in the form of tiodiue pills, of which the patient should take one or two a day. 334: THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. If the patient has already got hemiplegia, nothing in the way of anti-syphilitic treatment will do much good, but iodides ought certainly to be prescribed. Haemorrhagic encepJutlilis. — When this condition follows the second or the third injection of salvarsan in the generalisation stage, the patient, the moment he becomes unconscious or in any way strange, should receive intramuscular injections of adrenahn, and an intraspinal injection of his own serum, or of a serum obtained from another human being. In the lymphocytic type which occurs later in syphihs, and is usually independent of treatment, or, as I showed in Chapter XXIV, which may come on some weeks or months after inadequate treatment, the patient must be put under treatment before he loses consciousness, because, if there is any delay, death will ensue. Adrenalin should be given as before, and intrathecal injections of either ordinary serum or of salvarsanised serum should be prescribed as quickly as possible. There is no risk of producing reactionary inflammation in such a case with salvarsan or neo-salvarsan, provided an intrathecal injection of serum is given the following day. Once the patient has recovered, even in cases of haemorrhagic encephalitis, it is perfectly safe to continue the treatment as if nothing had happened. Coed. Meningeal. In all cases of meningitis of the cord, it must be assumed that there is intra- cranial meningitis also. This being the case, and since reactionary inflammation can never do any damage or produce serious symptoms, owing to the comparatively large space in which the cord lies, there is need only to think of what may happen in the cranium, hence the treatment just described will be equally applicable here. The same may be said about gummata and meningo-myelitis. In degenerative myelitis of meningeal origin, treatment should invariably be prescribed, should the symptoms be such as to worry the patient, or should the cerebro-spinal fluid show pathological changes, and the case appears obviously to be progressing. In such cases, eight to eleven intraspinal injections of salvar- sanised serum should be given, and mercury continued for one year, or perhaps two, if it appears to be benefiting the patient. The mercury should, preferably, be given in the form of intramuscular injections. If the cerebro-spinal fluid is normal, and the lesion appears to have spontaneously healed, which is, by the way, not at all an uncommon sequence, treatment should only be prescribed should troublesome symptoms still persist, and then the treatment should only be symptomatic. The following case will give the reader exactly what is meant by the above : — Case 50. — A man, aged 43, contracted syphilis when 19 years of age. Teu THE TREATMENT OF SYPHILIS. 335 years after infection, he developed typical signs of degenerative myelitis. I saw him first in December, 1909, when he had Argyll-Robertson's pupils, very slight rhombergism, altered sensations down the ulnar region of both arms and in both feet. The knee-jerks were absent. He complained of severe pains in his feet, ankles, and legs, and also that he could not get an erection. I advised mercurial inunctions, and potassium iodide and arsenic internally. I saw the patient about two years later, when he informed me that the pains were as bad as, if not worse than, ever. I then gave him foiu- intravenous injections of salvarsan, at about ten days' interval between each pair, after having first examined his cerebro-spinal fluid, which turned out to be normal. This treatment did not appear to do him much good. During the year 1912, I ordered him four courses, each course consisting of thirty intramuscular injections of oxycyanide of mercury and acoine (Hirsch's injection). These injections produced only a little temporary relief. I examined the cerebro-spinal fluid again in April, 1913, with the same result as before. I might say that the Wassermann reaction in the blood was negative throughout. In October, 1913, the pains were particularly severe, and the patient began to develop painless whitlows on both hands. No sooner had one healed than another appeared, so I gave him an intraspinal injection of salvarsanised serum. The injection produced such an aggravation of the pains that he had to be kept under morphia for two days, and, twenty-four hours after the injection, he developed the biggest whitlow that he liad ever had. When he recovered from the exacerbation of the symptoms, he remained practically free of pain for three months, when they recommenced, but not with the same severity. One or two small whitlow's occurred in the meantime. I repeated the intraspinal injection in February, 1914. The cerebro-spinal fluid was normal, as it has been since. The exacerbation of pains did not come on so quickly, it was not so severe, in fact no morphia was required, but it was longer in going off, and there was no whitlow. The patient had comparative freedom till June, 191-4, when the pains began again, but nothing like so severely as before, and he had only one whitlow. I gave the third intraspinal injection in July, 1914, and the fourth in December, 1914. Hardly any exacerbation of the pains was produced by either. The pains have been comparatively mild and easily assuaged by aspirin, and no whitlow has developed. The patient has put on weight, which is always an extremely good sign iu any syphiHtic nervous trouble, especially if it is degenerative, but the signs have throughout remained unaltered. Enesol is sometimes advocated for pains in cases of degenerative myeUtis, but I must admit, that in my hands, it has never produced any relief. Y 336 THE BIOLOGY, CLINICAL ASPECT AXD TREATMENT OF SYPHILIS. Anieningeal. Ill transverse myelitis, treatment mnst be begnn at once, and it shonld be the same as that described under the generaUsation stage. As it is an arterial lesion, therefore there is no need to give any intraspinal injections. To show the extra- ordinary benefits that may follow appropriate treatment, I will cite a case which I treated in 1912, ■when neo-salvarsan first came in. Case 51. — A man, aged 25, had contracted syphilis eighteen months prior to suddenly becommg paralysed in both his legs. When I saw him, he had complete paraplegia, and had lost the control of both his vesical and rectal sphincters. I gave him nine intravenous injections of neo-salvarsan, and mercury and iodides for two years. In August of 1912, the injections having been given in April, the patient was playing tennis. If the vessel has been allowed to become permanently blocked, treatment will aid the patient, but serious defects will naturally remain in spite of it, therefore it cannot be stated too often, that not an hour should be lost in putting under treatment every patient with an arterial lesion occurring in early s}'philis. In late cases of myelitis, in cases of lateral sclerosis and atrophic muscular paralysis, very little can be done by treatment, but, as treatment will do no harm, it should certainly be tried. If the condition appears to benefit by one or two intraspinal injections of salvarsanised serum, the treatment should be continued until about 8-11 have been given. If no improvement appears, then nothing is to be gained by persevering with treatment. If the cerebro-spinal fluid is examined first, and found to be normal, no treat- ment need be prescribed, and this apphes equally well to cases of degenerative myelitis of ameningeal origin. If, on the other hand, the fluid shows pathological changes, and the patient is worried by his symptoms, treatment should be given, as there is no fear of hastening the end, as is the case in amenmgeal degenerative encephalitis. Cases of combined degenerative myehtis and encephahtis are best treated with nucleinate of soda, and not with anti-syphihtic remedies. In no condition is individual treatment more necessary than in nervous s\-philis, and although I have attempted, as clearly as possible, to narrate the methods I employ, it must be understood that every case has to be judged upon its own merits. » McDonagh (1911), " Brit. .Journ. of Derm.," xxiii, 227. " Pilcz (1911), " Zeitschr. f. d. Ges. Neiir. u. Psych.," iv (orig.), 457. » Wagner v. Jauregg (1912), " Wien. klin. Woch.," xxv, 61. ' Homer Swift and Ellis (1913), " .Journ. of the Amer. Med. Assoc.," Ix. 1.576. CHAPTER XXX. DRUGS USED IN THE TREATMENT OF SYPHILIS, AND THE METHODS OF ADMINISTERING THEM. The di-ugs we have to consider are, salvarsan, neo-salvarsan, other arsenical compounds, antimony, mercury, iodine, and nucleinate of soda. Salvarsan and Neo-salvarsan. A. — Intramuscular Injection of Salvarsan. The yellow powder being acid, alkali must be added before its solution can be injected. Sodium hydrate is the alkali most frequently employed, and excess of it can be neutralised or not ; if it be neutralised, the pain is not so severe, and an emulsion is formed, which has the distinct disadvantage of not being so quickly absorbed, but may become encapsuled by the tissues, and an arsenic depot formed. As the pain produced by the injection is so severe, the method is seldom employed. It has another objection, in that the bulk of fluid is large, so that two injections have to be made. Dissolve the powder in alcohol — ethyl alcohol for choice — not methyl alcohol, as has been advocated, because, unless absolutely chemically pure, it may give rise to unpleasant symptoms, probably dependent on the presence of formaldehyde, which is not an uncommon impiirity. 0"5 c.c. of alcohol is used for every 0" 1 grm. of powder, and 20 c.c. of ordinary sterile warm M-ater are added, and the mixture stirred with a glass rod until every trace of the powder is dissolved ; then add slowly, mixing thoroughly while adding, 1 c.c. of decinormal sodiiim hydrate solution to each O'l grm. of powder used. Inject equal quantities into each buttock, at the junction of the outer and middle third of a line drawn from the top of the greater trochanter to the sacral spines, using a needle not less than 2 ins. long. The preparation which is now sold as salvarsan requires no alcohol to dissolve it, and thereby the pain is considerably modified. If the solution is intended to be neutralised, the best plan of procedure is as follows : — Put the powder into a mortar and add 1 c.c. of a saturated solution of sodium hydrate, mix, and then dissolve in 4 c.c. of very hot water ; as an indicator, 3 drops y2 338 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. of the standard alcoholic solution of phenolphthalein are added, which colour the solution a bright red ; then add glacial acetic acid, drop by drop, till a yellow emulsion is produced ; finall)', put in one or two drops of sodium hydrate until the emulsion assumes a rose-pink tint. This emidsion is taken up in the syringe, and any residue left in the mortar can be drawn up by adding another 1 to 2 c.c. of hot water. The injection need not necessarily be made in the glutei, a useful fact to remember with male patients who take to bed badly. Pain is often more severe in this situation when the patient is recumbent, than when he is up and about, but, unfortunately, movement excites local reaction, mth the result that the injected mass tends to gravitate downwards on to the sciatic nerve, producing sciatica, which necessitates a prolonged stay in bed. A favourite place for an injection is into the trapezius muscle, near the vertebral column, and just below the angle of the scapula, on the left side in right-handed individuals and vice versa. There is often, especially in plethoric subjects difEculty in breathing, owing to spasm of the intercostal muscles, immediately after injection into the shoulder, but it seldom lasts longer than a quarter of an hour. It is often accompanied by coughing, but in only one case did the patient become cyanosed and pleurisy develop. It is better to inject emphysematous patients in the glutei. The following is the best method of preparing a neutral emulsion . — Neutral Emulsion {Citron's Method). — The contents of a tube are emptied into a glass, and then 1 c.c. of absolute alcohol and 5 c.c. of hot water are added and the mixture stirred until all the powder is dissolved. Next, 40 drops of a 10 per cent, solution of potassium bicarbonate in normal saline are added. The mixture is now stirred carefull}' with a glass rod until an emulsion is produced, when it is drawn into the syringe, which must be inverted to get rid of the air. As this emulsion is sometimes thick, a pleural-efPusion needle should be employed, for preference a platinum one with an iridium point. Although the pain is very much lessened, there may be a very painful toxic oedema, unless the patient remains quiet for a few days. The injection should always be employed fresh, and preferably made at the bedside. Any tube opened and unused that day, must not be kept for another, as this procedure has in some cases resulted in toxic symptoms supervening, such as anuria, inflammation of the bladder, and atony of the large intestine. The best intramuscular injection is a new preparation called " loha." It contains 40 per cent, salvarsan in iodipin, and is already prepared for use. It keeps well, and the injection is practically painless. Intramuscular injections must always be preferred to subcutaneous ones, as the pain, swelling, and liability to necrosis are less. If complete aseptic precautions METHODS OF USING ANTI-SYPHILITIC DRUGS. 339 are taken, an abscess will not result from an intramuscular injection. Directly after the injection, the pain is very acute, owing to the sudden distension of the tissues. This persists for about ten or fifteen minutes, and is followed by a dull aching pain, which varies in its duration from one to three weeks. On the third day, a large tender swelling may form, due to toxic oedema, which is best relieved by alternate applica- tions of an icebag and hot fomentations. AVlien the swelling gets smaller, nothing gives the patient more relief than the application of a belladonna plaster, which also aids absorption. Morphia may or may not be necessarj-. Pain, which is less in women than in men, varies enormously with the individual, but is generally sufficient to prevent sleep for a few nights. Temperatm'e may rise the first night, but more frequently on the second and third ; on the fourth day it usuallj* falls, but it may persist for another day or two. Occasionally the temperature rises as high as 103°, and although the rise seems to be in direct ratio to the severity of the infection, it is not invariably so. Sometimes, on the second or third day, the patient complains of a sore throat. Constipation after injection is so usual, that a laxative the evening after the injection is advisable. Clinical Course after an Intrarmiscular Injection. — However the solution be prepared, and however carefidly it may be given, one can never say beforehand how much pain the patient is going to suffer. Some patients have little or none, whilst others have excruciating pain which may last as long as a week. Needless to say, the very greatest precaution should be taken in sterilising everything before use, since, if an abscess forms, the pain, will necessarily be severe. Even when the strictest antiseptic precautions are taken, swelling, softening, and necrosis of the part injected may take place. The swelling is a toxic oedema ; it comes on about the third day, diminishes rapidly in size at the end of a week or ten days, after which its diminution is so gradual that a small amount of infiltration may be perceptible months, and even years after. As a rule, the swelling is not painful ; it gives the sensation of fluctuation, but under no circumstances should it be opened, unless an obvious abscess forms, when it becomes acutely painful. The skin over it is at fii'st slightly red ; but if it becomes red for the first time at the end of a week, an abscess must be feared. The redness which appears with the swelling, is analogous to that met with in urticaria, and c^uickl}' disappears under an application of the following lotion : — R Plumbi subacetat. . . . . . . gr. x Liq. ammon. fort. . . . . . . n^v Spir. vini rect. . . . . . . . . 5] Solut. alumin. acetat., 3 per cent. . . ad j] 340 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. When the swelling appears, alternate hot and cold applications give the patient the most relief ; and, when up and about, a belladonna plaster helps to diminish the pain and increases absorption. Even after two or three weeks, the swelling may be so perceptible as to be visible through the patient's clothes. Occasionally the swelling resolves into fluid, and in such circumstances it is either best left alone — since it causes the patient no inconvenience — or the sterile pus may be aspirated. Under no circumstances should an incision be made, since a sterile abscess is thus almost certainly converted into an infected one. Necrosis, to a slight degree, occurs after every intramuscular injection, but a necrosis of the overlying skin occurs only when an injection is given subcutaneously, or when some of the mass is allowed to get into the subcutaneous tissue, as the needle is withdrawn from the muscle. One of the most important points, in giving an intramuscular injection, is to avoid the entrance of any of the emulsion into a vein. The needle should be first inserted, and from 30 seconds to a minute should elapse, before the syringe is fastened on to it. One case, where this precaution was neglected, resulted in the patient getting hemiplegia, and this complication was described as being due to the toxic action of " 606." Necrosis. — In the muscle, or in the subcutaneous tissue, lies a hardish mass of brownish-yellow colour, in the centre of which is a dark brown horny mass, which spreads out here and there into the tissues. The central portion is due to a chemical action which destroys the structure of the tissue. Around, there is usually a capsule and marked signs of chronic inflammation. Microscopically, the necrosis is found to affect muscle, fat, and connective tissue, the nuclei of which do not stain. The vessels in the immediate neighbourhood of the necrosis are thrombosed. Cases of pulmonary embolism and hemiplegia, coming on a week or two after an intramuscular injection, are probably due to a thrombus becoming detached and passing free into the blood stream, rather than to the toxic action of salvarsan. In the outer zone, the thrombosis is often only partial, or the vessels are found to contain collections of leucocytes. The nerves in the necrosis also degenerate. Arsenic is almost invariably to be found, often as late as three or foiir months after the injection was given. Necrosis occurs only when a large quantity of the preparation is injected in one spot, and not when several small points in both buttocks are chosen ; it is more common when the injection is given in the thoracic region than in the glutei. There is no doubt that one or two of the cases described, in which peroneal atrophy has set in after an injection, were due to an inflammation, or even to a degeneration of the sciatic nerve, caused by the necrosis, and not to a nem'otropic METHODS OF USING ANTI-SYPHILITIC DRUGS. 341 action of the drug. Moreover, some of the bladder and colon troubles, which have occurred more frequently after an intragluteal injection, may be reflex from an implication of the pudendal plexus, which lies in close relation to the sciatic nerve. B. — Intramuscular Injection of Neo-salvarsan. All that is necessary is to dissolve the salt in saline. As neo-salvarsan is readily soluble, it does not matter how much saline is used ; I grm. of neo-salvarsan can be dissolved in 10 c.c. of saline. Although the pain is not so acute as when salvarsan is used, it is not often that the patient will submit to a second injection. It has been frequently ad\'ised to give several injections of very small doses, but the therapeutic action of such a procedure is not very satisfactory, and this mancEuvre has the other disadvantage, in the fact that the cells soon become accustomed to the drug — that is to say, immune to it. C. — Intravenous Injection of Salvarsan. The contents of one tube of salvarsan should be slowly dissolved in 3 or 4 ozs. of warm physiological 0'9 per cent, saline which has been prepared with freshly distilled water, in a 10-oz. graduated glass measure. When the powder has completely dissolved after sufficient stirring with a glass rod, 10 c.c. of double decinormal* sodium hydrate solution should be added, with the result that a precipitate forms. This precipitate is dissolved by a further addition of sodium hydrate, usually about 10 c.c. — this may be either more or less, according to the actual acidity of the powder. The 10 c.c. should be added slowly, and the mixture stirred thoroughly. By using a weak solution of sodium hydrate, we avoid the risk of making the solution too alkaline, and the exact quantity required is more easily estimated. When the solution is quite cleared by adding the sodium hydrate, the measure should be filled with saline up to 10 ozs., and once or twice filtered through muslin or several layers of plain gauze, so as absolutely to exclude even the smallest solid particle from getting into the vein, where it might cause either a pulmonary embolism or hemiplegia ; 10 ozs. must be considered the maximum dose. Two points must be observed concerning the saline. In the first place, the sodium chloride must be chemically pure ; secondly, the solution must not be less than 0'8 per cent, or more than 1 per cent. A hypotonic solution is more dangerous than a hypertonic one, because the former causes haemolysis — setting free the haemoglobin from the red blood corpuscles. Should this happen, the * Double decinormal NaOH or % NaOH = 0-8 per cent., or 8 grm. to the litre of distilled water, normal sodium hydrate being a 4 per cent, solution. 342 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. patient may collapse after the injection, and there may be haemoglobinuria. Needless to say, every vessel used should be sterile, and the sodium hydrate solution should be boiled before use. Another vessel filled with saline is placed by the side of the one containing the " 606." The patient comes to the side of the bed and hangs his arm over, then a tourniquet* is placed on the arm, and the limb made to rest on a table in as comfortable a position as possible. The bend of the elbow is then sterilised, by first rubbing with acetone, and then with ordinary tinctm'e of iodine. When a vein cannot be seen, it can often be felt, and should be marked out with a blue pencil to indicate its course. If this cannot be done, a vein shovdd be exposed by an incision, either under a local or a general anaesthetic. There is no danger in a general anaesthetic, for the subsequent reaction is not in any way influenced. Bitting the bend of the elbow, or warming the arm with hot towels, will often make a vein prominent. An intravenous injection may be the simplest, or one of the most difficult operations possible. A common troiible is due to the vein slipping about when the needle tries to pierce it; extending the arm as much as possible, or pulling the skin taut to fix the vein, may prevent this. The solution can either be injected or transfused, injection being far preferable, as : — (1) The needle is not so easily dislodged. If this should occur while the solution is flowing in, by transfusion some must escape into the tissues before the flow can be stopped ; with the syrmge, merely a few drops need escape, as the tap can be turned ofi at once. (2) The operator has more control over the proceedings. (3) There is less danger of air or a solid particle gaining access to the vein. Air is easily seen in the syringe and remains at the top, never coming over the centre of the outlet unless the piston is pushed right home. A solid particle is also seen ; it falls to the bottom of the syringe and is not disturbed, provided that the solution is injected slowly and steadily and the piston not rammed home. (4) The operation is pleasanter from the patient's point of view, because it is so much quicker. (5) The operation can be performed without an assistant, and there is prac- tically no apparatus to carry about. A good syringe is one invented by Schreiber. The cannula is bayonet-shaped, bent, and fixed to a three-way metal stopcock, so that the fluid can be sucked uj) * The simplest and hes,t tourniquet is some rubber tubing, which should be wound tightly around the arm and the two ends fixed with pressure foiceps, which can be removed without disturbing the limb. METHODS OF USING AXTI-SYPHILITIC DRUGS. 343 from the vessel, and injected directly into the vein. The needle has also a plate at its base npon which a finger can rest to keep it steady. The one disadvantage of this syringe is, that the whole apparatus is rigid, therefore the slightest movement of the syringe may be sufficient to dislodge the needle. To overcome this difficulty Allen & Hanbury have constructed for me a needle which is Ij inches in length, behind which is a slightly concave metal plate, which rests on the arm, and which may be fixed by a piece of tape which runs under a metal bridge, and is tied under the arm should it be required. This needle is fixed Ki-i;5|'!«'!'i'^l'i'l'M*l'['''W'':ir ^^\ Scale £ ' itcDona^li's Syringe The same in use by means of a bayonet-catch to the three-way stopcock ; but connection between the needle and the bayonet-catch is made by a piece of thick rubber tubing, so that every movement of the stopcock or sninge behind is broken by this flexible connection, and does not affect the needle. The all-glass syringe, which should hold 20 or 30 c.c, fits on to the stopcock by means of a piece of stout rubber tubing, instead of being inserted into a metal tube, which may not fit every spinge. The best syringes are Luer's ; they are of French manufacture, but can be ordered in London through Allen & Hanbury. Both the English and the German makes are bad fits, and do not withstand frequent boilings. The s}'Tinge is first filled with saline solution, and all air is expressed both 344 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. through the tubing and the needle ; then the needle is inserted into the vein, with the stopcock open, being guided and held by the metal bridge above it. If the vein has been pierced, and this can at once be told by touch, or by blood flowing back into the syringe, the tourniquet should be removed and some saline injected. If the cannula is not completely in the vein, the sahne will produce infiltration ; this being the case, the needle should be withdrawn and another vein chosen, as it is most important to prevent any of the " 606 " solution getting under the skin, as considerable pain is caused thereby. If much escapes, there will be painful induration and oedema of the arm, and it takes weeks to disappear. ^^Tien the solution has all been injected, some saline should finally be used to avoid leakage of a drop or two of " 606," this is done by transferring the tubing from the " 606 " vessel to the one containing saline. If, during the injection, the needle slips, and some of the solution escapes — the patient complaining at the same moment of a burning sensation — one shoidd immediately take the needle out, apply a tourniquet to the arm, and allow the vein to bleed, which will often prevent infiltration forming. If the injection is skilfully done, the patient has no pain. Under no circumstances must the preparation be injected in a concentrated form, and great care should be taken not to inject it too quickly. D. — Intravenous Injection of Neo-salvarsan. Instead of sahne, pure distilled water is used, in which the powder is simply dissolved without the addition of any other substance, in the proportion of ' 1 grm. neo-salvarsan to 35 c.c. distilled water. The temperature of the water to be injected, should never be above that of the room. In other words, the water never requires heating. The resulting solution is hj-potonic, which might at first sight seem to be a disadvantage, but it causes no disturbance when it gets into the general circulation. The urine passed after the injection is often highly coloured, owing to the excess of pigments, which have resulted from the breaking down of some of the red blood corpuscles ; but no hismoglobinuria or other signs and symptoms, which might result from an haemolysis, are to be met with. Concentrated intravenous injections of neo-salvarsan can be given, but they have the disadvantage of producing more immediate unpleasant symptoms, such as headache, sickness, a rise of temperature, etc., and a local thrombosis of the vein is more apt to arise. The powder is dissolved in 10 to 30 c.c. of pure distilled water, and then injected directly into the vein. It does not appear to matter how much water is used. METHODS OF USING ANTI-SYPHILITIC DRUGS. 345 Another raetliod is to put the powder into the spinge, insert the needle whicli is attached to the syringe into the vein, and let the blood which flows back into the sjTinge dissolve the salt. When the powder is dissolved, the blood containing the neo-salvarsan in solution is re-injected into the vein. AATien the solution injected is below the body temperature, the median basiUc vein, should be used in preference to the median cephahc, since the distension of the vein and the cool solution running along it, irritates the circumflex nerve and causes considerable pain, in the region of the shoulder. There are now two points to be considered : One is, whether the intramuscular route is preferable to the intravenous, or vice versa ; and the other is, ^\hether salvarsan is better than neo-salvarsan, or ince versa. I am very stronglj^ of the opinion myself that the intravenous administration is better, in every way, than the intramuscular. The drug is excreted more quickly when given intravenously, and one knows when it is safe to repeat the injections. When given intramuscularly, one cannot tell how much has been absorbed, how much has been excreted, and therefore when it is safe to give the next injection. With these new arsenical preparations, it appears that, in order to get the best results, it is necessary to repeat the Injections at the shortest possible intervals, which can only be done when the intravenous route is chosen. When the drug is injected intravenously, more of it reaches the spot at which it is required than when given intramuscularly, and, moreover, it reaches the lesion more quickly. When a drug is slowly absorbed, as it is when given intramuscularly, the parasites against which it is directed, quickly become immune to its action. With these new arsenical preparations this is especially noticeable. The patient suffers very much less inconvenience when the drug is prescribed via the veins. These, and other minor points which could be brought forward, clearly indicate that the intravenous route is the route for choice. Concerning the advantages of one drug over the other, more than the mere potency has to be considered. Injection for injection, there is no doubt but that salvarsan is more potent than neo-salvarsan ; but the difference is becoming less and less marked, as the salvarsan now supplied does not appear to me to be as strong as that which was in use when neo-salvarsan first came in. Salvarsan causes more immediate disturbance than neo-salvarsan, therefore the intervals between the injections usually have to be longer, and the drug is not so suitable for out-patient work. Neo-salvarsan can be given every four days, and to out- patients with impunity ; and since as good results can be obtained with neo-salvarsan as with salvarsan, provided a few more injections are given, it will be seen that the 346 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. advantages of neo-salvarsan strongly outweigh the disadvantages of salvarsan. Owing largely to the fact that the patients need not go into a nursing home, and as equally good results may be obtained with the two drugs, I almost invariably use the neo-salvarsan now. E. — Infmtkecal Injection of Salvarsanised Serum. The method to be now described is that which has been elaborated by Homer Swift and Elhs.^ The patient is first given an intravenous injection of salvarsan or neo-salvarsan. One to two hours later, about 50 c.c. of blood are withdrawn from a vein into a sterile tube. The tube must be shaken occasionally, to prevent the clot from sticking to its sides, which prevents the separation of the serum. WTien the serum has separated out, the tube is placed in an incubator at 57° C, for one hour. The following day, the serum is collected, mixed with an equal quantity of saUne (about 25 c.c. of each), and, after an approximately corresponding amount of cerebro-spinal fluid has been withdrawn, the diluted serum is injected into the canal. (For the details of performing a lumbar puncture, vide Chapter XXII.) The best needles for performing lumbar puncture are Barker's, and both Messrs. Maw, Son & Sons, and Allen & Hanbury have constructed a mount for my three-way s)T.'inge, which makes the injection of salvarsanised serum a very simple matter. After the operation, the patient is placed with his head low down, and the bottom of the bed is well raised, so as to allow the fluid to gravitate towards the brain. Many observers^ have attempted to inject salvarsan and neo-salvarsan dii'ectly into the spinal canal, and also, in cases of degenerative encephalitis, into the lateral ventricles. The general consensus of opinion is that, the danger of toxic symptoms supervening contraindicates such measm-es being adopted. The very small doses of the drug which can in this way be injected, must, even by the enthusiasts, be considered msufiicient to be curative, and the good results which have been obtained, could have been equally well achieved with the salvar- sanised serum. We have yet to learn the future of the cases which have been treated with salvarsanised serum, since it is mainly on theoretical grounds that its administration is based. There is no doubt that it does good in meningeal lesions, but whether it is only palliative or curative, we have yet to learn. The intrathecal injections have unfortunately two very great disad- vantages. One is, that the symptoms are usually aggravated by the first two injections — this is true only of those that accompany degenerative lesions — and the other is, that patients do so object to repeated lumbar puncture, that they often refuse to continue the treatment. If the treatment is discontinued, METHODS OF USING ANTI- SYPHILITIC DRUGS. 347 the patient's condition is veiy often permanently aggravated. I think this rule may be safely made in the case of nerve syphihs, that it is useless, and often harmful, to prescribe treatment, unless it is intended to be drastic, or, in other ■words, sufficient to render the cerebro-spinal fluid approximately normal. I would here draw the reader's attention to the fact that the globuUn test may fail, after the first or second injection of salvarsanised serum. By the unwary, this is assumed to show that one or two injections have cured the patient. Not only may the globulin disappear, but the Wassermann reaction may become negative. Exactly the same thing may happen with the serum of a late case of s}'philis (vide Chapter XI). The decrease in globulin, and the negative Wassermann reaction is simply due to the fact that the existing lipoid -globulin particles become hydrolysed when salvarsan or salvarsanised serum is first given. This is the explanation of the so- called negative phase. Improvement follows only when the negative phase has passed off, and this is due to the destruction of the old Hpoid -globulin particles and the formation of new ones. It is, moreover, an indication for further treat- ment, not for a stoppage of the same. Other Arsenical Compounds. As the French laws deahng with the patenting of drugs differ from the Enghsh ones, and as their chemists show more enterprise than ours, not only have salvarsan and neo-salvarsan been prepared for some considerable time in France, but also other similar products have seen daylight. Mouneyrat has prepared what he calls " 1116 " (Galyl) and " 1151 " (Ludyl). Neither of these has any advantage over neo-salvarsan, and it would appear, from the small experience which observers have had with them, that they are not quite so potent. There is no doubt, but that, within a few years, the market will be flooded with synthetic drugs, which will differ little from the original salvarsan, although each will be said to be a distinct improvement. Chemotherapy is a very distinct advance upon our old empirical meth6d of prescribing drugs, but it must be remembered that the science is in its earliest infancy, and that even the foundation upon which salvarsan was built, has turned out to be unsound. Theoretically, Ehrlich's conceptions were brilliant, but unfortunately, having no first-hand knowledge of syphihs, he was obhged to rest upon the knowledge of others, whose work and conceptions now appear to be wrong. The Spirochaeta pallida is not the cause of s}'philis, and its destruction does not result in the cure of the disease. Ehrhch's work with salvarsan was only in connection with the Sjyirochaeta pallida ; the other phases of the Leucocytozoon syphilidis were unknown 3i8 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. to him. Ehrlich also was not familiar Avith the chemical points which have since been worked out, in connection with the organism and the host's serum, hence the description of the action of salvarsan which Ehrhch gives, is only a fraction of its manifold action, which naturally could not be discerned, until the other facts just mentioned had been discovered. Salvarsan will certainly be the starting point of many valuable future dis- coveries, and, even so far as syphilis is concerned, it is highly probable that it can and will be improved upon. For future research in this direction to be productive, special thought will have to be paid to the spore, and not to the SpirocJiaeta pallida, and as, in my opinion, the chemical nature of the spore will defy any direct attack against it, the indirect action of the proposed synthetic compounds will have to be taken into main consideration — not their du'ect action, the only action which has heretofore received any recognition whatsoever. The action of a drug can only be adequately gauged by clinical observation, hence my readers will be well advised to adhere to the drugs which have so far passed the test of time, before rushing to employ any new modification or so-called improvement, until it really has been proved by experience to be an improvement. So much work has been done with the idea of gauging how many injections of salvarsan should be given, the intervals at which they should be given, etc., that the phases we have gone through have been various, and existing opinions are legion. The only disadvantage that such a state of affairs has, is a disadvantage to which only the patient has to submit, and he is the individual for whom the drug was manufactured. Antimony. As an alternative, antimony is a useful drug to have up one's sleeve. I prefer intravenous injections, as intramuscular injections are apt to be very painful. I have not sampled all the antimony products which have, from time to time, been advocated, therefore I cannot say that any one preparation is any better than any other. As no preparation of antimony is as powerful as salvarsan, and therefore is not one's sheet anchor, but is used only as an alternative, it does not matter very much which preparation is employed. For intramuscular injections I have used antiluetin (bitartrate-potassium-ammonium-antimony oxide). The salt is readily soluble in water, and is best put up in ampoules containing 1 c.c. according to the following formula : — H. Antiluetin • 025-0 • 1 grm. Cocain. hydrochlor 0" 025 grm. Thymol q.s. Aq. distill. 1 c.c. METHODS OF USING ANTI-SYPHILITIC DRUtiS. 349 A course should consist of twelve injections, given daily or every other day, beginning with 0"025 grin, and ending up with 0'2 grni. For intravenous injections I employ either tartar emetic or antiluetin. If the former, I have ampoules made up containing 1 c.c. of distilled water and 1 to Ij grains of tartar emetic. I place the contents of one ampoule in 5 ozs. of distilled water, and give ten injections in all, twice or three times a week. Antiluetin is used in the same way, and for each injection 0'025 to 0'05 grm. is employed, without the cocaine. Toxic symptoms occurring after antimony injections are much like those occurring after intravenous injections of mercury, but even slight symptoms are ver}' rare. Although not a venereal disease, I should like to mention here that I have had great success in treating cases of bilharzia with intravenous injections of antimony. In my experience, salvarsan is of no use in this complaint. Mercury. A. — Intravenous Injection. A very good way of giving mercury is intravenously, and the two best salts are the cyanide and the bichloride. If the cyanide is going to be used, a stock solution of 1 in 100 should be made, and 0'5 c.c. to 1'5 c.c. of this solution may be injected daily or every other day. A course usually consists of ten to twelve injections. If the bichloride of mercury is preferred, ampoides of 1 c.c. should be made up, each containing \ gr. of the salt. A course should consist of ten to twelve injections, given twice or three times a week. For the first three doses only 0'5 c.c. should be used, and for the remaining doses 1 c.c. Instead of using the solutions concentrated, I think it is best to put the contents of an ampoule into a syringe holding 30 c.c. of pure distilled water. Diluting the solution diminishes the likelihood of producing local thrombosis, and also of toxic symptoms arising. I prefer myself to use as much as 5 ozs. of water. Toxic symptoms may follow intravenous injections of mercury, but they are of little note ; the commonest are abdominal pains and diarrhoea. A pecidiar sensation in the throat is sometimes complained of, and momentary congestion of the face and difficulty of breathing may now and again occur, almost immediately after the injection. 350 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. B. — Intramuscular Injection. There is a legion of preparations of mercury for intramuscular use, and they can be divided into two classes : (a) soluble ; and (6) insoluble. There is absolute!}' no doubt but that the insoluble salts are far more efficacious than the soluble ones. So far as the insoluble salts are concerned, one's choice Ues between three. One of these — and that is calomel — can, from my experience, be deleted, since, although it is perhaps more potent than grey oil, its administration is unfortunately so frequently very painful, that patients get frightened away from all kinds of intramuscular injections. Moreover, however careful one is, abscess formation is more hable to follow intramuscular injections of calomel than any other preparation I know. That leaves us with two preparations, and the choice between them will rest upon whether a quicker and a less potent action, or a slower and a more potent action is required. Before the salvarsan era, it was often necessary to get rid of the lesion as quickly as possible ; consequently, one preferred to use a preparation which was very quickly absorbed to one which was slowly absorbed, although the potency of the latter was greater than that of the former. With the exception of the insoluble salts, which are naturally rapidly abSo"rbed, but whose action, even in the maximum doses, does not amount to very much, no preparation is so suitable as the salicylate of mercury, because not only is it quickly absorbed, but its action exceeds the action of the maximum doses of the insoluble salts. The best preparation for injection is 1 c.c. of a 10 per cent, emulsion of mercury salicylate in liquid paraffin. Either 1 c.c. of this emulsion can be injected weekly, or 0"5 c.c. can be prescribed twice a week. As salvarsan has rendered the question of the rate of absorption of the mer- curial preparation of no account, one need' only consider the question of the ejB&cacy. In my opinion, the best mercmial preparation, and the one I now always use myself, is Adam's Cream. It is a grey oil preparation, which is liquid at the ordinary temperature, and therefore does not have to be heated ; its bulk is small and, therefore, practically painless. The grey oils in previous use have been- unsatisfactory, because they required heating. Now the action of heat is to cause the globules of mercury to conglomerate, so that, in time, most of the metal is at the bottom of the bottle, with the result that the first injections contain less mercury than the last. Their bulk was always great, consequently the patients frequently complained of pain. METHODS OF USING ANTI- SYPHILITIC DRUGS. 351 The following is the prescription of Adam's Cream, and it is prepared for me by Squire & Sons, 413, Oxford Street, London, W. : — R Hydrarg. 20 parts. Anhjalrous lanol. . . . . . . 30 ,, Chlorbutol • . . . . 2 „ All aa by weight. Liq. parafSn to 100 by measure. 5 minims = Hg. 1 grain. Inject 5-10)11 weekly. The injections should be made into the gluteal muscles, the scajjular muscles, or into the latissimus dorsi muscle below the ribs or the angle of the scapula. If the gluteal region is chosen, the injection should be made round about the upper and outer margin of the main fleshy mass. In the scapular region, the needle should be inserted from above downwards, deep into the muscles, about midway between the posterior border of the scapular and the spinous processes of the vertebrae. The best syringe to use is the Eecord syringe for intramuscular injections of mercury, supplied by the Holborn Surgical Instrument Co., 26 Thavies Inn, Holborn. The laws of asepsis having been strictly complied with, plunge the needle in quickly for 2| to 3 ins., but avoid touching the bone. Remove the syringe from the needle to see if any blood flows from it. If so, withdraw and plunge again, as the presence of blood shows that a vein has been entered, with obvious danger of embolism. Inject very slowly, then withdraw quickly, while pressing the skin around the pimcture, to prevent bleeding. Rub the part well for a few minutes, and send your patient for a brisk walk. As the soluble preparations are very seldom called for nowadays it is not necessary to mention all that have from time to time been used. If I ever use a soluble salt, I always prescribe enesol. Enesol is a useful mercurial preparation, especially in those cases to which salvarsan cannot be given, and in which it is wished to get the patient under the influence of mercury as quickly as possible. Enesol is a saHcyl-arsenate of mercury, readily soluble in water, and is put up in ampoules of 1 c.c. In each ampoule there is O'OllS grm. of mercury and 0'0043 grm. of arsenic. 1 to 3 c.c. may be injected intramuscidarly daily or every other day, until a marked improvement has taken place ; or the salt may be injected intravenously. The latter route being the better of the two, 1 to 4 c.c, in 5 ozs. of distilled water, may be injected intravenously every second day or twice a week, until twelve injections have been given. A mercurial preparation, which is sometimes useful in checking the lightning z 352 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. pains of degenerative myelitis when other preparations have failed, is the so-called Hirsch's injection. The solution contains 1 per cent, oxycyanide of mercury and 0"4 per cent, acoine ; 1 to 3 c.c. are injected intramuscularly daily or every other day, until 30 c.c. have been used. This preparation does undoubtedly, in some cases, give reUef, but, in my experience, the pains soon recur when the action of the drug has worn off. Acoine is a white crystalline powder, and is the name applied to the local anaesthetic di-para-anisyl-monophenetyl-guanidine hydrochloride, for which the British Pharmaceutical Codex, 1911, gives the short name guanicaine. C. — Inunction. There can be no doubt that the best way of administering mercury is by inunction, but unfortunately this method is valueless, unless it is carried out by a trained rubber. Inunction is one of the oldest methods of administration. It does not upset digestion, it gets the patient under the influence of mercury more quickly than oral administration, and it is easily regulated. It is best to use either unguent, cinereum, which consists of one part Hg. with two of lanoline and ung. simplex ; or mercury resorbin 1 to 2. The adult dose of ointment is from 1 to 7 drachms ; children take from J to 1 drachm. The following is a good order of inunction, one hour a day being given to the work : — 2nd „ . . Both legs. 3rd , . . Both arms. 4th . . Chest and abdomen. 5th , . . Back. 6th „ . . Hot bath. 7th , . . Re-commence as on 1st The inguinal region, nipples, and all hairy parts must be shunned, as acute pustular eczema may arise. The flat part of the palm should be used for rubbing, and a fair even pressure maintained. Inunction is contraiudicated by eczema, prurigo, and psoriasis. If the patient has rubbed himself, or has been rubbed, effectively, his skin — ^when all superfluous ointment has been removed %dth a towel — should show a number of black dots where the mercury has penetrated the pores. Mercury is in part absorbed through the pores of the skin, and in part evaporated by the heat of friction. The vapour so given off is inhaled, and inhaled mercurial vapour speedily gives rise to stomatitis. In a ward where syphilitic patients are using inunctions, it is not rare for non-s^'philitic ones to get mercurial stomatitis from evaporation and inhalation. It is, therefore, well that inunction be done METHODS OF USING ANTI-SYPHILITIC DRUGS. 353 in the early morning, in a well ventilated room in which the patient is not going to remain, and that the mouth be rinsed out several times with pot. chlor. while rubbing. A patient shoidd not keep to his room except in cold and windy weather, and his clothes should not be too warm. Menstruation is no bar to continuing inunction. A course of inunctions should consist of thirty to forty rubbings. A useful adjunct to mercury is sulphur. Sulphur, either in the form of baths or the drinking of waters which contain it, is always useful when a patient is undergoing mercurial treatment, be it in whatever form it is prescribed. D.— Baths. Baths are indicated in cases of ulcerative skin lesions which make inunctions impossible. They serve two purposes, for the sublimate is absorbed from the raw surfaces, and also acts as a local treatment to them. 10 to 30 grs. of sublimate are dissolved in a hot bath, in which the patient remains for half an hour, tem- perature being kept at about 95° F. by the addition of hot water or by a warming apparatus. A bath is given daily, and the patient is kept in bed for one hour after it. E. — Fumigation. Fumigation is only mentioned to be deprecated, since mercurialism is almost unavoidable. F. — Impregnation. Impregnating the underclothing with mercury, or spreading emplast. cinereum over a large surface of the body is quite a good method of treating infantile cases. G. — Supjyositories. Mercurial suppositories can sometimes be employed with advantage, if an alternative method of prescribing the drug is required. A suppository should be made up as follows : — B: Hydrarg. salicylatis . . . . . . gr. |-iij 01. theobromi . . . . . . . . q. s. One should be inserted every night just before going to bed, until either the rectiun begins to get sore, or the gums begin to get tender. If the suppositories cause much local pain, this may be obviated by adding a little cocaine to each. In tropical countries a httle white wax has to be added, owing to the low melting point of the ol. theobromi. H. — Internal. Internal treatment has the great disadvantage that, by irritation of the mucous membrane, digestion is upset. We also know not how much mercury is being z2 354 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. assimilated, because we know not how much is being passed per viam naturalem. The dose, therefore, has to be somewhat greater, so as to be on the safe side. It is useful in late stages of the disease, where it is not necessary to get the patient quickly under the influence of mercury, and as a change from inunctions and injections. Its great sphere of usefulness is in sucklings, in whom iimnctions are generally followed by eczema, but who stand J gr. of hydr. c cret. twice a day well. For adults, Hutchinson's pill is largely used in England : — R Hydrarg. c cret. Pulv. ipecac, co. . . . . . . aa gr. j One pill to be taken three times a day, after meals. Of greater utility is Ricord's pill, which contains iodine : — R Hydrarg. iod. virid. . . . . . . gr. | Ext. opii. . . . . . . . . gr. J Adjuvant. . . . . . . . . ci. s. One pill to be taken twice a day, after meals. The following formula is commendable, in that the mercury is in a form less likely to injure the mucous membrane, so upsetting digestion : — R Hydrarg. tannici oxydulat. . . . . gr. j Ext. opii. . . . . . . . . gr. J Adjuvant. . . . . . . . . q. s. One pill to be taken three times a day, after meals. Mercurial stomatitis is the complication which most usually besets us. It is also the most valuable guide b}' which to regulate the dose of mercury. Stomatitis must be solely dependent upon the teeth, for the toothless at both ends of life's ladder are never affected. If the teeth be well looked to — cavities filled, tartar scraped, and stumps removed — ^before commencing treatment, and well looked after during treatment, stomatitis will seldom become severe. The care of the teeth during treatment consists in absolute abstinence from both alcohol and tobacco, and the brisk use of the toothbrush after each and every meal, followed by an astringent mouthwash, as pot. chlor. gr. x ad ,^j or : — R Acid carbol. . . . . . . . . gr. x Spir. vini rect. Aq. dist. . . . . . . . . aa ad. 3j Put a teaspoonful into a tumbler of warm water. METHODS OF USING ANTI-SYPHILITIC DRUGS. 355 Should the gums bleed, the following should be painted on : — H Tint. gall. Tinct. rhatan. Tinct. myrrh., aeq. part. Or simply ghjcerinum acid, tannici. Should pus or ulceration be present, paint twice daily with tinct. iod. or perhydrol. A slight stomatitis is a valuable guide to the degree of mercurialism attained. It should be our aim to press mercurial treatment to the exact point at which slight stomatitis — a trace of salivation, with slight swelhng of the gums, a diminution of the papillae till the free edge of the gums forms a nearly straight hne — is reached and maintained. Mercurial treatment must be intermittent, because of the danger of mer- curialism. In whatever form mercury enters the system, it is eliminated as a sulphide via bowels, kidneys, and saliva. It is excreted very slowly, and therefore accumulates and becomes fixed in the system. It is only the excreted portion which has had any action on the virus. The fixed portion is harmful, and is the cause of the chain of symptoms known as mercurialism. These generally begin with fcetor of breath and soreness of gums, followed by a metallic taste in the mouth, swelling, softness, bleeding, and ulceration of gums. The salivary glands become enlarged and tender, causing increased salivation ; the tongue swells, teeth become loose, and ulceration of the mucous membrane of the mouth, even necrosis of the jaw, may foUow ; anaemia becomes marked, the blood becomes watery, and fails to coagulate, thereby increasing the liability to haemorrhage. Now, patients do not like these symptoms, and it is best to avoid them by inter- mitting the doses of mercury and varying the manner of getting that metal into the system, by changing from mouth administration to inunction through the skin. Treatment does not cease because the taking of mercury is given up for a period, since excretion goes on for some time after the last dose. It must not be forgotten that there are some patients who exhibit a marked idiosyncrasy to mercury, and there are several whom it makes very depressed. Depression and all the symptoms which constitute what we call mercurialism are far more likely to follow the internal administration than any other form, and this is not because more of the drug circulates in the system when it is prescribed fer OS — on the contrary, symptoms of mercurialism may become manifest long before the therapeutic action is making itself felt. I have no doubt in my own mind, that the reason why we see so much chronic superficial glossitis and carcinoma of the 356 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SYPHILIS. tongue in this country, is largely due to our routine treatment of syphilis by means of pills. In countries where it has been the rule for many years to treat syjjhilis with mercurial inunctions and injections, chronic superficial glossitis is a very rare condition. "\Mien I first became attached to the Lock Hospital and took over the cases of my predecessor, who had always used pills, I was obliged to examine the mouths of nearly every patient. Now that all my patients are treated with injections, it is very seldom that a mouth has to be examined, and patients, while under treatment, are almost unknown to complain of sore tongues, sore throats, &c. Different surgeons have different views on the matter, and some still maintain that pill treatment is the best. My best answer to this is, that several of their patients ask if they can come upon a day when mercurial injections are given, as they have noticed how much fitter the patients look who are having them. Out- patients in a large hospital, while waiting for their turn to be examined, have ample opportunities to discuss affairs with those around them, and as the average patient's main idea in attending a hospital is to get well as quickly as possible, the matter of treatment is uppermost in their minds ; consequently their opinion of what they consider to be the best is usually the correct one. Because of the great disadvantages of the oral administration of mercury, I always use mercurial injections or mercurial inunctions when the patient can afford the time and inconvenience caused by the latter. For reasons already stated, I prefer the grey oil to any other preparation. If the patient cannot have mercurial injections because he is travelling or something of that sort, then he must take mercury internally or in the form of suppositories. Iodine. The most potent iodine preparation which we have, is undoubtedly potassium iodide, but unfortunately there is a large number of patients who cannot take it, partly owing to its depressing action, and partly because of its readiness to produce iodism. The depressing action can often be overcome by using the ammonium and sodium salts, but those patients who readily exhibit the symptoms of iodism will usually do so with any inorganic salt. Sometimes the symptoms of iodism can be prevented by the administration of calcium lactate or sodium bicarbonate. Owing to the frequency of iodism with the inorganic salts, a legion of organic compounds have been put upon the market, all of which are stated to be equally potent as the inorganic preparations and absolutely innocuous. With many, iodism does not supervene, but I have yet to find one, which will be entirely innocuous, when given to a patient who exhibits a marked idiosyncrasy to any preparation of iodine, and such patients are not at all infrequently to be METHODS OF USING ANTI-SYPHILITIC DRUGS. 357 met with. No organic preparation appears to be as powerful as potassium iodide. The best organic preparations are iodoglidine, sajodin, and tiodine. NUCLEINATE OF SoDA. There is no doubt that nucleinate of soda will often produce a period of quiescence in a case of degenerative encephahtis, when every other kind of treatment has proved unavailing. It does not cure the disease, but a patient may be brought from the imbecile state into the normal state, and may remain in the latter for some months. This drug has been used on a fairly extensive scale by Fischer in Prague, and Donath in Budapest. In this country, Gordon Lane has used it in several cases with very satisfactory results. As the drug is not widely known, and as the dose varies with different observers, I will mention the methods of the three men whose names I have above referred to. Fischer^ * uses 0'5-3'0 grm. dissolved in water and injected intramuscularly every three to five days. Donath^ ® first recommended intramuscular injections of 50-100 c.c. of a 2'5-3'0 per cent, aqueous solution, and he gave eight injections at intervals of five to seven days. Donath^ now employs a 10 per cent, solution dissolved in normal saHne and injects from 10-50 c.c. every four or five days until six to twelve injections have been given. Gordon Lane tells me that he always employs a 2 per cent, solution and injects 50-100 c.c. once a week for about eight weeks. Some hours after the injection the patient gets a rise of temperature to about 104° F. The next day it falls, to rise slightly again, and as a rule the following day it falls and remains normal until the next injection is given. The rises of tem- perature may be higher, and may be maintained over a longer period than this. The injections also produce a hyper leucoc^'tosis. I have also tried nucleinate of soda injections in cases of dementia which have resulted from s}'philitic meningo-encephahtis, and with considerable improve- ment in the mental condition, in spite of the fact that the syphihtic process had spontaneously cured itself. It is highh' probable that nucleinate of soda would be beneficial in other syphilitic nervous manifestations, but as to whether it will, become a regular adjunct to the treatment of these only the future can show. ^ Homer Swift and Ellis (1914), '• Studies from Rockefeller Inst, for Med. Res.," xis, 471, 492, 573. - Ravaut (1914), '• Aiinales de Medecine." 3 Fischer (1909), " Prager. mediz. Woch.," x.N:xiv, 401. ^ IhkJ. (1911), " Zeitschrf. f. d. Ges. Neur. ii. Psych.," iv (orig.) 482. ^ Donath (1909), ■' Wicn. klin. Woch.," xxii, 1291. '•■ Ihid. (1910), " Berl. klin. Woch.," xlvii, 1057. CHAPTER XXXI. ULCUS MOLLE (SOFT SORE). A soft sore, or Ulcus molle, is a specific sore caused by Ducrey's bacillus. The sore, or sores, as they are most frequently multiple, occur usually on the genitals. They may occur on any part of the body, as they are easily inoculable, and are also autoinoculable. I have seen two cases of a .soft sore infection on the finger, followed by suppuration in the epitrochlear gland. The usual incubation period is about three days, when a tiny ulcer appears, and spreads rapidly. The sore is a true ulcer, the base of which is uneven and covered with pus. The circumference of the ulcer is sharply circumscribed, but irregular in outline, because, when it spreads, it does not do so evenly; often one part of an ulcer will heal, while the other end extends. The edge is slightly undermined. The ulcer is always surrounded by a marked inflammatory ring, the inflammation being most marked in the periphery of the spreading end. The ulcers tend to heal spontaneously, but treatment materially hastens the process. A lymphangitis is often to be observed, running from the sore along the penis to the inguinal lymphatic glands, on both sides, or only on one side, and not necessarily on that side on which the sore is situated. One of the most interesting points about the soft sore infection is the fact that a bubo, i.e., suppuration in the lymphatic glands, may not appear for weeks, and even for months after the sore has healed and has been forgotten. The organism which causes a soft sore was discovered by Ducreyi - ^, and hence is often called Ducrey's bacillus, or, because of its shape, the streptobacillus. To demonstrate the streptobacillus, the pus from the edge of a young ulcer must be taken ; the pus from an old ulcer, or from a bubo, when examined, often gives negative results. The best specimens are to be obtained from an inoculation ulcer. To prove that a bubo, or an Ulcus molle serpiginosum, is due to Ducrey's streptobacillus, it is sometimes necessary to produce an inoculation ulcer, since of all the known venereal infections which cause ulcers, the soft sore infection is the only one which is autoinoculable. If the observer wishes to produce an inoculation Plate 34. — A SmaLE Soft Sore. The sore is sharply circumscribed, the edge is raised and undermined, the base is covered with pus, the sore is surrounded Yiy acute inflanunation, which has produced a Paraphimosis interna and acute inflammatory oedema of the prepuce. Plate 34. Facing v. SS8. caii'^c ■ ;!nf!. Th< U : ■';'■■'. ,ii<.i)/;ii(iinillni oJu'iB \A bsbfu/onua.ai t^t>» "(jll ,honnclear leucocyte. In this fypt' of soft sore, which is the most common, the tissue is strongly oxyphilic. I.e. it exhibits a marked ailinity for tlie methyl green dj^e, when staiued sifter rajijienln'ini's nii'ilmd. The niuri- oxyphilic tissue is. and the fewer the plasma cells, and the largi-r the nuniln-r (-f lyniphucytes ami polymoi-phouuclear leucocytes, it contains, the greater tlie power tlu^ liost has over the disease, henfce the more beuigu the infection, and the greater the mpiditj- with whii'h it will vanish. Plate 35. Follou-8 rititc 34. Plate 3fi. This is a liigher power (x 1,500) still of the second figure on Plate 35, to show the type of organism, that is to be met with in the most common form of soft sore. It will be noticed that the bacilli are arranged in groups, and that each growp is. made up of chains, which vary somewhat in length. \^ Follows Plait 35. ,g£ aJfill no siugci hnoaoe eiii io liiis (006,1 x ) i9v/oq i9il§iif £ ai kWT no/tirnoo Jgoin adi iii diivi Jem sd o* ei iadi .roairifi^io io aq'{i arfl woria oj ,8qooi§ iii bsgnfiTi* 9i6 iUioeJ ari* icHi baoiJoii ad lliw .tl .9io8 ilos io irrio} .riisi"'5f ni Jeriwsniop. '^by doiri'w .snifirif) io qu ebeai ei qi/oii! riofia iadi has .as •toSS nioU«^ Plate 30. ULCUS MOLLE (SOFT SORE). 359 ulcer, the abdomen fshould always be chosen, since the skin of the arms or legs may fail to react. The streptobacillus stains well with most dyes, especially with carbolfnchsin, polychromemethylene blue, and pj-ronin, in Unna's carbolpyronin-methyl green mixture, but it is Gram negative. The streptobacillus is an extracellular organism, but sometimes it is found intracellularly situated, when it becomes polymorphic. The full significance of the intracellular habitat will be shown later. Even the extracellular forms are not always exactly alike, so it would be as well to enumerate them all, and I cannot do better than adopt Tomasczewski's* admirable classification. 1. Very short rods, which are difficult to distinguish from cocci, 0'4 /^ long and 0-3 to 0-35 /u wide. 2. Short, thick rods, with rounded ends, 1'5 to 1 '7 jii in length, and 0'4 fi in breadth. Bacilli of this form are usually found isolated. 3. Dumb-bell forms. These are usually found in groups. 4. Forms like diplococci, first described by Unna* as the " Doppelpunkt bacillus," and bv Ducreyi as the "Achterform." Length, I'O to 1'5 /x; breadth, 0'3 to 0-4 ft. 5. The "en navette" form of the French® ' or the "Schifichenformen" of the Germans. These are rods which have an unstained point in the centre. Length, I'l to 1'5 (U ; breadth, 0"5 to 0"6 /j. In films, the streptobacillus, as its name denotes, is frequently found in long chains, and this is characteristic of the specimens made from cultures. The streptobacillus can be demonstrated easily in sections, and it is always to be found in the neighbourhood of the undermined edge. This undermined edge alone usually suffices to allow one to make a good guess of the nature of a section shown for diagnosis. Barring this point, and, of course, finding the causative organism, a section of a soft sore is indistinguishable from that of any other granu- lomatous ulcer. In my opinion, the best method of showing up the bacilli in a section is to stain it with pyronin and methyl green (Plate 36). Culturing the organism is not an easy matter, partly owing to the fact that other organisms flourish readily on soft sores ; therefore, if a pure culture is desired, it is best to produce an inoculation sore ; and partly because a special medium is required. WTienever one wishes to make a culture of the causative organism of a lesion it may usually be taken for granted that the organism in question is more resistant to antiseptics than those which affect the lesion secondarily. 360 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF SOFT SORE. The streptobacillus is no exception to this rule ; hence, if there are reasons why an inoculation sore should not be made, a young sore can be well bathed with any mild antiseptic lotion, before the culture tubes are inoculated. Blood agar is the best mediimi on which to grow the streptobacillus. The blood must be fresh, and must be mixed in equal quantities with agar. Guinea-pig's, rabbit's, or human blood can be used. The medium must be moist, and it is necessary to have a fair quantity of condensation fluid at the bottom of the tube. If the inoculation has succeeded — and in about eight attempts out of ten it does not — a growth begins to appear in about 48 hours in the neighbourhood of the condensation fluid, in small, round, shiny colonies, which increase rapidly in size, and on about the third or fourth day they exhibit a grey-white to a grey-yellow tint. The colonies are firmly adherent to the medium, and can only be removed in toto. Once a pure colony has been obtained, it is a simple matter to inoculate other tubes with it, but these must be inoculated not later than the fourth day, as the streptobacillus in culture dies very quickly. The streptobacillus remains alive longer when kept at room temperature, than when kept in an incubator. The streptobacillus is very susceptible to rises in temperature, and this fact has largely been made use of in treating Ulcus molle. Treating the sores with hot-air baths is a favourite procedure with many clinicians. Films made from a colony show the bacilli in chains. Individually, the bacilli vary in length from 1'5 to 2'5 ju, and in breadth from O'-i to 0*5 //. The coccal- like form is also to be seen, but only in old cultures are the dimib-bell and "' doppel- punkt " foi'ms to be met. In the condensation fluid, the organism flourishes better than on the solid medium, the chains are longer, but the morphology of the bacillus is the same. In some specimens the bacilli seem to have capsules. The streptobacillus is non-motile, and it is only pathogenic for man and for the higher and lower apes. Vhus molle, although a widespread disease, favours some countries more than others. I have noticed over and over again how much more common it is on the Continent than in England, and, oddly enough, it appears to be more common in London at some times than at others. Whether there is a seasonal variation or not, I have been unable, as yet, to determine. In my experience, Ulcus molle is more frequently to be met with in men than in women. Ulcus molle afiects difierent individuals in various ways. In some, the sores heal spontaneously in a few days ; in others, especially those who have tight foreskins and have to take much exercise, the ulcers spread rapidly, and they may even become phagedaeuic. The patient has two sores, one on the penis and one on the scrotum. The penDe sore is sharply circumscribed, irregular in outline, an ulcer, which is slightly depressed beneath the surface, but the edge is not undermined and there is no circumferential inflammation. The scrotal sore is sharply circumscribed, more regular in outline, an ulcer, which is well raised above the surrounding and healthy skin. The edge is red and inflamed, but there is no area of acute inflammation exterior to it. It \vill be noticed that both sores are red, and that they are not covered with pus. The sores were rou^li on the surface and bled easily on friction. The sore on the scrotmu is a beautiful example of the so-called Ulcus molle devatum. The incubation period of this type of sore is often a long one, it may be a matter of weeks, and it may be extremely resistant to treatment. It was the boat-shaped form of the streptobaciUus which caused the sores in this case. The boat- shaped form of the bacillus is never found in such great numbers as the ordinary streptobaciUus, nor does it occur in groups of long chains. The bacilli are fewer in number and more irregularly scattered about. Facing p. 360. tin: iiif .Vfi a*.jq edX .omJoioa edJ xio atio biiu i-.ln-xi '^'" '"^ '"'o <8oio8 out gad JiioilBq oil'l' ei'iioiiiW .iooli; ttk'.on'diuo hi liilugatii .bsrfitasamotio T{fqT48if3 ai alda ann«r' bomnnsbnurlon'ai sgfae pdi iud ..soahiia ' adt . djfaspnod b^eapaqai) vjidsii^', :, XlqriJiiiii 81 810^ 1.^1013^. 9flT .iioil^;fuii.p[ixii l£iin9T9)xau3tia on-ci sisxil biii; svocIb bwim Hoy/ ai ^^''l"" .laalu fifi ^snittoo ai jfifi/ggT aiora .badhoexnumi ) oTjrit tijil .[j'tmeHni ban bei 111 ogba oriT .tiijla nrf3lfl«f ()fic gnibnuoTiiia sriJ tlJod iadi b'ljiio/i 9cf llr« Jl .Ji ot-ioiTjJxg iioijBuixafihrii !>}ijob to Bfcic oa ^i rigijoi oi9'« «8ioa 9dT .a«q rfliv/' fc(M6'?b3.jQi<,a(^«;itf)riJ lisrfj bnfi4><>^ 9i« aoiu' B ai uiuioiaa adJ no Ttoii pd|T .aoilohi no .uliaea, Iwld fauc MshiiB adJ no noiJBiiuofii ydT ,i«»sSn«3h alSom mjoJ'J bollBo-oa adi lo slqrufizo luliiuised ,«j(39v/ to ioUboi * dcf'^Bm ii ,9nb §noI js riaito ?ir oiop to tiq-f* eirfi to boiigqi beqiB/le-lBod ■ oril ac'w ^I .hiauiJaaiJ oi IneJKwai •^IsnoiJ/.s ad xsta ii bna -ieod srfT J9»fi? aiito nt aa-ioa ad* boatiaa il»id^. eutUo«fto>q?!K|avs4*;i,K«»-**»'^^*f'^**H,^ .V^ V 1. Tliis is a luw powur ( x 12) microscopic section of tlie scrotal sore ilcpictort ou plate 37. The elevated cliaracter of the ulcerate'l area is -well sho-i™, and the riiip represents tlie site where the bacilli were found. Contrasted with plate oo (1) it will be noticed that the epitlii-linni nearest to the nicer is markedly hypertrophied, that in the corium there is a prononncerl coum-ctive tissne hyperplasia and some afteratiou in the walls of the blood vessels. Tliis is a higher power (x 270;) microscopic section of the scrotal sore depicted on plate 37. The epithelinm is acanthotic, as it nsuallv is in chronic infections. There is a marked connective tissue and endothelial-celled hvperplasia, anil" instead of a preponderance of polymorphonuclear leucocytes, the cellular infiltration consists of mainly plasma cells and lymphocytes. The tissue in this type of sore, or indeed of any chronic sore, is i:)yrouiuophile. Plate 38. Folhirs Plate 37. ULCUS MOLLE (SOFT SORE). 361 Exercise is more likely to set up or to increase any tendency there may be to lymphangitis and suppurative adenitis. A sore, after it has persisted for some time, may develop what may be called a pseudo-induration, and hence suggests to the unwary a primary sore. Such a difficulty in diagnosis need never arise, if the observer will always remember that, however long a soft sore persists, and however wide its dimensions become, it never loses its clinical characters — the under- mined edge, with its surrounding area of inflammation, is practically always present. Every student is taught, and rightly so, too, that a soft sore may develop into a chancre, and that the change may be detected by the induration which supervenes. A soft sore may become a chancre, but not nearly so often as one is led to believe. A soft sore may become indurated, and yet not become a chancre. If a chancre is going to develop upon a soft sore, the change that takes place is the disappearance of the undermined edge, and a levelhng up of the base of the ulcer. When a soft sore is situated on the froenum, haemorrhage from the froenal artery, owing to the spread of the ulceration, is a complication which should always be borne in mind. The haemorrhage has never been, in my experience, severe, but it is usually quite severe enough to alarm the patient. Although the main characteristics of a soft sore are, practically always the same, there are some different clinical forms to be met with, which require very careful mention, owing to the difficulty they cause in differential diagnosis. Ulcus Molle Elevatum. This sore differs from the ordinary soft sore in being raised above the surface (Plate 37). It is, nevertheless, an ulcer, but the edge is not undermined. This type is often single, the surrounding inflammation is not so marked as it is in the ordinary sore, and it is extremely resistant to treatment. Pseudo- induration is liable to be met with in this type of sore ; hence it is very apt to be mistaken for a chancre. Another peculiarity that this type of sore presents, is its not infrequent long incubation period. Ulcus Molle Miliaee. According to Tomasczewski,* this type is more commonly to be met with in women than in men, and the sites of predilection in the former are the labia majora and the perineum. Each lesion is a raised papule, in the centre of which there is a crateriform ulcer, and it looks at first sight like a hair follicle infection. The lesions persist for some time, and there is usually a very great number of them. I 362 the biology, clinical aspect and treatment of soft sore. Ulcus Molle Phagedaenicum. A soft sore, as a rule, does not become phagedaenic unless it is hidden beneath a tight foreskin, and the first appearance of the phagedaena is a perforation of the foreskin. In very severe cases part of, or the whole penis, may be destroyed. Phagedaena is a not common complication of a soft sore ; it is certainly more often met with in syphilis, and I cannot help thinking that the free use of carbolic acid — a drug to which many individuals show a marked idiosyncrasy — has often been responsible for the complication. As is the case in syphilis, the specific organism is destroyed when a sore becomes phagedaenic. In nearly all phagedaenic sores, the fusiform bacilli and the spiro- chaetae which exist in symbiosis with them, organisms which appear to be the cause of Vincent's angina and Balanitis gangrenosa, are usually to be found. Indeed, they are really the cause of the phagedaena. Ulcus Molle Seepiginosum. I am here pubhshing a recent article of mine, which appeared in the " British Journal of Dermatology,"^ because the condition is much more common than is thought to be the case, and it is almost invariably wrongly diagnosed, and unless exactly the right treatment is given, curative measures are of no avail. The primary lesion is a furuncle, the edges of which become blue, bluish-white, and then break down until a distinct ulcer is formed. The base of the ulcer is fleshy, uneven, and secretes freely. The edges are ragged, look as if they had been gnawed, and are deeply undermined ; the over- hanging portion is cedematous and bluish- white in colour ; external to this the colour becomes purplish, and still further out, and spreading for some distance into the healthy tissue, one sees the red colour of inflammation. The inflammatory zone is most marked where the ulcer is spreading, as it invariably spreads in one part more than in another ; in fact, one pole may heal while the other is steadily advancing. A very favourite route for one tongue of the ulcer to take is down the genito-crural fold. Occasionally such a process reaches as far back as the anus. Case 52. — A man, aged 25 years, was shown by Mr. Shillitoe before the Dermatological Section of the Royal Society of Medicine, June 15th, 1911 (Plates 39 and 40 are from this case), as a case of (?) Granuloma inguinale. The patient consulted Mr. Shillitoe first on March 16th, 1911, and gave the following history : — " Just before last Christmas he developed multiple sores around the corona (soft sores), and a bubo, which was opened on January 10th, and which had "3 C J3 SO g >> 5 ^ »H t> 2 o a oi 4^ Cj CO _o O m 0) "*^ H -a - i,-; due tO thp i3) toxicurtu ic li>'peikeratosi!r. 'LESNORRHAGICim. > hic-h appear di; iused by ': era are ii^i/'h 'nor?* C'^rti) round t; *jt .-'.i Plate 41. gonococcal rashes. 425 Toxic Rashes. Toxic rashes, though seldom described, are quite frequently to be met with, if looked for. Winkelried Williams,^ in a recent article on Keratodennia blennor- rhagica, stated that, on searching the literature, he could fmd only fifteen recorded cases. At the London Lock Hospital we get about three cases per annum, and the numbers would doubtless be very much greater, if we examined the feet of every patient suffering from gonorrhoeal rheumatism and arthritis. The toxic erythemata are usually brushed aside at once, as being copaiba rashes, even if it be known that the patient has not taken any medicine. I have seen gonotoxic erythemata which could not be distinguished from a copaiba rash, and the similarity of some cases to scarlet fever and measles was very close. Conjunctivitis is not at all an uncommon gonotoxic symptom, and when it accompanies a discrete macular rash, a hasty diagnosis of measles may be very easily made. Some of the scarlatiniform rashes may be accompanied by a sore throat. Many of the rashes are ushered in with fever, and joint pains are not at all uncommon. True Erythema nodosum may undoubtedly be met with as a gonotoxic rash. I remember one case very well, as the patient suffered also from polyarticular arthritis, and died of gonococcal endocarditis. Microscopic sections of the cardiac valves revealed masses of Gram negative diplococci, and pure cultures of gonococci were obtained, post-mortem, from the heart's blood and, during life, from a venepuncture. Urticarial, haemorrhagic, and bullous exanthemata are rare, and only a very few cases have been described. I have seen purpura develop in severe cases of polyarticular arthritis, but I have never seen a case of tru.e urticaria or pemphigus. Perhaps the most interesting, because the most distinctive, gonotoxic rash, is the toxic hyperkeratosis, or, as it is more commonly called, Keratodermia hlennor- rhagica (Plate 41). The patient from whom this picture was made, was suffering from his first attack of polyarthritis. The rash had taken only four months to develop. The other leg was in a similar condition ; he also had lesions on both hands and arms, and the typical Balanitis circinata. The lesions are primarily vesicles ; these quickly become pustules, and then the wall of the pustule becomes keratinised. Several lesions may coalesce, or they may develop singly. Half-a-dozen lesions may appear on the big toes, and the condition may not develop further ; hence it can be readily understood that several cases are overlooked, as a slight eruption of this sort is by far the most connnon. After attacking the dorsimi of the big toe, the lesions extend inwardly, and ultimately reach the sole. If the lesions increase in size, they do so by adding on successive layers of keratin, so that it ultimately resembles a limpet shell. •126 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF GONORRHOEA. In the severe cases, any part of the bod)' may be affected, and, I may say, that in every case I have seen, mild or severe, the patient has always had a balanitis. Discrete circular lesions fir.st make their appearance on the glans penis, corona, and under-surface of the prepuce. As the surfaces continually rub together, the epithelium in between the areas soon becomes white, heaped up, and then entirely denuded, so that the true circinate areas can only be seen at the periphery. These circinate patches naturally never become keratinised, but true keratodermia may affect the skin of the penis. When the horny process is removed, no ulcer is exposed, but simply a denuded epithelium. Although the patient just referred to, from whom the painting illustrating this chapter was made, was suffering from his first attack of polyarthritis, it is more usual for the keratodermia to develop during the second or some subsequent attack. Another interesting feature of this condition is, that the patients usually have marked hyperidrosis, and this probably plays a large part in the causation of the horny excrescences. The lesions have been very carefully examined for gonococci, but always without success ; therefore, I think it may be assumed that Keratodermia blennorrkagica is a toxic manife.station. Treatment consists in merely scaling off the scales, and in giving vaccines, by which means the condition is very rapidly cured. The case from which the painting was made, ran a course, which I had never seen, or heard described before. Localised blue congested patches developed in the skin at the base of all the finger and toe nails. The congestion gradually spread backwards as far as the metacarpo- and metatarso-phalangeal joints respectively, the sweUing then subsided and gave way to horny bands, which appeared to con- strict the affected areas. To the proximal side of the congested digits, a skin lesion developed, which was absolutely indistinguishable from Psoriasis vulgaris. The psoriasiform rash on the feet spread as far as the ankles, and on the hands to above the wrists. Oddly enough both elbows and knees became covered with psoriasiform lesions, and even the nails developed the ridges and punctate depressions, which are so commonly to be seen in cases of psoriasis. For the opportunity of studying this unique case, I am indebted to Mr. Lane and Mr. Gibbs, under whose care the case was. ' Wiiikelreid Williams (1914), •' Brit. Med. Journ.," ii, 627. PAPERS CONSULTED. Buschke (1912), " Archiv. f. Derm. u. Syphilis," cxiii, 22.3. Arniug u. Meyer-Delius (1911), " Archiv. f. Derm. u. SyiA.," cviii, 1. CHAPTER XXXVIII. GONORRHOEA IN WOMEN. Gonorrhoea in women is, as is also the case with syphilis, the greatest curse of the disease. A man always contracts a urethritis, and knows at once when he is infected, and it is his own fault if he does not seek instant advice. Not so with a woman. The genital organs may be the first attacked, or, if the disease begins in the urethia, the symptoms may be so slight, and the trouble may spread to the genital tract so quickly, and, even having affected that, the symptoms may not be sufficiently severe to necessitate her taking advice. As a rule, a woman knows when she is infected ; at least she knows there is something wrong, although she may be in ignorance of the cause, so that she is usually to blame for not seeking medical opinion. Considering how widespread gonorrhoea and sj'philis must be in women, it is odd what a very small percentage of medical practice outside the hospitals, and even in hospital practice, is taken up by women. Where do women go for their treatment ? The answer is, that thev have none, at any rate not until the setting in of a compUcation demands surgical interference. The importance of the fact that women do not, generally speaking, seek advice during the acute and the most infectious period, cannot be over estimated, and it is a point which shoufd be most seriously considered by any committee formed to deal with the extirpation of venereal diseases. It is highly probable that druggists and charlatans are more frequently consulted by women than by men. The former could very easily be dealt with, but the latter unfortunately not so. Women who are the subjects of gonorrhoea are further placed at a greater disadvan- tage than men, in that menstruation stops the treatment and aggravates the disease. Moreover, once the cervix has become affected, the disease is far more difficult to cure than when the prostate in men is involved. Therefore, in no disease is an early diagnosis more to be wished for than in gonorrhoea in women. The gonococcus is also a greater cause of sterility in women than it is in men, but, oddly enough, it practically never causes sexual neurasthenia in women. Men can contract gonorrhoea from sexual connection only, and this is the most frequent source of 428 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF GONORRHOEA. infection in women ; but it must be remembered that, in the latter, there is another source of infection, which is too frequently overlooked. Many women have the habit of wiping themselves, after micturition, with any towel that may be handy. I have known of four cases in which virgins contracted gonorrhoea in this wa}'^ at ladies' clubs in London, and I also know of a family in which the mother and three daughters all contracted gonorrhoea, from presumably using the same bath towel. In most cases of gonorrhoea in women, the urethra is the site of infection. The disease then spreads to Bartholin's glands, and from here, via the vagina, to the cervix. The disease may remain localised in the cervix, or it may spread into the uterus, along the Fallopian tubes, into the general peritoneal cavity. Although a true gonococcal vaginitis is common in young girls, it is not often met with in adults. In adults it is more likely to occur in those patients who have had least sexual connection. Complications of the urinary tract are rarer in women than in men. Gonococcal proctitis is very much more common, and other complications, such as arthritis, etc., affect both sexes alike. In virgins, and in recently married women, in whom the disease is more likely to remain for some time in the vulva without spreading, great care should be taken not to insert any instrument into the vagina, as such a pro- cedure is sometimes a source of infection of a previously healthy cervix. In women who have been married some time, the cervix is apt to be the initial site of the infection. In them, vaginal douching can be started straight away. There are several reasons why colpitis should be less common in the sexually matured than in virgins. In the former, the mucous membrane is not so delicate, as the superficial layers of the epithelium make a more or less satis- factory attempt to form a horny layer. The adult vagina contains organisms which are not met with in the vagina of young maidens, and the gonococcus, as has been frequently pointed out before, vdW not live in symbiosis with other bacteria. Finally, the mucous membrane of the adult vagina secretes a mucinous substance, in which the gonococcus cannot flourish, while the vagina] mucous membrane of young girls has no secretion. Urethritis in the female tends to heal very quickly by itself, hence it can be easily reinfected. It is important to remember this, since, if a woman has .symptoms of a urethritis, one is apt to assume that she has just been infected, while it is by no means a rare occurrence for the cervix to be affected first and the urethra after- wards, by a spread of the organism from the cervix to the urethra, via the vagina. Bartholinitis is an extraordinarily chronic complication, and it may not only give rise to an auto-reinfection of the urethra and cervix, but also it is a frequent source of infection of a second party. GONORRHOEA IN WOMEN. 429 The ^nllvo -vaginitis of children is caused most frequently by the gonococcus, and it is usually contracted from dirty sponges and linen. The condition is very infectious, and may become almost epidemic — i.e., in a children's ward, if there is one case of gonococcal vulvo-vaginitis, unless the very greatest care be taken, every female child in the ward may be infected. The inflammatory process always involves the urethra and lower portion of the vagina. Vulvo-vaginitis may also affect new-born infants and maidens. The former infection can occur during birth, or a few weeks later. The latter infection is of importance from the forensic point of view. Vulvo-vaginitis of children is extremely painful, and the secretion of pus is usually profuse. The pus stains the linen and makes it stiff, and this is usually the first indication that anything is wrong, then the pain on passing water, etc., is noticed. On examination, the inflammation is found to have involved the labia, the clitoris, the hymen, the vestibule, the urethra and the vagina. These structiires are red, swollen, and covered with pus ; and, owing to the irritation of the pus, an intertrigo in the genito-criiral folds is the rule. The vestibule is often covered with small ulcers. The hymen is pushed forwards, owing to the quantity of pus that collects behind it. The inflammation of the labia and the intertrigo are caused, not by the gonococcus, but by the irritative nature of the pus, which comes from the vagina. The acute stage of vulvo-vaginitis is rather a long one, and the con- dition is rather obstinate to treatment. The acute stage ultimately passes into the chronic stage, and it is in this stage that spontaneous cure ultimately ensues. Spontaneous cure will take place, whether the case is treated or not, but the disease may persist for a very long time before this happens. Fortunately, cervicitis and Bartholinitis do not complicate viilvo-vaginitis. In adults, one does not speak of vulvo-vaginitis, owing to the fact that the vagina is so rarely affected, but otherwise there is practically no difference between the two conditions. Vulvitis occurs in adults ; it is an inflammation of the vestibulum and of Bartholin's glands, with sometimes ulceration. The gonococcal urethritis in women is of quite minor importance compared with that in man, but it may be complicated by a paraurethritis. There may be one or more canals, and the openings are just external to the urethral orifice. A paraurethritis does not give rise to symptoms, and it is, as a ride, only diagnosed by accident, when the secretion is pressed out of the urethra, by the finger in the vagina. These paraurethral canals are probably congenital, and possibly the em- bryonic remains of Skene's tubules. As a rule they are easily closed by electrolysis. ■430 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF GONORRHOEA. When Bartholin's gland becomes afEected, and not infrequently both are involved at the same time, the patient complains of acute pain on movement. On examination in the early cases, if pus has formed in the glands, it can usually be pressed out, but later the duct and orifice become closed. So long as the pus can find exit, it gets expressed at almost every movement on the part of the patient, and the swelling does not attain to a great size. The pain is naturally acutest when the swelling is greatest, therefore — when the only bearable position for the patient is to lie on her back with the legs wide apart — the diagnosis of an abscess in Bartholin's gland may be made. Once an abscess has formed, the chances are that the lining membrane of the gland has been destroyed. Consequent!}', when the pus has been evacuated and the abscess healed, a recurrence is unlikely to ensue. When Bartholin's gland merely becomes inflamed, the inflammation passes in time from the acute to the chronic form ; and, once it is chronically inflamed, frequently recurring retention cysts are liable to arise, or suppuration may at any time occur, due to a secondary infection. Owing to there being gonococci ever present in the chronically inflamed gland, it can be easily understood what a great source of infection a woman is likely to be ; and as a chronic Bartholonitis runs a symptomless course, except when retention cysts form, a woman may be quite unaware that she is infectious. As already stated, a true gonococcal vaginitis is most often seen in children, but it should not be forgotten that a gonococcal vaginitis is far from being uncommon in pregnant women. This is due to the fact that the mucous membrane is swollen and softer, and possibly its secretion is less acid. Anyhow, the gonococci can flourish in it. Gonococcal vaginitis is also met with in women who have had the uterus and ovaries removed. Castration causes shrinkage of the vaginal mucous membrane, reduces the number of layers of epithelial cells, diminishes the secretion, and in this way the gonococci are more readily able to penetrate into the connective tissue beneath. When the gonococci reach the cervix, in women who have had children, they readily gain access to the uterus ; but in all cases of cervicitis, whether in women who have had children, or in those who have not, the organisms quickly spread into the sub-epithelial tissue, and this is the reason why cervicitis is so difiicult to cure. The aflected cervdx is usually somew^hat oedematous, and there is always a purulent or a mucous discharge from the external os. As a rule, a cervicitis gives rise to no symptoms, but sometimes, during the menstrual periods, owing to the con- striction of the internal os and the canal which may be caused by chronic inflam mation, a patient may complain of dysmennorrhoea. GONORRHOEA IN WOMEN. 431 The constant discharge from the external os is very liable to cause an erosion. It is practically impossible to say when a cervicitis becomes an endometritis, but, from the extraordinary resistance to treatment of almost every case of so- called cervicitis, one would probably not be far wrong in stating that endometritis more often accompanies a cervicitis, than that a cervicitis exists alone. Once the organisms have gained entrance to the uterus, they rapidly spread over the surface and under the mucous membrane. The ease with which the gonococci invade the subepithelial tiss\;e is doubtless partly due to the changes the epithelium undergoes at each menstrual period, and to the increased vascularisation of the organ at this time. The utenis, in acute endometritis, is very painful on j)ressure, and the patient cannot endure sexual connection. General symptoms are usually severe, and the patient nearly always has to take to her bed. The acute stage ultimately runs into the chronic, and it is in this stage that the main symptoms are complained of. There are three regular symptoms : (1) dysmennorrhoea ; (2) menorrhagia ; (3) metrorrhagia. Unfortunately, those symptoms may persist, even after all the gonococci have vanished, probably because a secondary infection takes the place of the gonococci, and maintains the chronic inflammatory process. Gonococcal endometritis is a frequent cause of abortion, and naturally com- plicates and aggravates the after- results thereof. From the uterus, the gonococci travel to the Fallopian tubes, and as the organisms in most cases come from all over the uterus, a bilateral salpingitis is much more commonly met with than a unilateral one. The tubes swell, become oedamatous, and often the lumen is obliterated. The pus formed at first flows into the utenis, but it may easily get pent up, and so produce an abscess. As in all gonococcal affections, abscess formation is by no means the usual sequence of events, it being far more common for the acute inflam- mation to subside gradually into chronic inflammation. A chronic salpingitis runs a very similar course to a chronic Bartholinitis, that is to say, the openings become periodically blocked, the secretion can find no exit, and a retention cyst forms — a hydrosalpinx. A patient with salpingitis usually has endometritis as well, hence the symptoms are very much the same, but in the former, pain is com- plained of in the lateral portions of the abdomen. When occurring on the right side only, the pain is frequently mistaken for appendicitis. A certain diagnosis of salpingitis can only be made by a thorough digital and bimanual examination. Owing to the adhesions to which a chronically inflamed Fallopian tube is liable ) 2 E ■132 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF GONORRHOEA. to give rise, patients frequently have varied abdominal and pelvic pains, some of which suggest bowel trouble, others bladder trouble, and so forth. Owing to the patent external ostium of the Fallopian tube, the gonococci can reach both the ovary and the general peritoneal cavity. A corjDus luteum abscess is not infrequently of gonococcal origin. Pelvic gonorrhoea, a name which may well be given to a gonococcal infection of the organs just mentioned, almost invariably produces chronic invalidism. The patient has no regular symptoms, perhaps never has had them, but complains of vague pains, and always feels ill ; she is often anaemic, and is usually constipated. Unfortunately, it is in such a condition that the patient for the first time seeks advice, and although one knows that the gonococcus is at the bottom of the whole trouble, it is difficult to explain the situation to the patient, as in many cases the infection occurred many years back. Hence pelvic gonorrhoea is better treated by a gynaecologist than by a venereal specialist, and, moreover, an operation may at any fiiture time be required. Pelvic gonorrhoea is a frequent cause of functional neuroses in women, but, oddly enough, one seldom sees a condition exactly analogous to the sexual neuras- thenia, so common nowadays in men. Treatment. — The general treatment should be the same as that advised for men. In the acute stage, the patient should be kept in bed when possible. The greatest attention must be paid to the bowels, and urinary antiseptics inter- nally may be prescribed, such as sandalwood oil, urotropin, salicylic acid, or cystopurin. Vaccines from the very commencement are useful, as they increase the patient's natural protective power, and they no doubt check the spread of the disease. In chronic gonorrhoea, especially in pelvic gonorrhoea, vaccines may be the only treatment that exerts any influence oil the disease — indeed, in some cases of cervicitis and endometritis I have seen vaccines cure the patient. In acute urethritis, the patient should wash out the urethra twice a day with a 1 : 4000 solution of potassium permanganate or a 1 : 2000 sohition of hegonon. In chronic urethritis a 1 : 4000 solution of zinc permanganate, or a 1 : 2000 solution of albargin should be used. In cases of acute vuhHtis, the \ailva should be frequently washed with an antiseptic solution, then well dried, and a dusting powder used, because, the dryer the region, the less able is the gonococcus to live and multiply. The dusting j)owder should contain light magnesium carbonate, as this salt absorbs more than two and a-half times its own weight of water. GONOREHOEA IN WOMEN. 433 R Zinc oxide . . . . . . . . gr. x Magnes. carbon levis . . . . . . gr. xx Dermatol. . . . . . . . . gr. xx Piilv. Am}-!!. . . . . . . ad 3j M. f. pulv. On no account should the vagina be douched, for fear of carrying gonococci on the tip of the nozzle of the syringe from the vulva to the cervix. In cases of vaginitis, naturally the vagina must be douched, but the patient shoidd be warned against using too strong a solution, douching too often, or employing an instni- ment which sprays with any great force. In the acute stage, a 1 : 4000 solution of potassium permanganate, or a 1 : 2000 solution of hegonon are the best solutions to be employed. In the subacute or chronic, zinc permanganate, albargin, formalin, and lysol are the most suitable. In chronic cases of vaginitis and cer\'icitis, I have found it very useful to give the patient large doses of iodides, and to prescribe perhydrol as a douche. The iodide soon comes into contact with almost every cell in the body, and when it meets the hydrogen peroxide, free iodine and oxygen are given off. Under no condition should the cervix be dilated, in a case of cervicitis or endometritis. Small superficial injuries are bound to result, and, if the gonococci have not. already entered the subepithelial tissue, they are certain to do so now. Instrumentation of the cervix or uterus, in my opinion, aggravates eveiy case of gonorrhoea of these organs, whether the case is subacute or chronic. Curetting for endometritis I have never yet seen do any good. Furthermore, instrumentation of the cervix or the uterus, even in the chronic stage, is always liable to start up an acute salpingitis, with the additional risk of a peritonitis following. Applications of antiseptics can only kill those gonococci with which the solution comes in contact ; therefore dilating the cervix and painting the surface, or the interior of the uterus, is never going to affect those organisms which have already penetrated deeply into the connective and muscular tissue. These can only be reached by the blood stream, and as we have no drug in gonorrhoea analogous to salvarsan in syphilis, we must admit that chronic gonorrhoea in women is beyond our assistance at present. We have vaccines certainly, but the eclatant results which may sometimes be obtained with them are far from being universal. Some observers are in favour of cauterising the cervix and uteiiis in chronic cervicitis and endometritis with formalin, iodine, trichloracetic acid, or silver nitrate, biit I am, personally, very sceptical as to the amount of good it does. Menge lays a great deal of value on the treatment of chronic cervicitis and endometritis by cauterisation with formalin. In his hands it appears to have been ' 2 E 2 434 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF GONORRHOEA. successful, therefore, in those cases which have failed to respond to vaccines, one may fall back upon this as a reserve treatment. Menge uses formalin either undiluted, or in a 50 per cent, solution. He runs wool round a hard gum elastic uterine sound, soaks the wool with the solution, and swabs out the cavity. In Bartholinitis, with abscess formation, the pus should be evacuated through a small incision, and the abscess cavity washed out with normal saline or a weak antiseptic solution, and then the trouble usually cures itself. In chronic Bartho- linitis, in which cysts are continually forming, the onh' thing to do is to remove the sack. The treatment of vulvo-vaginitis in children merely consists in washing out the vagina with a 2 per cent, solution of sUvcr nitrate, and keeping the genitals and genito-crural folds dry, to prevent the spread of the dermatitis. If the skin be already inflamed, it is a good plan to apply liquid paraffin, to let this dry, and then to put on a weak Lassar's paste, which contains no salicylic acid. As the child usually struggles when being treated, and as the vaginal orifice is small, the best way to wash out the vagina is through a narrow rubber catheter. CHAPTER XXXIX. THE TREATMENT OF GONORRHOEAL INFECTIONS BY VACCINES, AND THE APPLICATION OF THE COMPLEMENT FIXATION TEST IN GONORRHOEA. Vaccines we owe to the brilliant work of Wright.' When they first came into use, the discoverer wisely suggested that the doses should be regulated by the opsonic index, as the correct doses had not been ascertained. We have since learnt that the opsonic index is not necessary. This is fortunate, because in gonococcal infections it is not only difficult to determine, but also the results obtained are very unsatisfactory. AVhy are the results unsatisfactory ? The opsonic index is supposed to be a measure of the protective capacity of the host, and is estimated by the number of organisms which a certain number of polymorphonuclear leucocytes have ingested. In other words, the opsonic index is the phagocytic index. Although phagocytosis is regarded by many as the premier protective mechanism of the body, it is possible that it may be only of very secondary importance. In gonorrhoea, I cannot help thinking, that the gonococcus lives at the expense of the polymorphonuclear leucocj^te ; in which case the opsonic index in this disease would certainly be untrustworthy. In my opinion, the main protective substance in the body is the lipoid-globulin, which has its origin in the lymphocytes, and which circulates in the serum. What probably happens in bacterial diseases is, that the bacteria are killed by the lipoid-globulin, and then are ingested by the polymorpho- nuclears, and so are removed. The polymorphonuclear leucocyte is a degenerate cell. The polymorphism of the nucleus is a sign of degeneracy, so is the fact that the nucleus contains no nucleolus, and added to this are the feeble staining properties of the protoplasm. Another sign of degeneracy is the fact, which no one seems to have observed, that a polymorphonuclear leucocyte cannot change ; in other words, it cannot be the starting point of a new growth, innocent or malignant, as a Ipnphocyte or an endothelial cell can be. Therefore, one could not expect it to be more than a 436 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF GONORRHOEA. scavenger of dead bacteria, and to be itself sometimes preyed iipon. If it be true that the chief protective mechanism of the host rests in the circulating lipoid- globulin, which is manufactured by the IjTnphocytes, and which kills the bacteria by a process of adsorption, it woidd be better to supplant the opsonic index test by one which measured the adsorptive capacity of the patient's serum. Although it is not necessary to regulate the dose of vaccine by estimating the adsorptive index, which is done by the complement fixation test, this test might be of great use in estimating the potency of the various vaccines. With these two \'iews before us, Klein and I^ undertook a series of experi- ments in 1912, and as most of the work is still up to date, I think it would be best to copy it here, adding any information which further experience has taught me. The special objects of the research were : (1) to study the sermn in gonococcal infections (by the complement fixation test) in a sufficient number of undoubted cases ; (2) to note what changes, if any, were produced by vaccine treatment in the sera of such cases ; (3) in this way to use the method, not so much for diagnosis, as for gauging the progress of a case under vaccine treatment ; and (i) to deduce, from these results, the indications for vaccines, and the best method of employing them. Details of the Complement Fixation Test. 1. Complement. — Guinea-pig's serum, not more than twenty-four hours old. Titrated before use with the standard dose of corpuscles and haemolytic serum, 1 in 10, 1 in 20, 1 in 30, etc. The dilution used for the test was three times the smallest amount of complement required to give complete haemolysis in 20 minutes. 2. Serum of Patients. — Inactivated by heating to 56° C. for half-an-hour. Diluted 1 in -5. Sera taken some days previously to being tested were kept sealed up, in the dark, at 0° C. In all cases, the serum was pipetted off from the blood corpuscles as soon as possible. 3. Antigen. — 24 to 48 hours' cultures, on freshly prepared ascites fluid or pleural fluid agar. (The melted agar was cooled to 45° C, and the fluid added in the proportion of 1 in 5. The media were incubated to ensure sterility before use.) The resulting growth was emulsified in normal saline containing 0'5 per cent, phenol, and the strength of the emulsion was found by counting against normal blood according to Wright's method. Titration before use. — This is done by taking various concentrations, and adding to them, in separate tubes, the standard dose of complement (previously determined, as above^, and the standard dose of a non-gonorrhoeal serum. After TREATMENT OF GONORRHOEAL INFECTIONS BY VACCINES. 437 incubating for one hour at 37° C, the sensitised corpuscles are added + "5 c.c. of saline. The most concentrated emulsion which permits complete haemolysis to occur is that used for the actual series of tests. Bacterial emulsions have the property of fixing complement to a considerable degree, without the presence of the corresponding antibody. For example, the following result, with the gonococcus emulsion, is typical of what was found : — With emulsion of 900 million gonococci per c.c. . . No haemolysis. ,, ,, 600 „ ,, . . Partial haemolysis. ,, ,, 300 ,, ,, . . Complete haemolysis. As a rule 300 to 500 million per c.c. are about the limits between which the strength of the emulsion is adapted to the successful working of the test. With weaker emulsions, positive results will be still obtained with sera highly immunised, but failures are the rule, with sera less rich in antibody. We employed, altogether, fifteen strains of gonococci. The ideal procedure is to make an emulsion, from a fresh 2-1 to -18 hours' culture, the clay before each series of tests. As soon as the strain with which we were working began to fail in subculture, a new one was obtained, if possible. Emulsions, if kept for further use, were stored in the dark at 0° C. ; in these conditions they appear to remain little impaired for 10 days, but slowly lose their power of combining with the specific antibody. In this respect, different strains vary, as one of our emulsions retained its antigen properties for considerably longer than the rest. 4. Corpuscles.^We used, throughout, sheep's blood corpuscles, thoroughly washed, in a 5 per cent, suspension in saline. 5. Amboceptor. — The haemol}i;ic serum of the rabbit is obtained in the dried form in sealed tubes. The contents of each tube are dissolved at the time of. use in a measured volume of distilled water and of saline, and provide a strongly haemolytic fluid (several times the minimum required). In this way one has a potent haemolytic serum of constant strength, with which one is certain of obtaining haemolysis, if complement is present. One-tenth c.c. each of complement, of antigen, and of serum to be tested, is taken. Control sera (both negative and positive controls) were also employed in every series, and used in the same way — "1 c.c. of a 1 in 5 dilution. For each serum there were two tubes — one containing serum and complement ; the other, serum, complement, and antigen. The former tube serves as the control, and must in every case show haemolysis at the conclusion of the experiment. Tube A, containing antigen and complement without serum, serves as a control for the whole series, and it must also show complete haemolysis. 438 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF GONORRHOEA. These tubes are incubated at 37° C. for one tour. To each tube is then added "1 c.c. each of corpuscles, and of haemolytic serum, and "5 c.c. saline. After 20 minutes at 37° C. the controls have, as a rule, all haemolysed, and the results can be read of?. KeMARKS on the above, AND ON THE INTERPRETATION OF THE KeSULTS. The dilution of sera to he tested. — As the result of preliminary work with the complement fixation test in bacterial infections, it has been found that the dilution of 1 in 10 (such as is usually employed In the syphilis test) is too high. In this dilution, only very strongly positive sera will cause fixation of complement. It was essential, for the object in hand, to be able to detect the presence of lesser degrees of immunity — 1 in 5 was found to be the most suitable dilution for the test. The quantitative test. — It is obviously desirable to have some means of estimating differences in the degree to which fixation of complement occurs — (a) Between different sera ; {h) still more between the samples of one patient's serum obtained at different stages in the progress of the treatment. Klein^ had previously noted the use of two methods of estimating the strength of the positive reaction in Wassermann's reaction : (a) By finding the amount of complement adsorbed ; (6) by finding the highest dilution of the serum with which a positive result is obtained. Neither of these methods is so easy to carry out in the true bacterial tests as in the syphilis reaction, and it was decided not to attempt them in these experiments. Instead, recourse was had to the following simple method. The varying results were indicated thus : — Complete fixation of complement, or no haemolysis, as shown by the corpuscles remaining in undiminished bulk and the fluid contents of the tube remaining perfectly clear . . . . + + + Almost complete fixation, or a trace of haemolysis, as shown by the bulk of corpuscles remaining undiminished, but the fluid being tinged with a trace of haemoglobin . . . . ... + + Partial haemolysis, where the total mass of corpuscles is diminished, but yet remains sufficient to form a precipitate + Doubtful result, where there remain insufficient corpuscles to form a precipitate, though their complete solution is not effected {i.e., so as to give a clear solution) . . . . . . + TREATMENT OF GONORRHOEAL INFECTIONS BY VACCINES. 439 " Control " sera. — In every series, at least one known positive and one known negative serum were included. For the latter, were tested, altogether, from 30 to 40 sera of normal persons and of patients suffering from diseases other than gonorrhoea — e.g., syphilis. In no single case has any fixation of complement been noted with these sera. For positive sera, it was always contrived to have available a serum with which a + + + result had already been obtained. (Sera remain active for at least a fortmght, if kept undiluted in the dark at 0° C. in sealed pipettes.) In addition, an. anti-gonococcal serum from Burroughs and Wellcome was always used (serum of a horse immunised by subcutaneous injections of cultures) ; with this serum a + + + result was obtained in dilutions up to 1 in 10. Antigens from different strains of the gonococcvs — the relative advantages of single and multiple antigens. — Amongst previous workers who have examined gonococcal infections by the complement fixation test, Teague and Torrey* found that the serum of an animal immunised to one strain of gonococcus, may fail to cause fixation of complement, in the presence of an antigen obtained from a different strain. Similarly, Watabiki,* having immunised rabbits against eight different strains of the gonococcus, found that six sera gave a strong reaction with six certain strains of gonococcus, and that two gave strong reactions with two other certain strains of gonococcus. Schwartz and McNeil* also found that various antigens differed in their reaction with gonorrhoeal sera. Of all the strains of gonococcus used in the complement fixation test, there was only one which entirely failed to act as an antigen. The first series of tests was performed with two separate antigens ; no difference was observed in the results. In passing from an old to a fresh antigen, both were tested against a known + + + serum. If the new strain also gave a + + + result, it was accepted as satisfactory, and was used until its subcultures began to fail. This method may be considered the best one for counteracting the differences that may exist between one strain and another. The American workers, quoted above, concluded that, in attempting the diagnosis of gonorrhoeal infections by the complement fixation test, the antigens used should be extracts of several different strains. This conclusion is not disputed, as regards diagnosis, but these experiments deal generally with cases in which the diagnosis was already established, and, therefore, the complement fixation test was employed rather to estimate the variations in the antibody present in the individual cases at different stages. On practical grounds two criticisms seem permissible : — (a) The different strains (as recommended by Teague and Torrey) — say, six in number — must either be combined to form a single emulsion, or they must be 4-10 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF GONORRHOEA. used separately. In the former case, supposing only one of the six is the true corresponding antigen for the serum tested, the effect is very much the same as if the antigen consisted of 1 part effective antigen, and 5 parts wa.ste products. In the latter case, for each serum tested, seven separate tubes will be required, and the test becomes unwieldy in dealing with a series of cases. (6) If the antigens employed are to be from tolerably recent cultures or sub- cultures (which has been shown to be deskable), a great amount of labour, and an abundant supply of fresh material is required, to maintain several strains of gonococcus in pure culture. The differences between several strains of the gonococcus, as regards the fixation of complement in the presence of the specific amboceptor. Are these differences related to the nature of the gonorrhoeal infection from which the strain u-as isolated ? — From a mild to a severe infection, all grades exist. The strains of gonococci employed were obtained from acute and subacute cases, not all of the same degree of severity. Some of the strains were further used as vaccines. Differences of two kinds were noted : — (1) Some were more potent than others, as antigens in the complement fixation test, with the same gonorrhoeal serum. (2) Some were more potent than others, as vaccines. There is a third difference, namely, the effect of the strains when inoculated into an animal. Differences have been shown, both as regards the toxic effect produced, and as regards the degree to which the formation of antibodies is stimvdated (Watabiki^). It is not made clear, however, whether such differences bear any definite relation to the severity or mildness of the case from which the strains of the organism were derived. Similarly, with regard to the differences noted in these experiments under headings (1) and (2) ; they do not correspond to the severity or mildness of the case from which the strain in question originated. A few examples will make this point clear. One can single out one strain of the series which was of marked potency in both (1) and (2). This strain was derived, not from a severe case, but from a case of acute anterior urethritis, which was cured in 10 days, with potassium permanganate injections as the sole treatment. On the other hand, an antigen prepared from a culture from the heart's blood of a fatal case of gonococcal septi- caemia was by no means so active. Again, one strain was grown from a subacute case of urethritis of average severity in a male ; the culture was not by any means abundant, but was undoubtedly the true gonococcus. The emulsion of this culture failed entirely to fix complement in the presence of a known -I- -t- -H serum. It appears, therefore, that no definite relation can be traced between the TREATMENT OF GONORRHOEAL INFECTIONS BY VACCINES. 441 nature of the case from which a strain of gonococcus is derived, and the properties of this strain, as tested by the complement fixation test. Such a conclusion is quite in harmony with the known facts witli regard to the relative virulence of strains of the diphtheria bacillus, or of the typhoid bacillus. For example, strains of the diphtheria bacillus, from such a mild affection as membraneous rhinitis, have been shown to have a marked virulence, when injected into guinea-pigs. Hence it may be inferred that the relative virulence of any given strain of the gonococcus is not the chief factor in determining the severity or mildness of the infection. There must be other factors, such, for example, as the resistance of the infected individual, the site of entrance of the micro-organism (cf . the different streptococcal diseases produced by the streptococcus pyogenes, according to the path by which it finds an entrance into the body), and the quantity of the virus which is implanted upon the host. Vaccines. — All that has been said of the method of obtaining the cultures, making, and counting the emulsions for the antigen in the complement fixation tests, applies to the preparation of vaccines. In fact, many of the strains were used for both purposes. Emulsions intended for use as vaccines were, however, autolysed for 24 hours at 37 C°., to kill the gonococci. No heat was employed. The gonococcus rapidly autolvses at blood heat, and no living cocci remain at the end of 24 hours. The Three Methods of Vaccine Treatment Employed. 1. Vaccines injected subcutaneoushj , in the usual way. — The initial doses were 5 to 10 million, then increasing to 50 million or 100 million, and occasionally 200 million were used. Our vaccines were prepared, when possible, from the primary culture ; when this was not practicable, from the earliest subculture possible. Generally, 48 hours' cultures were preferred. At the end of 24 hours, the growth is frequently not veiy copious. Stock emulsions of high concentration (1,000 million per c.c.) were stored in the dark at 0° C, for future use. In this condition they slowly lose their strength, but they remain active for 10 days or more, and may retain much of their original properties even after a month. Nevertheless, the most recently made vaccines at hand were always used, never more than a fortnight old, for the subcutaneous method. Therapeutic effects. — Such vaccines, I found, rarely failed to produce a certain reaction, sometunes a marked reaction, even in the moderate doses employed. I should not have been prepared to inject them in the large doses sometimes advocated. 442 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF GONORRHOEA. aud I am incliued to believe that the stock vaccines which cau with inipuuity be employed in doses of several thousand million must be either old preparations, or must be made from strains attenuated by repeated subculture. I did not use autogenous vaccines. In the chronic cases with arthritis, which formed the bulk of the cases, such a proceeding was difHcult, if not impossible. In general, I am of opinion that it is far more important in gonorrhoea to use a vaccine recently made from an original culture, or first subculture, than to lay great stress on the vaccine being autogenous. Two preparations on the market were also employed for subcutaneous injection, namely, " Gonargin " and " Arthigon." Tested by the complement fixation method, gonargin showed the presence of antigen, though not to anything like the extent to which it was present in the freshly made emulsions. Arthigon had very feeble properties as a vaccine, and in the complement fixation test no definite result could be obtained, unless the emulsion was so diluted as to make the test valueless. The emulsion per se fixed complement to an extraordinary degree, so that little use was made of the " Arthigon " preparation for treatment, for the above reasons. An increase is produced, temporarily, in the discharge in many cases, with all the ordinary subcutaneous vaccines employed, and this temporary increase tends to dmiinish with each succeeding injection. A negative phase almost invariably occurs after every subcutaneous injection, and its duration depends upon the dose used and upon the interval which elapses between successive doses. One case received 50® gonargin on three successive days, with the result that the complement fixation test did not return to positive, as it was before the first dose was given, for three weeks, during which time the discharge increased, and the epididjTnitis lighted up again. If, then, vaccines are to be used subcutaueously, or better intramuscularly, as by the latter route the local reaction is prevented, only small doses should be employed, and longer intervals should be allowed between the succeeding injections than are generally advised. The dose should range from 5 to 10 million, and should not be repeated for a fortnight, or even longer; then each future interval can be gradually shortened, as the duration of the negative phase diminishes. The value of gonococcal emulsions as vaccine and as antigen in the comjUement fixation test. — An emulsion of gonococci is an "antigen," i.e., it contains the bacterial bodies and endotoxines which, when inoculated into the living organism, give rise to the formation of specific antagonistic substances, or antibodies. The term antigen, perhaps unhappily, is also commonly used to denote that factor in the complement fixation test which combines with the antibody. The term, TREATMENT OF GONORRHOEAL INFECTIONS BY VACCINES. 443 ill both cases, is applied to the same thing — the bacterial emulsion, but to two different eiiects of it — one manifested in the living organism, the other in the experiment in vitro. Nevertheless, it is a probable inference that an emulsion of bacteria which has a high antigen value in the test, in vitro, will also have a high antigen value, when injected into a living animal or patient. Klein and I found in practice that the emulsions which most completely fixed complement (in the presence of positive sera), were most likely to provide potent vaccines. A curious phenomenon encountered, may be briefly alluded to in this place. A patient whose serum was repeatedly examined, was a man, A. K., set. 22, suffering from severe gonorrhoeal arthritis of many joints. His serum, at intervals of over a month, always gave a + + + with several antigens, with one exception, namely, the strain of gonococcus isolated from his own urethra after prostatic massage. With this strain the fixation of complement was incomplete ; it was recorded as ++. 2. Intravenous Injections of Vaccine. — Having ascertained how to obtain active vaccines for subcutaneous injection, the next experiments were directed to the use of them intravenously. For this purpose, an autolysed emulsion, containing originally 1,000 million gonococci per c.c, was used. It had been kept in a sealed tube at 0° C. for more than three weeks. On centrifugalisatioii, the amount of deposit was very slight. A comparatively old emulsion was purposely preferred to a more recent one, as being more completely autolysed, and as containing more of the active princij^le in solution. Obviously, it might be thought inadvisable to inject intravenously an emulsion containing bacterial bodies, even though dead. The supernatant fluid was pipetted off, and was ascertained, by culture, to be sterile. It was then tested for complement fixation, in the presence of a known + + + serum. Com- pared with a recent emulsion, which was in use at the time, it had lost some of its power, but retained sufficient to justify its use as a vaccine. I, therefore, started to use it in comparatively large doses, namely, 5 million. In diluting down, the fluid was reckoned as = 1000 million per c.c, and the smaller doses were calculated accordingly. Each injection was given in 5 oz. of saline, as by using a large bulk of fluid a more general distribution would be achieved. Effect of injections. — The above sterile fluid, injected subcutaneously in doses of 10 million, was followed by little reaction and good therapeutic effect. Intra- venous injections in smaller doses produced no reaction, and the beneficial effect was marked, even in doses of 1 million. i-li THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF GONORRHOEA. It is not necessary, or wise, to exceed a dose of 20 million ; probably, even with 5 or 10 million, just as good results are obtained. The doses used were probably too large. It might be better to start with 1 million, and then gradually increase by 1 million weekly. Contrary to what might be expected, the negative phase is negligible (judged by clinical signs and the serum reaction), after intravenous injecton of vaccine, provided too big a dose has not been given. In this respect, intravenous vaccines are preferable to subcutaneous ones. Effect on the jMiiienfs serum, as shown by the fixation of complement. — The patients treated by the intravenous injection of vaccine were mostly those who had given a strong positive reaction in the complement fixation test. Following the injections, the reaction underwent variations, very much in the same way as the serum reaction is changed, in syphilis, by salvarsan. During the course of intravenous vaccine injections, the positive reaction, in favourable cases, becomes less positive ; sometimes it returns for a time to a strong positive, and again becomes yet more diminished in intensity, until finally it becomes negative. The average number of injections required to obtain a negative reaction, is about 10. Sometimes even that number is insufficient. If too big doses are given, the complement fixation test becomes negative, but the symptoms are aggravated, and, when the latter have quietened down, the reaction becomes positive again. Three patients suffering from syphilis, but not infected with gonorrhoea, were injected intravenously with the vaccine. Their serum gave a negative result with the gonococcal fixation test, and remained negative after the injection. The Wassermanu reaction was also uninfluenced. If the reaction is negative, before treatment is commenced, it becomes positive immediately after, and if a negative reaction is gradually obtained by the use of several injections, a provocative injection some time later will not give rise to a positive reaction. If, on the other hand, the treatment is inadequate, and the reaction becomes negative as the result of a latent stage being produced, a provocative injection will in such cases give rise to a positive reaction. 3. Sensitised Vaccines. — Besredka^^"^^ originated this method, based, as it was, on the discovery by Ehrlich and Morgem-oth, that every cell, when brought into contact with its specific antibody, fixes it, to the exclusion of every other substance which may be present. Applying this principle, Besredka uses the vaccine to abstract specific antibody from an immune serum ; he then gets rid of the serum, and uses the combination of vaccine and antibody as sensitised vaccine. It has been experimentally proved that sensitisation of a vaccine enormously reduces its toxicity. Thus Besredka found that "2 to "1 c.c. of a 48 hours' agar TREATMENT OF GONOERHOEAL INFECTIONS BY VACCINES. 445 culture of plague destroyed by heat, killed a mouse in 48 hours, but that, after sensitisation, 20 to 30 tunes the dose could be injected without producing any symptoms at all. Similar observations have been made in the case of the dysentery bacillus and other micro-organisms. Further, the immunity conferred on animals injected with sensitised vaccines comes on very rapidly : in the case of typhoid, it has been found after only 24 hours. The details of these experiments, and the whole history of the method, with references to the literature, are to be found in a " Critical Eeview of the Sensitised Vaccine of Besredka," by M. H. Gordon.^ Preparation of the sensitised vaccine. — -This was carried out according to the method recommended by Besredka.^ ^° ^^ The bacterial emulsion of a fresh living culture is counted. It should be a strong emulsion (at least 1000 million per c.c). To a measured amount of this (2 c.c, for example), about 1 c.c. of the hnmune serum is added (Besredka prefers to use as little antibody as is compatible with sensitisation) ; the mixture is left at room temperature for 12 hours, as at the end of that time the bacteria are deposited at the bottom of the tube ; the serum is now pipetted off, and is replaced with saline, then the tube is shaken and centrifuged. The saline is then pipetted off, and replaced by more, and the tube again centrifuged ; the deposit of bacteria, washed free of serum, is finally made up to the original bulk with .5 per cent, phenol saline, and this constitutes the sensitised vaccine. The Immune Serum used in Sensitising. 1. Immune Horse Serum. — Burroughs and Wellcome's antigonococcus serum is the serum of a horse immunised by subcutaneous inoculation with several strains of the gonococcus. This serum gave complete fixation of complement; it was used, as already mentioned, as one of the + + + controls ; as it contained much anti- body, it was reasonable to suppose that it was well adapted to the preparation of a sensitised vaccine. This expectation, however, was not realised. The first experiments made with this sensitised vaccine were unsatisfactory. Local effects . were not bad ; unprovement was noted in the joints or other foci of infection, and no negative phase occurred, but bad general effects were produced — the patients had diffuse pains, felt ill, and rises of temperature occurred. 2. Human Immune Serum. — In consequence of these bad effects, it was decided to continue to work with sensitised vaccine, but in preparing it to use for immune serum, human serum taken from the vein of a gonorrhoeal patient. Such a serum was obtained from Case 74, taken at a time when it gave a strong positive result in the complement fixation test, subsequent to six intravenous injections of the autolysed vaccine, with doses at weekly intervals of 5 to 20 million. 446 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF GONORRHOEA. The sensitised vaccine made with this serum behaved very difierently from that prepared with the immune horse serum. Not oul}- did the symptoms of the disease disappear more quickly, but the reactions were practically nil, and no toxic phenomena occurred, and, as with the last described vaccine, no negative phase was produced. Equally beneficial results were obtained with a second sensitised vaccine (human), made with the serous effusion from the knee-joint of Case 75. A third preparation was made, with a human immune serum obtained from Case 72, but the results obtained were unsatisfactory, for the following reasons. The serum which was used for sensitisation was over five weeks old, and was + + + both before and after the process ; moreover, it was amphoteric, a property which was destroyed by reinactivating for an hour. From recent experience I have learnt that gonococcal joint fluid is the best with which to sensitise a vaccine, and, failing that, a serum, provided it gives a strongly positive complement fixation test with a gonococcal antigen. The superiority of gonococcal vaccine sensitised with human immune serum, over that sensitised with immune horse serum. — The causes of this marked difference seem to be as follows : — The gonococcus emulsion contains probably two constituents — {a) The killed bacteria themselves. (b) Endotoxines liberated from them. To produce a completely sensitised vaccine, which wiU not exert an}' deleterious effects, it is necessary to employ an immune serum which will combine with or neutralise both {a) and (6) ; in other words, the immune serum should contain both a bactericidal substance and an "anti-eudotoxine." Now, it is known from the experiments that the immune horse serum did undoubtedly contain some specific antibody, which gave a strong complement fixation test, and it probably possessed bacteriolytic properties which brought about an improvement in the diseased foci ; the toxic symptoms not being benefited, but often increased, leads one to assume that it contained no anti-endotoxines ; these soluble products, remaining uncombined, caused the ill effects which occurred. The human immune serum, on the other hand, contains all the antagonistic substances elaborated in the course of the natural disease. These will include both bactericidal and anti-endotoxic substances, since the micro-organisms are living and multiplying in the body, while, at the same time, some of them are continually being destroyed and setting free their endotoxines. The sensitised vaccines were first employed in doses of 20, 50, and 100 millions on three successive days. But, from recent experience, I have found it better to TREATMENT OF GONORRHOEAL INFECTIONS BY VACCINES. 447 start with 100^ and to increase the dose daily up to 5000" in the following doses : — 100«, 500«, 1000«, 2500«, 5000«, and to give the highest dose once a month afterwards for three mouths. If the patient exhibits toxic symptoms before the maxunum dose is reached, three weeks should be allowed to elapse before the dose that caused the toxic symptoms is repeated, and then the subsequent injections should be given monthly, and continued as before. In some cases, very much bigger doses than those mentioned can be given with impunity, and with very good results intravenously, but unfortunately the preparation of sensitised vaccines in big doses entails much labour. Changes produced in the Immune Serum by the Sensitising Process. Since the sensitisation process consists in the combination of the antigen with the antibody, it should be possible to show that the immune serum has lost part, or the whole, of its antibody content thereby, by testing the serum before and after the process. The following tests were made : — 1. Immune Horse Serum. — Sensitisation of an emulsion of a certain strain " A," 1 c.c. of serum to 1 c.c. of a 1000 million per c.c. emulsion — Serum before sensitisation process + + + (against several strains, including " A "). ,, after ,, ,, + + + (against " A "). I.e., no apparent loss of antibody, with 1 c.c. of serum to 1000 million cocci. 2. Immune Human Serum (Case 72). — Sensitisation with an emulsion of a certain strain " X," 1 c.c. of serum to 1 c.c. of a 5000 million per c.c. emulsion — Serum before sensitisation + + + (against several strains, including " X "). after „ + + + (against " X "). 3. The same Serum, No. 72 : Knee-joint Fluid, No. 75 — compared. — Both used for sensitising emulsions of two strains " C " and " L " in the proportion of 1 c.c. of fluid to 8000 million gonococci — No. 72. Before sensitisation. . .. .. .. ..[- + + „ After sensitisation with strain " C " . . . . + + „ After sensitisation with strain " L " . . . . + No. 75. Before sensitisation. . . . + + + (" C ") + with " L." „ After sensitisation with strain " C " . . . . — „ After sensitisation with strain " L " . . . . — 4. The same Two Fluids (72) and (75) were sunilarly placed with emulsions of four strains, including " C " and " L " in the proportion of 1 c.c. of the serous 2f 448 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF GONORRHOEA. fluid to 700 million cocci — and the complement fixation test showed no appreciable difference in the antibody before and after the sensitisatiou process. Inferences from the Above. Test 3 shows that the antibody may be more readily taken up b_y a given strain of gonococci from one immune serum than from another, although both give a strong fixation of complement in the presence of that strain. From the other tests it appears, that it is only when the quantity of gonococci is sufficiently large, in comparison with the amount of immune sermii, that the latter is robbed of its antibody to a sufficient degree for the loss to be detected by the complement fixation test. In other words, the gonococci do not absorb antibody to an unlimited extent. Conversely, a given volume of strongly immune serum will sensitise a comparatively enormous quantity of gonococci. Cases of Gonorrhoeal Infection in which the Complement Fixation Test WAS Negative or Doubtful. Before proceeding to the detailed account of the series of cases, which were systematically vaccinated with the aid of frequent serum tests, it is necessary to mention a few cases in which very little information could be gained by the test. This latter group is made up of scattered cases, not treated by me. Some received vaccines subcutaneously. For the most part the local treatment in these cases seemed inadequate. Of these doubtful cases, with regard to the first serum test made : four gave a complete — ; two gave a + result ; two gave a + result. As a means of diagnosis, the test was a failure in six out of the eight cases. Three gave a + result, at some time or other, whilst under observation. Three gave a + result, at some time or other, whilst under observation. One case, tested on only one occasion, was — ; one case, tested on only one occasion, was + . Two of these cases may serve as t5'pes : — A. Phyllis C, set. 21. — Gonorrhoea and arthritis of left knee and right ^\"iist. Irregular pyrexia. Vaginal discharge, in which the gonococcus was identified both in films and culture. Autogenous vaccines were used in doses of 2, 5, 10, 20 million at intervals of three days. Serum test. — May 21, 1912 (before vaccine) . . . . . . . . — „ May 23, 1912 (forty-eight hours after first vaccine) . . — „ June 13, 1912 (two weeks after fourth vaccine) . . . . — July 10, 1912 + TREATMENT OF GONORRHOEAL INFECTIONS BY VACCINES. 449 The vaccines in this case apparently did no good, though autogenous. Never- theless, this same strain fixed complement in the presence of a positive control serum. Such improvement as eventually resulted seemed to be due rather to a slow, naturally established immunity, than to one induced by vaccines. B. Stanley C, aet. 22. — Gonorrhoeal arthritis. Urethral discharge 14 weeks previously, followed 10 weeks later by pain and swelling of one testicle. Treatment with sensitised vaccine (made with the immune horse serum). Serum reaction before vaccine . . . . . . . . . . . . ± „ ,, forty-eight hours after . . . . . . . . . . — ,, ,, five days after . . . . . . . . . . . . — This patient responded unfavourably to the sensitised vaccine. Unfortunately I did not have the opportunity of trying the human serum sensitised vaccine. These failures to give a marked fixation of complement do not seem to be sufficiently explained on the theory that, in certain cases, the infection is by an atypical gonococcus {vide supra Teague and Torrey, and Watabiki). These doubtful or negative sera were tested with more than one strain of gonococcus. Case A gave a negative result, even against her own strain. It seems more likely that, for some reason or other, such cases fail to elaborate, or that they produce, very slowly, the specific antibodies necessary to recovery. Hence the small benefit of vaccine, as in Case A. One other case, not included in the series about to be described, may be briefly alluded to, namely, A.K. The serum of this patient was persistently -|- -F -I-, at intervals extending over a month. It has been referred to in the first part of the paper as having been used as a positive control. No change in this reaction occurred, even after vaccines. Now, no adequate local treatment was employed here. Hence the failure, either to alter the complement fixation test, or to cure the patient. There must be a continued production of antibodies in response to the continued presence of gonococci. The presence of the former alone may be insufficient. Hence the value of supplementary treatment. Complement Fixation Tests with the Exudates. The fluid from the affected joints was tested in three cases : — 1. Case 75 . . . . . . . . . . Result -I- -|- + ; do. with serum. 2. „ 76 „ + + +; 3. Louisa C, gonorrhoeal arthritis of knee ,, + ; ,. >, The effusions 1, 2, were tested for antigen, against a known positive serum. Even when used undiluted, the result was negative. The fluids were sterile in culture. ) 2f2 450 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF GONOKRHOEA. Injection of the exudates for therapeutic purposes.— In Cases 74 and 75 the joint fluid was injected subeutaneously. No improvement took place. Case 58. — Male, ^t. 35. Severe case. Subacute posterior urethritis, chronic prostatitis, and arthritis of both knees and ankles, with rheumatic pains about the right shoulder. Subcutaneous vaccines (freshly prepared, not autogenous). Serum Test. Injection of Vaccine subeutaneously. Therapeutic Effect. Before Forty- eight Vaccine. Hours after. First injection — 5 million + + + Marked local and general reaction. Second — 10 million (eighth day after + + + + Less local and general re- first). action. Third — 15 million (eighth day after + + + + + + Only slight reaction ; joints second). improved. Fourth — 25 million (two weeks after + + + + No reaction ; patient pre- third). viously crippled, able to walk with ease. Fifth — 50 million (eighth day after + + + + General health and nutrition fourth). improved. Case 59. — Male. Case illustrates diagnostic value of gonococcal fixation test. Gonorrhoea 12 years ago. Syphilis two and a half years ago, treated with 72 mercurial injections. No signs or symptoms for about two years. Six weeks ago iritis of left eye occurred. Wassermann reaction negative. Gonococcal fixation test positive. Iritis cured with gonococcal vaccines, without any anti-sj'philitic remedies. Subcutaneous Vaccine. Serum Test before Vaccine. Serum Test Forty- eight Hours after. First injection Second — eighth day after first Third „ „ second Fourtli ,, ,, third Fifth „ ., fourth Sixth ., „ fifth + + + + + + + I TREATMENT OF GONORRHOEAL INFECTIONS BY VACCINES. 451 Case 60. — Male. Chronic posterior urethritis and prostatitis, urethral strictures. Thickening of left epididymis (due to gonorrhoea! epididpiiitis five years previously). Subcutaneous vaccines — results as follows : — Injection of Vaccine subcutaneously. Serum Test. Before Vaccine. Forty-eight Hours after. Therapeutic Effect. First injection — 10 million - + + + Second — 50 million (fourth day after + + + + first). Third — 50 million (third day after + — second). One week later — serum test Two weeks later „ Six weeks later „ Severe local reaction. Ure- thral discharge increased ; pain in left testicle for twenty-four hours. Reaction as before, but less in degree. Local reaction worse than before ; general reaction marked ; no increase of dis- charge or pain in testicle. — Urethritis still persisted. -f Finally cured only after — gradual dilatation of strictures. Case 61. — Male, set. 31. Chronic posterior urethritis and prostatitis. Ordinary vaccine, subcutaneously (not autogenous). Eight weekly injections, from 5 to 200 million gonococci. Symptoms completely cleared up. No improvement before vaccine treatment. Purulent urethral discharge foUowed injections of vaccine, each succeeding discharge being progressively less in intensity and duration. The last injection of vaccine gave rise to no discharge. Case 62. — Female, aet. 29. Chronic gonorrhoea. Menstrual disorders. Vaccine treatment with^ — ■ (a) " Gonargin " (a commercial polyvalent vaccine), 50 million. (6) Two weeks later, 20, 50, and 100 million sensitised vaccine (hnraune horse serum) on three successive days. Time. Serum Test. Therapeutic Result. Before gonargin Before sensitised vaccine Forty-eight hours after Six days after Three weeks after Six „ + + -f + + + Local reaction slight ; general reaction very bad ; discharge temporarily increased, later less than before. Local reaction slight ; general reaction severe ; discharge increased. Still vaginal discharge ; muscular pains. General health improved ; stiU discharge. 452 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF GONORRHOEA. Case 63. — Male, ast. 32. Chronic posterior urethritis. Old epididjiiiitis (right). Vaccine treatment with — (a) " Gonargin " 50 million. (b) Five days later, 20, 50, 100 million sensitised vaccine (horse serum) on three successive days. Time. Serum Test. Condition of Patient. Before gonargin After Before sensitised vaccine ... Forty-eight hours after sensitised vaccine. Fifth day after sensitised vaccine Tenth Twenty-first day after sensitised vaccine. One month after sensitised vaccine + + + + Local reaction marked ; bad general reaction ; discharge increased ; right epidid\'niis pain- ful. First sensitised vaccine ; general reactions. Second sensitised vaccine ; general reactions. Third sensitised vaccine ; general reactions. Discharge considerably less. ,, less. „ ceased. Xo threads in urine. slight local and slight local and slight local and Case 6i. — Male. Chronic posterior utethritis and prostatitis. " Gonargin " three injections of 50 million. Human sensitised vaccine, three weeks later, 20, 50 and 100 million on successive days. Time. Serum Test. Therapeutic Effect. Day of first injection of gonargin... Forty- eight hours after first gonar- gin. + + Local reaction, no general ; discharge much increased. Forty-eight hours after second _ Less local reaction ; less marked increase of gonargin. Fort3'-eight hours after third gonargin. Day before sensitised vaccine + discharge. Sbght local reaction ; local condition no better. Local condition as bad as at the beginning of treatment. Forty-eight hours after trio + + + Xo general, very slight local reaction after first, second and third sensitised vaccine. One week later Three weeks later + + _ After first, discharge not increased. ,, second, chscharge diminished. „ third, discharge ceased entirely. Complete recovery. TREATMENT OF GONORRHOEAL INFECTIONS BY VACCINES. 453 Case 65. — Gonorrhoea of four months' duration. Unilateral epididymitis. Gonargiu." Sensitised vaccine (horse), 20, 50, 100 million. Day. Serum Test. Therapeutic Effect. First injection, gonargin ... ... Slight local and general reaction ; severe " focal " reaction, namely, acute discharge, and pain and swelling of affected testicle. Second injection, gonargin More marked local, no general reaction ; acute discharge ; no swelling of testicle. Day of sensitised vaccine, 20 — No reaction ; discharge diminished. million. Day of sensitised vaccine. .50 + _ Slight local and general reaction. million. Day of sensitised vaccine, 100 — Slight local, more general, reaction. million. Three davs later + + + Eight „ + + + Pains ; malaise ; discharge increased. Ten „ ... + + + C4eneral condition much the same. Seventeen days later + No malaise ; discharge ceased. Twenty-one daj-s later + Twenty-eight days later . . . + - Still slight discharge in the morning. Case G6. — Chronic gonorrhoea. Fourth recurrence. Strictures. Gonargin, 50 million. Fourteen days later, 20, 50, and 100 million sensitised vaccine (horse) on successive days. Time. Serum Test. Therapeutic Effect. Bejore treatment ... Gonargin injected Sixth day after gonargin Day of sensitised vaccine, 20 million. Tliird day after trio First week ,, Second week „ Third „ Fourth „ Sixth ,, „ Slight local, no general reaction ; discharge increased. Fever and general malaise ; discharge copious. No reaction ; discharge decreased. Slight discharge persisting, due to obstinate strictures. 454 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF GONORRHOEA. Case 67. — Female, set. 26. Latent case. Later arthritis of right knee-joint. Vague pains in limbs and pelvis. Time. Serum Test. Therapeutic Effect. Before treatment + + First injection of gonargin One week after Second injection of gonargin One week after Third injection of gonargin One week after + + Slight local, severe general reaction. Condition generally improved. Severe local and general reaction. Vaginal discharge. Severe general reaction. Two weeks after ... Sensitised vaccine, 20 million f, ,, 50 ,, 100 „ ■Portj^-eiglit hours later Two weeks later + No marked improvement. Reactions both local and general. + + + + + Fluid in knee-joint disappeared. Four „ Six „• + No pains or toxic symptoms ; patient's general condition enormously improved. Case 68. — Male. Pains in knee and finger-joints. Latent gonorrhoea. Treated with human sensitised vaccine. Eapidly improved. Time. Condition of Patient. Before treatment ... Sensitised vaccine, 20 million ,, ,, yO ,, 100 „ Three days later ... Fourteen days later Pains in joints ; threads in urine. No reaction ; threads fewer in urine. Joint pains disappeared ; a few threads xu'ine. Urine clear ; no symptoms. Cases 69 and 70. — Male, a3t. 56 ; woman, set. 29. Chronic arthritis (of osteo- arthritic type). Similar cases. Case 69 had chronic urethritis and old syphilis. The Wassermann reaction and gonococcal fixation test both positive. Partial improvement of joint after salvarsan ind a course of mercury and iodides. Wassermann reaction remained positive. Further improvement six weeks later, after the three injections of sensitised (horse) vaccine. As in other cases, toxic symptoms followed the injections of vaccine. Case 70. — No signs of gonorrhoea. Fixation test with gonococcus, positive. Human sensitised vaccine, 25, 50 and 100 million. No toxic symptoms at all. Some improvement in joint. In both the arthritis (hip) was of too long standing to be cured. In both cases the gonococcal fixation test became negative about three weeks after the last vaccine. TREATMENT OF GONORRHOEAL INFECTIONS BY VACCINES. 455 Case 71. — Female. Gonorrlioeal arthritis (knee-joint). Treated with human sensitised vaccine with marked success. Time. Serum Test. Condition of Patient. Before treatment + + Right knee swollen and painful, and con- taining fluid. Sensitised vaccine, 20 million 1 50 „ \ No general reaction ; no focal reaction in 100 ,. joint ; slight local reaction. Forty-eight hours later + + + One week later + + + No pain in joint ; fluid gone. Two weeks later + + Four weeks later ... Improvement maintained. Case 72. — Male. Gonorrhoeal arthritis. Severe case. Both knees, both ankles, both elbows and both shoulder-joints, also wrists and fingers were involved. Previous unsuccessful treatment with three injections of vaccine (commercial stock), and four injections of another stock, going up to doses of 2000 million. Treatment with sensitised vaccines (horse). 20 million ... 50 „ 100 „ Three days later Seven „ Thirteen „ Marked focal reaction in all affected joints. Bad local, slighter focal, reaction. Severe local, no focal, reaction. Swelling of -nTists and hands gone ; other joints better. Improvement in all joints very marked. General arthritis improved enormously ; patient able to walk, and gaining in health and nutrition. Serum reaction was positive { + + +) throughout. Case 73. — Male, set. 18. Subacute urethritis. Arthritis of left wrist-joint and tenosynovitis. No involvement of posterior urethra. Intravenous vaccine, autolysed, 3 million. Time. Serum Test. Result. Before vaccine Twenty-four hours after ... Forty-eight hours after Ten days after ^ + + — No reaction of any kind. + -f Arthritis entirely gone. + -f Discharge persisted. 456 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF GONORRHOEA. Case 74. — Chronic prostato-urethritis. Gonorrhoeal arthritis of both knees and ankles. Previously has had iritis four times. Intravenous vaccines (weekly). Much improved. • Time. Serum Test. Result. Before first vaccine (5 million) ... + + Forty-eight hours later + + Temporary pyrexia ; joints felt better. Five days later + Joints still felt better. Before second vaccine (5 million) + Fortj'-eight hours later + - No pyrexia or discomfort ; joints better. Before third vaccine (10 million)... + General condition improved. Forty-eight hours later + - Slight toxic pains ; joints better. Before fourth vaccine (10 million) + + Forty-eight hours later -f + No pyrexia ; pains in hip and back. Before fifth vaccine (15 million) ... + -f-f Swelling and fluid in joints gone ; discharge less. Iritis developed in right eye. Forty-eight hours after + + + Before sixth vaccine (20 million)... + - Forty-eight hours later + + + Bad toxic pains ; no pyrexia. Before seventh vaccine (20 million) + + Iritis improved. Forty-eight hours later + Iritis gone ; discharge ceased ; joints much better. Nine days after eighth vaccine + Patient walks well. (20 million). Three weeks after eighth vaccine — Improvement maintained. (20 million). Case 75. — Male, set. 21. Gonorrhoeal arthritis. Effusion in right knee-joint, pain and swelling of left ankle and right hand. Intravenous vaccines — five injections of 10 million doses. Time. Serum Test. Result. Before vaccines First injection Five days later Eight days later ... Forty-eight hours after second vaccine. Before third vaccine Forty-eight hours later Before fourth vaccine Forty-eight hours later Before fifth vaccine Forty-eight hours later + + + + + + -t- + + + + + -f -f -f-f + + + + -f + -f + + + No reaction ; joint movements freer. Fluid aspirated from joint.* Marked improvement ; slight pyrexia. Knee filled up again. No reaction; knee-joint unaltered; other joints much improved. General condition much improved ; all other joints recovered except knee. * Vide svpra, p. 445, with the Exudates." ' Human Immime Serum," and p. 449, " Complement Fixation Tests TREATMENT OF GONORRHOEAL INFECTIONS BY VACCINES. 457 Case 76. — Male, aet. 21. Gonorihoeal arthritis. Effusion in left knee-joint. Arthritis of both temporo-mandibular joints, and many other joints. Intravenous vaccines, five injections of 10 million doses. Time. Serum Test. Condition. Before vaccines + + Patient quite crippled ; very emaciated. Forty-eight hours after first + + Temperature rose to 100° -4 ; no discomfort. vaccine. Five days after first vaccine + Before second vaccine + - ■> Forty-eight hours after second + + No reaction ; patient feels better joint vaccine. > aspirated. * Four days after second vaccine ... + + J Forty-eight hours after third No reaction. vaccine. Four days after third vaccine — All the joints are better. Forty-eight hours after fourth + + + Toxic pains ; patient can walk a little. vaccine. Five days after fourth vaccine ... + + + General improvement very marked. Forty-eight hours after fifth — Temperature rose to 100° ; toxic pains. vaccine. Two weeks after fifth vaccine Enormous improvement in joints and general health. * Vkle supra, p. 44.5, " Human Immune Serum," p. 449, " Complement Fixation Tests with the Exudates." Summary of Results. (a) The serum of normal persons, and of patients suffering from diseases other than gonorrhoea (including syphilis), gives no fixation of complement in the presence of the gonococcal antigen. (b) The serum of the majority of gonorrhoeal cases with metastatic lesions, such as arthritis, gives a positive reaction, generally of marked degi-ee. (c) The serum of a minority of such cases gives either a feeble or negative reaction. As a rule, however, even in such cases, a positive or feebly positive reaction occurs at some time or other. The injection of vaccines may markedly alter the serum reaction in the following ways : — {a) Vaccine injection in normal or non-gonorrhoeal individuals produces no change in the serum reaction, which remains negative. (6) Vaccine injection may convert a strong positive to a less marked or even negative reaction, of temporary duration. This temporary change may be 458 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF GONORRHOEA. considered as a " negative phase." A second injection is followed by a similar phenomenon of lesser degree. Subsequently the reaction may remain positive for some time, even though improvement {e.g., Case 75) occurs. On the other hand, the positive reaction which returns after the temporary change, may progressively diminish, and finally the reaction becomes negative, and still remains negative weeks later {e.g., Case 74). After complete cure, the reaction eventually becomes negative, and remains negative after a " provocative injection " of vaccine. (c) The doubtful or negative result may be altered after vaccine treatment. It may become positive. A second injection may produce further change in the reverse direction. Further injections may render it entirely negative. {d) There is, therefore, an analogy between these phenomena and the changes in the serum reaction in syphilis, following the injection of salvarsan.* Conclusions. 1. The complement fixation test in gonorrhoea! infections is a valuable aid to diagnosis, and can be used for regulating vaccine treatment. 2. If the disease is in the latent stage, and the body has need to form antibodies, the result of an injection of potent vaccine will be to stimulate their production. If antibodies are already present, the injection of vaccine, in sufficient amount, will temporarUy neutralise or inhibit the same. What actually happens cannot be absolutely proved, but my own opinion is, that the lipoid-globulin molecule is broken up. The period of inhibition corresponds with that of the negative phase, therefore there may be some connection between this phase and the hydrolysis of the lipoid-protein molecule. Let us look at this problem a little more closely. There is no doubt that the lipoid-globuUn molecule, in syphilis, is broken up by the first and, occasionally, by the second dose of salvarsan. This is more likely to occur in the late than in the early stages of the disease. The previously positive Wassermann reaction becomes negative, and the serum globulin is diminished. If the serum globulin is diminished, it might be expected that any concurrent disease from which the patient was suffering would, during this period, be aggravated. Clinically, such is the case, and many are the patients who, con- sidering themselves cured of gonorrhoea, have noticed a short return within 24 hours after the salvarsan injection. Several instances relating to other diseases could be given. If the patient develops a negative phase after a gonococcal vaccine, note how the symptoms are temporarily aggravated, and how often an attack of Herpes 'preputialis supervenes. TREATMENT OF GONORRHOEAL INFECTIONS BY VACCINES. 459 The reason why salvarsan should exert this action in a more jnonounced degree in late than in early cases — and, after all, the negative phase is more common in the chrorue than in the acute stages of the infection — is possibly owing to the fact that the older the specificity in the lipoid-globuliu molecule, the greater the number of fatty acid-groups it will have attached to it. The greater the number of fatty acid-groups, the less potent the therapeutic action of the molecule becomes, and the greater the ease with which it can be hydrolysed. The lipoid-globulin appears to be manufactured in the lymphocytes ; hence one would expect, since improvement follows further administration of salvarsan and a vaccine, that the number of circulating lymphocytes is increased. Such is found to be the case, and many clinicians will, no doubt, have observed a swelling of the lymphatic glands after a few doses of salvarsan and a vaccine have been given. This results in new lipoid-globulin molecules being formed ; in other words, fresh antibody ; hence the unprovemeut in the condition when the negative phase has passed. 3. The injection of a potent vaccine promotes a new artificial kind of immunity, more effectual than that already established in the infected individual. Of the three methods of vaccine treatment tried, the intravenous autolysed solution comes midway in its therapeutic action between an ordinary vaccine and a sensitised vaccine — both the latter given subcutaneously, or intramuscularly. The vaccine sensitised with a human antigonococcal serum is far superior to the vaccine sensitised with immune horse serum, and its action is most marked when given intravenously. 4. Vaccine treatment, provided it is only supplementary to the right local and general treatment, is in many cases necessary, before a cure can be obtained. As it is not always possible to get a sensitised vaccine, one must be satisfied with an ordinary vaccine, prepared according to the directions above given. The doses will vary according to the potency of the vaccine, so one generally has to feel one's way, if the vaccine is entirely a new one. I usually begin with 5^, and gradually increase the dose weekly, until the last dose ceases to produce any focal reaction. When this dose has been ascertained, I then give it once a month for the next six months. This procedure, which is not yet in general use, will ver}^ often prevent a case from relapsing. I also think it is wise, even in the acute cases, while the disease is hmited to the urethra, to prescribe vaccines, as they are certain to raise the patient's natural immunity. Before closing this chapter, there is just one other point concerning which a little speculation is justifiable. I refer to the theory of sensitisation. From other 460 THE BIOLOGY, CLINICAL ASPECT AND TREATMENT OF GONORRHOEA. statements made in this book, the reader will remember that antigen and antibody contain homologous stereo-chemical molecules, and that, when they meet, adsorption results. There is a limit to the adsorptive capacity of an antigen ; therefore, if the antigen has been charged, so to speak, with antibody, before it is injected, it will be seen that it cannot take up any more when it enters the host. When an ordinary antigen is injected, it fixes itself on to the already existing antibody, adsorption results, lipoid-globulin molecules are precipitated, and then hydrolysed. If the antigen is already charged beforehand, it cannot adsorb more antibody ; therefore, there is no negative phase. From this the assumption may hastily be made that the end result is the same in both cases, or that the therapeutic result of an ordinary vaccine is the same as that of a sensitised vaccine. The apparent difference in the clinical results might be explained by the absence of the negative phase, when a sensitised vaccine is used, and by the fact that very much larger doses may be given. I think there is still another factor at work, and that is the physical alteration which takes place in the antigen, when it has adsorbed its homologous molecule in the body. As I have made no adequate study of this physical alteration, and as the possible results might have a considerable influence upon some of our therapeutic agents, it would be as well to leave the subject here, and wait till more experiments have been undertaken. REFERENCES. 1 Gordon, 1912, " Quart. Journ. Med.," v, 509. 2 Klein, 1910, " Lancet," i, 1255. 3 McDonagh, 1912, " Brit. Med. Journ.," i, 1287. ^ Schwartz and M'Xeil, 1911, " Am. Journ. Med. Sc," cxli, 693. " league and Torrey, 1907, " Studies from Dept. of Path., Cornell Univ., N.Y.," vii ; and " Journ. Med. Research," Boston, 1907-8, x\ii, 223. ° Watabiki, 1910, "Journ. Infect. Diseases," vii, 159. ' Wright (1909), " Studies in Immunisation," London. * McDonagh and Klein (1913), " Journ. of Path, and Bact.," xvii, 599 9 Besredka (1902), " Ann. de I'Instit. Past.," xvi, 918. >» Besredka (1902), " Compt. rend, de I'Acad. des Sci.," cxxxiv, 1330. " Besredka (1910), " Bull, de I'Instit. Past.," viii, 241. CHAPTER XL. PHIMOSIS AND PARAPHIMOSIS. Phimosis. The word phimosis is derived from the Greek (pifio^, a band. Phimosis may be congenital or acquired. Only the acquired form need be discussed, because the only thing to say about the congenital form is, that the patient should be ciicumcised. Acquired phunosis is due to inflammation, and it may be caused by any venereal disease. There are, clinically, two kinds of phimosis, and if this point be borne in mind, it is usually possible to make a diagnosis of the underlying condition at sight. If a man with phunosis consults you, first notice if the prepuce is very red and swollen ; if so, then it is an acute inflammatory phimosis, and is probably caused by gonorrhoea, a soft sore, or Balanitis erosiva et gangraenosa. If the prepuce is red and swollen, the swelling is uniform, painful to the touch, and there is always a purulent discharge. A phimosis caused by Balanitis erosiva et gangraenosa is the most painful, then that caused by a soft sore, while a gonococcal phimosis is not, as a rule, very painful. If the j^repuce is not red, and is swollen in only one part, or is only red in that part which is swollen, and if the discharge is thin, you may be quite sure that the patient has a primary sore in the corona, and that that part of the foreskin which is the mo.st swollen marks its position. A syphilitic phimosis is generally painless. In the acute inflammatory phunosis, the foreskin should be slit up at once, but circumci.sion should not be done. In the, so to speak, non-inflammatory phimosis, i.e., the syphilitic phimosis, non-inflammatory, since the phimosis is really due to a diffuse sj-philitic lymphangitis of the prepuce, circumcision can be delayed until the lymphangitis has subsided somewhat under salvarsan. Cir- cumcision should be done later, so that mercurial ointment may be rubbed into the chancre. Another clinical point in the soft sore phimosis, is that, in several cases, there are some sores on the tip of the foreskin. When a phimosis is very red, shiny, and stony hard, the diagnosis of a malignant epithelioma should be considered. 462 subsidiary venereal diseases. Paraphimosis. Paraphimosis may occur mechanically, by a patient's retracting his foreskin and being unable to pull it forward again, but it is more often due to some inflammatory condition. There are two kinds of paraphimosis — ihe Paraphimosis interna and the Paraphimosis externa, the former being the rarer of the two. Paraphimosis externa can only occur if the limbus of the prepuce is particularly narrow. The limbus is formed by circular fibres of connective tissue in the fore part of the prepuce. If the limbus is narrow, it will naturally follow that retraction of the foreskin may be possible, but that the corona will make reposition difficult. This, then, leads to considerable swelling of the external lamella of the prepuce. Owing to the narrowness of the limbus, and to the fact that the inner lamella of the prepuce is turned in, it wUl follow that all the pus that was in the corona will now be in between the two lamellae of the foreskin. Therefore, unless the condition be relieved quickly, the increased inflammation will further aggravate the condition, so that sloughing of the foreskin may easily occur. Provided gangrene has not set in, attempts at reposition should be made. As the corona is the hindrance to natural reposition, the first thing to do is to reduce the size of the glans penis. Cold applications or tying round with indiaiubber will usually effect reduction ; then reposition becomes simple. As Paraphimosis interna is not so noticeable as Paraphimosis externa, most of the cases seek advice when it is too late. Under these circumstances, the best procedure is to cut the limbus, wash out all the discharge with hydrogen peroxide, and then keep the area as dry as possible, by using iodoform, isoform, or dermatol powder. Owing to the pent up pus between the two lamellae of the prepuce, a dorsal lymphangitis of the penis, and bilateral inguinal adenitis, with abscess formation in either condition, is a complication which often has to be feared. In the Paraphimosis externa, the limbus is usually wide enough, the condition being produced primarily by an oedema of the inner lamella of the prepuce. If a case of Paraphimosis externa be examined, it will be noted that a band usually exists only on the dorsum, and, according to its severity, on the lateral walls of the penis, posterior to the prepuce. The base is, as a rule, not constricted, but it is very oedematous. Unless the condition be quickly relieved, a fissure is very likely to occur in the dorsal constriction, and this is often the beginning of gangrene. In trying to replace the prepuce, the oedematous foreskin should be held with the fingers of both hands and pushed forwards over the glans, which should at the same time be pressed backwards with both thumbs. If there is a fissure already, or if there is a good chance of producing one, by prolonged inability at reposition, it is best to resort to another method. PHIMOSIS AND PARAPfflMOSIS. 463 The chief cause which prevents reposition is the oedema of the dorsal part of the foreskin ; therefore, if this can be reduced, replacing the foreskin is an easy matter. Therefore, a good plan is to press out the oedema, either backwards under the dorsal constriction or downwards into the preputial swelling underneath. If both these manoeuvres fail, it is best to employ the debridement method, or to remove the incarcerated portion totally. The former can be done, however fissured the dorsal constriction may be, and even if gangrene has set in. It is best performed by retracting the skin of the penis, and then dividing the dorsal constriction with a bistoury in the middle line. The incision should be from 1 to 1'5 cm. long, and the depth can be ascertained by the feel, as one knows at once when the fibres have been severed. Total removal should be performed only when there is no fissure, and when the area is moderately clean. The two oedematous preputial swellings are removed between two parallel incisions, and then the edges are sewn together. This operation produces a good cosmetic effect, as it obviates a chronic fibrous swelling, which often results from the oedema of the basal portion of the prepuce. 2g CHAPTER XLI. BALANITIS, CONDYLOMA ACUMINATUM, MOLLUSCUM CONTAGIOSUM, HERPES GENITALIS, GRANULOMA INGUINALE, INDXIRATIO PENIS PLASTICA AND PEDICULOSIS PUBIS. Balanitis. Simple balanitis. — Simple balanitis is a very common condition, and is one for which patients frequently seek advice. It is most common in patients with long foreskins. It often gives rise to considerable local irritation, and may in consequence be the cause of subsequent self abuse. The secretion may be even sufficient to give rise to a discharge, and this may, in its turn, set up a urethritis, or, more often, may cause a phimosis. On withdrawal of the foreskin, white or yellowish-white material will be seen, which can be brushed away easily, and which has a peculiar odour. This white material usually goes by the name of smegma, and is supposed to be secreted by special glands, which are called Tyson's glands. It is extremely doubtful whether such glands really exist. It is far more likely that it is merely the sodden and desquamating epithelium of the surface of the glans and the under .surface of the prepuce. In this sodden epithelium, all manner of organisms flourish ; urine collects in the corona glandis, and supplies the pabulum with moisture. The prodigious growiih of organisms soon gives rise to inflammation, and to the symptoms arising therefrom. Organisms which, under ordinary circumstances, are saprophytic, may become pathogenic, as such a con- dition can be conveyed to a woman, in whom it may set up vulvitis and urethritis. An analogous condition may occur in the female, and it commences around the clitoris. Cleanliness is at once the cure and the prevention. There can be no doubt that Moses was right in making circumcision compulsory, and it was doubtless his knowledge of the nmltitude of evils for which a foreskin may be responsible that led him to make the law, which only later developed a religious significance. Most of the Jewish laws were primarily preventive measures against disease. It is highly probable that pork was forbidden because of the prevalence of trichinosis in Palestine, and so on. Failing circumcision, the foreskin should BALANITIS. 465 be withdrawn daily, and the glans penis, sulciiw coronaiius, and the under surface of the prepuce should be well washed. Then the foreskin should not be replaced until the surfaces have been well dried. In acute cases of simple balanitis, a mild antiseptic lotion should be employed, and, after bathing the surfaces with it, an antiseptic powder should be used. Balanitis erosiva et circinata. — Was first described by Bataille and Berdal,* * in 1889. The lesion commences as a small circular greyish-white patch, which is merely the erosion of surface epithelium. As more epithelium becomes eroded, the surface of the lesion becomes red, moist, and shiny ; then all the lesions begin to coalesce. The desquamated epithehum collects in the sulcus coronarius, and quickly becomes transformed into pus, which has a charac- teristic odour. The discharge is infectious. The organisms which cause this condition appear to be able to flourish only under anaerobic conditions, since it occurs only in patients with foreskins, and, if the prepuce is withdrawn, the lesion does not advance. Hence the best treatment is to bathe the area with nascent oxygen, as may be done by employing hydrogen peroxide or perhydrol, and by leaving the wounds uncovered, exposed to the air. In severe cases in which the foreskin is tight, and the discharge is fairly abundant, the prepuce itself may become eroded, and an inflammatory oedema of the prepuce, leading to almost complete phimosis, may ensue. In such cases there may be a dorsal lymphangitis of the penis, with marked pain and swelling of the inguinal lymphatic glands ; but, oddly enough, the lymphatic glands never suppurate. Occasionally the erosions may become ulcers, and this transformation is most likely to be met with in the sulcus coronarius, and in the neighbourhood of the froenum. The ulcers are deep, the edges are regular, and the base is covered with a diphtheritic-like membrane which is adherent. In every case in which ulcers form, there is always a bad phimosis. The ulcers may sometimes be found on the under surface of the prepuce, and, at first sight, resemble soft sores. The ulcers in question are more or less funnel-shaped, and the edges are smooth and regular — not irregular like the edges of soft sores. In a few cases, the ulcers may extend so rapidly as to perforate the prepuce, and even the whole prepuce may be destroyed. In most of the cases, the local pain is more or less severe, and the patient usually has a rise of temperature. The Balanitis gangrenosa is really the same condition as the Balanitis erosiva, with the difference that, in the former, the ulceration is not preceded by erosions. In Balanitis gangrenosa, the discharge is, as a rule, profuse, and often blood-stained, 2g2 466 SUBSIDIARY VENEREAL DISEASES. the pain is very acute, and the ulcers are, as the name implies, gangrenous, i.e., the ulcers are surrounded by a dusky-red zone, the edges are raised and acutely inflamed, and the base is covered with a yellow, brown, greenish, or ahnost black diphtheritic membrane which cannot be removed. The organisms responsible for this condition may also be the cause of a soft sore or chancre becoming gangrenous. The gangrene may become so extensive as to destroy the whole of the penis, and such a state of affairs is often brought about by the use of strong disinfectants, such as carbolic acid and potassium permanganate. Almost any lotion other than the one specific, hydrogen peroxide, may aggravate the condition. I have seen fatal results in two cases in which carbolic acid had been used. In both, the gangrene extended so rapidly as to involve the whole of the scrotum, and it spread up over the abdominal wall before any measure could be taken to check it. An analogous condition to Balanitis erosiva et gangrenosa cannot be reproduced elsewhere, unless the skin at the site of inoculation has been badly injured and in part rendered necrotic. Therefore, strictly sjieakiiag. Balanitis gangrenosa is not autoinoculable, and this point serves to distinguish it from the soft sore infection. Balanitis erosiva et gangrenosa usually results from coitus, and sets in about 2 to 14 days afterwards. The condition is due to two organisms existing in a state of symbiosis. One is a Gram positive vibrio-shaped organism which varies from 2-3 "25 fi in length; one end is often thicker than the other, and the organism is usually curved. The other organism is a Gram negative spirochaeta. The spirochaeta varies in length from 4-16 /(, it is much thinner than the vibrio, it stains violet with Giemsa, and the coils are very irregular ; in fact, there may be only one or two. Occasionally, quite regularly coiled spirochaetae are to be seen, but the coils are large, and never more than five in number. Both the spirochaeta and the vibrio are actively motile, and are indistinguishable from the organisms which cause Vincent's angina. Clinically, Balanitis erosiva et gangrenosa resembles the lesions of Vincent's angina, and both conditions are readily cured by salvarsan. In my experience, the condition is much more common on the Continent than in England. In any inflammation of a mucous membrane, vibrio-shaped organisms and spirochaetae can be demonstrated, and, owing to the numerous folds and crypts which exist in the valva, vagina, and tonsil, these organisms can flourish anaerobically. A woman need not necessarily have an acute vulvitis or vaginitis to be infectious ; the mere implantation of a few of these organisms on a glans penis which is covered with a tight foreskin will be quite sufficient for the few CONDYLOMA ACUMINATUM. -167 implanted to flourish ou tlie desquamated epithelium, and to reach the corona, where the most favourable anaerobic conditions prevail. I should think it is highly probable that a man with a tight foreskin may even develop this condition Avithout the infection coming from the female — the starting point being the irritation and slight inflammation caused by the coitus. In the se^'ere cases, the question of operation often arises. Let me warn the reader that, with the exception of shtting up a tight foreskin, operative interference may often do more harm than good. The main object must be to keep the gan- grenous parts as dry as possible, and therefore after bathing them with perhydrol 1 in 20, some powder should be applied, and the part exposed to the air, or covered up as hghtly as possible. Equal parts of dermatol and magnesium carbonate (levis) form an efiicient dusting powder. Magnesium carbonate is used because of its power of absorbing moisture. Magnesium perhydrol, or, as it is sometimes called, pergenol, is a useful powder because it liberates oxygen. In closing my remarks on balanitis, I should like to draw attention to one or two other points, which, although not venereal, may easily be mistaken for such. Unless the diagnosis is absolutely obvious, it is wise in cases of balanitis to test the urine, as balanitis is not an uncommon complication of certain general disorders — for instance, diabetes. Diffuse lymphogenic syphilitic infiltration of the glans penis may be mistaken for a simple balanitis, but it may readily be distinguished by the violaceous tint of the organ. A syphilitic balanitis may be confounded with Lichen 'planus or psoriasis, two diseases which not only not uncommonly affect the glans penis, but also are occasionally limited to this organ. Erythema multiforme may cause a balanitis very difScult to distinguish from a case of Balanitis erosiva, and, in gonorrhoea, a circinate form of balanitis is not at all uncommon. The gonococcal balanitis may or may not be a specific balanitis. If specific, it is due to the gonotoxine ; if not, it is merely produced by the irritative discharge. Condyloma Acuminatum. The terms venereal warts and gonococcal warts are often applied to this condition. The lesions do not differ from ordinary warts, except that they spread and grow more rapidly, and this is simply due to the moisture and warmth of the regions in which they occur. A wart is nothing more nor less than a hypertrophy of epithelium surmounting an inflamed area of corium, the blood supply of which 468 SUBSIDIARY VENEREAL DISEASES. is consideiably increased. Condylomata acuminata may be caused hy any infective agent, except perhaps the gouococcus. The reason why venereal warts are more common in patients who are or have been suffering from gonorrhoea, is simply due to the fact that owing to the discharge caused thereby, saprojihytic organisms can flourish, and it is these saprophytic bacteria which are responsible. Moisture is absolutely necessary for the gi'owth of Condylomata acuminata, and it is owing to this fact that they may sometimes be met with in the umbilicus and the axillae, and the avoidance of moisture is the main factor to be borne in mind when treatment is considered. If the area is kejit absolutely dry, the warts may disappear .spontaneously. If there are only one or two, they are best removed with a Yolkmann's spoon, after being frozen with ethyl chloride, and the base should then be cauterised with silver nitrate stick to stop the bleeding. Condylomata in the urethra must always be removed, as it is impossible to keep the urethra dry. Large masses are best bathed twice a day with either a 4 per cent, solution of formahn or a 2 per cent, solution of lactic acid, then dried, and the dermatol magnesium carbonate powder dusted on. MoLLUSCUM CONTAGIOSUM. Under this name we understand papular lesions which vary from the size of a pin's head to that of a pea. The lesions are usually discrete, non-inflammatory, unless secondarily infected ; they are whitish and waxen in appearance ; they are depressed in the centre, in which there is a httle plug, capable of being pressed out. The matter, which can be pressed out, can be examined without staining under the microscope, and the typical even sized and shaped degenerated epithehal cells, characteristic of the condition, may be recognised. In men. they are most commonly found on the skin of the penis and scrotum ; in women, on the labia ; and in children, on the face. Occasionally several lesions may coalesce and cover quite a wide area with a whitish waxen mass, which is raised above the surface of the skin, is flat on the surface, and has little or no inflammation surrounding it. Such a condition is rncst commonly seen somewhere on the trunk. Histologically, Molluscum contagiosum gives one of the prettiest and most characteristic of pictures, and it is only necessary to be seen once to be never forgotten, and to see it without knowing it is one of the greatest puzzles. The epithelial cells are the cells aSected ; they increase in size, the nucleus swells and disappears, the nucleoli first increase in number and then vanish, so that the cell, which retains its outline almost to the end, is filled with homogeneous MOLLUSCXnH CONTAGIOSUM AND HERPES GENITALIS. 460 material or debris. The epithelial cells exhibit all the changes which are to be met with in the hydrolysis of the protein, down to and including the amino-acid stage, according, naturally, to the extent to which they have degenerated. The different analytic products of protein have different actions ; some are basic, others are acidic, some have a reducing action, others have none, hence the reason why, with almost any dye that is used, the picture of the epithelial cells reminds one of Joseph's coat of many colours. It is highly probable that the cause of Molluscum, contagiosum is an ultra- microscopic organism, but little is known about it at present. I have seen similar bodies to those described by Borrel^ and Lipschiitz,^ ^ but it is practically impossible to distinguish them from the debris in the cells, and no reliance can be placed upon the way they stain, owing to the fact that some of the amino-acids present stain in the .same way. The best treatment is to remove the lesions with a sharp spoon, and to cauterise the base with silver nitrate. If there are several, and if many have coalesced, it is best to cover them with a .strong salicylic acid plaster. Unna's salicylic acid and creosote, or salicylic acid and soap plastermulls are very efficacious. Herpes Genitalis. Although most common in patients who have suffered from a venereal disease, especially from gonorrhoea, it may occur in thoSe who have not. The clinical course of the condition is nearly always unvarying. The patient first complains of itching, examines the region, and finds a group of tiny discrete vesicles on an inflamed area. When the vesicles are well pronounced, as a rule the subjective symptoms vanish, and the condition may spontaneou.sly disappear, to recur and recur, at varying intervals, later. On the other hand, the vesicles may become pustules, and these in turn become ulcers. Several of the lesions may coalesce, and the loss of surface caused by them may have an irregular outline, and may closely simulate a soft sore. Many patients periodically have local pain and itching, and all that is to be seen is a red urticarial-like lesion, which vanishes before any vesicles appear. Some women have an attack of herpes every time that they are unwell. In men, the most common positions to find herpes are on the skin of the penis, on the under surface of the prepuce, aird on the glans. In women, herpes is most frequently seen on both the inner and outer surfaces of the labia majora and minora. i 470 SUBSIDIARY VENEREAL DISEASES. Herpes genitalis is frequently accompanied by aphthoiis ulcers, which are very apt to appear on a mucous membrane where there is any irritation ; indeed the two conditions are probably identical. Irritation is the prime cause of Herpes genitalis, and the toxine which gives rise to the irritation no doubt affects the sensory nerves peripherally in some way or other. Once the latter are affected, the original cause of the irritation need not necessarily be repeated, as the patient being below par is sufficient to cause a recurrence, and even a dream often starts it ; so, too, will an injection of a gonococcal vaccine, or of salvarsan. The recurrences will often occur in the same area, and the site of a chancre is not at all an uncommon spot. Herpes genitalis is frequently a very troublesome condition, as it may cause sexual neurasthenia (vide Chapter XLII). Every case of herpes, in which it is the patient's initial attack, must be watched, as it is sometimes the premonitory sign of a chancre. Be herpes destined to be followed by a chancre or not, under no circumstance whatever must any irritative application be used. Any form of irritation only aggravates the condition, and it may set up an induration which is often mistaken by the unw"ary for a syphilitic lesion. Herpes is certainly more common in Gentiles than in Jews, so we have again another indication for circumcision. The only treatment necessary is an antiseptic evaporating lotion, after the application of which a non-irritating dusting powder should be used. Granuloma Inguinale. This is a tropical disease, and it is found most frequently in British Guiana, West Africa, South China and Australia. It is occasionally seen in Ceylon, the Malay Peninsula, and Central Africa. It is highly probable that the condition is to be met with in every tropical country. The Italians came across it in Tripoli.^ As the disease more commonly affects women than men, it is often called Granuloma pudendi. In the female, the labia majora and vagina are the parts first affected, then the granulomatous masses spread to the mons veneris, to the genito-crural folds, and backwards to the anus, which they not infrequently surround . In the male, the groins, prepuce, glans penis, and the anus are usually involved. The penis is affected first of all. In both sexes, the inguinal lymphatic glands are enlarged. The granulomatous masses are often accompanied by ulcers, and it is on this account that the condition is sometimes confused with the Ulcus molle serpiginosum. The growth and rate of spread is extremely slow ; often a matter of several years. GRANXJLOMA INGUINALE. 471 The disease has a natural tendency to cure itself, but the scar tissue formed is so dense, that the cicatrisation may be very disfiguring. The widest diversity of opinion prevails as to the nature of the condition. The disease is certainly infectious and auto-inoculable, and no ordinary remedial treatment appears to be of much avail, although the cases described in Tripoli' healed up with salvarsan are the only instances of their kind. The best method of curing the disease is by surgical removal. Dr. Wise has WTitten to me several tunes from British Guiana, and he has informed me that since he has made it a rule to operate upon every case, the disease is becoming rare in the country. MacLeod^" reports a case which he cured with X-rays. Since the discovery of the Spirochaeta pallida, in nearly all diseases the aetiology of which was unknown, spirachaetae have been found, and these have often been held to be the specific organism by the observer. Granuloma pudendi is one of the many instances. The extreme chronicity of the lesion, and the fact that salvarsan in the hands of most observers has failed to influence the condition, suffices to rule out a spirochaeta as being the causative organism. Wise,^^ in 1906, found some curious bodies to which he refers as follows : — " There are present masses of small bodies which seem to represent some phase in the life history of a protozoal organism. Stained by either Leishmann's or Giemsa's stain, a thin capsule is apparent surrounding a clear unstained space ; in the middle of the space is a chromatin staining curved rod, thin in the middle and thicker club-shaped at each end. These bodies appear massed together in numbers varying from 2 to 25, and are often found within the leucocytic cells present." Donovan,^^ about the same time, described some intracellular bodies which, he said, looked like gigantic short bacilli with rounded ends. In 1910, Carter^^ described a protozoal parasite which he found intracellularly situated. He says : " The cytoplasm of the infected cells contains from 15 to 20 protozoal parasites arranged roughly in groups round a central homogeneous mass simulating the zooglia mass of Leishmania in cultivation." Carter regards these bodies as the gregariniform stages of a herpetomonas or crithidium. Steele, in Australia, in 1912, observed the same bodies in large mononuclear leucocytes. To this observer they resembled enlarged coccobacilli, sometimes kidney-shaped, not unlike huge gonococci. Wise,^^ in a later communication, in examining 62 cases, found these bodies in 90 per cent, of them. Many specimens he examined in vivo with polyclirome methylene blue, and what he found is best described in his own words : — " Careful observation reveals in the smallest of these bodies one or two nuclear 472 SUBSIDIARY VENEREAL DISEASES. points which later become 4, 8, or 12 nuclear points ; finally in the larger bodies 12 to 20 nuclear masses are readily detected. If watched further, the proto- plasm will be seen to divide around these nuclear points and form a number of spores. " These spores when massed in this way are very noticeable and readily seen. They are sometimes present in hundreds all over the specimens. They are very beautiful objects, in some ways resembling the rosettes of malarial parasites (the pigment, of course, being absent). The size of each spore is about 2/1000 mm., they are bronze coloured, slightly pear shaped, being pointed towards the centre of the rosette and arranged regularly around the centre. Probably the real position of these sporulating bodies is within mononuclear cells, but in the scraping during preparation for observation, many of the sporulating bodies are forced outside the cells and broken, so that scattered fours, eights and twelves of these spores may be found extracellularly situated. It is easy to find six or seven of these sporulating rosettes in a single bloated, tensely-filled mononuclear cell. The further stages of existence as noted under the microscope, show that the spores remain in the rosette formation, but finally the cell bursts, or some surrounding invisible envelope bvirsts, and the spores are shot out into the surrounding plasma. These are non- motile, and remain wherever spread. Finally the slow dissolution of death steals across their existence, the nucleus of the spore takes on a curved-rod shape slightl}- thicker at each end, the protoplasm fades away into a colourless indistinct envelope. The appearance then is exactly that which I described in 1906 as a thin capsule surroTinding a clear unstained space in the middle of which is a chromatin-stained curved rod, thin in the middle and thicker club-shaped at each end. It would thus appear that the protozoa-like bodies seen in the dried stained films are the dead distorted remnants of a singularly beautiful rosette-like protozoal sporulation. In preserving material from Granuloma pudendi, death of this parasite and the same distorting processes occur. As by the disruption of the protoplasm the sole colourable matter left is the nuclear particles, the detection of these bodies in sections of preserved material is rendered very difficult, and rests largely on the recognition of the nuclear arrangement in enlarged mononuclear cells. " My own experience shows that this is difficult, and it is only in well and specially preserved material, stained carefully, that search is rewarded. Carter found the bodies with Giemsa staining and with eosin and methylene blue methods. I have repeated his methods and have been able to confirm his results. I obtain better and clearer pictures with the Borrel staining, viz., rosanilin hydrochloride followed by indigo carmin and picric acid. I consider that the peculiar bodies described in smears from Granuloma fude^xdi by many observers, and occasionally in sections. Plate 42. Section of Oranvloma inguinale stained with pyroiiin and methyl green. A. Intracellular bacilloid stage. A few bodies like bacilli are to lie seen outside the cell, some of which are diplococcal in form. B. A further stage of the preceding, in which the diplococcal bodies have increased in size. C. A still further stage, in which toui' bodies have been formed, every one of which is ready to develop into two and then into four distinct bodies. D. A further stage of the preceding. One body has escaped outside (K), and the three remaining are becoming separated into three anfl more bodies. E. An escaped body from (D). F. An escaped body from (C). G. An embryo lymphocyte. 'LATE 42. Facing p. -172. finallv in the !a~2f7 cells, but in the sfraping dHri ' I oi» illiojiil oJil aeibodi wai A .egfila InoUioBd ibLjUso^iJiiI ./ .anoi fir ljiioooblqi6'9'i.B rtoJifW'Ib'oHfo'si .Ilso" 4rlit- abiyilo iaida Bsibocf Jido3oo;- i:' ■ ■■ ,• .asi«jaib33«3ionc.,9Y£ffj,. ,,,jvel( ■mo yiovo .bauno^ upail evad soibod iiio\ doiil'' iil .oiicjg lodtini iJit« A .0 tjiiii^il iiKit oim nsdi' bae ow* oirn for ei doidw lo ■■'■'■■'■'■• '* •■ ■ •' ■ • .gaifcod .(H) obiaJiiQ toq.EOB» B6d>yi)6d aaO' ■.^(nibso^iq mii io e^eis ledh'^ A.dr it olii^ . Ita^jiqaa gaunqoed, 9T« ^ giiirii^insi aavli adi bar. , .89ibod 8iom (G)' caoil'i^bocf baq'fiogs ah '.ST .(0) moii 7bod fesqkoWft/t !;V .3lY^90di(fnyl ovidrrrainA iO! l*^-'lrV"i^"'^ Plate 42. GRANULOMA INGUINALE. 473 more particular!)' by Carter, are really the distorted spores of the asexual cycle of a protozoal parasite. " The nature aud exact zoological position of the parasite remains the subject of further examination. I have found no evidence of a crithidial or herpetomonad origin." Wise then goes on to note a resemblance of these bodies to those which I had discovered as being the phases of the life-cycle of the organism of syphilis. Wise very kindly sent me some material, and as I have made full use of it, it would be as well to describe what I found. Of course, I have been unable to examine tissue in vivo and have, therefore, had to rely upon fixed specimens, and these I have submitted to the same micro-chemical tests as those which I employed for the study of the Leucocytozoon st/philidis. The bodies about to be described are found both intracellularly and extracellularly. The former are parasitic upon the protoplasm of the large mononuclears, bulging the protoplasm and pushing the nucleus aside, as is seen in the intracellular stages of the Leucocytozoon syphilidis. As it is impossible, from fixed material alone, to work out a life history, I can only describe the different phases which I have seen (Plate 42). Intracellular bodies. — («) In the protoplasm of a large mononuclear leucocyte, tiny punctate bodies are seen, and several bodies which look like bacilli. Most of the latter seem to occur in pairs, each lying parallel to the other. All variations in size, between the coccal-like bodies and the diplobacilli, are to be met with, so that one is tempted to suggest that the latter develop from the former. (6) Other mononuclear leucocytes contain one or more of these diplobacilli-like bodies. In this case the diplobacilli are very much bigger, and they appear to have a capsule. (c) These diplobacilli-like bodies increase and increase in size, at the expense of the protoplasm of the leucocyte, until a three or four-lobed body is to be seen. These latter are nuclear structures, lying in their own protoplasm, which exists in what looks like an empty sack. The empty sack is the remains of the protoplasm of the leucocyte. The nuclear bodies are either circular, horse-shoe, or ovoid in shape, and sometimes they give the appearance of each unit's consisting of more than one part. The bacilloid bodies are probably the same as those described by Siebert^- and Flu." Extracellular bodies. — These are obviously the same as, or parts of, the intra- cellular bodies. These bodies are undoubtedly parasitic : they are rich in nucleic acid, and the nuclei are surrounded by a resistant Hpoid-globulin envelope. They give 474 SUBSIDIARY VENEREAL DISEASES. exactly the same micro-chemical tests as the phases of the Leucocytozoon syphilidis : they are, moreover, optically active, and very strongly pyroninophile. It is highly probable that they are protozoal in nature, and possibly represent the asexual stage of an unknown coccidium. The degree of resistance of the Upoid- globuhn envelope to reagents, corresponds with that of the asexual phases of the syphilitic parasite, and is less than that of the gametal forms. That the lesion does not usually clear up under salvarsan, is not against a protozoal aetiology, since, as the reader will remember, I showed that when the Leucocytozoon syphilidis developed aberrantly, salvarsan did not cure the lesions produced by it. Induratio Penis Plastica. Induratio penis plastica, or, as it is sometimes called, van Buren's disease, although not a venereal disease, usually comes under the observation of venereal and genito-urinary specialists. Therefore, I feel that I ought to devote some space to it. Induratio penis plastica is a disease of unknown origin, and it appears to be independent of any local trouble. It begins as a very gradual aud painless thickening of the tunica albuglnea of the corpora cavernosa. It may occasionally begin in the septum, between the two corpora cavernosa, but, in either case, it is almost invariably on the dorsum of the penis that the process takes place. The condition is called van Buren's^' disease, after an observer of that name. He called attention to the disease in America, in 1874, but it had been well known in Great Britain and on the Continent for several years previously.^^ ^* '" ^^ Induratio jyenis plastica is not a cavernitis, and, therefore, it must not be confused with those hard nodules resulting from a cavernitis of gonococcal origin. S3rphilis, trauma, and, very rarely, leucaemia, may give rise to a dense cavernitis, but it has nothing to do with the diseases mentioned, and it may be stated here and now, that Induratio penis plastica is never of venereal origin, nor is it secondary to any local lesion. Generally speaking, the aetiology is quite unknown, but in a few cases the condition is obviously a symptom of a known and general disease or diathesis. A large number of the cases definitely suffer from gout and rheumatism, others have sugar in the urine, and, in nearly all, the patient is over forty years of age. One of the most extraordinary points in the disease is the fact that the patient may also be suffering from a Dupu}i;ren's contraction, and, if he is not suffering from it himself, a male relation of his often is a sufferer. The association with Dupuytren's contraction is so frequent, that it certainly looks as if Induratio penis 'plastica was due to what we loosely call a uric acid diathesis or arthritism. INDURATIO PENIS PLASTICA. 475 Assuming that it is a symptom of arthritism, the question naturally arises as to why the penis in the first place is involved, and, second, why only a special portion of the connective tissue is affected. One is tempted to invoke the aid of atavism in order to find a solution, and it will be remembered that the so-called septum pectiniforme, i.e., the septum between the two corpora cavernosa, is ossified in many mammals. Many observers look upon Induratio penis plastica as being merely the extension of a localised arteriosclerotic process. Owing to the peculiar family history which one gets in nearly all cases, history of the same condition, of Dupuytren's contraction, or of gout, it looks very much as if the disposition is embryonic, but what is the cause of the disposition must at present remain a mystery. The lesion is situated on the dorsum of the penis, by the symphysis. In its early stage, it feels like a nodule ; then this spreads superficially, i.e., lengthwise and anteriorly, until it becomes ribbon-shaped. The ribbon is thickest in the centre, because of the implication of the septum pectiniforme, and its edges are usually thin. It does not become attached to the skin above. The ribbon, though usually flat on the surface, may occasionally be uneven, owing to there being denser masses of fibrous tissue in some parts than in others. The densest part of the ribbon is the end by the symphysis, where the growth starts. As a rule, the patient is unaware of his condition until he finds that the penis has a peculiar shape when erected. The kinking caused may prevent sexual connection, and, very often, from the start, coitus is painful, especially during the act of ejaculation, owing to the swelling causing a mechanical narrowing of the urethra. The act of micturition is never interfered with. There is nothing characteristic in the pathological anatomy of the induration. The induration is composed of fibrous tissue, and the vessels in it do not show any morbid changes, hence the view, that Induratio penis plastica is only a sign of a general arteriosclerosis, cannot be held. Occasionally, typical bone cells may be found in the tissue. Treatment is, unfortunately, almost hopeless. Some observers state that they have had success with the various methods which have, from time to time, been advocated, but most of these I have tried religiously on five patients, and all without success. Surgical removal is almost invariably followed by a recurrence soon after the wound has healed, and there is often a risk of making the last state worse than the first. Other local measures, such as massage, electric treatment, and ionisation are useless. 476 SUBSIDIARY VENEREAL DISEASES. Some improveiueiit appears to have followed vigorous local inunction. Shillitoe tells me of a case which he benefited with unguentum iodex. Iodides internally appear to be given by all observers, and there is one drug which is specially in favour, namely, tiodine, of which 3 to 6 pills are to be taken daily. Tiodine is an ethyliodide compound of thiosinamine. Intramuscular injections of thiosinamine and fibrolysin, if the manufacturer's reports are correct, should certainly be prescribed. Personally, I have had no success with these drugs, and on two occasions I have observed severe toxic symptoms to supervene. Fibrolysin is merely a sodium salicylate compoimd of thiosinamine. Pediculosis Pubis. The insect, whose chief haunt is the pubic hair, is often called the crab louse, or Phthirius inguinalis ; the fii'st word of which is merely the Greek word for a louse. The Pediculus pubis is much broader and flatter in proportion than the other pedicuh — indeed its body is more or less square shaped. The male is about O'6-l "0 mm. in length, and the female 1 "1-1 '4 mm. The terminal segment of the abdomen is rounded m the male and notched in the female. The ova are about 10 to 1.5 in number, they are fixed to the hair by a chitinous substance, they hatch out in a week, and the young are sexually mature in about a fortnight. The pediculi first affect the pubic hair from which they spread up the lateral walls of the abdomen and thorax to the axillae ; they may affect the whiskers and beard, and in children they may be found only in the eyelashes and eyebrows. The scalp is very rarely affected, but the lanugo hairs on the body may be, in which case the most common sites are the sternal region, the sacral region, and the thighs and legs. As the pediculus is small, Ues flat on the skin and looks Uke a little brown spot when casually noticed, it is usually mistaken for a small mole, hence its wide dis- tribution is not generally recognised. As a rule, the pediculus causes itching, but the pruritus is by no means constant. If the itching is intense, a pyogenic dermatitis usually results from the continued scratching. Although it is only in the minority of cases that the blue spots are seen, the so-called Maculae coeruleae are absolutely pathognomonic of the condition. The Maculae coeruleae are blue, or rather steel-grey spots, which appear to be slightly depressed ; they vary from the size of a pin's head to that of a sixpenny piece, and they may be circular or irregular in outline. The lesions are, as a rule, grouped, and are generally to be found on the antero-lateral walls of the abdomen and the sides of the thorax, or in other words, along the com-se of their journey from the pubis to the axillae. PEDICULOSIS PUBIS. 477 The Maculae coeruleae disappear in a week or two after the destruction of the pediculi. They are merely stains in the skin, and the connection between them and Phthirius inguinalis was first noticed by Mourson.- Duguet,^ by rubbing into the skin an extract of the pedicuU, was able to produce the lesions. Oppenheim^ demonstrated a pigment in the bodies of the pediculi, and he considers that the blue spots are produced by a bite from the insect. The bite results in an excretion of this coloiu'ing matter, this forms a compound with the haemoglobin, which results in the appearance of the blue spots. The lice themselves are easy to kill, but the ova are more difficult to exter- minate. The pubis should not be shaved, as the discomfort following the growth of the new hair is out of all proportion to the benefit to be derived from such a measure. The best method of treatment is to spray the affected jjarts with 96 per cent, alcohol, and then to rub in the imguentum hydrarcj. ammnn. or the plain unguentum hydrarg. of the British Pharmacopeia. A peculiarity of this form of phthiriasis is, that some individuals are much more prone to be affected than others, and no prophylactic measures appear to save them. Hospital students sometimes get an attack whenever they return to hospital after being away for some time. I know of one case of a medical student who was obliged to give up his work, because, whenever he was at hospital, he used to get these lice all over his body — even constant shaving of the pubis and axillae did not save him. ' Duguet (1880), " Gaz. des hopit.," liii, 362. - Mourson (1878), " Annates de Derm, et Syph.," i.x. 198. ' Oppenheim (1901), "' Arohiv. f. Derm. u. Syph.," Ivii, 235. ^ Bataille et Berdal (1889), " Compt.-rend de la Soc. de Biol.," sli, 689. 5 Berdal (1897). " Traits des Malades Ven." Paris. « Borrel (1904), " Compt.-rend. de la Soc. de Biol.," Ivii, 642. ' Lipschiitz (1907), " Wien. klin. Woch.," xx, 253. « Lipschiitz (1908), " Zentralblatt f. Bakteriol.," xlvi (orig.), 609. ' Sabella (1913), " Giom. Ital. d. Malattie ven. c d. Pelle," liv, 306. i» MacLeod (1913), " Brit. Journ. of Dennat.," xxv, 66. " Wise (1914), " Brit. Guiana Med. Annual." Garden City Press, Letchworth. ■■- Siebert (1908), " Archiv f. Schifis- u. Tropenhyg.," xii, 291. " Flu (1911), " Archiv f. SchilTs- u. Tropenhyg." (Beiheft 9), xv. 481. '1 Donovan (1905), " Ind. Med. Gaz.," xl, 414. '5 Carter (1910), "Lancet," i, 1128. "= Wise (1906), " Brit. Med. Journ.," i, 1274. " van Buren and Keyes (1874), " Xew York Med. Journ.," xix, 390. '* Cullerier (1866), " Maladies Veneriennes," p. 72. " Fiirster (1863), " Handb. d. spez. path. Anatomic," 2 Aufl., s. 372. Leipzig. -■'' Kirby (1849), "Dublin Med. Press," xxii, 210. -' MacClellan (1828), " Journ. univ. des scienc. nied.," xlix, 340. CHAPTER XLII. SEXUAL NEURASTHENIA. There are three kinds of sexual neurasthenia : (1) the form that occurs in patients who have never had a sexual disease ; (2) the form that occurs in patients who have had gonorrhoea ; (3) the form that occurs in patients who have had sj^hilis. The fornr of sexual neurasthenia which is sometimes met with in patients who are continually suffering from recurrences of Herpes genitalis, is usually the same as that form which follows gonorrhoea. Herpes genitalis cannot strictly be called a sexual disease, in the light in which we regard gonorrhoea and syphilis, but as most of the cases have had gonorrhoea, it is always wise thoroughly to examine every neurasthenic who complains of frequent attacks of Herpes genitalis, so as to see if he has a chronic prostatis or spermatocystitis. Patients who suffer from sexual neurasthenia, but who have never had a sexual disease, are, as a rule, patients particularly deficient in intellect or effeminate, or those who have especially given way to self-abuse in their early youth. Such patients either complain of constant nocturnal emissions, or that they cannot perform the sexual act. Those who complain of the former, are generally men between 20 and 30 years of age, men who have to work hard in a stuffy office, who can get but little exercise, and who have their meals irregularly, and not- good ones at that. They come home brain-fagged but not bodily fagged, and, having had little or no exercise, they feel the cold very much, with the result that they load their beds with heaps of clothes. A too warm bed is a very frequent cause of nocturn&,l emissions. These patients will not infrequently tell you that they suffer from nocturnal emissions much more frequently when they lie on their backs than on their sides, and when the head is not well raised above the rest of the body. These patients are almost invariably very constipated, and not infirequently they have a varicocele. A great deal can be done by hygienic treatment for this class of case. If the patient has a varicocele, he should wear a suspensory bandage, the bowels should be piit in order, meals should be taken at regular intervals, and SEXUAL NEURASTHENIA. 479 a carbohydrate diet should be avoided. A little red wine is beneficial, but malt liquors should not be taken. Tonics containing strychnine, iron, arsenic, and phosphoric acid shoidd be prescribed. The patient should be advised to take a certain amount of exercise every day ; he should not go to bed for three or four hours after his dinner, nor have a nightcap of whisky and soda, nor have too many clothes on his bed ; he should have a pillow and a bolster, or two pillows, and his wndows should be wde open, winter and summer alike. A great deal can be done by an occasional talk with the patient, and it is a good plan to urge him to take up a hobby, and, in all cases, the literature he reads should be considered by the physician in charge. Even medical men are inclined to ridicule the condition. Those who do, little know what a serious condition it is; it is a disease, and should be regarded as such. There can be little doubt that there is a lesion somewhere which we are not advanced enough to detect, but the fact that it is hidden does not warrant us in assuming that there is nothing wrong. I mention this particidarly, because the sweating and mode of living of a large proportion of the population, in big cities, is very conducive to this form of sexual neurasthenia. The disease is undoubtedly on the increase, the " World War " is certain to aggravate it, and those who are accustomed to see cases know well what havoc it can play with a man's life. Those patients who complain that they cannot perform the sexual act, if they have had no venereal disease, are generally men who may be said to have passed the sexual period, or men who have an enlarged prostate, or men who have lived in tropical climates. Other causes are alcohol, and more or less sudden adiposity. In spite of the literature, and of the manifold ''tips" which are widely circulated in all Continental cities, there is no cure whatever for this condition. Aphrodisiacs, such as damiana, muiracethin, yohimbin, etc., and the various forms of electrical treatment and appliances which are advocated, are useless. It is the duty of the physician to explain to the patient that the condition is a physiological one, and that he must make the best of what, perhaps, may be to the patient a bad job. I had one very interesting case, in which a man, aged 39, consulted me re the question of marriage. For the last two years he had been unable to have sexual connection, as he could not get an erection. Three years ago, the patient had a bad attack of blackwater fever in the Gold Coast, and ever since his convalescence he had been gradually putting on weight, so that he w^eighed, when I first saw him, 19 stone, his previous weight having been only 12 stone. In spite of reducing his weight somewhat with careful exercise, massage, and the administration of thyroid extract, the patient has never been able to get an erection. Since then I have seen other cases of adiposity, which were accompanied by a loss of sexual function. 2h 480 SEXUAL NEURASTHENIA. If the patient has had syphilis, and is on the right side of 45, a loss of sexual function generally signifies that he has a degenerative myelitis. As in many cases of degenerative myelitis there is no history of syphilis, it is always wise to bear this trouble in mind, if a patient seeks advice for loss of sexual power. Another very common cause of sexual neurasthenia is coitus intenuptus, a continued practice of which may even lead to dementia. The gonorrhoeal form of sexual neurasthenia is quite different from the syphilitic form. In the former, the patient usually has a gonococcal lesion, and the neuras- thenia is doubtless a toxic manifestation of the disease. In the latter, the patient is either cured of his syphilis, or he has never had syphilis, but imagines that he has had it. Putting aside for a moment the neurasthenia which patients are liable to get when they first get syphilis, and know that it is syphilis that they have got, I have only seen one case in which syphilitic neurasthenia occurred in a patient with an active lesion, and then it was a symptom of degenerative encephalitis, from which he ultimately died. Syphilitic neurasthenia is not due to the toxine of the syphilitic organism, because toxines do not play a marked role in protozoal diseases, because the type of neurasthenia is seen in patients who have never had syphilis, because I have seen very bad cases in which the patient never had more than the primary sore, as the treatment was begun early, and because extraneous catastrophes often bring it on or aggravate it. Syphilitic neurasthenia is very apt to affect patients who have had an attack of neurasthenia before, patients, one can say, who have a mental family history. The " World War " has been a potent cause of syphilitic neurasthenia, as well as every other form of neurasthenia ; indeed, it has caused a neurasthenia of its own. None of these factors affect gonorrhoeal neurasthenia, therefore, in mj' opinion, gonorrhoeal nem'asthenia is a true toxic manifestation of the disease, since it often disappears when the patient is cured, while syphilitic neurasthenia does not differ from an ordinary neurasthenia, except in so much as it is the idea of the syphilis which has started the ball rolling, in a patient who is normally unstable or mentally weak. Syphilitic neurasthenia does not differ from war neurasthenia, hence neither the cure of the syphilis nor the cessation of the war would cure the patient. We will first of all discuss the gonorrhoeal neurasthenia. The symptoms complained of vary, but they may all be described as disturbances of the sexual function. The sexual desire may be abnormally augmented, or the patient may be impotent. Patients frequently complain of what they commonly call sexual weakness, that is. inability to get full erections, ejaculatio ■praecox, loss SEXUAL NEURASTHENIA. 48 i of sensation, or even extreme pain, just prior to and during the ejaculation. Patients frequently note that the amount of seminal fluid passed is very small. Some patients complain bitterly of prostatorrhoea, which they always mistake for spermatorrhoea ; and the constant passage of what they think to be their semen, which they usually seem to look upon as part of their spinal cord, has a most baneful influence on their mental condition. The symptoms just mentioned, which are typical of gonorrhoea! neurasthenia, are also the symptoms of a chronic inflammation of the coUiculus, the prostate, and the vesiculae seminales. The great pain sometimes complained of, prior to and during the seminal ejaculation, is due to a narrowing or closure of the ejaculator}- ducts, or of some of the ducts of the prostate, hence in these cases the amount of seminal fluid passed is often far below the normal. Once a patient begins to worry about these symptoms, he quickly loses weight, is usually constipated, and complains of headaches, vague pains over the body, indigestion, and inability to work or sleep. Some patients who have been under treatment for some time, and who look upon gonorrhoea as an incurable disease, or with as much awe as syphilis is commonly regarded, are naturally apt, if their mental balance is not properly adjusted, to develop a form of neurasthenia indistinguishable from that met with in syphilis. Theso are patients who would have developed neurasthenia on any very strong provocation, and the only way to treat them is by suggestion. Because a patient has gonorrhoeal neurasthenia, it must not be hastily assumed that he has an active gonococcal lesion, since the prostatitis, or whatever organ it is that is affected, may be kept up by a secondary infection, and this may keep the neurasthenia going. That gonorrhoeal neurasthenia may be, and is often met with long after all gonococci have vanished, might throw doubt upon the gonotoxic origin of it. Not at all. Herpes genitalis is a very frequent gonotoxic symptom, but, nevertheless, the condition may go on recurring and recurring long after the gonorrhoea has been cured and forgotten. Take again a syphilitic neuritis. Once the sensory fibres have been affected, in spite of treatment and the disappearance of the syphilitic process, pains and other symptoms may still persist. In cases of gonorrhoeal neurasthenia, it is necessary to find out, first of all, if the lesion of the prostate or seminal vesicles is still due to the gonococcus, or to a secondary infection. If due to the gonococcus, the patient should be treated according to the trouble found, and should be under vaccine treatment for about six or nine months. Such a course usually suffices to cure the case. If, on the other hand, no gonococci are 2h 2 482 SEXUAL NEURASTHENIA. found, and it is tolerably certain that a secondary infection persists, the patient should be treated on hygienic lines, and by suggestion. Cold applications to the prostate by means of the psychrophore often do a great deal of good, and, in very obstinate cases, it might be advisable to treat the patient with a mixed autogenous vaccine made from his prostatic secretion. In these cases, instrumentation of the urethra, and the injection of antiseptics should be avoided as far as possible. It is a very odd fact that many patients with gonorrhoeal nem'asthenia develop — when the neurasthenic symptoms appear — phosphaturia, oxaluria, or uraturia. The thickness of the urine caused by these salts is often a very great source of worry to the patient, and, of course, an excess of crystals in the urine is apt to aggravate any chronic inflammation of the prostate. As so many of the other symptoms of gonorrhoeal neurasthenia— such as the neuralgic pains, errors of digestion, chronic constipation, cardiac neuroses — are suggestive of an affection of the sympathetic nerves, it is possible that the polyuria, phosphaturia, etc., is also a sympathetic nerve disturbance. Although the hypochondria which sometimes accompanies gonorrhoeal neurasthenia is not, as a rule, so severe as that that follows syphilitic neurasthenia, it should not be forgotten that several cases have been known to commit suicide. Syphilitic Neurasthenia. The type of person usually affected with this form is mentally weak, conscientious in his work and habits, and one who has always had an awful di-ead of catching syphilis. Consequently, such patients come for advice very early, and therefore they can generally be cured, before they develop any further manifestations of the disease. In spite of being cured, and in spite of what you tell them, this class of patient cannot be convinced. They may even realise that they are foohsh, and they may be impressed for the moment by the rosy picture painted for them ; but, on leaving the source of comfort, they recede to their melanchohc state. The worst cases commit suicide. I have been unfortunate enough to have had two such cases. Both these cases, and milder ones which I have had, I have sent on to physicians who practise psychotherapy, but I have never yet seen a case which has been cured by hypnotism or suggestion. Not all these cases have the same ideas. Some imagine that they cannot be cured, and that they will ultimately become mad through the syphilis. Others, on the other hand, imagine that they are a continual source of infection to others. One of my cases — who terminated his own existence — first imagined that he had infected all his relations. To please him, I saw his relations in turn, and tried to convince him that his idea was foolish. He next said that anyone who passed him in the street became SEXUAL NEURASTHENIA. 483 infected, and he would often cross over on to the other side, to avoid them. He was so perturbed at thinking he had infected so many people, that he never went about without a pistol in his pocket, as he expected any moment that one of his victims would shoot him in the back. When I suggested to him that he did not appear to mind whether his frequent visits to me infected me or not, he imagined that I could protect myself and all those around me. He, moreover, accused me of not protecting all those whom he had already infected. This man ended his life by cutting his throat. Syphilitic neurasthenia is on the increase. Life being more strenuous and more of a bustle, especially in densely populated cities, than it was, is one of the causes. The more ready access which patients have to medical literature, and the intelligent interest that a very large proportion of the lay public take in matters medical, is another cause. The lay Press has recently allowed a few words con- cerning the disease to appear in its columns. The way these words are veiled, the peculiar heading that is attached to them — " Hidden Plague " — defeats its purpose, and is enough to put the fear of God into anyone. All deaths from salvarsan, upon which there is an inquest, find their way into the papers. The patient is said to have died from arsenical poisoning, which, of course, is absolutely untrue. The number of cases of blindness following salvarsan, which have appeared in the Daily Press, is legion. What effect must this have on a neurasthenic youth? In the first place, the syphilis makes him look upon himself as a leper ; he regards the disease as incurable, and he makes up his mind that he is going to develop syphilitic madness. In the second place, he dare not have salvarsan, for fear it is going to kill him or make him blind. This line of argument is a very common one with patients, and is one of the reasons why they first consult a druggist or a quack, because they know they will be told that the sore is onh' a chafe. The "World War " is a very fruitful cause of syphilitic neurasthenia, and I have already seen a few cases, the symptoms being of this nature. The patient dare not go to a Recruiting Office for fear the examining doctor may perceive that he has had syphilis, and he dare not go about the streets in daylight, for fear of being scoffed at for not joining the Colours. These two points weigh so much upon the patient's mind as almost to drive him mad. The type of man who used to commit suicide when he knew that he had contracted syphilis, fortunately is not met with nowadays. The man was not a neurasthenic, but simply committed suicide to save himself the horror and misery of being an invalid for the rest of his life, and then ending it in a madhouse. This type of man is open to reason, and, once he is told that he can be cured, he no longer^ worries. A strong, healthy looking man with early generalised syphilis once 484 SEXUAL NEURASTHENIA. consulted me. His first question was, Have I syphilis ? His second question was, Can I be cured? He afterwards informed me that, if I had not answered his second question in the afErmative, he would have done away with himself. Every venereal patient should be looked upon as a special sort of individual, and the physician in charge should always adopt a most optimistic tone. The knowledge that many patients have of medical science is often much greater than that with which they are accredited, so that, in any suspicious patient, I have always found it to be a good plan to let him follow my line of argument, and to tell him the reason why so and so many injections are given, and why the treatment is continued for so and so long. When the position is laid before them, they naturally ask questions, the answers of which can always be true, and 3'et be quite optimistically painted. Answers to questions, put to you by a patient, penetrate far deeper into the patient's mind than all the talk in the world from the doctor. The present-day patient is flattered, when the physician takes him into his confidence and explains to him the rationale of every step he takes. For the bad cases of syphilitic neurasthenia one certainly can do nothing. Mild cases can often be cured in time, and any number of susceptible patients can be prevented from developing neurasthenia, if they are dealt with as I have described above. Con- sidering that neurasthenia is such a common disease of the female sex, it is an odd fact that one seldom sees a case of sexual neurasthenia, i.e., neurasthenia caused by either gonorrhoea or syphilis, in a woman. CHAPTER XLIII. VENEREAL DISEASE AND MARRIAC4E. Syphilis. All authors, in discussing the question of syphilis and marriage, have hitherto pinned themselves down to a time limit. For instance, Hutchinson^ said that a man might marry with safety, if he had continued treatment for two years from the date of his chancre. Fournier- said that four or five years should elapse, and most other authors more or less echo Fournier's views. When either the cause of syphihs was unknown, or was thought to be only the Spirochaela j)allida, theoretically it would have been justifiable to fix a time limit, and still greater would this justification be, now that salvarsan has seen daylight, for the simple reason that we are told that all the spirochaetae in the body are killed by this drug. I cannot help thinking that all authors who have advocated a time limit have done so on theory alone, and have not allowed their clinical experience to influence them. My own clinical experience is not so great as that of Hutchinson,^ Fournier,^ Gougerot,^ and some of the other writers on this subject whom I have in mind, but yet I have learnt that a time limit is futile and untrustworthy. The reader will see later on, from the cases I am bringing forward, and from the previous pages, that the Spirochaeta pallida cannot be the actual cause of the disease itself, but that some other phase or phases must exist, which can lie dormant for an indefinite period, and then re-awaken and cause symptoms again. The spore is the dormant phase ; it is the actual cause of the disease, and it may lie dormant in any part of the body, without causing any disturbance of the host's cells in the locality in which it is situated. Although it may lie dormant, it may re-awaken and give rise to other phases which will cause symptoms, or it may never re-awaken until it gains entrance to a new host, hence, if a patient is harbouring spores, he is harbouring a potentially harmful infective agent. If the spore remains dormant for a sufficiently long time, the host will cease to 486 EUGENIC ASPECT OF VENEREAL DISEASE. form protective bodies ; but the fact that the Wassermann reaction is negative, is no proof tliat the patient is not harbouring the infective agent. Many individuals — and I am inclined to believe that the kind of infection plays a role — will, pro\'ided the organisms have been present for a certain period (the period varies enormously in different persons), continue to form protective bodies long after the organisms have been killed. Therefore, because a patient gives a positive Wassermann reaction, it does not necessarily follow that he has active syphilis, and so must not consider himself a candidate for marriage. As far as we can see then, at present it would appear that neither by clinical nor by pathological means, can we say for certain when a patient may marry without risk. Tf we go more carefully into the matter, and bring every point into con- sideration, we can be more definite than this. S^^hilis in the man will be dealt with first. If a man has been put under treatment before he has reached the generalisation stage, and provided that treatment has been adequate, he can maiTy at any time. I should consider four to five consecutive injections of salvarsan or neo-salvarsan and mercury for a year, to be adequate treatment. In such an early case as this, a Wassermann reaction would be of value, since, if a positive result were obtained, it would obviously mean that the patient had entered the generalisation stage while under treatment. Such a thing is possible, but fortu2iately it very seldom occurs. Case 77. — I was consulted by a man ^ith a primary sore on the corona, and the sore could not be removed. The Wassermann reaction was negative, both before and directly after treatment was inaugurated. I gave him five injections of neo-salvarsan, allowing four days to elapse between each pair of injections. As he had to leave England almost immediately, he was obhged to take mercury internally, and so could not have intramuscular injections. I saw him again, nine months later, when he presented mucous papules in his mouth, a general adenitis, and a positive Wassermann reaction. He also informed me that the site of his primary sore had swollen up and had become very red a month or two previously. To make absolutely sure that a case is cured, a provocative injection of salvarsan may be given, and the patient may be passed, if the blood test is negative before, and forty-eight hours after, the injection. If the provocative injection is to be given, it must be ascertained that the patient has had no treatment for six months. Speaking broadly then, if a patient has been put under treatment before he has reached the generalisation stage, he may marry without risk. If treatment is not begun until the generalisation stage has been reached, provided the patient has had about nine injections of salvarsan and thorough MARRIAGE. 487 mercurial treatment for two years, the risks of his infecting his wife are small, but they exist theoretically. I have actually seen such recurrences, although I have never known of an infection of another party. If only two or three injections of salvarsan have been given, and even if mercury is prescribed for two years, the risks are certainly much greater, as I have already seen ten cases in which a wife has become infected. These cases had all been treated by other men, and they came to me because of what had occurred. It is therefore possible that my failures have also gone elsewhere. I do not think that this explanation is the correct one, otherwise many articles would have appeared in the medical journals, to the effect that the treatment, even with several injections of salvarsan and mercury for two j'ears, does not cure syphilis. The treatment which I have advocated for the past four years is, I think, generally considered, in this country, to be unnecessarily severe. I am quite positive that recurrences are far more freqiient when only two or three injections are given at first, than when nine are prescribed, therefore I think I am probably right in assuming, that a man who has been treated in the latter way is a better candidate for marriage than one who has undergone the former treatment. Once a patient has reached the generalisation stage, spores may have settled in any corner of the body, and, being only potentially harmful, neither a Wasser- mann reaction nor a provocative injection at a later date will give results from which an absolutely trustworthy statement re a cure can be made. Here, again, we can be more exact, since it \vill naturally depend upon how long the patient has been in the generalisation stage. The shorter the time, the greater the value of a Wassermann reaction and a provocative injection later, and vice versa. In actual practice we know that, provided the patient has been well treated — and I am now thinking of those who never had salvarsan — and that, provided four or five years have elapsed before marriage, the percentage of those who infect their wives is so ridiculously small, that, when a patient comes for advice upon this point, one almost feels inclined to tell him that there is no risk. Then the cases in which infection has been conveyed pass through one's mind, and as such instances are often such sad ones, it requires many hundreds of successful cases to set off against one unsuccessful one. I will now mention two cases. In one the husband had no salvarsan before marriage, and in the other he had. Case 78. — ^The patient contracted syphihs five years before he married, and for the first three of those }'ears, he was treated with mercury. He had never developed a recurrence, and, wlien his wife became infected, his Wassermann reaction was negative. They had been married for twelve years, and, with the exception of the 488 EUGENIC ASPECT OF VENEREAL DISEASE. occasion upon which the infection was conveyed, the luisband had always worn a preventative. The wife developed very severe syphilis. Within a few weelcs of the appearance of the rash, she developed a unilateral optic neuritis. She quickly became blind in the affected eye, in spite of treatment, and ultimately the blind eye had to be removed. Case 79. — The husband contracted syphilis in 1906. He was treated with mercury for three years, and took mercurj^ again for one year before he married, and as an extra precaution he had three injections of salvarsan. There had never been a recurrence. The patient married in June, 1912, and in October, 1913, he brought his wife to see me, and she had well marked generalised syphilis. I could cite other cases, but these two will suffice to show how difficult it is to advise a patient, and what a slender reed to lean upon is the time limit. Every case should be considered individually, and, when I am consulted upon this point, I first of all find out whether the treatment has been adequate or inadequate. I then attempt to gain as much knowledge of the " man " as I can. and, finally, I try to ascertain the kind of sore which the patient had, and the amount of resistance he brought up to combat the infection. The question of treatment we have already considered, and we have now the " man" himself to discuss. If the patient is an intelligent man, and if there is reason to think that he will be able to follow the line of argument which is passing through one's own brain, the whole matter should be laid before him, and he should be left to choose whether he will run the infinitesimal risk or not. If the patient is nervous, and if there is reason to think that his future life would be rendered miserable by being told that a risk existed, provided other things are equal, it is best to take the risk upon one's own shoulders, and to tell him that he may marry without entertaining any qualms. Since we do not at present discriminate between our cases of syphilis, but regard all cases as being alike, and prescribe the same treatment for all, we always must be indefinite when we are requested to advise on the matter of marriage. I have no doubt in my own mind, that cases of syphilis vary enormously, and that a relationship exists between the kind of sore, the degree of the enlargement of the lymphatic glands, and the future course of the disease, hence, indirectly, its degree of infectivity. I am unable at present to lay down any hard and fast rules, since the matter can only be solved by chnical methods, and these have not yet been sufficiently long in force. The plan is to note very carefully the kind of sore which the patient has, the phases of the Leucoctjtozoon sypJiiUdis which it reveals in section, and the degree MARRIAGE. 489 of the enlargement of tlie lymijhatic glands. Then to watch the career of the patient, and to note what happens when he marries. Although I can only speak in general terms at present, I can say that the risks of a man infecting his wife are greater when the sore is of the papulo-indurative- erosive type than when the sore is of the papulo-uou-indurative-ulcerative type. The prognosis is distinctly better in those cases in which the lymphatic glands are markedly enlarged, than in those in which they are scarcely enlarged, but are abnormally hard. It must be remembered that, in the papulo-ulcerative chancre, the lymphatic glands may remain unaltered, and that in many of the cases in which they become enlarged, the enlargement is due to a secondary infection. If a man has had a recurrence, it does not follow that the risks of his marrying are any greater than those of a man who has had no recurrence, since the fact that a man gets an orbicular syphilide of his arm, does not mean that he is any more likely to have dormant spores in his sexual organs than a man who has never had a recurrence. In actual practice, we think that a man who has had a recurrence runs greater risks. As our knowledge is so incomplete at present, it is as well to think that this is true, as it is well to err on the side of caution. Another factor which has to be taken into account, is the part of the body which has been attacked by the syphilis. This aspect of the question has nothing to do with the risk of infection, but only concerns the future of the man and wife. If the patient has a high blood pressure, caused by the syphilis, and ther is any reason to fear that an arterial lesion is likely to cut short his life, new points are presented, and they require very careful consideration, before marriage is advised or not. Again, if the patient has a lesion of his central nervous system, and it is feared that he may later develop a degenerative lesion, the doctor must carefully consider whether a few years of conjugal happiness are compensated by the, maybe, many years of chronic invalidism of the husband. For some reason or other, recent authorities have imagined that there is a special breed of spirochaeta which will give rise to nervous lesions, and another breed which will give rise to systemic lesions, and so on. Hence, if a man who develops a degenerative nervous lesion infects his wife or his children, it is assumed that the wife or the children are more likely to develop nervous syphilis than systemic svphilis. I mention this, because, if such a view were true, the advice one would give to a patient who one feared might develop a degenerative nervous lesion, would , on this score alone, be certainly not to marry. I have had the opportunity of seeing and examining many families in which 490 EUGENIC ASPECT OF VENEREAL DISEASE. the husband had a degenerative nervous lesion. I have notes of five, in which the wife, or the wife and children, were syphilitic ; but I have never seen a case in which the wife or children had a nervous lesion. Cases have been reported in books, and the same cases have been copied from one book into another, so that, at first sight, a reader might imagine that these commonly occurred. I feel certain that they are only coincidences, because all experimental work completely negatives the idea that there are special breeds of organisms that, on the one hand, produce nervous syphilis, and, on the other hand, systemic syphilis. If a woman has had svphilis, and has been well treated, the chances of her infecting her husband are nil ; but, however drastic the treatment has been, there is always a risk that her children will be syphilitic. Therefore, as has been already stated, once a woman has had syphilis, in spite of the treatment she has already had, she must be treated throughout the whole period of each succeeding pregnancy. Gonorrhoea. Although gonorrhoea is a less serious disease than syphilis, when it becomes chronic it is certainly more difficult by treatment to render the patient non- infectious. The man and the woman will be considered separately, but, before going deeply into the subject, I would like to give the warning that a negative bacteriological diagnosis has absolutely no significance whatsoever. When the question of infectivity is concerned, it is a waste of time and money to examine bacteriologically the urethral and prostatic secretions of the man and the cervical secretion of the woman. The advice to be given in the case of gonorrhoea, as in syphilis, depends mainly upon clinical experience. When a man seeks advice on the question of marriage, the first point to be ascertained is as to whether he has ever had a recurrence or a metastatic lesion. If not, the prospects are good from the start, while if he has had a recurrence or a metastatic lesion, the risks of his infecting his wife are infinitely greater. We will first of all consider the patient who has never had a recurrence or a metastatic lesion. From such a patient, it is important to ascertain when he became infected, the period that has elapsed since he last had any signs of a discharge, and whether the infection reached the posterior part of his urethra and prostate, or not. He should then be asked whether sexual connection, nocturnal emissions, and alcohol have any effect upon the condition. If not, the chances are that he is cured, while if the status quo is not maintained, the chances are that he is not cured, and there- fore is infectious. MARRIAGE. 491 The urethra and prostate should then be very carefully examined, and great attention should be paid to the dilatability of the urethra ; this can be gauged by Kollmann's anterior and posterior dilators. If the dilatability is below the normal, the chances are that there are gonococci hidden in the follicles or in the subepithelial tissue. Dilatation will probably wake them up, and a big injection of a potent non-sensitised vaccine will also help to do this. If the dilatability is normal, and if a vaccine does not alter the statua quo, the patient can be passed as a fit candidate for marriage. If the patient has had a recurrence or a metastatic lesion, the same tests should be applied, but the additional factor of a secondary infection comes in. In other words, the tests employed above are not quite so conclusive, in a recurrent case. A peculiarity of some of these cases is, that an occasional sexual connection may not alter the status quo, but, when marital connection is indulged in, it may set up a copious discharge, which wall, in its turn, be certain to infect the wife. Occasionally the discharge may not be copious ; indeed, it may not even be increased, and yet the wife becomes infected. The infection runs its usual course — that is, it is first acute, then subacute, and finally chronic, or the wife's infection may be — to use an Irishism — chronic from the start. It is odd how frequently gonococcal lesions are chronic from the start, and yet the point appears never to have received any recognition. I have seen cases of gonococcal epididy- mitis, in which the whole of the caput minor has become stone-like, without the patient's ever being aware that he had had an infection there. I mention the epididymis, because it occurs in such a tender organ that an acute or a subacute infection of it could scarcely be overlooked. An analogy exists between a man who has entered the generahsation stage of syphilis and the man who has a recurrent urethritis or a metastatic gonococcal lesion. That is to say, in both cases one may make a mistake in advising a patient to marry. All the tests just mentioned should be tried, and, if the patient is an intelligent man, the position should be discussed openly with him ; if not, then the doctor must run the risk of making a mistake, and being blamed afterwards by the patient for it. Speaking generally, it is not difficult to tell when a man is cured. In the case of a woman, it is well nigh impossible. In a woman there may be gonococci hidden in Bartholin's glands or in the cervix, for years. They may be the source of infection, without necessarily producing any signs or symptoms in the person who harbours them. The provocative vaccine test is difficult to interpret in a woman, and even if Bartholin's glands and the cervix are harbouring gonococci in a chronic infection, a bacteriological examination will, 492 EUGENIC ASPECT OF VENEREAL DISEASE. in iiine cases out of ten, fail to reveal them. If the patient has never had sexual connection, the chances are that the cervix has never been infected. In such a case, provided the treatment has been good, marriage may be advised. In a patient who has had sexual connection, the chances are that she has had a cervicitis. The long presence of gonococci in the cervix leads to fibrous tissue formation, and destroys the dilatability, as is the case with the urethra. If the dilatability of the cervix is destroyed, the patient will almost certainly suffer from dysmennorrhoea, hence some information may be gained by going into this question. If the patient suffers from mennorrhagia or metrorrhagia, the chances are that she still has an active gonococcal infection. It is extremely seldom that the true position of affairs can be pointed out to a woman, therefore, in advising women re marriage, we must all expect to make mistakes. 1 Hutchinson (1899 and 1902), Internat. Congress for the Proph_ylaxis of Venereal Diseases. Brussel.s. 2 Fournier (1890), " Syphilis et Mariage." Paris. 3 Gougerot (1914), "Le Traitement d. 1. Syph. en Clientele." A. Maloine. Paris. CHAPTER XLIV. VENEREAL DISEASE AND PUBLIC HEALTH. Venereal diseases cannot as yet be regarded as having come within the scope of preventive medicine. The advances made during the present century have tended rather to the improvement in diagnosis and treatment, than to the pre- vention of the spread of infection. The importance of these additions to the sum of our knowledge is, however, apparent, if it be reaUsed that the disease nuist be diagnosed before the spread of infection can be prevented. On the other hand, there is an unfortunate tendency at the present time to rely upon the aid of bacteriology and pathology for diagnosis, rather than upon cHnical evidence. The various tests which have been discovered and taught render the medical practitioner more dependent upon the work of a laboratory than upon his own knowledge of the cHnical aspect of the disease. Many of these tests do not prove to be so accurate as they were beheved to be, when they were first of all discovered ; cUnical knowledge of disease must always remain the most reliable basis for work. This is, perhaps, especially the case in regard to syphihs, when the trained eye can frequently enable a decision to be made some considerable period before the diagnostic tests are appHcable. Broadly speaking, a case of syphiUs is not diagnosed to-day at a much earlier period of the disease than was done many years ago. This regrettable fact is largely owing to the absence of chnical tuition in the diagnosis of the disease, in the medical schools of this country. Earlier and more accurate diagnosis of the disease is essential, if the period of infection is to be shortened, and such diagnosis must be made upon clinical evidence. We do not as yet know whether the incidence of venereal disease is increasing or decreasing. It is hkely, however, that, were the full extent of this social evil disclosed, the pubHc would be awakened somewhat rudely to the dangers by which they are surrounded, as regards the possibility of infection by venereal disease. Considerable attention has recently been paid to the relation of venereal 494 EUGENIC ASPECT OF VENEREAL DISEASE. diseases to public health, and a part of the subject, upon which there has been much criticism, is notification. Before notification could be advised, very careful attention would have to be paid to the effects it has had in the case of those diseases which have been notifiable for some time past. It is only natural that the advocates for notification, say of scarlet fever, for instance, should be able to produce statistics, to the effect that notification has resulted in a diminished incidence of the disease. All statistics are apt to be fallacious, and perhaps none more so than medical statistics, for the simple reason that it requires very expert knowledge to draw up accurate figures, and, in compiling medical statistics, there are more paths open for the entrance of error than in the other sciences. There are many people who do not beheve that notification has had any appreciable result in lessening such a disease as scarlet fever. In the case of most of the notifiable diseases, the most infectious and contagious period has been passed, before the case is diagnosed, and therefore can be notified. If syphihs were made a notifiable disease, the difficulty just raised would have to be most carefully considered. Furthermore, there are many objections to notification. In the first place, there is no a priori reason for assuming that there would be less syphilis, if it were made a notifiable disease. In the second place, men would not be prepared — even if they knew — to state their source of infection, and women would in many cases not know from whom they had contracted the disease. For notification to be as successful as possible, it would be necessary, in every case, to trace the source of infection. When preventive measures are under consideration, the greatest difficulty arises from the woman's side, owing to the fact that many women are entirely ignorant of the presence of a sore, and all women who contract syphilis are infectious for a long period, without being aware of the fact. I think it may safely be said, that notification of syphiUs would be devoid of any success. The next point to be considered is the registration of prostitutes. The registration of prostitutes, and the sanctioning of Ucensed houses has had a trial of many years' duration on the Continent, with httle or no success. The main reason for the failure is the enormous increase in clandestine prostitution which notification has produced. The time is probably not very far distant, when we shall see these measures abohshed. On the face of it, it seems grossly unfair that women should be punished when they contract a venereal disease, and that men should be allowed to go scot free. For a law to be of any use, it must be just, and, in this case, it nnist apply equally to both sexes. One thing, I think, is certain, and that is, that prostitution can never be abohshed ; another thing, equally certain, is, that men are never going to be dissuaded from ha\'ing sexual connection. Both PUBLIC HEALTH. 495 may be lessened, perhaps, but never \\ill they be exterminated ; therefore, whatever may be done in the future, with the idea of diminishing venereal disease, must be undertaken, with a full recognition of these facts. Several attempts have been made to - engage public opinion upon this subject, and recently two committees have been formed in this country, to inquire into the means which might diminish the incidence of syphihs. One committee has been formed at the instigation of the Eugenic Society, and the other constitutes the Royal Commission. The aims of the former appear to be, to lessen syphilis by minimising the risks which people run. As an indirect method, probably none better exists. The public are to be warned of the risks they run, when they indulge in extra-matri- monial intercourse. Lectures are to be given to young adults, and it is hoped not onty that Universities and Schools will assist in the matter, but also that all mothers and fathers will take their children into theu' confidence, pointing out to them the enormous dangers they run, the sequelae that may follow, and, above all, that they will withhold any threat in case a misfortune should occur. One of the greatest difficulties we have now to contend with, is the attitude which many sons assume will be adopted towards them by their fathers, should the fathers learn that they have contracted a venereal disease. This often results in a man coming up for advice, when it is too late. Most fathers have themselves run the risk in their youths, but it is a peculiarity of the British mind that it regards extra-matrimonial intercom-se as a sin, only when a venereal disease results from it. The Eugenic Committee have very wisely made up their minds to refrain from the mention, in their lectures, of all Malthusian apphances. Holding out preventatives before the hearers would naturally defeat their purpose. Malthusian apphances are by no means always such a safeguard as they are supposed to be. For instance, I have frequently seen a chancre on the pubis or scrotum in patients, who habitually wore condoms, and the only two patients I have come across, whose custom it was to use Metschnikoff's ointment (calomel), both contracted syphihs. There is no doubt that the anti-alcohol crusade has exerted, and will still more, in the future, exert a beneficial action, since a very large percentage of cases of venereal disease are contracted, while the patient is under the influence of alcohol. The greatest proof we have that these indirect measures are productive of good is seen in the diminution of venereal disease in the Navy and Ai-my, during recent years. ) This decrease of venereal disease in the Services can in no way be caused by 496 EUGENIC ASPECT OF VENEREAL DISEASE. our better methods of treatment, since the source of the infection — the women- is not considered. The decrease is due to the greater abstinence from alcohol, to an improvement in the moral tone of the men, to the greater attention that is paid to outdoor exercises, and to the less wide social gulf between the officers and their men. The aim of the Eoyal Commission appeared to be, to collect statistics of the incidence of syphilis, with the idea of seeing whether the disease was on the increase or decrease ; of the role syphilis plays in the causation of other diseases ; of the number of deaths attributable to this disease ; and of the results of treatment. The report has not been issued yet, but, from the evidence already given, it would appear that, so far as obtaining these statistics is concerned, the Commission has, unfortunately, not been very successful. It is the general impression, that the great strides which treatment has made, in the last few years, are going very materially to diminish the amount of syphilis, even if they do not abohsh it. Supposing that we could get every patient under treatment the moment that he or she was conscious of infection with syphilis, it would certainly diminish syphilis, but it is doubtful whether the decrease would be very appreciable, smce, after all, it is only shutting the stable door after the horse is gone. No disease has ever yet been stamped out by treating it, nor is it ever likely that such will be the case. In the first place, patients cannot be put under treatment the moment the initial lesion appears — for two main reasons : (1) because of the lack of clinical knowledge of those who are called upon to diagnose the early syphilitic lesions ; (2) because many women contract syphilis without knowing it until the rash appears. In the second place, it must not be .forgotten that, however good may be statistics dealing with the results of treatment, such statistics will only hold good for the time being, for syphilologists are by no means agreed upon the best method of treatment, and none of us yet knows how all the cases treated by these up-to-date methods will fare in the future. Added to this, is the fact that all the statistics deaUng with treatment have been based not upon clinical experience but upon laboratory methods, which have since been shown to be less accurate than was at first beUeved. Apart from the idea that treatment is seriously going to diminish syphilis, which I do not for one moment think, we have to consider the patient who is infected. Every one is now agreed that, for a cure of syphilis to be guaranteed, the patient must be put under treatment before he enters the generalisation stage. PtJBLIC HEALTH. -197 This necessitates two things : (1) that the patient seeks advice the moment he notices a sore ; (2) that the medical man knows what the sore is, when he sees it. Point number one will be achieved partly by the wide dissemination of proper knowledge upon the subject, and this is part of the programme of the Eugenic Society ; partly by the Government stepping in and making quackery illegal, and preventing druggists from either givmg advice or seOing remedies for this complaint, without a prescription signed by a medical man, and partly by every- body realising that syphilis is a disease, and not a punishment for immorality. Point number two will be achieved, when every medical student of the present and future is given clinical tuition in venereal diseases. The London Lock Hospital has the finest cHnical material in the world, yet, from the point of view of tuition, this splendid material is all wasted. Men prefer to learn all about the SpirocJiaeia pallida and the Wassermann reaction, mainly because laboratory knowledge is easier to acquire than is clinical knowledge, but it is also very largely due to the fact that there are not enough men, whose knowledge of venereal diseases is sufficient to warrant them in undertaking tuition in this subject. An early diagnosis needs clinical experience, not expert bacteriological knowledge as to how to look for spirochaetae, and how to be able to recognise the Spirochaeta pallida when seen. The hasty search for an organism, which is sometimes not present, and for the application of an empirical pathological test, is hindering advance considerably. Let us see for a moment what effect it has had upon the evidence which the Royal Commission has so far obtained. Summing up the evidence, it can be arranged thus : — (a) An examination of all sores for the Spirochaeta pallida should become more general. (b) The Wassermann reaction should be carried out more generally than is now the case. (c) There should be a widespread distribution of public laboratories, in which these tests could be carried out gratuitously. {d) All special hospitals for venereal diseases should be abohshed. I need not dilate upon the futihty of putting the first tw^o points into practice, as the reader will have seen the reason by now, if he has read the earher chapters of this book. As regards the other points. Better chnical training would render public laboratories superfluous ; but let lis look at the suggestion from other points of view. It is proposed to do away with special hospitals, because the patients do not like attending them, and hence many are kept away from treatment. Most of the 2i2 498 EUGENIC ASPECT OF VENEREAL DISEASE. witnesses who were of this mind had never been in a special hospital for venereal diseases. Let us take the London Lock Hospital, and see what the true state of affairs is. The numbers attending are steadily increasing. Several hundreds of the patients were asked if they minded coming to the Lock Hospital. None appeared to have any objection. Asked, further, why they attended, they were unanimous in saying, that it was because they received better treatment there than elsewhere. The main object of the average hospital patient is to get well, and he will go where the treatment is best. He would not mind, if the hospital was called " Hell." If special hospitals are so undesirable, why put up special laboratories ? It is simply jumping from the frying-pan into the fire. Supposing, on the other hand, special laboratories were erected, what criterion have the authorities got, that they are going to get able men to work them, or patients to attend them ? PubUc laboratories are not going to make the average hospital patient seek the advice of a general practitioner any sooner than he does now, and it will have to be through a general practitioner that he finds his way to a laboratory. Assuming, for the sake of argument, that it did so, the practitioner's acumen for interpreting a pathological report would probably not be of the best ; hence, the pathologist would have to be a clinician as well, without the latter's knowledge or experience. To Sum Up. Treatment is going to diminish syphilis, but a diminished consumption of alcohol is going to do more towards this end, and a raising of the standard of public morahty is going to do most. Unfortunately, however great the influence of all three will be, it will not mean the abohtion of syphihs. If syphihs is to be stamped out, a means of preventing it will have to be found ; hence, one thing that the Commission might do would be to impress upon the Government the importance of prevention. First-rate workers might be obtained to tackle the subject, and there is no reason why as much success should not be achieved in syphilis, as Jenner achieved in smallpox. In the meantime, the pubhc should be warned of the seriousness of syphihs, and of the necessity for instant medical advice. The present and the future generations of medical men could, with advantage, be taught the clinical side of syphihs, the London Lock Hospital should be much more freely used for this purpose than is now the case, and it occurs to me that instead of having pubhc laboratories, it would be more to the point to have, in every town of a certain size, one or more experts, according to the size, to whom a case could be referred immediately for a chnical diagnosis. Part II. THE BIOLOGY OF INFLAMMATION, AND ITS RELATIONSHIP TO MALIGNANT DISEASE. INTRODUCTIOiV. No book on Sjrphilis would be considered complete, unless it contained a chapter on the histology of the vario\is lesions. Looking at a skin section under the microscope, and given no clue as to the clinical aspect of the case, it is almost impossible to make a correct diagnosis of the disease, unless, of course, the picture has marked characteristics as, for instance, are to be seen in Molluscum conlagiosum Syphilitic lesions are granulomata ; that is to sa\% the cellular infiltration is made up chiefly of lymphocytes and plasma cells. There may be some giant cells, and the vessels usually exhibit varying degrees of arteritis and endarteritis. Almost all chronic inflammatory lesions become granulomata, and any granuloma may present the above features in diverse degrees of sharpness or intensity. Although an arteritis and endarteritis are more marked in a syphilitic granuloma than in any other, owing to the fact that the organism has a predilection for developing in the walls of vessels, these changes may be absent in the section under examination, and they may be found in a tuberculous granuloma, for instance. Hence, broadly speaking, unless the observer has the clinical knowledge of the case, it is impossible to distinguish a syphilitic from any other granuloma. Fortunately, the phases of the Leucocytozoon syphilidis can be so easily demonstrated in the sections, that there is no difficidty now in making a diagnosis from a histological specimen, provided it has been stained according to the details given in Chapter VI. When the asexual stage only develops, it may be practically impossible to dis- tinguish between a section from a case of syphilitic coccidiosis, and a section from a case of the other forms of coccidiosis which I have described. ^^ When one considers that the host protects itself against an infection by an increased formation of its leucocytes, and that the leucocyte relied upon in all chronic infections is the 500 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. lymphocyte, one would not reasonably expect to find histological differences in the granulomata of varied origin. The difference in the nature of the host's response against syphilis, tubercle, &c., which in each case is specific, does not lie in an altered form of lymphocyte or plasma cell, but in the stereo-chemical molecular configuration of the lipoid- globulin in the protoplasm of these cells. Our present knowledge only enables us to tell, by micro-chemical and micro- physical tests, that the protective substance in all chronic inflammatory diseases is a lipoid-globulin. We have yet to discover tests which -ttill differentiate the various specific stereo-chemical properties of these lipoid-globulins. Since we cannot diagnose, by pure histology, a syphilitic from any other granuloma, I have thought it wiser to describe the changes which the epithelial cells, lymphocytes, and other cells undergo in any chronic inflammation. A description of this kind will cover a wider field than could otherwise have been the case, it will throw light upon various points which have hitherto remained enigmas, and I trust it will make a very large chapter in histology much simpler, and at the same time more interesting. To attain this end, I will first consider the role played by epithehum in inflammation, and its probable relationship to malignant epithehoma. CHAPTER XLV. THE ROLE PLAYED BY AN EPITHELIAI- CELL IN INFLAMIVUTION, AND ITS PROBABLE RELATIONSHIP TO MALIGNANT EPITHELIOMA.! "- =» Many of us still have clear memories of the pictures of cells described as the parasites of cancer, and of the rapid way in which one view after another found its way to the grave. This activity was followed by a spell of silence, broken by Unna's paper, " Ueher PseudoparasUen der Carcinome,"* and since then the subject has again passed into oblivion. For many 3'ears, it seems to have been the custom to regard every cell, which differed morphologically from the few known fixed types, as a form of degenera- tion. If a cell degenerates, surely its protoplasm and nucleus will break down into the same products as would follow both its peptic and pancreatic digestion. Such products are chemical entities, and may be even recognised as such, in the cells, by micro-chemical tests. In discussing the products of digestion, we never use the terms hyaline or colloid. AVhy should we do so, when we refer to the degeneration of cells ? Both hyaline and colloid are words which mean nothing, when applied to cells, and the sooner they are dropped, the sooner will histology be simplified. The term hyaline was first employed by v. Recklinghausen,^ and it has been very largely used since by Unna,* who ascribes to it the following characteristics : — (1) It is homogeneous and highly refractile, and it differs from fibrin in not splitting into fibres on digestion. (2) It is resistant to acids and alkalis, but will swell up under the influence of the latter. (3) It is distinguished from the protoplasm of the cells from which it arises, by having a sharp contour. (4) It arises from, the granoplasm of the cells, especially from the plasma cells, in the form of either small particles or balls, regular and irregular in shape, which prefer acid to basic stains. 502 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. (5) It has no relationship to the spongioplasm of the cells, nor to the nucleus. The above five points hold good for the so-called hyaline masses of plasma cells, for some of the molluscum bodies, and for a portion of the stratimi corneum. The hyaline masses of plasma cells result from a breaking down of the protein portion of the protoplasm of the cells. They are distinguished by preferring acid to basic stains, by being resistant to acids and alkalis, and by having a very strong reducing action. The latter is demonstrated by the Berlin blue colour which follows treatment with ferri-ferricyanide. In between the masses are often to be found strands, which no doubt form the spongioplasm of Unna. These strands have practically no reducing action ; they prefer basic stains, and behave to reagents like globulin. The reducing action of Unna's hyaline masses is due to tyrosine, or tryptophane, as I showed in my joint article with Mackenzie Wallis on " The Chemistry of the Leucocytozoon Syphilidis and of the Host's Protecting Cells,"* and, in consequence thereof, we called these masses Aminoplasma cells. When stained in vivo with borax methylene blue, the aminoplasma cells are not broken up into masses, such as one sees in fixed specimens. Owing to their reducing action, they stain deeply with the methylene red moiety of the dye. Inside the cell, are to be seen masses, strands, or fine filaments, all of which stain deeply with the methylene violet moiety. They have nothing to do with the nucleus, which has, as often as not, disappeared. The portions of the cell which stain with methylene violet are analogoiis to, and identical with, those masses seen in the protoplasm of lymphocytes, and in certain red blood corpuscles. The other structure which stains in vivo, in the same way, is the nucleolus. Often in red blood corpuscles, especially in cases of severe anaemia, or in animals after they have been bled, among the dark blue masses can be seen some which take the methylene red stain. In other words, some of the masses possess reducing properties. There are other substances which have a strong reducing action in addition to tyrosine and tryptophane, namely, fatty acids. Fatty acids exist in a cell in a colloidal complex, which is made up of lecithin and globulin. Because portions of certain red blood corpuscles stain with methylene red, and hence resemble the aminoplasma cells, it must not be assumed that the two substances are identical ; in this example they are diametrically opposite. The top stone in the synthesis of a cell is this lecithin-globulin adsorption compound. In the stone below, the globulin is the same, but its associated lipoid is less. In the stone below, again, the globulin exists alone. That portion of the aminoplasma cell which stains in vivo with methylene ROLE PLAYED BY EPITHELIAL CELL. 503 violet, in fixed specimens, stains better with pyronin than with eosin, safranin or acid fuchsin, and hence is easily distinguished from the rest of the cell, which stains better with acid than with basic dyes. The masses of the aniinoplasma cell are stones in the analysis of the granoplasm of the cell ; the strands, of the spongioplasm of the cell. My own view is that the fine pyroninophile protoplasm of plasma cells is a colloidal membrane, and consists of a globulin in the form of a complex with a lipoid ; while that part of the protoplasm under the lipoid envelope is albumin. Because it is so difficult to tell when the lipoid envelope has disappeared under the action of the reagent used, it is impossible to test accurately by micro-chemical means the substance it covers. No doubt this is the reason why Unna became so involved in all the different kinds of albumoses' which he described. Personally, I do not believe in the existence of albumoses in a functional cell, but I look upon them as analytic products of proteins, which can be divided simply into albumin, globulin, and globulin-lipoid complexes. Should these degenerate, or become analysed below the albumose stage, in time the amino-acid stage is reached, but it will be reached more quickly in the case of albumin than in that of globulin, and in the case of globulin more quickly than in a globulin-lipoid complex, with the result that one has no means of telling whether one is dealing with a pure substance or not. I do not for one moment imagine that the so-called hyaline masses of plasma cells consist entirely and solely of amino-acids ; other broken down products of protein digestion are surely also present ; but as the tyrosine is easily demonstrated, it seems better to call them aminoplasma cells than hyaline plasma cells, since the former term denotes something, while the latter denotes nothing. The deduction that the pyroninophile protoplasm of plasma cells is of the nature of a lipoid envelope, is fully justified from my work on the pyroninophile protein of the Leucocytozoon sypliilidis,^ and also from the well-known fact that, although the nucleolus of a cell shows a great affinity for pyronin, it contains in its interior a mass of nucleo-protein. The nucleo-protein, or nuclein, consists of nucleic acid, and proteins which have received the names of histone and protamine. Doubtless these two substances are really identical with, and indistinguishable from, albumin ; therefore, in the nucleus, we have the same state of afl'airs as that already described in the protoplasm of the cell — the pyroninophile reducing substance in the form of a lipoid envelope, the protein of which is globulin, encasing within it albumin on the one hand, and a mixture of nucleic acid and albumin on the other hand. These lipoid-globulin complexes are by no means identical, and there is a marked specificity about them, which is explained better by physico-chemical than by micro-chemical means. The point to which I wish to draw attention 50i BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. here is, that although all will stain with both acid and basic dyes, some globulin complexes are more acidophilic than others, and vice versa. Let me return to what Unna calls the hyaline degeneration of carcinoma epithelium,* which, by the way, is by no means linuted to cancerous tissue. It is demonstrated beautifully, for instance, in Molluscum contagiosum. The hyaline degeneration product of epithelial cells resembles the hyaline degeneration of plasma cells, i.e., it resists acids and alkalis, gives the Berlin blue reaction, and prefers acid to basic stains ; but this degeneration product should be very carefully distinguished from other hyaline bodies, which Unna described as occurring in carcinoma — Russell's^ and Plimmer's' bodies. Although the latter prefer acid to basic stains, they are far more nearly amphoteric than the former ; moreover, they are not resistant to acids or alkalis, and they do not give the Berlin blue reaction. It was the omission of these important tests which led everyone to imagine that Russell's* and Plimmer's' bodies were cell degenerations, and identical with that degeneration witnessed in epithelial cells, as in Molluscum contagiosum and in plasma cells, as in cases of verj" chronic inflammation ; especially, according to my experience, in cases of Ehinoscleroma and Ulcus molle serpiginosum. Another very important difference lies in the fact that, in hyaline degeneration crystal formation is frequently to be observed, and this is never the case with the bodies described by Russell* and Plimmer.' The crystals may be in the form of sheaths and rectangular prisms, and all I can say at present, is that they are probably polypeptides, because they do not give amino-acid reactions, and the cell is not so degenerated as the amino cell. The past workers on the cause of cancer may be divided into two schools : those who thought that certain bodies which they described were protozoa, and those who considered those bodies to be cell degenerations. To the former school belonged Plimmer,* Russell* and others ; to the latter school Unna,' Apolant^" and others. Unna says : " Fdrht sicli der Kern eines solchen Gebildes wie Chromatin und ist dabei punJdfdrmig, so Jcann es einem Proiozoon agnehCu'en : fdrbt er sicli wie Nucleolin, so hat er audi wenn er nur jmnktformig ist, mit einem Protozoon nichts zu thun, da bei Protozoen iiberhaupt keine KernkOrperchensubstanz vorkommt."^ This supposed difference does not exist. Hence, whatever deductions Unna made from his observations must be false, as he placed so much faith upon the above statement. I have already shown, by micro-chemical means, what a nucleohxs is ; now let me dwell a little upon its function. ROLE PLAYED BY EPITHELIAL CELL. 505 The nucleolus is made up of a lipoid-globulin complex, which exists in the form of a colloidal membrane, enclosing nuclein within it. The nucleolus comes into greatest prominence when the cell is about to divide ; in fact it starts the ball of division rolling, and is, to all intents and purposes, entirely responsible for the process. The nuclein becomes transformed into chromosomes, and, bv a process which is too well known to require description, gives rise to two nuclei. It is not always easy to follow what happens to the lipoid-globulin fraction, but a bright pyroninophile spot is seen at either pole of the chromosomes, and it eventually becomes the nucleolus of the newly-formed nucleus, although it does not take up its central position till later. The nucleoli are doubtless those centrosomes which are conspicuous at the commencement of cell division. This lipoid-globulin complex appears to be the very essence of life, and is always prominent when division, mitotic or amitotic, is about to take place. Note how extremely well marked it is in cancer cells, where cell division takes place at a much faster rate than normally. The nuclein of protozoa divides at a still greater pace, but the results of division remain in the cell itself, until, in time, the whole cell is filled with the products of this division, cf., the changes from the zygote to the spore cyst. It would naturally be expected that the cell would be rich in the essential lipoid- globulin compound, and that the envelope would cover the whole cell, rather than be limited to the nucleus only. In the chapter on the chemistry of the Leucocytozoon sijpJiilidis, it was shown that the parasite consisted of an envelope which was chemically lecithin-globulin, that this envelope had nuclein enclosed, and that the envelope was thickest over the nuclear area. This envelope plays the part of the nucleolus, and becomes used up by the time the final stage is reached. Hence the reason why the sporozoites do not show such a great affinity for pyronin as the zygotes do. Owing to the fact that it has little or no lecithin-globulin in its structure, when a sporozoite takes upon itself to develop further, and to start the life-cycle again, it is obliged to enter a cell, in which it has the capacity of forming the compoimd from the simple protein of the cell's protoplasm. It may be safely said that the male element has a greater function to perform than the female one, partly owing to the fact of its being motile. Therefore it would be expected that the male gamete, or Spirochaeta pallida, was richer in this essential of life — lecithin-globulin — than the female gamete. That this is actually the case is seen from my observation that the reducing action of the female cell becomes greater after 'the entrance of the male. The reducing action is due to 506 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. the fatty acid radicle of the lecithin-globuHn which the male possesses, and wliich it imparts to the female during the act of impregnation so that division and sub-division can go along smoothly, until the spores are formed. It is highly probable that the extreme richness of the male gamete in lecithin-globulin is due to the fact that the male gametocyte develops intracellularly, while the female gametocyte does not. From what has just been said, it will be noted that there is already a chemical relationship between the cancer cell and a protozoon, in that they are both rich in a lipoid-globulin complex. As we proceed, I will endeavour to show that the relationship is very much closer still. Before describing those bodies which have so frequently been called the parasites of cancer, I would like to draw attention to that most important clinical observation, that pseudo-chjdous ascites may be found in patients suffering either from cancer or from syphilis.i^ i- This applies also to the finding of globulin in the urine. The fluid from a case of pseudo-chylous ascites is rich in lecithin-globulin, and so is the urine from that form of so-called syphilitic albuminuria "syhich occurs early in the generahsation stage of syphilis, and which may also be met with in late cases of the disease — another important similarity between cancer and syphihs. The Description of the so-called Parasites of Cancer. Hitherto these bodies have been looked upon as protozoa, which had entered the cells of their host, and as nuclear degenerations. They are neither ; and if the illustrations are closely followed it will be seen how these bodies arise. In short, they develop from the nucleoli. In Plate 43 (1) A, (stained with pyronin and methyl green) a nucleolus is seen leaving the nucleus of an epithelial cell. B shows the nucleolus almost outside the nucleus. C shows a nucleolus which has become transformed into pigment. This will be referred to again, but I wish to direct attention to the nucleus on the left. The nucleus has divided : one half contains a nucleolus ; the other half has expelled the nucleolus, which has become pigmented. The expelled nucleolus consists of a lecithin-globulin envelope, enclosing some nuclein. The nucleolus increases in size, until a cell is seen which can be divided into two parts— protoplasm and a nucleus (vide Plate 44 (1 )). The resemblance of this cell to the syphilitic female gametocyte is very close, and it stiU further resembles it chemically, in that the nucleus is covered by a Upoid-globiilin structure, which, owing to its reducing action, prevents the nucleus from staining ^ith methyl green. On Plate 44 (2, 3) are two pseudo-parasitic cells, in which the lipoid-globulin envelope has disappeared, and this allows the nucleus to stain in the ordinary way. Plate 43. Section of a malignant ijrickle-celled epithelioma, stained with pyronin and methyl green. A. A nucleolus is to be seen leaving the nucleus of an ipithelial cell. B. The nucleolus is now almost outside the nucleus. C. The nucleolus has become transformed into pigment. D. A pseudo-parasitic body, which has become transformed into pigment. 2. Section of a malignant prickle-celled epitheUoma (same case as aliove), stained with Ehrlich's triacid mixture. A, B, C, D, E, P. Show pseudo-parasitic bodies in various stages of development. Each one has arisen from a nucleolus of an epithelial cell. The lecithin-globulin portion of the nucleolus has , become the protopla.smic part, and the nuclein portion, the nuclear part of the pseudo-parasitic cell. It will be seen that the pseudo-parasitic lipoid-globulin shows a marked affinity for acid fuchsm. m m Pl^TE 43. Facing p. 608. .i)t; •odies \\L • ..^wt'iiA ■ vv attention ' I, that pseu. ,r ■j-sHohq IjciJBU'i J case, oi ij'fT .^^)^^g J^riJam bra; Ju^insiq ■ i^imiJ 3fjioo'3i( ejifl rioid-w .vfxjd oiJi>.ciJi(j-ol)i/oaq A .(I ,( vii ■; ^1, oKjio erne?.) empil'iiitiq^i boll^o-abbhq JriJsXii^il^fn is lo (ioi)ao<< * ' ' ' .aiutzim biochif a'lloil'ija di'ni I)3ni,Bia io gejcta auohcv ni aaibod 9E)i«ii«q-obiJ9aq woil8 .1 ,H ,Q[ ,0 ,8 ,A Ijjiiejidiqs aa in eiiiooloiiti e moil apuii^ aed aoo dsf^^jh-^xi^aicprfay^H ^moood ?Jid mitosloua odi io (loWioq^ aijifdolg-njfffeal «dT-ij.iI' lo :fi/;q melbna orfi ,noiJioq nialoDfi adJ bnc ,ixBq oiifiKisIqoioiq odi oilfeiii^q-obtiapq arii issii ti9&s')d''Vhf it'^.O^'oMkihsq-dfitn^qodi .HierioolbioBiOl ^i*iBiSifl lMQJtfitfiis»'^afih)d6iniIiJcfeIg*bioqiJ ' %vili be referred to The nuclcnv v.,, 1 the nu! ■11 furtlier re^ obulin struct ain in the G^^imw*"* ■V, Platb 43. f^ / « Platk 44. . i Pseudo-parasitic bodies from a case of malignant prickle-celled epithelioma. Plate 44. FoUom Plate 43. .4 t in A.l'T .tiiiioiJ^iliiqo balbo-oldoiiq iaeir^ilem lo oseo ts moil esibod oiliaJtifiq-obiree*! ,8J. »U>J1 »)H>VW4 tl •M. ♦' •l«***i 10. « 11. ^•* 12. 14. 13. Plate 44. EOLE PLAYED BY EPITHELIAL CELL. 507 The nucleus of the pseudo-parasite differs from that of a protozoon in one respect, in that it can divide by mitosis ; but resembles it in the other respect, in that it can also divide by amitosis or after the budding fashion. Plate 44 (4, 5) demonstrates the former — division by mitosis. Plate 44 (6, 7) demonstrates the latter — division by amitosis. Note how closely Plate 44 (7) resembles the spore cyst in syphilis. Plate 44 (6, 8) represents specimens specially treated with boric acid, which dissolves out the albumin of the cell, but leaves the globvdin. In Plate 44 (6) it will be seen that the protoplasm of the cell has vanished, that the nucleus has divided into two, but that it refuses to stain with methyl green, owing to the lipoid-globulin membrane which still covers it. A mass of this protein complex is also seen between the two portions. In Plate 44 (8) the nucleus is uncovered, but two masses of lipoid-globulin exist in the cell. This uneven distribution of the lecithin-globulin at once distinguishes these cells from protozoa. Moreover, it is not in such quantity, nor so resistant to reagents, as that found in the Leucocytozoon syphilidis, for instance. The nucleolus, which becomes the pseudo-parasite, need not necessarily be discharged from the cell. It may develop in the protoplasm of the epithelial cell, as in Plate 44 (9), or in the nucleus, as in Plate 44 (10), or in a part of the nucleus, as in Plate 44 (11) How close is now the resemblance to the Plimmer* and Russell* bodies. Plate 43 (2) is stained with Ehrhch's triacid stain, in order to show the strong affinity which the protoplasm — or, to be more accurate, the lecithin- globulin — of the pseudo -parasites shows for acid fuchsin. Plate 44 (12) shows pigment formation, in the protoplasm of an epithelial cell. Plate 44 (13) shows pigment in the process of production in a pseudo-parasitic cell, and Plate 44 (14) shows a further stage of the proceeding, which is also demonstrated by D in Plate 43 (I). This pigment is not haemosiderin, and it differs from the ordinary melanin of the epithehum in being insoluble in hydrogen peroxide, bromine water, acids, and allcaUs. It forms BerUn blue from ferri-ferricyanide, and it is highly probable • that it related to tvrosine, and is dependent upon an oxydase reaction. The formation of pigment from globulin is well known, but its exact chemical nature is, as yet, unsolved. A fluid containing lecithin-globulin, a urine for instance, may suddenly go jet black, and the pigment formed is resistant to every reagent. Therefore it is quite distinct from haemosiderin, and it does not quite conform to melanin, as it is generally known. I have particularly called attention to this pigment for two reasons. First, because it develops fi-om globuHn, which supports 508 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. my chemical investigations into the psendo-parasites ; secondly, because it is rare in malignant epitheliomata. Without recapitulation, it will be seen how close is the resemblance between these pseudo-parasites of cancer and protozoa, the great and important difference lying solely in the nature and distribution of the lipoid-globulin. The lipoid- globulin of the cancer cells is less organised, shows a greater affinity for acid than for basic dyes than does that of the syphilitic parasite, and, furthermore, it has not such a strong reducing action as has the latter. From what I have already stated, it will at once be clear to the reader in what respects cancer differs from an infection ; for instance, from syphilis. A cancer cell has less lecithin-globulin ; its division cannot proceed so rapidly, and, when the lecithin-globidin is exhausted, the cell is entirely used up, as the nuclein left behind cannot enter another cell and start a cycle again. I do not wish to infer that the life history of cancer is always similar to what I have described, as plain nuclear division and sub-division may be all that is seen, and, in fact, in Plate 43 (1) this multiplication of the nucleus is clearly depicted. All variations, from simple nuclear division, to the formation of nucleolar pseudo-parasitic bodies, exist in both carcinomata and sarcomata, and a study of the nucleolus in a doubtful section is of much greater value than determining whether the growth is infiltrating or not. All cases vary in the degree of the transformations undergone by the nucleoli. It may be as regular as I have depicted in the accompanying figures, or so irregular that a description would be impossible. The reason why I have chosen these clear forms to discuss is, partly because it has been suggested that the phases I described of the life history of the organism of syphilis were the same bodies as Plimmer and Kussell described in cancer, and partly because I wanted to prove how valuable Plimmer's and Russell's observations were, arid what a mistake it was to class the bodies described as nucleai' degenerations, withoiit doing more work on the subject. I cannot help feeling, in my own nund, that there is no one and specific cause of cancer, but that as inflammation is the result of an infection, and inflammation can precede a cancer ; therefore, both inflammation and cancer are two links in a chain of events which result from no one specific cause, and therefore, this chain represents a sequence of events in the protective mechanism of the body against that cause. In inflammation of the skin, the epithelium plays a very important part. Note the so-called acanthosis in warts, which not infrequently become malignant. A hypertrophy of the stratum malpighii is the rule in many syphilitic and tubercular affections of the skin, and there are plenty of cases on record, in which malignant ROLE PLAYED BY EPITHELIAL CELL. 509 epitheliomata have occurred on Lupus vulgaris and guminata. I have seen even a primaiy syphilitic lesion become mahgnant, indeed I have had two cases recently under my care. The epithelium takes part in the inflammation caused by the sun's rays and by X-rays, and to show how commonly mahgnant epithehomata result, one need only mention Kaposi's disease Xerodermia pigmentosa, if an example is required. I hold that cancer is not an entity, but, with inflammation, and the inter- mediary stages between the two, it forms a link of a chain, which one may call the protective mechanism of the body against all enemies. Therefore, if my theories be correct, there is no one single cause of malignant disease. All we can say is, that cancer will result, should one of the enemies of the host be powerful enough to make the host cells form more than the usual amount of a certain chemical substance, which is of the nature of a lipoid-globulin adsorption compound. Summary. 1. That the pseudo-parasites of malignant epithelioma are transformations which the nucleoli have undergone, to protect the host against some uncertain cause. 2. That the pseudo-parasites are neither true parasites, because they do not behave as such, nor are they cell degenerations, because they consist chemically of a very highly complex body, lecithin-globulin. 3. That chronic inflammation may start the production of these bodies, and that a relationship exists between inflammation and malignant disease. 4. That this relationship may be followed in its different phases which con- stitute the links of a chain, which may te called for convenience the " epiblastic chain." I will now pass on to a classification of the cutaneous epitheliomata, and will close this chapter with a description of them. A Classification of the Cutaneous Epitheliomata. Before proceeding to draw up a classification of the cutaneous epitheliomata, we must first of all banish the difference of meaning which the word epithelioma possesses in this country and on the Continent. The word epithelioma clearly means a tumour of epithelium, and there is nothing in the word to suggest mahgnancy. Therefore, the Continental meaning of the word is the con^ct one. Epithelioma alone should signify merely a growth of epithelial tissue, and a 510 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. prefix slioiild be added, when it is required to state what kind of epithelial tissue is referred to. Prickle-celled epithelioma would mean an epithelioma beginning in the stratum malpighii, and the nature of the growth, whether innocent or not, could be told by putting the word benign or malignant in front. A rodent ulcer would become basal-celled epithelioma ; an epithelioma of the hair follicles, trichoepithelioma ; of the sebacous glands, sebaceous epithelioma ; of the sweat glands, syringoepithelioma. Intermediary types, maybe differing both clinically and histologically from the groundwork types, and linking up the latter into a chain, which will be described later, might still receive the name which the first describer gave to them. Beginning with the prickle-celled epitheUoma, we have the common benign papilloma, in which the cells still retain their prickles ; we then come to a peculiar form of papilloma which is clinically indistinguishable from the simple papilloma, but differs from it in that, even if it is widely removed, it will recur in situ, and others may appear in different parts of the body. The growths neither spread nor ulcerate, nor do they have metastases. Histologically, more epitheUal tissue is seen in this than in a simple papilloma, and in some cases it is extremely difficult to say whether the epithelial tissue is invading healthy tissue or not. The epithelial cells are not so well formed as those met with in a simple papilloma, and, moreover, prickles are not discernible. The type should receive the name of benign reciuring prickle-celled epithelioma. Not infrequently, more than one member of the family is affected with this t^-pe of growth. We come next to the pure basal-celled epithelioma, or rodent ulcer, and between this and the maHgnant prickle-celled epithelioma, with its typical cell nests of horny material, all grades of epitheliomata exist, which vary according to the layer or layers of epithelium from which the growth originates. The epithelioma following X-rays is an epithelioma of the uppermost layers of the stratum malpighii, hence the enormous richness of cell nests. The epithelioma following the sun's rays is an epithelioma of the lowest layers, including the basal cell layer ; hence many have the histological features of a rodent ulcer, but they differ from it, in that cell nests can usually be found. Cell nests, then, in a section which resembles a rodent ulcer, merely mean that layers of epithelium above the basal cell layer have been implicated. Therefore, a sharp distinction between malignant- squamous-celled epithelioma and rodent ulcer does not exist ; reh-ing upon the absence or presence of cell nests to clear the diagnosis is unjustifiable, as all grades between the two may occur. AVe can now pass on to the new growths of the epithelial appendages. ROLE PLAYED BY EPITHELIAL CELL. 51 I The trichoepithelioma, the so-called sebaceous adenoma and syringoma, are typical epitheliomata of specialised epithelial cells. These tumours all have a point in common, in that they are mostly very benign, do not even tend to increase in size, and do not ulcerate. Mahgnant trichoepithelioma does not exist, though theoretically, there is no reason why it should not ; recurrent syringoepithelioma is excessively rare, but recurring sebaceous epithehoma, although rare, is occasionally met with. Very rarely a mahgnant sebaceous epithehoma may be met with. The groundwork cells of the epithelial appendages are the same, and it is not until they near the stage of maturity, that one can say that this group of cells is to form hair follicles, and that group sebaceous glands, and the other group sweat glands. Now, new growths of these groundwork cells can occur ; a tumour may arise just when the epithelial cells are on the point of setting ofE cells destined to form the appendages, when the histological appearances will closely resemble a rodent ulcer. On the other hand, a tumour may arise when the cells which have been set ofE have become so specialised as to be almost distinguishable as lanugo hair follicle cells. Between the two, all grades of tumours may be met with. The most embryomc tumour is the so-called multiple rodent ulcer, and the more mature tumour is the so-called Epithelioma adenoides cysticum. If sections from different cases of these two types of tumour are examined, it will be found that no two are exactly alike; in one, the resemblance to rodent ulcer may not be so marked, and in the other, it would be stretching the imagination to say that the tumour had anything to do with the lanugo hair follicles. Whether a tumom- is benign or malignant depends, in my mind, partly upon the stage in. the development of the cells from which the tumour arises, and partly upon the resistance of the cells involved, against the exciting cause. In very early embryonic life, the epidermis consists of one layer of epithelium, the cells of which resemble the later basal-celled layer or stratum spinosum. Therefore, a tumour arising therefrom will have a great capacity for activit}^ or, in other words, malignancy, while tumours arising from mature and highly speciahsed sebaceous gland cells — cells which have reached their zenith, or have performed their function — have httle or no capacity lor activity, and therefore are benign. As the term malignant is apphed to the activit}^ just referred to, as well as to the pseudo-parasitic development of nucleoh, it would be better to reserve the term for the latter, and to call the former merely " embryonic activity." Tumours arising from cells in their intermediate stages are neither so active, and therefore malignant, as the former group, nor so mature and benign as the latter group, so they are able to recur only after removal. 2k 512 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. However active or embryonic cells may be, a tumour arising therefrom, whatever its dimensions, will still consist, morphologically, of the same cells, or, in other words, the cells constituting the growth do not become more mature or specialised. It will now be best to append my classification of the cutaneous epitheliomata, and then to describe more fully each of the chief types met with. The cutaneous epithehomata should be divided into three main groups : — 1. Epidermic. 2. Appendicular. 3. Mixed epidermic appendicular. The epidermic class should be divided up into prickle-celled epithelioma, mixed- celled epithelioma, and basal-celled epithelioma. The prickle-celled epitheliomata should be further subdivided into benign prickle-celled epithelioma or papilloma, recurring prickle-celled epithelioma, and malignant prickle-celled epithelioma. The appendicular class should be divided into trichoepithelioma, sebaceous epi- thelioma, and syringoepithelioma, the two last having a subdivision of recurring sebaceous epithelioma, and syringoepithelioma. The mixed epidermic appendicular class should be subdivided into multiple rodent ulcer, and EpitJielioma adenoides cysticum. A Description of the Embryonic Cutaneous Epitheliomata. Concerning most of the epitheliomata of the skin, there are four very striking points, to which I was the first to refer : — 1. The mixture of types. By the side of a rodent ulcer, a sebaceous epithelioma is not at all uncommon. Most sebaceous and syringoepitheliomata are accom- panied by trichoepitheliomatous elements. A combined sebaceous and s3rringo- epithelioma is not at all imcommon. Clinically, there is no differentiation. 2. The almost constant occurrence of milia. 3. The predilection which the tumours have for the oculo-facial and naso-facial grooves. 4. The frequent occurrence of mole or naevus cells (endothehal cells) in the more embryonic types of growths. It must have struck man}', how frequently new growths of the face have occurred in the oculo-facial and naso-facial folds. There is scarcely a human being whose skin, below the lower eyelid or at the junction of the nose and the cheeks, when carefully examined, does not reveal the appearance of several small glands, some of which may be so enlarged as to be pathological. ROLE PLAYED BY EPITHELL\L CELL. 513 P.T3 Id- w o I— I W H P-l O ^ 2 OS'S 'TS ^ s Oi o OJ tv »< w be a P5 a so pq so 13 M PL, W a -60 a bo c rt ao_3 Cm o d bo M 2k2 514 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. The mere fact that the looseness of the skin over this area makes the under- lying structures more apparent, will not account for the phenomenon, the explana- tion being forthcoming, only when the same regions in the lower mammaha are studied. If a microscopical examination of the skin at the base of the lower eyelid is made, it will reveal, in almost every individual, specialised embryonic epithelial structures, as lanugo hair follicles, sweat glands, and sebaceous glands. On a larger scale they may be considered pathological, and, when the growth is limited to the lanugo hair follicles, the term Trichoepithelioma may be applied, when to sebaceous glands. Sebaceous adenoma, and when to sweat glands, Si/ringoma. The tumour may consist of any one of these, alone or mixed, and, when mixed, the different types may be present in the same area, or a type may be found pure in one part of the section, and another type pure in another part of the section. None of these types increase in size, ulcerate, or become malignant, for the simple reason that they consist of nearly mature epithelial cells, or perhaps it would be better to say, cells which cannot wander from a special form, because they have arrived at that stage when a function has been appointed them, and because they occur in tissue in which they normally would be, viz., corium. This is not the case with rare tumours, which, when present, are common in the situations under discussion, viz.. Epithelioma adenoides cysticum, and Ulcus rodens multiplex. The swellings not only increase in size up to a certain point, they also ulcerate, but without extending further, or giving rise to metastases. The cells of the tumours are epithelial in origin, but whether of the type destined to be hair-folhcles or sweat glands, etc., cannot alw^ays be ascertained, since in some cases the cells have not arrived at the stage when they are to serve a purpose, i.e., they are more embryonic than the cells of the trichoepithelioma, sj'ringoma, etc. Still more is this the case with a tumour which is most commonly situated in the orbito-facial and naso-facial folds, and which, once it has ulcerated, tends to spread and destroy all the structures in the neighbourhood, but without giving rise to metastases or glandular enlargements — the so-called Ulcus rodens. The controversy as to the origin of a rodent ulcer, whether it arises from the inner root sheath of the hair follicle, or at the point of exit of the sebaceous gland into the hair folhcle, because the cells are spindle in form, seems so much waste of energy, as the cells constituting a rodent ulcer are embryonic epithelial cells of a very early type, when the spindle shape is the rule rather than the exception ; the cells being laid down at a time when hair follicles and sebaceous glands, etc., are unthought of. "When development takes place in an area in which the structures have matured, Section tlii'oug-li ;i ililiuiii. Triclioppitlielioma I'.-i[iuI.isum. Plate 45. Fuciwj p. 514. :-■■•?. ■ ■ ■ ■ vjff''-..'''-'--^ ---■•■■-. ^\-.-;»«?^ ■■■•«.>' i'^i,": I ■X">...-/.vV.-\-:;;;;\|:^r^-o;r ;^f<-V .^ < fS~ •■•4"^.?'AV, -.-. ;■•"■•— -^:.^ / ., ..- . j-J- ' -X :;••.••.•.•.:??**•;'—.:■ •■-• .-^r-. ■•..•• . •■:\^'V?;v;-. ■::, •■. Av • .?i«:Si|* ^^"Ik 1 i'/J^'l'i^S-:.-;?; -^Sga?:-- - f^ g Folhirs Plate 45. ROLE PLAYED BY EPITUELIAL CELL. 515 and in tissue in which they are not wont to occur, the cells grow in a peculiar way, and so constitute what I have called embryonic activity. The presence of cell nests in a rodent ulcer have raised many difficulties, both as regards the diagnosis between a rodent ulcer and squamous-celled epithelioma, and as regards the origin of the former ; but quite unnecessarily. Characters typical of an epithelioma may be found alongside a rodent ulcer, but not vice versa, and the explanation lies, no doubt, in the fact that the rodent ulcer acts as an irritant, and so causes an abnormal epithelial growth with cell- nests, as occurs in a skin exposed to the sun's rays or to X-rays. Again, small horny nests may be found in the rodent ulcer tissue itself, but it will be noticed that the cells around are cubical, more like the normal rete cells than like the typical spindle cells. The epidermis primarily consists of one layer of spindle cells, and from this layer other cells, cubical in form, arise, and these in turn become transformed into horny tissue, at quite an early stage in embryonic existence, before hair follicles and other specialised epithelial structures are considered. Then is it not possible that such rodent ulcers arise from rests of a later date, when the cells have already learnt the transformation into horny tissue ? A concomitant feature, in nearly all cases of growths from these regions, is the presence of milia (Plate 45 (1)). How are these tiny round hard white swellings formed ? Opinions differ widely. They shell out on incising the covering skin, and, under the microscope, appear as cysts filled with some homogeneous substance. No doubt they are formed in various ways : (1) From a dilated lanugo hair follicle. Plate 46 shows this admirably. This is a case of a rodent ulcer, in the surrounding inflammatory tissue of which is seen a typical milium, to which is attached part of a sebaceous gland, and below is the hair root with its papilla. (2) From a dilated sweat duct : Schidachi was able to produce sweat gland cysts by shaving off a piece of skin from the pad of a cat's foot parallel to the surface, stretching the same, and then laying it back to let it grow. As the sweat ducts did not overlap, cysts were produced. (3) From an epidermic inclusion, which has become cystic, since they occur in skin which has formed over a burn, in the new skin which develops after a bulla, in pemphigus. Epidermolysis bullosa, etc. I will now mention a typical case of each type of epithelial growth referred to above. Case 80. — Trichoepithelioma papuhsum. — E. D., aged 48 years, housewife, came up to St. Bartholomew's Hospital complaining of a scaly eruption on her right shin. She was also noticed to have some pale, slightly raised nodules on her face. When attention was drawn to these the patient said that they were of no moment, gave rise to no inconvenience, and that she had had them for years. 516 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. These nodules were about the size of a lentil, about ten in number, and situated on the lower border of the lower eyelid, and extending from the inner to near the outer canthus, where they somewhat decreased in number and size. Both sides of the face were equally affected. One or two nodules were found on the upper eyelid, and at the outer canthus there were a few milia. Each lesion was about the size of a lentil, circular, very slightly raised above the level of the skin, flat on the surface, and the skin covering them was paler than it was elsewhere. They felt hard, did not disappear on pressure, but became quite white. Patient said she had had them as long as she could remember, but she believed they first appeared when she was 14 or 15 years of age. The mother and one sister had the same condition. Three other sisters were free. There was no history of any male member of the family being affected. A nodule was excised for microscopical examination (Plate 45 (2)). The epidermis is flattened, all papillary arrangement has disappeared. The number of layers of the epidermis is somewhat smaller than normal, but the gradual transition, from the basal cell layer to the stratum corneum, remains intact. The basal cell layer is pigmented more than usual. Along the epidermis, processes are to be seen dipping down into the coriuin ; each process is cystic, the space being filled with horny material, in the centre of which lies a lanugo hair. Oddly enough, in some of the cysts acne bacilli are to be seen. These have probably penetrated from the surface, and might have had some- thing to do with stimulating the growth formation. Notice the age at which the tumours occurred, the age when acne most commonly commences. In places where the lanugo hair has been able to penetrate the epidermis, it is surrounded with several layers of horny material, having the arrangement, as seen in a transverse section, of an onion through its middle. Around these epidermal processes, there is no cellular infiltration (inflammation). In the corium are numerous hair follicles, all of which are cystic. The walls show the transition stages from the stratum spinosum to the stratum corneum, as is seen in the epidermis, with the only difference that the basal cell layer remains quite free from pigment. In the centre is a mass of horny material ; distinct cells are to be seen con- taining eleidin granides. In the centre of each horny cyst, a lanugo hair is to be found. Only here and there are any of the hair follicles surrounded by, or have in their neighbourhood sebaceous gland elements. ROLE PLAYED BY EPITHELIAL CELL. 517 Around each hair folhcle is well organised connective tissue, arranged circularly, and consisting of spindle cells with well stained elongated nuclei. The vessels running in this connective tissue are dilated, and the walls are thickened. Also surrounding the hair follicles, especially marked at the base and sides, is a dense cellular infiltration. This cellidar infiltration consists largely of plasma cells and small round cells. The marked feature of this cellular infiltration is the abundance of mast cells, many of which, as usual, stain red with polychrome methylene blue, but the proto- plasma is homogeneous, mucinous in appearance, non-granular, a type of mast cell which Unna described in Molluscum fibrosum. In the centre of the tumour is a large horny cyst, surrounded by epithelium which branches in a few places. Towards the centre of these branches the cells become larger, stain less dis- tinctly, and the spongioplasm becomes divided up into loculi — in short, the cell becomes a sebaceous gland cell. The transformation is not quite complete, since there is ncit that well marked differentiation of the cells, and the clear, well stained nucleus and network-like protoplasm, which is to be seen in normal secreting sebaceous gland tissue. These cells obviously are embryonic and functionless. In other places, scarcely any transition can be made out ; the epithelial cells have simply become swollen, refuse the stain, have lost their nuclei, and are degenerated cells. The collagenous bundles are broken up, and are not found in the new growth. The elastic tissue has in part disappeared, and nowhere shows its fine fibrillary character ; instead, it is broken up and occurs in clumps or masses. In no part of this section are there any traces of either sweat glands or sweat ducts. One of the cysts in the section shows an intra-cystic epithelial growth. In this cyst there is no lanugo hair, and no horny material ; the cells of the wall are not so well differentiated as those elsewhere, the cellular infiltration around is very much more marked, and no doubt the cells constituting this cyst are of an earlier date than the rest. Case 81. — Syringoma. — A girl, aged 12 years, came up to hospital, complaining of some spots on her chest. According to the mother's history, the spots appeared when the child was one year old. No other member of the family was affected. The lesions were very faint yellowish white, raised above the surface of the skin, and varied in size from that of a pin's head to that of a lentil. The lesions were 518 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. smooth on the surface and embedded in the corium, so that the skin was not mov- able over them ; they were sharply circumscribed, although the bigger ones were not invariably regular in outline. The lesions gave rise to no subjective symptoms. The area most affected was the chest, over the sternum and beneath the clavicles, and in these situations the largest lesions were to be found. The neck was also involved, lower eyelid on left side, lateral walls of thorax and abdomen, and inner sides of thighs. Histology (Plates 47 (1, 2) and 48). — The epidermis over the new growth, which is situated in the upper portion of the corium, is tmaltered. The corium itself is unchanged, except for the presence of the epithelial elements, from which the new growth arises, and also for a slight increase in the fixed connective-tissue cells. The new growth consists of the following structures : — (1) Solid cords and nests of epithelial cells. (2) Cords and nests of epithelial cells which are hollowed out in the centre, the walls of the former being made up of two layers of epithelial cells, the walls of latter of several layers, with the central cells degenerated and staining badly. The hollow cords resemble in every way the normal sweat ducts. (3) Small cystic spaces with a colloid content. The walls are made up of one or two layers of epithelial cells ; in parts, the cells are indistinct, and the nuclei, when present, are elongated. The colloid material is most marked in those cells in the walls which have degenerated, and appears to be a degeneration product of those cells. Although the case just mentioned is one in which the lesions are widely dis- tributed over the body, the lesions on the left lower eyelid are identical with those seen so commonly only in these situations, which cannot be distinguished from a trichoepithelioma or from a sebaceous adenoma, imtil a biopsy has been made. This is the condition first described and christened by Kaposi^^ and Biesiadecki^® as Lymphangioma tuberosum multiplex, a name which should no longer appear in any textbook, as the lesion is a sweat gland tumour, and has nothing to do with the lymphatics. The few cases described of hyaline degeneration of the skin — a painting of a case with a microscopic section is to be seen in Morgan Dockrell's^^ atlas — are nothing more or less than typical cases of sjTingomata. Case 82, Sebaceous Adenoma, was a man, aged 43 years, who had had flat whitish lesions in his oculo-facial folds, as long as he could remember. The lesions were sharply circumscribed, and about the size of lentils. The only clinical difference that I could ascertain between this condition and those already described, was that each papule seemed to be divided up into loculi, not unlike a wasp's nest, and the loculi were slightly more transparent than usual. T"f 1. Svi'iiigoina. ^ -#> Syriniioiiia, witli trii-liocpitliclioinntmis ■•IrmiMits. Plate 47. Facing p. 518. / ^"-N . ' '°«:-'> ' Syringoma. A ''\ i-<»ll'" Plate 48. Follows Phile 47. mt Follows Plate 48. ROLE PLAYED BY EPITHELIAL CELL. 519 Histologically, the coriiim was filled with sebaceous gland tissue, either fully formed, or, in parts, partly transformed from the epithelial cells, from which the gland cells took their origin. Case 83. — Mixed Tumour. — A woman, aged 36 years, had noticed some " white spots " beneath her lower eyelids since she reached the age of puberty. The lesions were round, white, smooth on the surface, slightly raised, and clinically quite in- distinguishable from any we have already described. A histological examination of this mixed tumour showed the following points (Plate 49). In the left-hand part of the section, beneath some lanugo hair follicles (tricho- epithelioma), are some small cysts, below which again are some solid cords of epi- thelial cells, both constituting a syringoma. The lanugo hair follicles persist in all parts of the section, but in the right-hand side is seen a typical sebaceous adenoma. Some of the cells are well formed sebaceous gland cells, while others have not yet been formed from the epithelial cells destined for the purjiose. Another type of tumour occurring in these situations, is the EjjitheUoma adenoides cysticum of Brooke. The lesions are more widely spread on the face than in the cases just described, are rather larger, more elevated, and not so flat on the surface. The condition occurs in women, and the lesions appear in childhood. The marked feature about the disease is the strong hereditary element, mother and daughter being usually affected. Histologically, the lesions consist of masses of epithelial cells, which are highly branched ; in the centre of the masses, there may be a cyst in which lies a lanugo hair, or the cyst is filled wholly or in part with some homogeneous substance, as is found in a milium. Another condition found also in the same regions, the earlier lesions of which are with difficulty to be distinguished from the case just described, is the Ulcus rodens multiplex. This case has been previously recorded by Dr. Adamson,^^ ^* : — " ' D — C — , aged 37 years. History of condition : Two and a-half years ago he first noticed a small red spot near the outer canthus of the left eye, which gradually grew in size. Seven months later a second spot occurred near the outer canthus of the right eye and increased slowly in si^e. At about the same time another ulcer appeared on the forehead above the right eyebrow. This one has healed of its own accord, but has left a scar exactly similar to the scarring which has occurred round the ulcer underneath the eye. There is another ulcer on the inner side of his nose, and one on the under lip and another on the side of his neck, but he cannot give any accurate account of the dates at which these appeared. 520 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. Present condition : In addition to these six patches which have been already described, there are numerous pimples on his face. They vary from the size of a millet seed to that of a split pea. As many as twenty or thirty of these can easily be counted. Were it not for the fact that he states that the ulcerated patches all began viith. simple pimples, they would perhaps barely deserve attention, as they have the appearance of small sebaceous glands in which the ducts are blocked. Two of these pimples have been excised and examined microscopically, as well as pieces from the six ulcerated patches above alluded to. They one and all exhibit the microscopical appearance of typical rodent ulcers, as are displayed under the microscope. The patient is now undergoing electrical treatment with X-rays four times a week, and is deriving considerable benefit from it. The ulcers are healing rapidly. N.B. : The patient remained in hospital about six weeks after he was shown, during which time the ulcers completely healed ; but the pimples, though they improved and diminished in size, and in some instances entirely dis- appeared, had not altogether vanished. The patient declined to remain any longer.' " Later the patient was again in the hospital, and many of the lesions were excised and others were scraped. In 1907, by the kindness of Mr. Bruce Clarke, I (Dr. Adamson) had an opportunity of seeing this patient. There were then altogether seventeen lesions upon the face, varying in size from small nodules of the dimensions of a pin's head up to ulcerated lesions of 1| in. in diameter. There were also scars marking the excision or scraping of former lesions. For purposes of description the lesions then present may be divided into groups as follows : — " (1) Six nodules, reddish in colour and serai-translucent, of the size of a large pin's head to that of a millet seed, and distributed over the left cheek and the fore- head. " (2) Nodules of the size of a millet seed to that of a split pea, dull red in colour, raised, but flat on their surface, firm and semi-translucent ; a grouj) of three upon the right temple at the outer angle of the orbit, two just below the left ala of the nose, one on the left upper eyelid, and one on the left brow. " (3) Larger lesions, which have undergone treatment on a former occasion ; two on the forehead, one on the left ala of the nose. These were from J in. to | in. in diameter, with a central scar and a marginal rolled edge. " (-i) An irregularly shaped lesion, partly scarred, partly ulcerating, and partly crusted, extending from the inner canthus of the right eye on the right cheek, here and there showing a raised nodular edge. This lesion measures 1| in. in length by f in. in diameter. ROLE PLAYED BY EPITHELIAL CELL. 521 " (5) A similar iilcer, 1 in. by 11- in., involving the inner canthus on the left side, the lower lid, and the left cheek. " (6) About the forehead and cheeks there are scattered a few niilia, but there are none on the lesions themselves." Histology (from sections kindly given to me by Mr. Onslow Ford). — Beneath the ulcerating surface, is a new growth of spindle cells ; the cellular masses are irregular in outline, and in many places branch — features typical of a rodent ulcer. Only here and there are cysts to be found in the spindle celled masses, but they are not of the type found in those cases described by Jarisch. Those present in this section are empty and, probably, spurious. Around the new growth is a dense cellular infiltration, consisting of polymorphonuclear leucocytes, plasma cells and lymphocytes. The most interesting part of the section is the occurrence of a true sebaceous adenoma in the healthy corium siuTOunding the new growth, and also masses of epithelial cells not quite mature, on their way to form sebaceous gland tissue. It is not uncommon to find a trichoepithelioma and a sebaceous adenoma in the same section as a rodent ulcer {vide Plate 46), although the simultaneous occurrence has, as far as I know, not been described. The combined growth undoubtedly speaks largely in favour of a rodent ulcer being a neevus, and having its origin in epithelial cells which are not mature enough to form any specialised epithelial structure. In these sections, and in others from smiilar cases, which I have examined since, I have frequently found mole elements, that is to say, locaHsed collections of embryonic endothelial cells in the periphery of the epithelioraatous growth. Although I have described only one case of each type, it is only with the idea of giving the main clinical and histological features thereof, since, if several cases be microscopically examined, although the clinical aspect of all may be the same, extraordinary variations are to be met with. * For instance, in the so-called Epithelioma adenoides cysticum — a bad name, as it gives no clue to the adenoid tissue affected — one may find lesions more closely resembling the Trichoepithelioma papulosum, as described in Case 80, while, on the ' other hand, the origin of the epithelial masses from the lanugo hair follicles may be so difficult to make out, because of the more embryonic nature of the cells, that the condition becomes more like that seen in multiple rodent ulcer. Take multiple rodent ulcer ; in some cases, cysts are evident, hence the name multiple benign cystic epithelioma. The walls of the cysts consist of cubical cells, almost indistinguishable from mature rete cells, so that the epithelial masses in which the cysts occur suggest an origin from the lanugo hair follicles. In other 522 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. cases, again, the epithelial masses consist of spindle cells only, and a diagnosis could not be made from an ordinary rodent ulcer. See again how the common single rodent ulcer itself varies. Some consist of pure spindle cells, while in others cubical cells are found, with horny matter in the centre. These variations are links in one pathological chain, and entirely depend upon the time the cells forming the tumour were laid down in their embryonic life. The most mature are the true adenomata, %az., trichoepithelioma, sebaceous adenoma, and syringoma. Going back, we meet with a condition which can be said to arise from lanugo hair follicles — a trichoepithelioma, but at a period when sebaceous gland and sweat gland tissue has not been organised, as seen in Brooke's type, which would be better called Trichoepitkelmna jiapidosum (Brooke). Still further receding, we reach the condition when the origin of the epithelial masses from the lanugo hair follicles is by no means clear, although suggested. As the lesioias in which this condition is found histologically, ulcerate clinically, they should be called Trichoepithelioma papulosum ulcerans. Lastly, in those cases in which the cells are too embryonic, when the epithelial masses are formed from the primary epithelial cells, before hair folhcles are even conceived, the term Ulcus rodeiis, be they single or multiple, should stand. If we regard rodent ulcer as a malignant disease, and this is quite logical, although it does not form metastases, the reader will at once observe that there are two kinds of mahgnancy — one which affects embryonic cells, the other which affects mature cells. Embryonic-cell malignancy, as far as the epithelium is concerned, differs from the mature-cell malignancy in several ways. The cells are more closely packed together, ail the cells are the same, i.e., there is no nuclear or nucleolar activity to make them differ from one another morphologically. The gix)wth is more regular ; there is not so much tissue invasion, the protective leucocytic infiltration is less marked — indeed it may be almost entirely absent ; it does not form meta- stases, or give rise to lymphatic gland enlargement ; and, lastly, the malignancy is less pronounced. The tumour is malignant in the sense that, if allowed to do so, it will extend and eat through any tissue that bars its progress. As the term malignancy, used in this sense, is apt to be confounded with the usual meaning of the ^^'ord, I cannot help thinking that it would be better to designate the malignancy of embryonic cells as simply "' embryonic activity," and to use the term " mahgnant," when matitre cells behave pseudo-parasitically, or exhibit the nuclear and nucleolar activity, which I have just described. WTiat is the reason for the frequency of these growths in the orbito-facial ROLE PLAYED BY EPITHELIAL CELL. 523 and naso-facial grooves ? Generally speaking, cutaneous new growths, which are usually of epithelial origin, are more common in raan than in tlie rest of the mammalia, and new growths are more hkely to occur in situations which once served a purpose. Most mammals have speciaHsed hairs in the orbito-facial fold, corre- sponding to the supra-orbital eyebrows, and no doubt serving the same purpose ; further important glands occur in both the orbito-facial and naso-facial folds of many animals. Owing to a more or less uniform distribution of sebaceous and sweat glands, man stands in no need of those facial glands, so characteristic of many antelopes. The commonest epithelial growth is in connection with the lanugo hair follicles — trichoepithelioma — growths which are usually limited to the face, and which, in my opinion, arise in those lanugo hair follicles which are atavistic of the lower eyebrows. Lanugo hair is embryonic, is atavistic, and a remnant of the complete body hair-covering, whicli is typical of most of the mammals. The adult members of the orders Sirenia and Cetacea are hairless, but the young of the former are covered with hair, and in the young of the latter, the hair IS Hrnited to the face. Tlie only exceptions are the Beluga or White Whale, and the Monodon or Narwhal. Young elephants have lanugo hair, like the liuman hair; The lanugo hair folhcles soon disappear, but some on the face remain, and they are those which are atavistic of the specialised hairs, which ought to have formed the lower eyebrows. Syringoma is, again, a common new growth. In man, the sweat glands are uniformly distributed over the body, but in many animals they are localised — for instance, to the soles of the feet in some of the rodentia — or they may be completely absent, as in the Sirenia and Cetacea. In animals, most of the sweat glands open into the hair follicles, but some have their own point of exit in the epidermis, the latter being the case in adult life only. As in man, the sebaceous glands in animals are usually associated with the hair follicles, but may be found alone, viz., peri-anal glands, etc., but these are probably specialised glands. So closely are the sebaceous glands connected with the hair follicles, that when the hair of the Cetacea disappears, the sebaceous glands vanish also. Like the sweat glands, the sebaceous glands are in some animals localised, for instance, to the snout and anus in the Manis or long-tailed Pangolin, or they may be absent altogether, although the animal be well covered with hair, viz., Cholcepus and Chrysochloris. With the possible exception of the peri-anal glands, man possesses no specialised skin glands, which are so characteristic in other mammals, and which are made 524 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. up of either sweat or sebaceous glands, or of a mixture of the two. They are situated in different parts of the body, in the various orders, the face glands being t^-pical of the Artiodactyla and so on. Of the face glands there are two kinds : — • (a) Supra-orbital, as in the Beisa {Oryx heisa). (b) Sub-orbital or ante-orbital. The second group is typical of certain deer, and, in most cases, is designated by a fold of skin or pocket, the edges of which are sometimes inverted ; these are the so-called tear grooves — folUculi lacrymales. In my opinion, the small tumours so frequent below the lower eyelid, which may be made up of lanugo hair follicles, and often of sebaceous and sweat gland tissue, are reversions to the face glands of deer. The tumours are often mixed, which is another point in favour, since the ante- orbital gland of the Gnu is made up of both sebaceous and sweat glands, which may open separately in the epidermis, or direct into the hair follicles. If the sebaceous gland type of tumour be carefully examined, it is often found with remains of a lanugo hair follicle in the centre. Human beings are not only those affected with epithelial growths below the lower eyelid ; I have seen the same in monkeys. For my animal material I am indebted to Dr. Plimmer, pathologist to the Zoological Society. Summary. Tumours affecting the orbito-facial and naso-facial grooves are of epithelial origin, and atavistic of both the lower eyebrows and the specialised glands found in these regions in many of the mammalia. There is probably not an individual which will not show some trace of epithelial embryonic tissue (naevus), when a section is made from the skin of these grooves. All the tumours, from a simple lanugo hair follicle growth, to a rodent ulcer, are links in one chain, the former being the head or most mature, the latter the tail or most embryonic. As they are all links, the histological difEerences of one clinical entity is at once explained. There are two kinds of malignancy. One which is better called embryonic activit)', of which an example is. the rodent ulcer. The more embryonic tissue is, the greater its activity, and hence the less benign it is. The other form of malignancy is the true malignancy, i.e., the condition which gives rise to lymphatic gland enlargement and metastases. It is due to nuclear and nucleolar activity of the mature cells. True malignancy can probably be ROLE PLAYED BY EPITHELIAL CELL. 525 produced by many causes, all of which are irritative. It is also probable that true malignancy is really a localised effort on the part of the host to combat the irritation which commenced the process. The more pressing the stimulus, the greater the response, until the host's cells themselves become parasitic upon the host. 1 McDonagh (1912), " Brit. Journ. of Derm.," xxiv, 291. - McDonagh (1914), " Journ. of Cutan. Dis.," xxxii, 11. ' McDonagh (1914), '• Arcliiv f. Derm. u. Syph.," cxx, 289. * Urma (1905), " Zcitschrf. f. Krebsforschung," iii, 218. ^ V. Recklinghausen (1894), " Monatsh. f. Prak. Dermat.," xix, 595. " McDonagh and Wallis (1913), " Bioch. Journ.," vii, 517. ' Unna (1913), " Biochem. der Haut." G. Fischer. Jena. » Russell (1890), " Brit. Med. Journ.," ii, 1297. » Plimmer (1899), "Practitioner," Ixii, 453. '" Apolant u. Embden (1905) " Zeitsohrf. f. Krebsforschung," iii, 579. " Wallis and Soholberg (1910), " Quart. Journ. of Med.," iii, 301. '- Ibid. (1911), iv, 153. " Adamson (1908), "Lancet," ii, 1133. " Bruce Clark (1903), "Transact, of Clin. Soc," xx-xvi, 271. '^ Kaposi (1899), " Handatlas der Hautkrankheiten." Wien. '" Biesiadecki (1892), " Untersuch. aus dem path. Instit. zu Krakau." " Morgan Dookrell (1905), " An Atlas of Dermatology." Longmans, Green & Co. London. '8 McDonagh (1915), "Brit. Journ. of Derm.," xxvii, 91. WORKS CONSULTED. Max Weber (1904), " Die Saugetiere." G. Fischer. Jena. Brinkmann (1911), " Bidrag til Kundskaben cm Drovtyggernes." Kobenhavn, CHAPTER XLVI. THE ROLE PLAYED BY A LYiffHOCYTE IN INFLAMIVIATION, .iND ITS PROBABI-E EEL4TI0NSHIP TO SARCOMA. Introduction. The first consideration will be given to the life history of the lymphocyte, including its origin, and the cell to which it gives rise. The biology and biochemistry of the plasma cell will be discussed, then the role which the lymphocytes and plasma cells play in acute and chronic inflammation, and, finally, the probable relationship which exists between the latter and sarcoma will be dealt with. Origin of Lymphocytes. Lymphocytes have their origin in the granoplasm of endothelial cells (Plate 21 (1, 2)), and they are formed mosb abundantly in the spleen and in the lymphatic glands. They may also be formed in the bone-marrow, and in any tissue where their presence is required. It is owing to their capacity for being formed in the skin, that a few observers have stated that the corium is studded with minute lymphatic gland elements, which, of course, is not the case, strictly speaking. It is generally held that lymphocytes are formed only in the lymphatic glands, spleen, and bone-marrow, and that if they are required at a certain spot, in the skin for instance, that a message is conveyed to the nearest lymphatic glands to elaborate lymphocytes which, when formed, travel the round of the systemic blood stream, before arriving at the station from which the call came. What the nature of the message is, how it travels along the different lymphatics, and how the lymphocytes enter the circulation, are points which are not explained. It would not be nearly so hypothetical to assume that lymphocytes are formed in situ, that the lymphatic vessels are capable of forming more if required, and that the lymphatic glands are of the nature of a base, wherein an almost inexhaustible supply can be produced. In order to see what really happened, I removed chancres ROLE PLAYED BY LYMPHOCYTE. 527 in all stages, with a long strip of skin posterior to them, which is a simple matter when the sores are situated on the tip of a long foreskin. If the patient is circum- cised, transverse sections may be obtained of the base, and an examination, therefore, will give the clue as to what is happening between the sore and the nearest chain of lymphatic glands. So far as the l3nnphatic system is concerned, one finds a dilatation of the vessels with a proliferation of the endothelial cells, surrounded by a collection of mixed, small round cells (lymphocytes) and plasma cells. Here and there, an enormous collection of cells is to be seen, in the area covering the whole field of the microscope. In the centre, instead of finding a gaping lymphatic vessel, a collection of endothelial cells is to be seen, some of which have become fused together to form a giant cell, while the protoplasm of others is in the process of giving rise to lympho- cytes, as in Plate 21 (1, 2). Outside this endothelial collection, are to be seen numerous large mononuclear leucocytes and plasma cells. Seeing such a field under the microscope, and being unaware what the tissue was, one would imme- diately say that it was a section from a lymphatic gland. The endothelial proliferation is in some places so marked, that the lymphatic vessel becomes obliterated ; hence the nature of the lymphangitis or lymphatic cords that are so commonly to be felt running between the sore and the glands. In some cases, as serial sections show, the cellular infiltration is more marked in some areas than in others, hence the explanation of the nodular character that the lymphangitis or lymphatic chain of beads sometimes takes. From what has been mentioned, there is now proof that lymphocytes may be formed from the endothelial cells of the lymphatics. From repeated examina- tions, I cannot help coming to the conclusion, that the giant cells which are to be met with in chronic inflammation are nothing more nor less than a fusion of endo- thelial cells which block the lymphatic, of the nature of an endolymphangitis, a.nalogous to an endophlebitis or endarteritis. The fact of the nuclei collecting together at one pole of a giant cell, as they not infrequently do, does not argue against the correctness of the above theory, since endothelial proliferation ma}^ take place in one area, and not around the whole circumference of a vessel, as is again witnessed in veins and arteries. In a chancre, local lymphangitis is well marked, and typical endothelial cells with embryo hanphocytes in their protoplasm are also to be seen, before the lymphatic vessels posterior to the sore show a similar change, so it follows that lymphocytes can be formed in the site of the infection. In the lymphatic glp,nds, lymphocytic formation is at its zenith, and, at first sight, it appears difficult to say whether the lymphocytes so formed are destined 2l 528 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. to remain therein to do their work in hco, or whether they are sent out to the site of infection. On further examination, it is clear that many, if not the majority, of the lymphocytes formed in a lymphatic gland, remain to act where they are formed, for the following reasons : In early generahsed syphihs, there is a marked lymphocytosis, which is more pronounced in the severe than in the light cases, and which is increased by treatment ^^. The greatest enlargement of the lymphatic glands is not in the severe cases, and, moreover, there exists no ratio between the degree of lymphoc\i;osis and the enlargement of the lymphatic glands. On the contrarj^, the greatest lymphocjiiosis is most marked in those cases in which the glands are only shghtly enlarged. In Hodgkin's disease, the glandular enlargement may be enormous, but there is no lymphocytosis. Furthermore, if the bone-marrow is examined post-mortem, in every case which has succumbed to a lymphocytoraa, it will be found to be diseased only in those cases, in which, during Hfe, the patient had a lymphocytosis, or in other words, it gives the blood picture of a lymphatic leucaemia. Hence the probability is, that all the lymphocytes which circulate in the blood stream, are of bone-marrow orisin. Staining Characters of Lymphocytes. An endothelial cell containing embryo lymphocj-tes, when examined in vivo stained with borax methylene blue, appears to be full of numerous small round cells. ^Vhen examined in fixed specimens (Plate 21 (1, 2)), the cells in process of formation are found scattered about in the protoplasm, and frequently appear to be divided into groups by septa. The endothelial cell degenerates after the lymphocjiies have left it. The embryo lymphooiies stain deeply with haematoxyhn and basic dyes and in sections stained ^vith Pappenheim's mixture of pjTonin and methyl green, some stain a brilhant red, and some a brilhant green. Chemically, they consist of nucleo-protein and a hpoid-globulin adsorption compound. It is the prevalence of one substance over the other, which determines as to whether they will stain with the pyronin or the methyl green, the latter being practically specific for nuclein, and the former for lipoid-globulin. The stained masses are distributed unevenly in the cell, but in nearly every case they cover practically the whole cell, hence the reason why a lymphocyte looks as if it is all nucleus. It is not until the cells become adult, that the nucleo-protein becomes differen- tiated into chromatin threads and dots, then the lipoid-globulin becomes the ROLE PLAYED BY LYMPHOCYTE. 529 colloidal membrane of the nucleolus — the vital part of the nucleus. When this is complete we have the small lymphocyte. Function of a Lymphocyte. Now what is the function of the small h'mphocyte ? One answer can be given with certainty, and that is, that it is '" not " phagocytic ; its function is doubtless a chemical one, of the nature of a ferment action, an action which is probably more marked in the cell to which it gives rise than in its own self. If sections are stained with rongaht white, nuclei stain blue, which proves that they contain free oxygen^. If sections are treated with benzidine and hydrogen peroxide, the nuclei also stain blue, which proves the presence of a peroxydase. Therefore, nuclei contain free oxygen and a ferment for activating the same, and the action of the latter is doubtless accelerated by the iron, as in the ease of the red blood corpuscles. The oxidising action of a lymphocyte may be used directly against the cause for which the cell is elaborated ; or indirectly, by gi\'ing up the oxygen to the protoplasm of the cell to which it gives rise. The Cell which Develops from Lymphocytes. This now brings me to describe the cell which develops from the small mono- nuclear leucocyte, viz., the plasma cell. Plasma cell. — The general opinion prevails that a plasma cell originates from a lymphocyte, but there are still a few observers who hold the view that a connective tissue cell is its progenitor. Connective-tissue cells are in a way insignificant cells, as their function in inflammation is mainly mechanical ; they act as a barrier, which is still further strengthened by multiple division of the parent cells into young connective-tissue cells. Collagen and elastin result from the old connective-tissue cells, and the disappearance of the former, with first clumping, and then disappearance of the latter, which is frequently referred to by skin histologists as being diagnostic of certain affections, is what always takes place when there are sufficient inflammatory cells present. Connective-tissue cells, hke other cells, degenerate ; hence ib might be expected that certain chemical entities are to be met with, in the degenerated products. The name collagen is given to one form of degeneration of a connective-tissue cell, and it is a substance which is recognised by the affinity it has for acid stains such as acid fuchsin and water blue. This acidophilia is due to the presence of basic 2l2 530 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. amino-acids. iiame]}% arginine, lysine and histidine, as Unna ^ has ingeniously uhown. As stated in Chapter XLV., degenerations such as colloid, hyaline, etc., are true T?liemical substances, or, in other words, analytic products of protein metabolism. In some degenerations, certain amino-acids are more active than in others, some amino-acids act as acids, others as bases, some have a strong reducing action, others have none ; hence it is at once obvious why the different forms of degenerations have not got identical staining properties. Elastin is, doubtless, likewise a degeneration product of connective-tissue cells, and the way in which it differs from collagen is entirely dependent upon the predominating amino-acids. Elastin is basophilic, owing to the excess of glycocoll, leucine, alanine and phenylalanine over the other amino-acids^ ; moreover, reducing amino-acids are found in elastin, namely, leucine and tyrosine, therefore it is clear why the staining properties of these two degeneration products should be so different. By an increase in the size of the protoplasm of a lymphocyte, a plasma cell is formed ; the protoplasm bulges in one diameter more than in another, so that the cell has a " cottage loaf " appearance, or in other words, the nucleus looks as if it was excentrically placed. The nucleus of a plasma cell does not differ from that of a lymphocyte ; it is di%'ided up into chromatin masses and threads, in the centre of which a nucleolus is generally to be seen. It is in the protoplasm that the chief difference lies, for, in fixed specimens, a small lymphocyte appears to have no protoplasm, while a plasma cell has about three times as much as the nucleus, and it stains brilliantly with pyronin. If the cells are examined in vivo, stained with borax methylene blue, the distinction is less evident, as the nucleus of the plasma cell is more centrally placed, and, if one depends upon the amount of protoplasm surrounding the nucleus to draw the distinction, one is at once confronted with the similarity of a plasma cell to a large mononuclear. In many cases, it is extremely difficult to differentiate between the two cells, the plasma cell and the large lymphoc^iie ; but the following four points will materially assist one in the task : — (1) One pole of the nucleus generally touches the circumference of the proto- plasm in one place, in a plasma cell. (2) In the protoplasm of a plasma cell, irregular masses are to be seen, and they stain deeply with the methylene violet moiety of the borax methylene blue. (.3) The nucleus of a plasma cell stains more deeply. (4) The nucleus of the large mononuclear usually contains more than one nucleolus. ROLE PLAYED BY LYMPHOCYTE. 531 The deep blue staining, taken on by these masses which are to be seen in the protoplasm, is copied by the nucleolus, therefore the two structures have one point in common. Since the methylene violet is the basic half of the borax methylene blue, it may be assumed that both the masses and the nucleolus prefer basic stains. Further than this, staining in vivo will not take us. If we now turn our attention to fixed specimens, and «tain them with Pappenheim's stain, we inuuediately notice that the protoplasm of the plasma cell stains homogeneously with pyronin, that it is not divided up into masses, and that the nucleolus also stains a brilliant red. If sections are left for some hours in weak solutions of various reagents, and then stained with Pappenheim's stain, it is found that the protoplasma of the plasma cells and the nucleolus are far more resistant than the protoplasm of other cells, and that they behave hke a globulin. Owing to the optical activity of both the nucleolus and the protoplasm, the globulin is shown to be in a colloidal adsorption compound with a lipoid.^ All cells contain lipoids, and observers who have paid attention to the chemistry of cells, have always been careful to treat their material first with alcohol and ether, so as to remove the lipoids. No one has hitherto recognised that all the lipoids cannot be extracted by alcohol and ether; in fact, those which are in an adsorption compound with globulin are untouched. These lipoid-globuhn adsorption com- pounds are the very essence of the existence of the cells, indeed of life itself. I need only mention that the granules of the choroid plexus, and NissFs granules are made up of lipoid-globulin complexes,* to substantiate my statement. Hitherto, the most resistant part of the protoplasm has been looked upon as being a nucleo-protein, and to-day it is generally held that Nissl's granules are of the same nature. The name " plastein " has frequently been given to this resistant substance, and to several other substances of which the observer has no knowledge. Without going into the history of nucleo-proteins in the protoplasm of cells, I may say that they are not nucleo-proteins at all, but lipoid-globuhns. The marked avidity for pyronin which both the nucleolus and the protoplasm of plasma cells show, the fact that they are both resistant to reagents, the fact that both are feebly optically active, and the fact that both have feeble reducing pro- perties, brings them into line with the phases of the Leucocytozoon sypJiilidis. The resemblance is only superficially close, as when one attempts to measure the degree of resistance to reagents, etc., the protoplasm of the plasma cells and nucleoli falls far behind that of the parasitic bodies.^ The divisou of a cell is dependent upon the presence of this lipoid-globuhn complex, and as it is the nucleus which is concerned in this process, the nucleolus is found in the nucleus, and not in the protoplasm of the cell. 532 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. The lipoid-globulin in the protoplasm of the plasma cell is present for quite a different purpose, since, when the protoplasm of a plasma cell breaks up, and it often does so without interfering in any way with the nucleus, the fragments still have the properties of Hpoid-globulin. The function of a plasma cell is certainly not phagocjiiic, but, from analogy to other cells which also contain hpoid-protein, it would appear to be a carrier of a ferment, the function of the ferment being to stimulate or to activate the adsorptive action of the protein. The plasma cell is not present in sj^hihs only, for it is seen in any chronic inflammation, such as tuberculosis, or the chronic inflammation which may be produced by a piece of silk or wax. In all cases, the plasma cell is morphologically the same, and although its gross action may be similar in every instance, it is, nevertheless, specific in each case. Take, for example, three plasmomata, one caused by syphihs, another by tuberculosis, and the third by a foreign body. Give an injection of salvarsan, and then make sections of all three again, when, on examination, it will be found that the only plasma cells which have altered, are those of syphilitic origin. To explain this specificity, we must probe the chemistry and physico-chemistry of the plasma cell, and this has been fully described in Chapter VI. ; there is no need to reproduce it again here. All my recent work on this subject leads me to believe that specificity rests in the way in which the Upoid-globulin particles are built up. An homologous stereo-chemical molecular configuration exists between the lipoid-globuUn particles of the host (some are in the plasma cell) and those of the parasite. The lipoid- globuUn particles of the host constitute his protective machine, the action of which is to destroy the Hpoid-globuHn particles of the parasite, by means of adsorption, and consequent precipitation, and ultimate hydrolysis. It is the oxidising ferments that activate the adsorption. Degenerate Forms of the Plasma Cell. I will now pass on to the degenerate forms of the plasma cell, which have never been fully described before, although Unna, some years ago, drew attention to them,^^ and which have frequently given rise to faulty histological interpretations. "When examined in vivo (Plate 20), stained with borax methylene blue, large round cells, which stain red, are sometimes to be seen. They may contain no nucleus, or the nucleus may be found outside the cell, lying on a portion of its circumference. In some of the cells, dots, masses and strands may be seen, which stain with the methylene violet, and are situated anywhere, and scattered about i rregularly in the cell. These bodies may have no connection with the nucleus « »**© /■ i •A '9 ^ % Plate 50. Crystalline forms of aminoplasma cells from a syphilitic lyni|ilin,tic gland. The section has been stained with pjToniii and methyl green. 2. Section of a lymphatic gland from the neck of a rat which had died of trypanosomiasis. Stained with pyronin and metliyl green. Note the dilated vessel, with endothelial cells in the lumen. Similar endothelial cells are also to he seen in the tissues around. Some of the endothelial cells are multi- nucleated ; in the nucleus of others, two or more nucleoli are to he seen, in a few the nucleus has vanished altogether, and in aU, the chromatin stains badly, and there is no attempt at the formation of lymphocytes. Many of the plasma cells will be seen to have two or more nuclei. Here and there in the section, amorphous pyroninophile masses are visible which have originated from the protoplasm of some of the plasma cells. Facing p. 532 . -M- ueuh any clu l;ich may 06 aTAJ^^^'^'^''^®^^^' specific in rnrh. • Hiomata, one caused by ■ign brfey. Give an injection oi salva, .n-^OTj IvriJ-Hii Iirii: (liiior/q fitivr fi9fii(i1>-. ns-aJ Bnil noiJoee sdT u'O-cher::' J', ijiil) buti >{■ l-)m odJ uionl btiiilg ailBiliimv.l ); lo rioiiaife fii allao iaihatobaf) Airii ,ha837 ' -i:!UIM nK ^iiv) ij;lliliiul-li-. -n, n. n.iwr. LfUfOf* 83038** 8d* HI n6^ sdOi'' '■ (li ,riooa wi .o* o-wiloaloiiaaiom ao ow* .eaodio io aasloun 9(t> aL^jf^iitefi^w'^jr;! r -■A.i.U ai'tfiutcwlp odJ ,11^ oi bus .isiliogoJte b9d8i(tJiY sfid auebuii add ■wsl- e ;; oi'A&8'id'f6W^*i^|ji^^'^d^ b'jljJiiiMlTJ ■■i>V(;il il;lil/I «iHlwiY'yH: fcn-;^ii:ii fiiriiqOf(afOItjq'g}JoBcfIOHLft'',!flB5ij9089ilJ interpi' .vitii Lni' \lene bl y be set iiere, and sc; nection witL 'J.i-. .SS3 .fK Vt'^>o^ [©-Sis' Q ^ - \ Plate 50. ROLE PLAYED BY LYMPHOCYTE. 533 and the larger the cell, the fewer there are to be found, and in many of the largest cells none at all are to be seen. In fixed .specimens (Plate 23 (1, 2)) the appearance of these cells is very difJerent, and instead of being round homogeneous cells, they are often irregular in shape, and divided up into irregular sized loculi, or balls of protoplasm, many of which become loose and scattered about in the tissue. These balls stain with safranin, acid fuschsin, and give a berlin blue reaction with a mixture of potassium ferricyanide and ferric chloride. They do not stain well with pyronin, but, in some specimens, strands of protoplasm, which do stain with pyronin, are to be noticed in between the loculi. The strands are, no doubt, the same as the dots, masses, and strands, which were described in the in vivo method, as showing an affinity for methylene violet. The.se ballooned plasma cells have, in some cases, lost their nuclei, while in others, the nucleus has lengthened out, and fits one apex of the cell, like a cap does the head, and not infrecjuently it sends string-like processes down over the cell protopla.sm. The.se cells are, no doubt, degenerated plasma cells, because the protopla.sm gives amino-acid reactions, and the nucleus fails to stain with methyl green, owing to the disappearance of the nucleic acid radicle, which leaves the protein radicle (histone and protamine) behind. The aminoplasma cell is a form of plasma cell which Unna^^ has called, from his examinations thereof in fixed specimens, hyaline plasma cell. The term " hyaline " rather suggests some relationship to cartilage, although it is very largely used for substances of which the observer has no knowledge. Now hyaline cartilage is a strongly basophilic substance, owing to its chondroitin sulphuric acid radicle. Unna's hyaline plasma cells are, on the other hand, acidophilic, and contain no acid radicle ; furthermore, they have very strong reducing properties, and so cannot stain with methyl green, and, as I have shown that this reducing action is due to tryosine or trypophane, I consider that the best name for them is aminoplasma cells. The cells are frequently to be met with in syphilitic material, but they are also to be found in any very chronic inflammatory lesion, viz., RJiinoscleroma and Ulcus molle serpiginosum. It rarely occurs that plasma cells degenerate into crystalline forms (Plate 50 (1)), either as .sheaves or as rectangular prisms. The nucleus in these cases remains intact, and stains fairly well with methyl green, and this is not invariably the case in the aminoplasma cells, a point which suggests that the crystalline degeneration is higher in the scale than the amino-acid degeneration. Further examinations also bear this out, because the crystals stain better with pyronin, and they have a feeble reducing action in comparison with the ordinary aminoplasma cells. 534 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. If a cell degenerates, the products formed thereby must be chemical entities, which probably do not differ from those formed in the process of digestion. Between the albumose and amino-acid stages, one finds the polypeptides ; therefore, as these crystalline cells are not so degenerate as the aminoplasma cells, one is tempted to call them polypeptide cells, since we are all aware that polypeptides can exist in the crystalline form. Summary. A lymphocyte originates from endothelial cells. A lymphocyte gives rise to plasma cells. The function of a plasma cell is to protect its host against an enemy, by adsorping his specific lipoid-globuUn, which results in his disintegration, and this adsorption phenomenon is activated and stimulated by oxydising ferments, which are ever present, but are not specific. Plasma cells undergo degeneration into polypeptide and aminoplasma cells, the latter form being hitherto regarded as hyaline degeneration. The Parts which Lymphocytes and Plasma Cells Play in Disease. Let us now turn our attention to the study of the lymphocyte in disease, and note the morphological changes it and the plasma cell undergo in inflammation, in the so-called leucaemic affections, and in sarcoma. (a) Inflammation. In inflammation, a phenomenon which may be caused by various diverse factors, one sees a lymphocytic and plasma-celled infiltration, which disappears when the cause of the inflammation vanishes. Supposing, on the other hand, that the cause does not vanish, and that the host dies as the result thereof, is there any difference in the morphological characters of the protecting cells ? A plasma cell infiltration, par excellence, is to be seen in protozoal infections ; therefore, to get cases which have succumbed to the infection, I have had to use rats which have died of sleeping sickness — material with which the London School of Tropical Medicine very kindly supplied me. I have chosen chiefly lymphatic glands for my study throughout this part of the work, because they may be looked upon as one of the best measurements of the protective capacity of the host. Plate 50 (2) is a section of a lymphatic gland removed from the neck of a rat which died of trypanosomiasis. One notices first of all a marked dilatation of a lymphatic vessel, with numerous free endothelial cells in its lumen. In the surrounding tissue, there are also many endothelial cells. There is a well-marked plasmoma, in which the plasma cells ROLE PLAYED BY LYMrHOCYTE. 535 show a distinct change, from the normal, in that the nuclei are freely dividing, and, in some cells, even three and four nuclei are discernible. This picture, I feel, should be interpreted in the following light : Owing to the demand upon protective cells, those already formed are doing their best to multiply of their own accord to form double, treble, or quadruple the number of plasma cells by simple amitotic division. More plasma cells have to be formed, so there will have to be a heavy production of lymphocytes, and this necessitates prunarily an increase in the number of endothehal cells. In any infection, the cause thereof will be combated first by those cells which are already formed ; if these suffice to conquer, then all is well. If, on the other hand, they lose, they will have to call up their reserve forces, but in the meantune they will make an extra effort of tlieir own, by trying to multipl}'. Therefore, in a very severe infection which speedily causes the death of the host, you will get the multiplication of the forces already there, also an increase of the forces at the base, but the latter will be prevented from coming to the front ; hence the reason why, in this section, the endothelial cells are not to be found in the active condition of manufacturing lymphocytes, why many of them contain more than one nucleus, and why very few lymphocjrtes are to be seen. (b) Leucaemia. The term " leucaemia " is an unfortunate one, as it means only leucocytes in the blood. Now, leucocj^tes are not manufactured in the blood, therefore they must be formed somewhere before they can get into the blood stream. They may be formed in many places, viz., in the lymphatic glands, spleen, and bone-marrow. However many are formed in the first two organs, none will get into the general circulation, this being the case only when the bone-marrow is the depot. Since the cause of leucaemia does not necessarily attack the bone-marrow first, it is at once seen that the blood-picture can only be a symptom of the disease, and it may be either absent or present. Therefore a patient may suffer from leucaemia for years, without there being any change in the blood at all. Hence the reason why I have chosen the lymphatic gland as the best organ in which to study the lymphocyte, because, in practically all conditions affecting lymphocytes, the lymphatic gland plays a role. The leucaemias are generally divided into three main types : (a) lymphatic leucaemia ; (6) myeloid leucaemia ; (c) pseudo-leucaemia. Lymphatic and myeloid leucaemias never mix, i.e., one form never runs into the other. Myeloid tissue is, in adults at all events, limited to the bone-marrow, and when myeloid tissue has been found in the skin, lymphatic glands, spleen, etc., it has either arrived there as a metastasis, or has been formed in loco as a metaplasia. 536 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. Whether both views are possible, or only one, does not at present concern me ; but I would like to make the remark that many of the so-called myeloid metaplasias in the lymphatic glands are not myelocytes at all, but merely endothelial cells such as are depicted in Plate 50 (2). It is more than probable, that the endothelial cells of Kanphatics, or such as one sees in large numbers in Ipiiphatic glands, are analogous to the myeloblasts of the bone-marrow. In both instances, they are the parents of leucocytes. One of the most important points which a repeated examination of leucaemic tissue has brought out, is the tendency of the affected cell to approach to its embryonic morphology, a point which is strongly in favour of a probable bridge between leucaemia and sarcoma. The peculiar localisation of the leucaemic process is again another suggestion of a relationship between leucaemia and sarcoma. Owing to the fact that a case of lymphatic leucaemia may begin without any attendant changes in the blood at all, but simply as an enlargement of one or more groups of lymphatic glands, the term " lymphadenosis " has been frequently used instead of Ijonphatic leucaemia. Up to the present, lymphadenosis appears to be the better name, as, by using it, such terms as the " pseudo-leucaemia of Pinkus," the " aleucaemia of Pappenheim," etc., are avoided, provided that it always be remembered that the disease may at any time develop the t}'pical blood-picture of lymphatic leucaemia. Unfortunately, the English have a term " Ijnnphadenoma," which means a new growth of lymph gland tissue. It is used to designate enlarged glands, which upon examination show no evidence of having increased in size, due to inflammation, such as might be caused by tubercle, etc. With many observers, lymphadenoma and Hodgkin's disease are two names for the same condition. The lymphadenoma, as seen by the English, is never followed by changes in the blood, such as are met with in lymphatic leucaemia. Therefore confusion may easily arise, when the same term is applied in England and on the Continent to apparently widely different conditions. Is it not possible that these various types are links in one chain of events, along which we can trace the connections, as was done in Chapter XLV., between inflammation and new gro\\i:h of epithelial tissue ? An enlargement of lymphatic glands may result from inflammation ; if the cause of the inflammation is continuous, other stations along the line may be attacked. The stations along the line in which lymphoc3'tes are formed may, for sake of convenience, be divided into three : (1) lymphatic glands ; (2) spleen ; ROLE PLAYED BY LYMPHOCYTE. 537 (3) boue-maiTOw. It is well known that, in persistent inflammation, the body is continually drawing upon its reserve forces, until the most important and the last card is played. If station (1) is attacked, there will merely be an enlargement of one or more groups of lymphatic glands, to accommodate the increased local production of lymphocytes. However severely station (1) may be attacked, i.e., however large the glands may get, no lymphocytes get into the general circulation. If the inflammation continues, and the lymphatic glands can do no more, the next station — the spleen — is attacked. To whatever size the spleen may be enlarged, none of the lymphocx'tes formed therein reach the general blood stream. If the inflam- mation still continues, station (3) is attacked, and when that is the case, the lymphocytes formed in the bone-marrow find their way into the circulation. So long as only stations (1) and (2) are affected, the condition is one of lymphadenosis ; when station (.')) is involved, the condition becomes lymphatic leucaemia. The course just depicted diagrammatically, is also frequently seen to be the same clinically. A patient complains of enlargement of the lymphatic glands — blood-picture normal. Later, the spleen, and perhaps the liver, become enlarged, blood-picture still normal. Gradually the lymphocytes in the blood increase, absolutely and relatively, until the white blood corpuscles are composed of nothing but lymphocytes, when the patient dies. Post-moHem, the bone-marrow is found to be affected. Station (1) is not always the first affected ; it may be station (2) or station (3). Clinically, cases have been described in which there was an enormous enlargement of the spleen, with little or no enlargement of the lymphatic glands, and with a normal blood picture, which later developed the typical blood count of l}'mphatic leucaemia. If station (3) is affected first, the disease runs an extremely rapid course, often killing the patient in a few weeks. In such cases, the blood-picture is present from the start, and there may be little or no enlargement of the spleen and the lymphatic glands. It would appear from the foregoing, that of the three stations the third was- the most important ; in other words, the base, in which operations were not carried on by the host until the resisting capacity of the Ijnnphatic glands and spleen had been overcome. As the base may be primarily attacked, it would not be of much avail to call upon the other two stations for assistance, hence the glands and spleen are usually not involved to any great extent when such is the case. It might be said that when the bone-marrow is affected, the patient dies before the glands and spleen have had time to come to the rescue, but, in support of the view 538 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. that they are of minor importance, is the fact that when station (2) is attacked first, the lymphatic glands do not, as a rule, become implicated, and when the attack continues, it is the bone-marrow that comes to the rescue, and not the glands. AATiether the cause of inflammation which gives rise to that group of lymph- adenosis, ending in lymphatic leucaemia, is always the same, or whether there is more than one cause, or what the cause or causes, are by no means settled. (c) Sarcoma. The epithelial cells nndtiply in inflammation ; they may also multiply when there is no inflammation, when they constitute what is called a new growth. The same with the lymphocji^e. Lpnphocytes may multiply rapidly in inflammation, or they may multiply rapidly after the nature of a new growth. If the cells of a Ijmiphatic gland, or a group of lymphatic glands, take on the characteristics of new growth, when a certain number have been formed, they will break through the capsule of the gland, invade all neighbouiing organs, and give rise to metastases. The cause of the initial onset of the new growth fonnation is unknown ; but, nevertheless, its action is generally highly localised, with the result that the spleen and bone-marrow are never called upon to assist, which means that there will be no increased lyniphocj'tosis. Lymphadenosis could be divided into two classes : («) inflammatory lymph- adenosis ; (6) new growth lymphadenosis. The most interesting point that now arises is, whether there is any connection between these types of lymphadenosis ; if so, then the lymphocytic chain is complete. As the inflamed epithehum in a chancre or a gumma may assume malignant characteristics, therefore, if there is a connecting link between the two types of lymphadenosis, it will be found in the inflammatory class, i.e., the lymphocytes in a gland from a case of inflammatory lymphadenosis will become converted into a new growth lymphadenosis. Clinically it may be easy to tell when a malignant epithelioma develops, but it is not so in the case of a maUgnant lymphadenoma. In both cases, a microscopic examination is generally necessary to settle the diagnosis. One point which suggests malignancy in epithelial tissue is the invasion of the corium by the epithelial cells. Invasion, in the case of a Ijmiphatic gland, occurs, but it is not easy to recognise. Moreover, the capsule thickens when the gland enlarges, and acts as a protective barrier for some time. Histological examination, and a close study of the lymphocytes, is the only means of telling whether the enlargement of a gland is due to inflammation, or to a new growth. Before describing the EOLE PLAYED BY LYMPHOCYTE. 539 lymphocyte in lymphadenosis, I would just like to call attention to the fact that myeloid leucaemia may be divided up like lymphatic leucaemia. The myelosis can be separated into inflammatory myelosis and new-growth myelosis. In the former, myelocytes are found in the blood, but not so in the latter. The inflammatory type may run an acute or chronic course, and, in every other detail, myelosis may be found to resemble lymphadenosis, and connecting links exist between the inflammatory and new-growth types of both. With epithelimii, it is noticed that different irritants affect different epithelial cells. The sun's rays, for instance, seem to affect the^lowest layers for preference, as the epithelioma resulting therefrom closely resembles a rodent ulcer. The X-rays, on the other hand, seem to affect the upper layers, as horny tissue and cell nests are the main features of the epithelioma. This is likewise the case with the IjTnphocyte. It may be attacked while a plasma cell, while a lymphocj-te just after it has left the endothelial cell, and even the endothelial cell itself may be affected. In the inflammatory lymphadenosis, the lymphoc3rtes are increased in loco ; if the cause of the inflammation continues, not only the spleen and bone-marrow try to come to the rescue, but the cells themselves in the primarily affected glands will make every effort to protect the host. Therefore, in different cases there will be a different call upon the various phases in the life history of the Ijnnphocyte, so that even the parent cells may be involved. Therefore, in the inflammatory cases, the increase of the cells will not necessarily be all of one type, as is the rule in the new growth cases. As will be seen later, all the phases in the life history of the lymphocyte are not invariably involved, however persistent be the action of the irritant. Anj'- one phase may take upon itself to multiply, in such a way that it constitutes malignancy. Therefore, the difference between inflammatory and malignant lymphadenosis will not depend upon whether the growth invades healthy tissue or not, since more often than not invasion cannot bo determined ; but it will depend upon whether the phases in the life history of the lymphocyte from plasma cell to endothelial- cell come to the rescue in their turn, should their help be required, or upon w'hether any one phase takes the whole protective work upon itself. The foniier signifies inflammation, the latter malignancy, but when the histological details of the various phases are dealt with, it will be seen that a hard and fast line between inflam- mation and sarcoma does not exist. In other words, it will be seen that there is a chain, the first link of which is inflammation, and the last link of which is sarcoma, and that there are other Unks in between which comiect the two. 540 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. If l)Tiiphatic glands are removed from cases of lymphadenosis, both from the clinically inflammatory and from the new-growth types, it will be found, when they are examined histologically, that scarcely any two are exactly alike. In many cases it is, moreover, impossible to distinguish between a gland removed from a case of inflammatory lymphadenosis, and one removed from a case of malignant l)rmphadenosis. The extreme types of each condition are easily distinguished, and as their characteristics are to be found in all the text-books deahng with the subject, I only propose to refer to the intermediary types. The more chronic the condition, the longer the structure of the gland will be maintained, and the less likelihood will there be of the parent cell being called upon to assist. The more acute the condition, the less will the structure of the gland be maintained, and the greater will be the call upon the endothehal cells. Since the endothelial cells are to be found in the follicles, it will stand to reason that in some of the acute glands only follicles, or, better to say, only foUicular-hke tissue is seen. In the still more acute glands, the follicles are all broken up and the gland merely consists of irregularh^ scattered and irregularly formed cells, not necessarily many in number ; on the contrary, there are less than might be expected. Connective tissue strands are to be found amongst the cells. Naturally, cases are to be met with between the chronic and acute forms, and a chronic case may suddenly become acute. It is with these intermediary forms that the malignant type is to be most frequently confused, the distinction being often impossible. In the so-called chronic lymphadenosis, the capsule of the gland may be infiltrated with lymphocytes, and these cells may even be found in the surrounding glandular tissue. The same appearances are to be met with in glands removed from cases of Hodgkin's disease and from the so-called lymphosarcomatosis. In chronic inflammatory lymphadenosis, but more often in the subacute form, enormous numbers of endothelial cells may be seen, giving birth to Ijinphocytes. These are also to be seen in glands from Hodgkin's disease. In both cases plasma cells are to be found, some of which are dividing and subdividing. Primary and secondary division of lymphocytes is to be seen, and, in some cases, the nucleoli of the lymphocyte are found to be enormously increased in size, and often in number, in the one cell. If my remarks upon the pseudo-parasites of malignant epithelioma are referred to (Chapter XLV.), it will be noticed that the pseudo-parasite was the nucleolus, which, after being discharged from the cell, took upon itself parasitic characters by dividing and subdividing, both by mitosis and amitosis, after the budding fashion. ROLE PLAYED BY LYMPHOCYTE. 541 Although the various phases, which one of the iUustratioiis .shows as occurring in mahgnant epithehouia, appear to be perfectly regular and straightforward, they are by no means so in every case of malignant epithehoma, and although the .same process may be witnessed in both inflammatory lymphadenosis and Hodgkin's disease, it is still less regular and straightforward. Now Hodgkin's disease is no doubt ultimately a mahgnant disease of the lymphatic glands. No two glands are microscopically the same, and frequently the histological characters are identical with those from a case of inflammatory lymphadenosis, which ultimately ends in lymphatic leucaemia. Therefore, it can be said that there is no hard and fast line between hyperplasia and lympho-sarcomatous growth. After all, there is no .sharp distinction between inflammation and malignancy, and the main determining point appears to be as to whether the further phase is called up to protect, or whether the nucleolus of the phase affected takes upon itself the sole responsibihty. As the nucleoli of lymphocytes may behave p.seudo-parasitically, in what we clinically call inflammatory lymphadenosis, it is at once clear that, when such is the case, the case is really malignant. In .support of the statement above mentioned, i.e., that a case of lymphatic leucaemia may really be malignant in the latter stage of its course, mention need only be made of the chloromata, or, as they are frequently called, the chloro- lymphadenoses. Chloromata have, by most observers, been looked upon as malignant growths, but since they are so frequently associated with blood changes which are characteristic of lymphatic and myeloid leucaemias, they may be equally regarded as inflammatory growths. There are two forms of chloromata — the lymphatic and the myeloid. Both may run an aleucaemic course, and not differ from the analogous condition.s — Hodgkin's disease and new-growth myelosis— while, on the other hand, although clinically and histologically the same, they may run a leucaemic course, thereby simulating inflammatory lymphadenosis and myelosis. As we shall soon see, lymphadenosis is occa.sionally accompanied by skin lesions ; such is the case, although much more rarely, with chloro-lymphadenosis. The green colour is not necessarily seen in every hyperplasia, or metastasis in every case of chloroma, which strongly suggests that the condition is not originally an entity, but only becomes so when the cells — lymphocytes and myelocytes — undergo some chemical change to which the green colour is due. The colour rapidly disappears, but is restored again by HnO., a fact which permits one to theorise that the green colour is due to an oxydase reaction upon the protein, or Upoid-protein molecule of the cell. I have noticed a similar green colour result from the 542 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. oxidation of protagon and cerebrin adsorption compounds with globulin. Fortunately, and unfortunately, the condition is so rare that an exhaustive chemical investigation is not easily to be pursued. PSEUDO-LEUCAEMLA. We can now pass on to the so-called pseudo-leucaemias. The supposed difference between pseudo-leucaemia and leucaemia rests upon whether there are changes in the blood, or not. There is no histological difference in the skin or glandular lesions of the two conditions, and since a case of leucaemia may run an aleucaemic course for months, or even for years, it looks as if the difference is purely arbitrary. Clinically, it would appear, at first sight, that the division of the two conditions is justifiable, but when the reason which accounts for the different clinical pictures is explained, it will be readily seen that the pseudo-leucaemias are merely some of the links in my lymphocytic chain. If the term " pseudo-leucaemia " is applied to those conditions in which the histological appearances of the lymphatic glands are the same, but only to that class which to the end runs an aleucaemic course, Hodgkin's disease must be included therein. To my mind, Hodgkin's disease partly resembles lymphatic leucaemia, with one main difference, that the lymphocytes in loco assume malignant characters in the former, while in the latter, before the lymphocytes assume malignant characters, the spleen and bone-marrow come to the rescue. A clinical entity of the group of pseudo-leucaemias is Miculicz's disease, in which a leucaemic infiltration of the eyelids, cheeks, orbits, lachrymal, salivary, and mannnary glands occurs. Here we have the first indication of a lymphocytic growth occurring elsewhere than in the lymphatic glands, spleen, or bone-marrow. Many skin diseases com- mence as a l)niiphocytic growth, during the course of which the lymphatic glands become enlarged. If, then, an irritant makes itself felt first in the skin, and the irritant happens to be one which gives rise to the formation of lymphocytes only, it stands to reason that a long time may have to elapse, before the spleen and the bone-marrow are called upon as last resources. The risk of such a case dying, before the bone-marrow is affected, is greater than when the disease starts in the lymphatic glands; therefore, it can easily be understood that it would only be natural for a leucaemic affection of the skin to run an aleucaemic course for a considerable period. Just as the lymphocytic growth, starting in the Ivmphatic glands, may assume malignant characteristics as an extra protective measure, as is seen in Hodgkin's disease, so may the lymphocytic growth which starts in the skin. I ROLE PLAYED BY LYMPHOCYTE. 543 As the lymphocytic growth in a lymphatic gland may be malignant from the start, as in Ipnphosarcomatosis, so may the lymphocytic growth in the skin. Therefore, the same events may take place in the skin as in the lymphatic glands ; in other words, the leucaemic conditions of the two are analogous. There is less likeUhood of the skin form running a leucaemia course, but it is possible, therefore the term " pseudo-leucaemia " may become ambiguous. One of the reasons why this subject is so difficult to render intelligible, is because the word leucaemia is used to mean only part of what it really imphes. If the myelocytes and the lympho- cytes in the blood are increased, the condition is called leucaemia, provided only that the cUnical condition is of a certain nature. However big be the increase of lymphoc}i;es in the blood, say, for instance, in a case of syphihs, the terra leucaemia cannot be used. However marked be the eosinophiha, even in a case of lympho- cj^oma, the terra leucaemia cannot be employed. It would probably be better to drop the term pseudo-leucaemia altogether, to do away also with the word lymphadenosis, and to adopt the classification shown on page 544. LyMPHOCYTOM ATA . A lymphocytoma may begin in the skin, other organs of the body, lymphatic glands, spleen, or bone-marrow. In all cases but the last, it may run a leucaemic or an aleucaemic course. The leucaemic course ends fatally, and so quickly that no true division between benignity and mahgnancy is possible or necessary, since the cells in any case finally take on raahgnant characters. AVith the aleucaeraic Ijanphocytomata the case is different ; the condition may be primarily innocent or primarily malignant (sarcoma). Intennediary stages exist, such as Mycosis fungoides in the case of the skin, and Hodgkin's disease in the case of the lymphatic glands. It is the study of Mycosis fungoides, Lymphodermia perniciosa, and Hodgkin's disease which enables one to make a chain consisting of several links, of which the first is an inflammatory lymphocytoma, and the last a raahgnant lymphocytoma — a mesoblastic chain analogous to my epiblastic chain. We come now to describe the various skin lesions to be met with. They will naturally fall into two classes : («) Those which start in the skin, true lympho- cytomata ; (6) those which are secondary to lymiihocytomata, which have com- menced elsewhere, i.e., symptomatic. We will consider the latter first, as, from our point of view, they are relatively ununportant. In cases of chronic inflammatory lymphocytomata the patient frequently complains of itching, the skin is usually dry, and occasional attacks of Urticaria papulosa et vesiculosa arise. If the 2 M 544 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. 1 Spleen 1 1 leucaeniic aleucaemic 1 1 1 innocent = malignant (sarcoma) ]?one-i leuca organs !' disease, lata, etc. 1 . aleucaemic 1 S cS C a 0) t other MiculiCi ■ ohlorou 1 o 'a -i 3 03 —.§)£; .— . K cS tc s ^ 'a a S >> 0) OJ . — ' X -S- 11^1 3 &0 0) a^i le cS a — 2 1 nocent plasmo (Hodg S ^ g — 1 3 .2 >^ c B t: r^ O _tp o ,^-^ fft 7i 0) a w o II n T != O O 8 C &, S O ROLE PLAYED BY LYMPHOCY^TE. 545 itching is intense, the urticarial wheals may, owing to scratching and the secondary infection arising therefrom, become converted into small granulation tumours, which in tune spontaneously disappear. In cases of acute inflammatory Icucaemic l}inphocytomata, the most common skin lesion is a haemorrhagic one, in the form of petechiae, which, in some cases, become so big that the skin ov^^ them necroses. Of the true cutaneous lymphocytomata there are several varieties, and although, chnically, two cases are alike, a normal blood-count may be obtained from one, and from the other a hmiphocytosis, or a marked eosinophilia ; in other words, the lesions belonging to the leucaemic and aleucaemic divisions are in many other ways the same. Leucaemia Cutis. This condition is characterised by swellings in the skin, which vary from the size of a small pea to that of a pigeon's egg, and bigger. They are adherent to the skin, but movable on the deeper structures. They are smooth and often flat on the surface, and mostly soft to the touch. They vary in colour from a bluish-red to a brown-red, the variation depending upon the depth in the cutis at which they are situated. Occasionally large areas of skin are affected with a difl'use swelling, and several cases have been described in which the face, forehead, cheeks, lips, and ears have been implicated. In the classical case, of wliicli there is a moulage in Finger's clinic in Vienna, the face is so involved that the patient looks as if she were sufiering from tlie leontiasic condition to be met with in leprosy. The tumours may remain unchanged for years, or some may spontaneously disappear, or the disease may rapidly spread and kill the patient. The blood- count may be normal, or there may be a lymphocytosis. Histologically, one finds in the cutis a collection of cells, which consists entirely of lymphocytes. It is stated that a space is always left free between the tumour and the epidermis, which is not the case in Mycosis fungoides, hence a ready means of distinguishing the two conditions. The statement is totally incorrect, since not infrequently in Leucaemia cutis — ■ especially in the diffuse infiltrated lesions — the collection of lymphocytes reaches up to, and presses upon, the epidermis ; while, in several cases of Mycosis fungoides, a free space exists between the epidermis and the cellular infiltration, depending entirely upon whether an early or late lesion is examined, upon whether the lesion is small or large, and upon the area through which the section is made. Several of the tumours of Leucaemia cutis have been known to ulcerate, and in this fact lies the close resemblance between this condition and Mycosis fungoides. A leucaemic lesion of the skin may have a green colour, and so be a chloroma, but the condition is extremely rare. The starting point of the new growth may 2 M 2 546 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. not be in the lymphocyte, but in the plasma cell, the cell to which it gives rise. The same occurs in epithelioma. The process may originate in the basal cell layer, or in the layers above, which develop therefrom. Aleucaemia Cutis. If the process is a malignant one, the growth will consist entirely of the cell primarily attacked, i.e., a Ijmiphosarcoma will consist of only lymphocytes possessing mahgnant characters. A sarcoma arising in plasma cells will consist of only plasma cells possessing mahgnant characters. Instead of either of these cells, the endothelial cell may be primarily attacked, the growth of which may be either innocent or mahgnant. As a plasma cell arises from a lymphocyte, any new growth thereof should be considered here. Plasmosarcomatosis (Plate 52 (2)). — The condition appears to be extra- ordinarily rare, and, as I have had a case under my care, it would be as well to publish it in full." Case 84. — A man, aged 32 years, came up for advice, complaining of an ulcer in the middle of the upper third of the thigh. The ulcer was hard, crateriform, and the skin for some distance round was markedly indurated. The forerunner of the ulcer was a small hard and painful hunp, which made its appearance six months previously. As the lump began to soften in the middle, it was incised, but only a very small quantity of pus came from it. From this tiaie onward, the ulcer rapidly increased in size. When I first saw the patient, the ulcer was \\ in. in diameter, bled freely on touching it, and was extremely hard. The surrounding skin was stretched, of a brownish-red colour, indurated, and immov- able. The inguinal glands on the affected side were enlarged and hard. The patient had never had a venereal disease. In spite of all treatment, which was unavailing, the ulcer readily increased in depth and size, the inguinal glands on both sides became affected, and the patient died six months later, in a condition of cachexia. Post-mortem secondary growths were found in the spleen, in the kidneys, in the mesenteric glands, and in the walls of the small intestine. A microscopic examination of the margin of the ulcer showed the following characters (Plate 52 (2)) :— The epithelium is hypertrophied and acanthotic, the papillae are enlarged, otherwise the epidermis is normal. The corium is filled with new-formed connective- tissue cells and plasma cells. The capillaries are dilated, but are of normal I ROLE PLAYED BY LYiMPHOCYTE. 547 structure. Deeper in the corium, the walls of the blood vessels arc h3'pertrophied and infiltrated with lymphocytes. Arranged perivascularly are numerous plasma cells, which, iu some places, can be clearly seen to have originated from lymphocytes, which, in their turn, have arisen from the endothelial cells. Deeper still in the corium or subcutaneous tissue, a mass of cells is to be seen, between which there is no connective tissue. Each cell is three or four times as large as a normal plasma cell, and the nucleus takes up the greater part. The protoplasm stains faintly and is granular, and, in many of the cells, the outline of the protoplasm is broken, so that the granules appear to be extra- cellularly situated. The nucleus stains faintly, contains little chromatin, but one or more brightly staining nucleoli. Some cells contain two or three nuclei, each of which may contain more than one nucleolus. Here and there, bare nuclei are to be seen, owing to the degeneration of the protoplasm which once surrounded them. The nuclei have divided neither by mitosis nor by true amitosis, but have been merely split up irregularly, according to the arrangement of the existing chromatin strands. In the margin of the new growth, numerous plasma cells are to be seen, and the gradual transition from these plasma cells into the sarcoma cells is in several places evident. To a similar condition the terms " lymphosarcomatosis " and " leucosar- comatosis " have been applied. The disease may start as an ulcer, with intense brawny induration of the tissue around, as in the case described, or it may be the end of many of the cases belonging to the Mycosis fungoides group. The so-called Sarcomatosis cutis (Kaposi) (one type), is the same condition as the Leucaemia cutis. The other type is a distinct condition, which has no immediate relationship to the lesions under discussion. The Sarcomatosis cutis (Spiegler) is cjuite another condition, and is identical with the so-called sarcoid, which is not a new growth at all, but an ordinary inflammatory lesion, due to the tubercle bacillus or its toxine. Endothelial lymjihocytoma. — Sibley has recently had a case of what one may call the endotheUal type of a cutaneous lymphocytoma. I have been able to make a pathological report upon this case, and, with Dr. Sibley's kind permission, I am able to reproduce it here. Histology. ^k\t\:iO\\g\i there are main masses of cellular infiltration, which 548 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. are more or less circumscribed, and do not invade tlie subcutaneous tissue, the whole of the corium is studded with a cellular infiltration to a greater or to a less degree. In the periphery of the main masses, what at once strikes the eye is the marked dilatation of the capillaries and lymphatics, the perivascular arrangement of the infiltration, and the great number of mast cells. In some sections there are numerous eosinophile cells. If the vessels and lymphatics are more closely studied, one notices that there is a marked endothelial proliferation, which, in some places, 'is sufficient to block the lumen. Some of the endothehal cells have extended excentrically, and here the main increase of cells is made up of connective-tissue cells and lymphocytes. There are no plasma cells. The main masses are less cellular, owing to the fact that several of the cells have degenerated, and that the cell playing the most part in the infiltration is the large, badly staining endothelial cell. In the main masses there are not many lymphocytes, and no plasma cells or mast cells ; but here and there, where a few endothelial cells have coalesced, typical giant cells are to be seen. In the immediate periphery, the number of lymphocytes is increased, there are a few mast cells, no plasma cells, but a very marked increase of connective-tissue cells. Especially noticeable about the cellular infiltration, as a whole, is the poor affinity which the endothelial cells and lymphocytes show for pyronin and methyl green, especially for the former. This means not only that the protoplasm of the cells is very poor in hpoid-globulin, and therefore markedly degenerate, but also that the nucleic acid content is diminished, which renders the cell more degenerate still. Examining the cells individually, the following characters are to be noted : — Endothelial cells. — The protoplasm is swollen, stains faintly, and is sometimes granular. In a few of the cells, embryo lymphocytes are to be found, but they are very few in number, and not pyroninophile. On the other hand, they show a great affinity for methyl green, with which they stain very deeply. Instead of the embryo lymphocytes being well formed, their nuclei are more often to be seen broken up, so that the protoplasm of the endothelial cell appears to be crowded with small masses which stain almost black with methyl green. The nuclei of the endothelial cells are swollen, many cells have one or more nuclei, and the nuclei may contain one or more nucleoli. The nucleoli are remark- able in being so faintly p^Toninophile. Lymphocytes. — Those ahead}' formed stain faintly with methyl green, and are degenerated. Here and there, is to be seen a feeble attempt to form plasma cells, the protoplasm of which is irregular, and only stains faintly with pjTonin. A few ROLE PLAYED BY LYMPHOCYTE. 549 embryo lymphocytes are to be found, but it is an exception for them to contain a iipoid-iilobuUn and pyroninophile protoplasm. Most of the embryo lymphocytes are merely masses of nuclcin. Lymphatic gland from axilla. — The gland is a very small one, but practically the whole of its structure is altered. There is very little cortex, as most of the gland consists of abnormal follicular tissue. The number of lymphocytes is diminished, while the endothelial cells are very much increased. In the gland section there are a few plasma cells, and more normal embrj'o lymphocytes. The endothelial cells resemble those already described in the skin section. The sections of both the skin and the lymphatic gland resemb'e Plate 52 (1), but with certain differences. The endothelial cells are the cells attacked, consequently there is a great multi- plication of them, and, owing to their great desire to increase, as shown by their being nmltiimcleated, they are unable to generate lymphocytes. The few lymphocytes formed will also be degenerated, hence they lack their characteristic lipoid-globulin envelope, and consist of irregular masses of nuclein. The cHnical history of this case is interesting, as it throws light upon other cases I have seen, which have been less severe, and to which a name has never yet been given. Case 85. — The patient^* was a boy, aged 1 6, whc- is stated to have had an eruption for eight years. The patient had a diffuse papular eruption with a marked pigmentation of the skin, and a general adenitis. In many places the papules had coalesced, and all that could be said of the wide area of skin affected, notably on the upper part of the thighs, was that the skin presented a condition of chronic dermatitis. The rash was irritable. The patient was hoarse, he ran an evening temperature, his blood count was normal at first, but it later developed a leucaemie picture (eosinophilia). Otherwise nothing else abnormal was found. I have seen, as just stated, similar although less severe cases, in which the whole skin was in a condition of chronic dermatitis, with what might be called granulation tumoiu's scattered over it. Sibley's case had, just prior to examination, gone through a severe attack of impetigo, and I have noticed, in some of the cases just referred to, that recurrent attacks of a generalised pyogenic infection are not at all uncommon. The itching is always intense ; all the lymphatic glands of the body swell in time, but those fii-st to become enlarged are the femoral and inguinal sets. The blood picture is at first normal, but later it may show a pronounced eosinophilia ; the eosinophiles, being both absolutely and relatively increased. The disease is essentially chronic, but ultimately fatal, and all the cases I have seen, five in all, have been Polish Jews. I have studied the histology of the skin 550 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. and lymphatic glands in these cases, and not only are no two exactly aUke, but also the histology varies in the same case, according to the length of time during which the various lesions have been present. The cellular infiltration may be at one time lymphocytic, at another it may consist mainly of plasma cells, and at another of endothelial cells, as in Sibley's case. The characters of the cell affected may vary ; for instance, the protoplasm of the plasma cells may be broken up {vide Plate 51 (1)) ; the plasma cells or the endothehal cells may exhibit pronounced nuclear or even nucleolar activity. Hence in these cases alone, the various Hnks of my lymphocytic chain may be met with. This case, from its histological features, would probably have been called lymphogranulomatosis on the Continent, and lymphadenoma or Hodgkin's disease affecting the skin in this country. There was a leucocytosis of over 25.000, the feature of Avhich, was a very pronounced eosinophilia. Strictly speaking, the blood picture is leucaemic. but as the usual meaning of the word is so restricted, it has to receive the appellation — aleucaemic. Intermediary Aleucaemia Cutis. Mycosis Fungoides. As everyone is aware, Mycosis fungoides is regarded by some observers as a form of sarcoma, and by others as a form of leucaemia, or rather pseudo- leucaemia. The latest opinion is that Mycosis fungoides lesions are made up of pure granulation tissue, and have no relationship to either sarcoma or leucaemia ; in other words, that it is a disease sui generis. One of the reasons for classifying the disease among the sarcomata was the fact that lesions similar to those occurring in the skin were also to be found in the internal organs. Paltauf and v. Zumbusch* have recently described two cases of Mycosis futigoides, in which lesions were found ■post-mortem in the internal viscera. In the one case there was an infiltration of the pleura, nodules in the lungs, and infiltration with ulceration of the walls of the stomach. The coloured plates illustrating the article depict the le.sions of the viscera as yellow nodules with a marked red inflammatory circumference, and they do not suggest metastases of a primary malignant growth. Microscopically, these lesions were made up of granulation tissue, which was especially rich in plasma cells, resembhng the cutaneous lesions. In both cases, necrosis was to be met with. Unfortunately, no detailed description of the morphology of the plasma cells is given. In the other case, nodules were to be found in the lungs, liver, and spleen, and macroscopically and microscopically they were identical with the cutaneous ROLE PLAYED BY LYMPHOCYTE. 551 lesions, having the characteristics of an inflammatory ratiier than of a malignant growth. On the other hand, cases have been described in wiiicii the lesions of the internal viscera were sharply' circumscribed, non-inflammatory — in short, having all the phenomena of secondary malignant growths. Tiic cases were described some time ago, and the histology of these so-called metastatic lesions was not adequately worked out. It is possible that some of the cases described, in which secondary malignant growths have been found, have been cases in which a primary malignant growth existed mdependently of the Mycosis fungoides. Adamson recently had a case of Mycosis fungoides in a woman, and it was marked by generalised pigmentation, in which — post-moHem — a secondary growth was found in the liver. The secondary growth was sharply circumscribed, non- inflammatory, about the size of a filbert, and it was deeply pigmented in parts. Histologically it was clearly a metastatic melanotic malignant epithelioma. Some years previously, the left eye had been removed, possibly for a growth, but no further details on this point are at present obtainable. In some of the cutaneous mycosis lesions, removed post-mortem, metastatic malignant epitheliomatous deposits are to be seen. The reason for classifying Mycosis fungoides among the leucaemias is due to the fact, that the statement has crept into text-books, that the disease is sometimes associated with a blood-count, suggestive of lymphatic leucaemia. It is extremely doubtful whether the blood-count is often altered in Mycosis fungoides, except beyond an increase of eosinophiles in some cases, and poly- morphonuclear leucocytes in others, which are accompanied by necroses. Person- ally, I have not come across a case with a pronounced mononuclear leucoc)'tosis, but a small increase in. the large mononuclears may sometimes be met with. As to whether Mycosis fungoides should be classed with the pseudo-leucaemias, depends upon what one recognises as pseudo-leucaemia. The best known example of a pseudo-leucaemic condition is what we, in England, call Hodgkiu's disease. On the Continent the same condition usually goes by the name of lymphogranulomatosis. Many observers hold that Mycosis fungoides and lymphogranulomatosis are one and the same condition, affecting different parts of the body. On the other hand, other observers maintain that they have nothing in common, although the reasons given for the statement are far from convincing. Their chief reason for separating the two conditions is, that IjTnphogranulomatosis is preceded by urticarial and prurigo-like lesions of the skin, with occasionally a widespread erythrodermia, while Mijcosis fungoides is usually preceded by an eczema or a psoriasis. 552 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. As far as my limited experience goes, in cases of so-called pseudoleucaemia with skin lesions resembling urticaria and prurigo, the skin lesions either appear some time after one or more sets of lymphatic glands have become enlarged, or they appear before there is any enlargement of the palpable lymphatic glands. The point I wish to bring out is, not whether the skin lesions precede or succeed lymphatic gland enlargement, but that in the majority of the cases the skin lesions do not alter. Some of the prurigo papules may increase in size, but it seems doubtful whether they ever give rise to such nodules as are seen in Mycosis fungoides. Skin lesions such as just described, I take to be entirely secondary to the main condition and not homologous parts of it. Some of these cases may run an extremely rapid course, death ensuing in a few weeks, but more often the disease lasts over many years. Whether the course is rapid or slow, the blood-count usually remains the same. There is generally a diminution of lymphocytes, an increase of eosinophiles often to .30 per cent., and an increase of polymorphonuclears, the last being dependent upon the secondary infection which is liable to result from the continued scratching. On the other hand, the blood-count may remain normal to the end. The cases exhibiting erythrodermia may be divided into two classes : those in which the erythrodermia is widespread and often sufficient to produce total alopecia, and those in which the erythrodermia is localised to one or more patches. In both cases, the erythrodermia may disappear before any tumour formation is seen, leaving either no trace behind it, or, more often, a marked pigmentation ; or the tumour formation, especially in the localised cases, may appear in the centre of the patches of erythrodermia. The tumours may ulcerate, a process which usually results in their spontaneous cure — not in a cure of the disease, because fresh patches of erythrodermia, with ultimate tumour formation, will appear elsewhere. I have had one singular case under my care, an exact replica of which I have never seen described. Case 86. — A man, aged -17 years, having had syphiUs over tw^enty years before, sought advice for a skin lesion he had had for the last three years. The patient had a rash which extended over the upper half of the left side of the chest, the left shoulder, and down the left arm to about the lower third. The rash was typical of Dermatitis atrophicans, the skin rolled and looked thin, like cigarette paper, and the vessels were clearly discernible underneath. The periphery of the lesion simulated exactly the localised patches of erythrodermia, which precede the condition called Lym'pliogranuloinatosis cutis. The itching was intense, and the skin trouble was undoubtedly spreading. On the arm, where the skin had not become atrophic, was a very slowly spreading ulcer, which simulated closely Plate 51. Section of a lymphatic gland stained with pyronin and methyl green, from a case of intermediary l3miphatio aleucsemie lymphooytoma. The patient had a wide-s])read prurigo-likc exanthem. The blood-coimt showed a shght diminution of lymphocytes, and a slight increase of polymorphonuclear leuco- cytes and eosinophiles. The characteristic feature of the section is the manner in which the protoplasm of the plasma cells has broken up, into pyioninopliile amorphous masses. This section is from a case of intermediary aleucaemic cutaneous lympho- oytoma, near the malignant end of the chain. The patient was a man, aged 50 years, who had patches of erythrodermia, in the centre of which were several nodules, some of which had ulcerated. The nodules and ulcers after a time disappeared spontaneously. Twenty-five years previously he had had syphilis, and at time of examination the Wassermann reaction was strongly positive. His mother died, aged 78 years, and his father, aged 82 years, was still alive. Patient was steadily losing weight, and all the hair on the body was rapidly coming off. Occasionally the itching was very severe. Glandular enlargement was very marked. The blood examination showed an eosinophilia and a slight increase of the large mononuclears. Histologically, the points to be noticed are, the granulation and breaking away of the protoplasm of the plasma cells, an increase in the size and number of the nuclei of the plasma cells, a diminution in staining properties of their chromatin, and an increase in size and number of the nucleoli. 3. Section of a IjTnphatio gland from a rapid, fatally terminating case of intei-mediary lymphatic aleuoaemic lymphocytoma. The patient had an acute universal prurigo-like exanthem. The points to be noted are, that the protoplasm of some of the plasma cells has broken up, the nuclei of most of the plasma cells have increased in size, some have divided, and man}' contain more than one nucleolus, and some of the nuclei of the plasma cells and lymphocytes have been displaced by a strongly pyroninophile body — the nucleolus, which has increased tremendously in size. Elsewhere in the section, nucleoli are to be seen forming cells of their own and dividing, behaving like the pseudo-parasites of malignant epithelioma. Facing p. 552. je ai'Aj'l incni .nseig I^riJeni bna ainoTi{q dim bsurAie briflg'ailjiifqliiy,) ii Wndiiiite "'' JiisiJEfi 9frr .BmohjoorfqmYl •nmasow^rffl 'siljstlqnr^l ifT«i()9rti*J:ni"io ■3f»a»-« iflgilB A f)9V7ori« Jfli/oo-booJd «riT .aisiitnaza ajlil-ogiiiriq bB'nqa-.obtw b IjBff - -oanol •ifisbi/noiJq'iomYloq )o eaemoiy iif^ik « fans .eaiijfiodqtji^^l io noiii;nu;r:i; adi ai noiiosa od* lo a^aifiel oiiahatajjTJsrfo sdT .asIidqbniB'oa Kn« saji^o ojni .qu oejloid Bri.f-.-'.'.i !.^-.i ml,/ i-Tf...-, (ir, iiHj; - I'lolii ijiij; ^''IiiijOd ii(T .'■ bf,d Imri ad -^lauoivo'iq ai£dy, ovil ■^jn:)/;T iiioq^: boij;jqqj;.iib aiaiJ ji ' vlgiicnji asTf noij-wn flHJSfrtTOBSeW sdJ fi^ to aini^ i« haa ,eiJidqy'i -• Rsw ,3*B» lijjd jadJ 11^ baa .Jdgiaw gtiiri' •' ' t;- saw inar,tB'I t ' "-- iiJufan«10 .ai3T98 yiov e*w gniftati adi 7 i .Bo gniraoa /i liliifqoiiigoa nt: bawnd^'aontfinixd^T^bboW ydT .ij->;li«rn vi'jt rB'w trt -irdoq adi .-^IkoiaoloiJaiH .«i«aloiiflonor(i &gml ad* Jo 9hb)]!)ii1 .11!'- lo ai3eIq(Ktuiq,.8d} YaX'^^o ^ii^^aridi , hue miisUio^T^od adl to iaiaun adj io ladinun fane asia adi ni aaaaioni un .hjiot j :m?jilq •jsiS nr. I)(iB .nilJurtoTdo liadt to f.-iijnafjoiq sninifija ni noiiirnirnib D ,allaa fim^flq ■ ' '■ ' ■ "' ' ':, with _}; _ .11: casp lo eaaa sniianutnat'^ltBiJiI ,bi^ ^i:>u'V Plate 51. ROLE PLAYED BY LYMPHOCYTE. 553 a rodent ulcer. All treatment was unavailing. The patient was not clear as to whether the ulcer had been preceded by a swelling in the skin or not. The tumours which form on the patches of erythrodormia are clinically indistinguishable from those which succeed an eczematous or psoriatic condition, or from those which arise independently of an}' preceding dermatitis {Mycosis d'emblee). Therefore, clinically it would appear that there is no difference between Mycosis fwngoides and Lymjihogranuhmatosis cutis. Broadly speaking, when a histological examination of any of the afore-mentioned cases is made, one may say that scarcely any two are alike. They all have a feature in common, viz.. that the predominating cell of the infiltration is a lymphoc)i:e. The varied microscopic pictures obtained, are accounted for by the presence or ahnost total absence of plasma cells in some cases, upon the presence or absence of the forerunners of lymphocytes, and upon the variation in the number of polymorphonuclear leucocytes, mast cells and eosino- philes. In some cases, the tumour may be made up almost entirely of plasma cells ; they ma V be normal, the protoplasm maybe broken up in the cells of which the nucleus remains unchanged (Plate 51 (1)) ; the protoplasm may be granular (Plate .51 (2)), in the cells of which the nucleus is either increased in size or there is more than one, and the nucleoli are also increased both in size and numerically (Plate 52 (2)) ; or the protoplasm may have practically vanished, also the nucleus, the nucleolus only being left behind, which divides and subdivides, or, in other words, behaves pseudo-parasitically (Plate 51 (3)), a phenomenon I have de.scribed as occurring in the epitheUal cells of mahgnant epitheliomata. In other cases, tliere are no plasma cells at all, the infiltration being made up of small and large lymphocytes. In such cases, it is usual to find many endothelial cells with embryo Innphocytes in their protoplasm. In other .such cases, there may be numerous large cells containing one or several nuclei in their feebly-staining protoplasm. Sternberg' first called attention to these cells, and held them for characteristic of lymphogranulomatosis. These large cells are mostly round, and contain, as ju.st stated, one nucleus or more. The nucleus or nuclei may be centrally or peripherally situated, they vary in shape, contain httle chromatic substance, but one or more deeply-.staining nucleoH. The greatest difference of opinion prevails as to the origin of these cells. Personally, I think they are the endothelial cells of the local lymph vessels, which have been unable to generate lymphocytes, and that they are identical with the large cells depicted in the section of a lymphatic gland from the neck of a rat which died of trypanosomiasis (Plate 50 (2)). In all cases, there is a greater or less proliferation of the fixed connective-tissue cells, and it occurs whenever there is an inflammatory infiltration of the skin, and is therefore in no wise specific. 554 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. In other cases (Plate 52 (1)), embryonic lymphocytes predominate, and they behave in a manner that has never hitherto been described. The parent endothelial cells of these embryonic lymphoc3rtes are, owing to degeneration, difficult to see. These embryonic lymphocytes vary in size and shape, but all stain homogeneously and very deeply with methyl green, polychrome methylene blue, etc. These darkly staining masses which consist of nuclein, which has not yet become differen- tiated into chromatin threads and dots, are sometimes seen to be lying in a mass of protoplasm which takes the pyronin stain. Either very little protoplasm is seen or a considerable amount, and, in the latter instance, one or more strongly pyronino- phile bodies are generally visible, one of which lies invariably at one pole of the nucleus. These pvi'oninophile bodies are presumably nucleoli. What has just been stated is well depicted in Plate 52 (1), and one cannot help noticing the close similarity between the various stages met with in the lymphocyte and the epithelial cell when pseudo-parasitism occurs. The section is taken from a case of Mycosis fungoides and the interpretation I would put upon it is as follows : — The attacking force strikes the lymphocytes just after they have been expelled from the endothelial cells, therefore the resistance will be shown by the embryonic lymphocytes and the endothelial cells. In this case, although numerous endothelial cells are to be seen in the section, the brunt of the resistance is being borne by the young lymphocytes, a point in favour of regarding the case as being nearer the malignant than the innocent end of the chain. The embryo lymphocytes divide and subdivide amitotically, which accounts for the great difference in size of the nuclein masses ; others develop a large area of protoplasm in their abortive attempt to form plasma cells ; in some of the latter, and in some of the non-protoplasmic embryo lymphocytes, the nucleolus is beginning to behave as a pseudo-parasite. Some of the larger young lymphocytes have broken up into several small nuclein masses, possibly with the hope of forming several distinct lymphocytes, and in these cells the nucleolus is also active. The most interesting point about this case, which was under Dr. Adamson's care, is that, when the case was first seen, the lesions were rapidly getting better, and microscopically were typical plasmomata. When the condition recurred and ended fatally, practically no plasma cells at all were to be found in the sections. The case had, in short, become more malignant. It is frequently to be noticed that the histology of a recurrent mycosis lesion differs from that of one of the primary lesions. tf/i Plate 52. 1. A section from a recurrent case of intermediary cutaneous aleucaemic lymphocytoraa after X-rays. Before treatment, the lesions were histologically true plasmomata. Now, several endothelial cells are to be seen, some of which have given, and are giving rise to lymphocytes. The embryo lympho- cytes instead of forming adult lymphocytes and plasma cells, are undergoing multiple division, and some of them have formed a large area of protoplasm. In a few of these, the nucleolus is active. Is a section from a sarcomatous ulcer, which arose from plasma cells. The points to be noted are, the granulation and disappearance of the proto- plasm of the plasma or sarcoma cells, the large size and number of the nuclei, the feeble staining properties of the chromatin, and the increase in size and number of the nucleoli. ,, . --. 1 PX^TH 52. .openeo\isl ,• more st- ' . ! rielp no do,-!e mphocvte &■ .1 ..,.f<.m/l o^nJi.i'i ■idT f.av iiififfdvl o,1 -iiiiT gnivig 318 bflc ,n9Yig evjsd doidw -.r.iiik{uiozi.\ to ii'jiii ygijjl fi bom-iot 'j/'iii nigrfJ lo amoa biiB '.'nowivib elqil;; ' .<\i- '_< Krf\>.rAii inoTi 'Kinji [ir^inv/ ,r»-i!U -u>Mjiii'M.'iij-. t, ui'^ii lU-' ' -'o-' ^ ^i oJoiq adl io soxuruisqqAeib bo* noLlfik/n«-ig eiU ^th titiioiii^l.f^ (sftaioqifntftiit riid /ijloirn idi \o ladfuiiii bos asia agiel oilJ .alloo sfliooifiB lo Btneslq oril 5o ineBlq .iifi -ivTv rii ivmiTiiii 5irU hrij! .fiil);i!!-niphoc}'tonia may result. As to which one results, will depend upon the situation of the call, the concentration of the call, etc., so that if it starts in the skin, it will be a form of 2n2 562 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. what was called Mycosis fungoides ; if it begins in the salivary glands, it will be a form of Miculicz's disease ; and if it commences in the lymphatic glands, it will be a form of what was called Hodgkin's disease. The concentration or severity of the call will be gauged by that stage in the life history of the lymphocyte which. pre- dominates. According to which stage is aiTected, the degree of malignancy or innocency can be determined. As to whether the condition is malignant or not, can be ascertained by judging the degree of the nuclear and nucleolar activity of the cells. Wliat has just been stated about the skin, may be applied equally well to the lymphatic glands and the spleen, hence an enumeration of the various lymphocytomata affecting these organs, requires no furtlier elaboration. > Untia (1913), " Biochemie dcr Haut," Gustav Fischer, Jena. - McDonagh (1914), " Aichiv. fur Derm. u. Syph.," cxx, 289. 3 McDonagh and Mackenzie Wallis (1913), " Biochemical .Journ.," vii, 517. •• McDonagh (1914). — " A report upon the Biology of Syphilis," Harrison & Sons, London. 5 Pighini (1912), " Biochem. Zcit.." xlii, 124 " Paltauf u. V. Zumbusch (1914), " Archiv fiir Derm. u. Syph.," cxviii, 699. ' Sternberg (1898), " Ztschr. f. Heilk.," cxix, 21. « Anidt (1912), " Virehow's Archiv.," ocix, 432. '■> Zeigler (1911), " Die Hodgldnsche Krankheit," Gustav Fischer, Jena. "^ Naegoli (1913), " Leukamie u. Pseudoleukamie," Alfred Holder, Wien u. Leipzig. " McDonagh (1911), '" Archiv. fur Derm. u. Syph.," cix, 441. '2 Hazen (1913), "Journ. Cut. Dis.," xxxi, 618, 759. " Unna (1910), " Histolog. Atlas zur Path, der Haut," L. Voss, Leipzig. '' Sibley (1914), " Brit. Journ. of Dermat.," xxvi, 3(51. '* Ziegler (1906), " Histogenese der Myeloiden Leukamie," G. Fischer, Jena. CHAPTER XLVII. THE ROLE PLAYED BY AN ENDOTHELIAL CELL IN INFLAMMATION, AND ITS PROBABLE RELATIONSHIP TO SARCOMA. Ill the last chapter, the endothelial cell was considered secondarily, or only in so far as it affected the lymphocyte. The sum of the evidence brought forward relating to the endothelial cell was, that if the call for protection affected the lymphocyte-producing endothelial cells first and foremost, the endothelial cells behaved like sarcoma cells, so that the lesion or lesions produced were actually malignant. The lymphocyte-producing endothelial cells are probably the endothelial cells of the lymphatic system only, and those which we are about to discuss are probably the endothelial cells of the vascular system mainly. The vascular endothelial cells can be aft'ected in inflammation and in new growth, and a chain can be formed connecting these two terminal links, similar to the epithelial and lymphocytic chains already described. Inflamm.\tory Endothelioma. Chemical poisons appear to be the chief cause of inflammatory cndotheliomata, the following case being a verA' good example of this group : — Case 89. — A woman, over 3.5 years of age, whenever she took iodides internally — as she was accustomed to do, by taking Clarke's blood mixture periodically — used to develop peculiar papular skin lesions around the elbows and knees. When the rash came out, she would lose her voice and get threatened attacks of oedema of the glottis. The papular lesions varied in size according to the stage of their development, the biggest being not larger than a pea. The early lesions had a central haemorrhagic spot, which in the older papules had given way to a yellow spot, considerably bigger than the original haemorrhagic spot. In some of the oldest papules, a crust occupied the centre. The skin lesions disappeared in course of time when the iodides were stopped. On examination, nothing abnormal was found, and the urine was natural. 564 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. A histological examination of a very early lesion revealed the following points. The epithelium was thinned over the centre of the papule, and directly under it was a dilated capillary almost filled with endothelial cells. Many of the endothelial cells had reached the tissue outside. In the endothelial infiltration were numerous red blood corpuscles and leucocytes. In the corium on either side of this central cellular mass, all the capillaries were dilated and filled with numerous endothelial cells, many of which had extended outside the walls, where there were no red or white blood corpuscles. In the later lesions, the peripheral endothelial proliferation was more pro- nounced, but in the central mass the endothelial cells had degenerated and practically the whole space was taken up with leucocytes. Many of these leucocytes were pus cells ; hence the disappearance of the epithelium above them, and the explanation of the crust. Except for a fatty degeneration which some of the endothelial cells in the central mass had undergone, those in the peripher}^ had not altered. The j^ellow colour and xanthomatous appearance of the late lesions was probably partly due to this fatty degeneration. The endothelial cells were somewhat swollen, but both the protoplasm and the nuclei stained well. The protoplasm was sharply circumscribed, the cells were always mononuclear, and each nucleus had its single nucleolus. Histologically, the lesion was a true inflammatory endothelioma, and the leucocj^ic infiltration, which never extended beyond the centre of the lesion, was purely secondary. Xanthoma and xanthelasma are, in my opinion, inflammatory endotheliomata, caused by variou.s chemical poisons which are not uncommonly generated in metabolic diseases, such as diabetes, etc. Xanthoma has always received a great deal of attention, because of the striking appearance of the lesions. The yellow colour is due to a peculiar degeneration which the protoplasm of the endothelial cells undergoes. It is of the nature of a fatty degeneration, but the chemical products formed are not the same in all instances. Sometimes the xanthoma masses stain with both osmic acid and Sudan III. In other cases they stain only with Sudan III. The masses may be very optically active, and may be found to consist of cholesterol, but this is not true of all cases. Pigment, in the epithelial cells, is a degeneration product of the protein of the cell, and its formation is, at the same time, a functional action. In some inflammatory conditions, the pigment is very markedly increased, so that one can draw a parallel between the pigment degeneration of the epithelial cells and the xanthomatous degeneration of the endothelial cells. ROLE PLAYED BY ENDOTHELIAL CELL. 565 The so-called senile angiomata, are, most probably, inflammatory endo- theliomata. New Growth Endotheliomata. Instead of behaving as they do in inflammation, a group of endothelial cells may multiply and form a new growth, and this new growth may be either innocent or malignant. There is a type of cutaneous endothelioma, thoiigh rare, which corresponds to the basal-celled epithelioma (rodent ulcer). I have had two cases. Cases 90, 91. — Both cases were men nearly 50 years of age. In the one, a growth appeared on the ala of one nostril, and gradually grew to the size of a pea ; the tumour then ulcerated and looked very much Uke a rodent ulcer — indeed, it was diagnosed as such. The growth was removed and microscopically examined, when it turned out to be a true endothelioma. The growth recurred. In the other case, two growths appeared on the back ; they were about the same size as that just described, but they did not ulcerate. When removed they did not recur, and histologically, the characters of all three growths were the same. The endotheliomata about to be described correspond to the papillomata, and like them, they may be either innocent or malignant. Moles. A mole is frequently called a naevus, and as there appears to be so much confusion about these two words, no harm will be done by analysing the true meanings of the two words. The word mole comes from the Anglo-Saxon word "mfil," which means a spot,, and the Latin word " naevus" means a blemish. Hence the two words have the same meaning. The word mole is most frequently given to the pigmented or non- pigmented congenital growths of the skin, while the word naevus is usually meant to designate some congenital vascular growth, although very often the two words are used indiscriminately for the same lesion. As so much confusion surrounds these two words, it would be very convenient if we used them loosely for any blemish of the skin, remembering at the same time that both words meant the same thing. If we wanted to discriminate between the various kinds of lesions which fall under these two names, pathological aid should be invoked, and the growth named according to the cells of which it was constituted. Moles and naevi are epitheliomata and endotheliomata. The latter may be roughly divided into pigmented and non-pigmented endotheliomata, haemangioendotheliomata, and lymphangioendotheliomata. 566 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. Pigmented and Non-pigmented Endotheliomata. Discussion lias raged for years about the origin of mole cells, and the question is by no means settled yet. Doubtless some of the confusion is due to the fact that the words, moles and naevi, have not the same significance for any two observers. Moles and naevi can be either epitheliomata or endotheliomata, the latter being more frequently met with than the former. The epitheliomata have already been discussed, so in this chapter the endotheliomata will be considered. What most people commonly regard as moles, are, in my opinion, endothe- liomata. Some of the pigmented endotheliomata are difficult to distinguish clinically from the pigmented epitheliomata. Microscopically, they can be more easily differentiated. As the name mole is given to the clinical condition, whether the lesion is microscopically an epithehoma or an endothelioma, it has resulted in the formation of two camps. -^ 2 3 6 7 8 9 lo q,^ ^jjg q^^ ^-^^^ j|- jg thought that all moles are epitheliomatous, while on the other side the opinion is held that they are all endotheliomatous. At one time, all histologists considered moles to be endotheliomata, but now most are leaning towards the other view. As already stated, I think moles may be either epithehomata or endothehomata, but that the latter are more commonly to be met with than the former. Hence I propose to advance points against those who maintain a common epithelial origin, as their case is certainly the weaker. The two reasons which are given by those who maintain the epithelial origin view are : (1) that they have witnessed the gradual transition of epithelial cells into mole cells ; (2) because the mole cells sometimes contain pigment. In ordinary inflammatory skin lesions, it is not at all uncommon to see several stray epithelial cells in the inflammatory infiltration. The inflammatory infiltration very often reaches right up to, and presses on the epidermis, but as the wandering epithelial cells are so distinct from the inflammatory cells, a transition between the two is inconceivable. If, on the other hand, mole cells are in place of the inflammatory cells, one might easily run away with the idea that in those cases in which the mole cells had encroached to the epidermis and the basal layer had been broken, owing to the obliquity of the cut section, several epithelial cells might be seen amongst the mole cells, and, owing to the similarity of the two, that a gradual transition had taken place. Naturally, in the epitheliomatous moles a transition can be seen, but it does not follow that such a transition is to be seen, somewhere, in all moles. That the cells are sometimes pigmented, is no evidence, since pigmentation is, after all, only a degeneration product of protein, and is by no means peculiar to epithelial cells. Plates 43 and 44 are from a pigmented epitheliomatous mole. ROLE PLAYED BY ENDOTHELIAL CELL. 567 In favour of mole cells usually being endothelial cells are the following facts : — They most commonly occur in the centre between two papillary processes, and it is in the centre that the capillaries are most abundant. The papillary processes are often greatly lengthened, but still a wide space often exists between the mole cells and the epidermis above, and the papillae laterally. The basal layer of the epidermis is often markedly pigmented when the mole cells contain no pigment. Mole cells may become malignant, and then they behave as sarcomata. Let us consider a rodent ulcer for a moment. A rodent ulcer is a basal-celled epithelioma and. in every case, a connection can be traced between the growth and the epidermis. This is likewise the case with all new growth epitheliomata. Those which have no connection with the epidermis itself are appendicular epitheliomata, and the cells of the growth correspond to the layer of the appendicular structure from which it arises. If it forms from mature tissue, the cells constituting the growth will resemble those of hair follicles, or sweat or sebaceous glands. If it forms from embryonic tissue, the growth will be like a rodent ulcer, made up of basal epidermal cells, the basal epidermal cell being the embryonic epidermal cell, from which all the other cells ultimately mature. The mole cells are always the same ; they are mature endothelial cells. If they arise from epithelial cells, they must arise from mature epithelial cells and alwavs from the same layer, as the mole cells do not vary. The epithelial cell layer, to which the mole cell most approximates, is the third or fourth, and this is usually not pigmented. If the mole cells arise from such a mature epithelial cell, how can it be explained that they never arise from the mature appendicular cells, but onl}' from the epidermis proper ? and why, in over 90 per cent, of the specimens, does a space separate the epithelial cells from the mole cells — a phenomenon which is never witnessed in new growth epitheliomata arising from the epidermis proper ? Furthermore, keratinisation is a common feature of epitheliomata, while mole cells are unknown to develop keratin. When an epithelial cell forms pigment, the nucleus is somewhat swollen, and there is a marked activity of the nucleoli. The pigment is granular, and, in most cases, limited to the cell. When a mole cell is pigmented, there appears to be no increased activity of tlie nucleus or of the nucleolus, i.e., provided it is not malignant. Note that the nucleoh in the mole cells are not so well marked as they are in epithelial cells. The pigment is more massted, not so distinctly granular, and is far from being limited to the cell in which it is formed, it is often fainter in colour, and although 568 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. true melanin, it behaves differently to reagents from the normal epithelial melanin. Moles, or naevi, which may be either pigmented or unpigmented, are, in my opinion, usually new growth endotheliomata. The epitheliomatous mole can readily be distinguished microscopically from the endotheliomatous mole, and very often the two can be differentiated clinically, since ulceration is a common feature of the former, and not of the latter. The so-called melanotic sarcomata, or melanomata, are, in my opinion, new growth endothelial cells, the nuclei and nucleoli of which behave in the same way as those of the cancer and sarcoma cells already described. These malignant endotheliomata need not necessarily be pigmented. They may start de novo as sarcomata, or the ordinary mole cells, i.e., the ordinary new-gro^vth endotheliomata, rnay become malignant. The endotheliomata to be now described, correspond to the appendicular epitheliomata and the mixed epithelial and appendicular epitheliomata, and, hke them, are practically never malignant, because the cells in all are onl}' semi- embryonic. Haemangioendotheliomata. Although haemangioendotheliomata are congenital growths, the patient need not necessarily be born with them. Usually they appear within a few years of birth, but occasionally they may not become manifest until the patient has reached middle life. The lesions are multiple, they occur anywhere on the skin, they vary from the size of a pin's head to that of a sixpenny piece, they are raised above the surface of the skin, and have a red or brownish-red colour. The lesions may spontaneously disappear, or they may undergo changes before they vanish, in which case the colour of the lesions varies enormously, some may be brown, others yellow-, and others quite white. Having had some cases under my care, the pathology of which I have had ample opportunities for studying, it would be as well to copy the paper which appeared in the " British Journal of Dermatology," under the name of Naevo-Xantho-Endothehomata.* : — Case 92. — In June, 1906, a child was brought up by its mother to St. Bartholomew's Hospital, under the care of Dr. Morley Fletcher, to whom I am indebted for the case, for some " yellow swellings " which it had scattered about the bod3^ The face was the part most affected, especially the eyelids. There were two swellings in the neck, one on the left arm, one or two on both legs, and a few scattered about the trunk. To look at, they were bright yellow, slightly depressed ♦ - ,«. \ * V . • ♦ ^\ •^iSf ■•>0::rv?:-v:'>-7»:i Facing p. 568. ROLE PLAYED BY ENDOTHELIAL CELL. 569 in the centre, and had a glazed surface resembling very closely Xanthoma j^lanum. The edge of each swelling was reddish, and the vessels could plainly be seen. The tumours in size varied from \ in. to J in. in diameter. They were raised about 3 or 4 mm. above the surface, were of firm consistency, and moved with the surrounding skin, which was in every way normal. In other respects the child was quite healthy. AVhat urine could be obtained was carefully examined, but nothing abnormal was discovered — no sugar, bile or albumin. These swellings were present at birth, and the following account is taken from the notes of Mr. Woodman, who attended the confinement : — Born April 7th, 1906. L.O.A. position. Weight lOj- lbs. About the body were scattered brownish-red swellings, raised well above the surface of the skin, of firm consistency, elastic, almost cartilaginous. The surface of the tumours was quite smooth, and showed numerous small injected capillaries. In June, 1906, some of the nodules were removed for microscopic examination, and a painting was made. I did not see the child again for a year. When in April, 1907, I wi'ote and asked the mother to bring the child up to hospital, I found that the swellings were of the same size, not such a bright yellow in colour, and quite flush with the surface of the surrounding skin. The lesions still had the glazed appearance, the central depression had disappeared, the edges were of the same colour as the re.st of the swelling, and showed no dilated capillaries. Urine quite normal. Some more nodules were removed for microscopic examination. Owing to my being abroad, I was unable to see the child again till June, 1909, when I was surprised to find all the swellings had disappeared. The old scars resulting from the biopsies were scarcely visible, and there was no keloid formation in them. The scar over the right eyebrow had, according to the mother, given the child a good deal of pain, which had for a few months past quite disappeared. I searched the legs, where I knew there had been some swellings, and all I could find in their place was a piece of skin which was whiter and of a more glazed porcelain- like appearance than elsewhere; so slight was the difference that, had I not known that something had been there, I should have overlooked any change. The mother has had fourteen children ; this child was the thirteenth, but none of the others had a similar condition and no member of the family had ever suffered from any " swellings of the skin." Examination oj nodule removed June, 1906, Plate 53 (1). — The swelling is made up of a cellular infiltrationj which extends from the epidermis down into the subcutis, and measures 5 mm . in diameter. It has a capsule, at the base but not laterally, consisting 570 BIOLOCJY OF INFLAMMATION AND MALIGNANT DISEASE. of collagenous and elastic tissue. At the sides, the tumour runs into the normal connective tissue of the corium. Above, the cells of the growth encroach so closely on to the epidermis that it is difficult to say where one begins and the other ends. Lower down there is a sharp division of the cutis from the subcutis by bands of normal connective tissue which send numerous processes into the cellular mass above, but none below, so that that part of the growth situated in the subcutis appears more cellular. Here and there, the boundary line is broken, so that the cells of the cutis are continuous with those of the subcutis. The cells in the subcutis are loosely packed together, except at the base ; they lie in a groundwork of connective tissue, and here and there processes from the capsule, often containing normal blood vessels, are to be traced up into the growth. The epidermis and cutis on either side of the swelling are quite normal, and in the latter there is no sign of inflammation, such as a small round-celled infiltration, etc. Over the centre of the tumour, the epidermis is markedly thinned, has almost completely lost its papillary arrangement, and contains no pigment in the basal cell layer. There is a parakeratosis. The cellular mass, reaching as it does right up as far as the epidermis, and the similarity of the cells to epidermal cells, at first sight gives the impression that the tumour is epithelial in origin. On careful examination, the basal cell layer has not given way in any part, and no migration of an epidermal cell into the gi'owth can be found. The cells in the cutis are mainly polygonal in form, others are spindle-shaped or round ; each contains a well-stained nucleus which is either centrally or excentrically situated. There is a good deal of connective ti.s.sue, which consists of both collagenous and elastic tissue, between the groups of cells, and, on examining with a high power, the cellular mass can be distinctly seen to be in a connective tissue groundwork. The cells of the subcutis tend to be more spindle-shaped, and there is not .so much intervening connective tissue. Throughout the specimen, the large blood vessels are quite normal, and are to be found in the connective tis.sue processes. The capillaries and Ipuphatics show an endothelial proliferation, which sometimes occludes the lumen, and always extends outwards, invading the sur- rounding tissue, so that the endothelial cells cannot be differentiated from the cells of the growth. Here and there, these cells show signs of degeneration, many cells put out KOLE FLAYED BY ENDOTHELIAL CELL. 571 processes and join together, resembling a grauuloina wliere f-o many epithelioid cells join together to form a giant-cell in the centre. This degenerative condition is most marked in the subcntis. The microscopic picture is strongly suggestive of an endothelioma. Microscopical examination of nodule removed April, 1907 (Plate 53 (2)). — The width of the cellular infiltration is now only 2 mm. With a low power, the tumour seems to consist of a mass of loose cellular connective tissue, extending upwards almost as far as the epidermis, but separated by an interval of denser connective tissue which is slightly more cellular than normal. Downwards, the mass invades the orbicularis palpebrarum mu.scle. The epidermis has regained, to a great extent, its papillary arrangement ; in some parts the papillae are increased, a fact which is made still more evident by the flattening out in other portions. The rete, as before, does not consist of so many layers; there is still absence of pigment in the basal cell-layer, and no parakeratosis. In the tumour mass, several large and quite normal vessels are to be seen. Staining with van Gieson shows a cellular mass interspersed with fibrous tissue, to a much greater extent than in the previous specimen, and also a layer of fibrous tissue between the mass and the epidermis. Acid orcein shows a network of normal elastic tissue, underneath the epidermis and scattered about in the tumour. In places it is very well marked. This stain also makes the vessels in the section prominent. In the healthy tissue around the tumour, there are no signs of inflammation. The endothelial cells have now undergone degeneration, each cell is very much swollen, and many have joined together to form a protoplasmic mass ; the proto- plasm appears granular, probably granuloplasm, which give the cells a honeycombed appearance ; between individual cells, or groups of colls, there is a strand of formed connective tissue, which comes from the normal surrounding connective tissue (Plate 53 (3)). Many cells contain two or three nuclei. The nuclei are large, irregular in outline, and stain badly; all stages can be seen, from commencing degeneration to complete disappearance of the cells. Some of the blood vessels, those surrounded closely by the tumour cells, have their one or two layers of endothelial cells. enormously swollen, usually completely occluding the lumen, and their nuclei .stain faintly. The connective tissue of the walls is likewise swollen, and contains no nuclei. Other blood vessels are to be seen, apparently of new formation, since they show no endothelial proliferation, and the nuclei stain well. 572 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. Around most of these vessels is a number of mononuclear leucocytes, easily distinguished from the nuclei of the degenerating endothelial cells, by being perfectly regular in outline and by staining deeply. Owing to the clinical similarity with xanthoma, sections were treated with 1 per cent, osmic acid and Flemming, but, when examined histologically, no deposits of fat, as in a xanthoma, were noticed, but some of the cells, markedly those situated nearest the epidermis, contained fatty granules. Unfortunately none of the sections were stained with Sudan III. Except that no fatty droplets are found, the cells simulate xanthoma cells in every respect. There are very few hair follicles, but those present show no pathological change. The ducts of the sweat glands cannot be followed up to the epidermis, but the coils do not depart in any way from the normal. The xanthoma-like cells surround, but are never found intunately connected with the cells of the glands. The sebaceous glands are few and far between, but quite normal. There is a strong similarity between the cells of the sebaceous glands and the cells under discussion, but nowhere is any connection to be found. Owing to this resemblance, it was originally supposed that xanthoma cells were derived from those of the sebaceous glands, a fact entirely disproved by the occurrence of xanthoma masses in the mucous membranes and internal organs. In searching the literature, I found a case described by Sachs^ under the name of a Xantlwmartiger naevus verrucosus, the histological appearances of which coincide with the specimen just described. The affection appeared in the axilla of a girl a few days after birth. The cells depicted resembled abnost exactly the large cells described in my second specimen, but differed in that they contained fat-droplets. The cells extended up close to the epidermis, but did not go down as far as the subcutis. They contained one or two nuclei which were either central or excentric. Many of the nuclei showed nucleoli, and in many cases the nucleus was shrunken. The cells resembled very closely those met with in xanthoma. By ordinary hardening and staining, vacuoles took the place of the fat-droplets, thereby giving the cells a honeycombed appearance. The blood vessels were somewhat dilated, walls thickened, and the endothelial cells were swollen, and projected into the lumen of the vessel. The lymphatics were likewise affected. These xanthoma-like cells occurring in a naevus led Sachs to consider as to whether he was dealing with a pure Xanthoma tuberosum, or with a soft non-pigmented Naevus verrucosus. These xanthoma-like cells differed from ordinary xanthoma cells, in that they were arranged in the papillae, in close WVi'3^MMMM ^%^^?^ '-■:>•< v<^^; '^■'^'•^ • ■ ^■'S^'-^^i^^^^ *~^^'* f -^ S^'J' ''% ■ -••-•■' I'\iring p. 572, ROLE PLAYED BY EXDOTlIELrAL CELL. 573 connection with the epidermis, while the cells of Xanthoma tuberosum are mainly found in the deeper layers of the cutis. Sachs' case was one of a naevus, which had undergone, presumably, some fatty degeneration resembling xanthoma. The cells in my case had undoubtedly under- gone further degeneration, which is not unlikely, since spontaneous cure was the ultimate result, while Sachs' case remained stationary, and it is quite likely that had I been able to make a biopsy between the two periods, the cells would have contained fatty droplets, and would have resembled Sachs' in every respect. From the foregoing, I should regard the case as being a naeviis of endotheUal origin, which, while on its way to spontaneous cure, underwent changes of a fatty nature, giving the lesions the clinical aspect of xanthoma. Case 93. — D. H — , a girl, aged 5 months, was brought up to the hospital by her mother for some swelHngs in the skin, which made tlieir first appear- ance fourteen days after birth. There was absolutely nothing on the skin when the child was born ; the swelUngs, scattered over the body, having no predilection for a site, were about the size of a lentil when they appeared, and red in colour. Many of these disappeared soon afterwards, while others increased in size, became yellow, and were surrounded by a reddish halo ; the yellow swellings then got smaller and disappeared spontaneously. The mother states that she was born with similar swellings, which appeared and disappeared up to the age of fourteen. In the patient, fresh swellings have appeared since the initial outbreak. Although the tumours resemble, clinically, those met with in Case 92, they differ in that they were not present at birth, and fresh lesions were formed, but they are the same, inasmuch as spontaneous cure was the ultimate result. Histology. — The tumour is a cellular one, which reaches from the subcutis (Plate 54 (1) ) up as far as the epidermis, being more cellular in the subcutis. In the cutis, the new-formed connective tissue appears prominent in places, owing probably to its taking the place of the cells which are degenerating. Such an appearance of the connective tissue is only to be seen in the centre of the tumour ; directly over the tumour, the epithelium is straight, the papillary bodies are longer and narrower, their differentiation from the cellular growth underneath is difficult to make out, the epithelial cells are degenerated, but under the high power no connection between the epidermis cells and the cells of the tumour can be demonstrated. On either side of the centre, the cellular growth does not reach up as far as the epidermis, and the epidermis over it is normal. Examining the cellular growth with a high power, it is impossible to differentiate each individual cell, since two or more appear massed together in a homogeneous way with a hyaline background which stains faintly, while the nuclei stain well. Between the cells 574 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. are numerous spaces, many of which are undoubted capillaries, since red blood - corpuscles are to be demonstrated therein. Many of these spaces are lined by endo- thelial cells which are continuous with the cells around, and the latter appear to be of the same origin. In other places where the capillaries are distinct, the lumen is obliterated by a hyaline mass, around which are the well-stained nuclei of the endothelium, giving the appearance of a giant-cell. This hyaline mass is found to consist of several endothelial cells. These endothelial giant cells are most marked just underneath the epidermis. A section .stained with Sudan III proves the presence of fat in the cell masses and in the protoplasm of the individual cell ; and those cells which fill the lumen of the vessels, and which give the appearance of a giant-cell, contain fat in their .spongioplasm. In the epithelial downgro\\-ths, there is no trace of fat. Osmic acid preparations bring out the same characteristics as just described with Sudan III. A van Gieson preparation shows that these cells are not of connective tissue origin. A polychrome methylene blue preparation differentiates well the epidermis from the cellular growiih, and as the connective tissue is not stained, the characters of the cells are more easily to be made out. Everywhere they can be found continuous with the endothelium of the blood- vessels, and, in most cases, they bear an exact resemblance to the cells thereof. Some are large polygonal cells with a central nucleus, others are spindle-shaped ; here and there, cells are to be found dividing by amitosis ; in other places, the protoplasm of the cell has disintegrated, leaving only the nucleus, which stains faintly, and shows a nucleolus. Case 94. — A boy, aged 10 months, was shown by Dr. F. Parkes Weber before the Dermatological Section of the Ro^^al Society of Medicine, May, 1908, as multiple xanthoma. The eruption was confined to the forehead and upper part of the face. It consisted of irregularly distributed papules and raised spots, measuring 1-7 mm. in diameter, which varied in colour from a brownish-red to a yellow. The child had nothing else abnormal, and no fre.sh lesions appeared while the child was under observation, and all of them spontaneously disappeared. At the meeting, the case was regarded as Urticaria pigmentosa, a diagnosis which a microscopic specimen showed to be incorrect. Unfortunately, the histological examination was not worked out, but there is no doubt that the case belongs to the group under discussion. Case 95. — In this patient, a girl, the yellow swellings appeared about three weeks after birth. According to the mother's account, they fii'st appeared as small red raised spots, and became yellow later ; and further, that some of the yellow spots remained, while others disappeared spontaneously, leaving no trace behind them. In this case, there was no family hi.story. Microscopic examination only ROLE PLAYED BY ENDOTHELIAL CELL. 575 differed from the preceding specimens, in that the cellular gi-owth was not so large, that there were no giant cells, and that the epithelial elements were in more abundance and more pronounced. Case 96. — This case was shown by Dr. Bunch at the Dermatological Society of November, 1911. as a case of multiple augiomata. The child was first seen when three weeks old, and the lesions had been present since birth. These consisted of more than a hundred small, purple, raised tumours, from a pea to a small nut in size, on the trunk, limbs, face, and scalp. They became pale when pressed with a diascope, and w«re in most cases soft to the touch, but one or two on the legs seemed sUghtly firmer in consistence. I suggested at the time, that this case might belong to the group of multiple benign endotheliomata of the congenital xanthoma type ; that some of the lesions would ultiniatel}^ become yellow and then spontaneously disappear. On making a histological examination, the following was revealed (Plate 54 (2)): — • Before coming to the centre of the tumour, the early sections showed an increase in the sweat glands and ducts, of a naevoid character. On the left side of the figure, sweat ducts can be seen appearing on the right wall of the commencing endothelial growth. As sections nearer the centre were examined (Plate 54 (3)), this cellular endothelial growth increased in size, and in it were spaces, undoubted capillaries, the endothelial cells of which were continuous with, and of the same nature as those surrounding them. The cellular growth, then, was an endothelioma. On the epidermal side of the cellular mass were several sweat ducts, which, as still deeper sections showed, were no longer visible, owing to the spreading out of the growth. Unfortunately, no fresh specunens were examined, so it is impossible to say whether any of the cells contained fat or not. There were no giant cells. The jjurple colour of the lesions was probably due to the depth at which the cellular growth was situated, as the tissues in between it and the epidermis were normal, and also to the fact that the cells had not yet degenerated. Summary of histological a pjjea ranees. — First of all, there is a dense cellular growth, most marked in the deeper layers of the skin, the cells of which take their origin from the endothelium of the capillaries. Then many of these cells disappear, while new-formed connective tissue takes their place. It is in this stage that the giant cells are to be seen, some of which are formed by the endothelial cells blocking a capillary, because some which are not completely blocked contain red blood- corpuscles ; these giant cells are to be seen under the epidermis. Others — and these occiir deeper in the corium — are fomiecl by the fusion together of some of the cells of the growth.) The grouping together of a dozen or more cells is probably caused by the growth of fibrous tissue which separates them. The cells contain 2o 57G BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. fat. This is the stage in which the lesion microscopically resembles a soft fibroma or connective tissue tumour. On careful examination of the cells at the base of a tumour removed in this stage, some are found to have swollen and taken on the appearance of the honeycombed cells to be now described. These cells contain less fat than those met with in the upper layers of the skin, and the fat appears in the form of granules only. The stage further is when all the cells are swollen, contain one or more nuclei well outlined by a strand of connective tissue, and have the honeycombed appearance. It is now that the new vessels appear so prominent, and signs of inflammation as a small round-celled infiltration are to be seen. The final stage is reached when these cells also disappear. Conclusions. — From the foregoing it will be seen that there is a special form of multiple growths in the skin, and they are conspicuous from their yellow colour. These growths may be present at birth, or they may not appear till later, and there is sometimes a family history. They may persist for many years, but they tend to ultimate spontaneous cure. They may commence as red tiunours, like angiomata, to become yellow later. The tumours are not necessarily limited to the skin, and there is no_ evidence that they are dependent upon any visceral disturbance. They are new growths, and not inflammatory swellings. Concerning the histology, the views are various, and observers have, no doubt, rather been led astray by the yellow colour, to seek for them the same origin as Xanthoma planum — an inflammatory lesion, not a new growth ; and as the sebaceous gland-cells contain fat and the cells of xanthoma are not uiJike them, these growths were said to have origin from sebaceous glands. Without enumerating point for point against this view, it sufiicies merely to mention that these tumours have been found in situations where there are no sebaceous glands ; for instance, in the endothelium of the aorta. The next common view held was, that they were made up of connective-tissue cells, and that the giant cells which were sometimes to be met with, were formed by the fusion of some of these cells. If the figures of my section are studied, one cannot help being struck with the spaces, the lining cells of which are continuous with, and indistinguishable from, those surrounding them — a condition one would not expect to meet with in a connective tissue tumour. Some of these spaces, which I take to be capillaries and lymphatics, have blood-cells in them. ROLE PLAYED BY ENDOTHELIAL CELL. 577 Some of the giant cells are clearly capillaries blocked by swollen endothelial cells, since in some which are not completely blocked, red blood corpuscles are visible ; further, the giant cells do not resemble ordinary giant cells — a mass of protoplasm with nuclei collected at one pole ; on the contrary, the nuclei are arranged equally all round the centre, and the protoplasmic mass can be demonstrated in fresh specimens to be made up of distinct cells — endothelial cells ; the nucleus of each staining only faintly. These cells contain a substance which stains with Sudan III, and in the form of granules, with osmic acid. The cells surrounding these capillaries, which resemble the swollen endothelial cells, also stain with Sudan III. The primary lesion is probably an overgrowth of the cells which should form the capillaries and lymphatics, affecting only a group of these — to the sweat glands, for instance, as in Case 96. Then the cells undergo some form of fatty degeneration. As a result of the disappearance of several of the cells, the remainder become more distinct ; but owing to the presence of two or more nuclei, the protoplasm being honeycombed, and the presence of inflammatory cells, these cells gradually become more and more degenerate, until they themselves completely disappear, normal blood vessels and connective-tissue cells taking their place. The tumours, in my opinion, are endotheliomata, and belong to that big class — nae\nis. Just the same as we can get an overgrowth of embryonic epithelial tissue, in the one case affecting those cells destined to form sebaceous gland tissue, in another case sweat gland tissue, and so on, we can get an overgrowth of the embryonic cells which are destined to form the capillaries. The l3aiiphatic vessels and capillaries apparently develop from cords of cells that arc of direct mesodermic origin. These solid cords are afterwards hollowed out, and become tubes. The lining of the tubes is formed from some of the cells of the cords, while the remainder form the coats of the vessels and the other structures which make up the connective tissue. According to Schultze, the earliest lymphatics and capillaries formed are those in the subcutaneous tissue. Since the cells constituting the tumours are undoubtedly embryonic, one cannot say for certain whether the tumours should be classed as endotheliomata or as connective tissue tumours, because the cells are probably in that stage where the differentiation is incomplete, and, as the origin of both is the same, it matters little. It is on account of the hollowing out of the solid cords, as in Plate 54 (.3), and the later behaviour of the cells, which are undoubtedly endothelial, that I prefer to call them endotheliomata. It is just possible, and Case 96 bears this out, that the overgrowth of the embryonic cells which are destined to form capillaries, oiJy takes place round about epithelial 2o2 578 BIOLOGY OF INFLAMMATION AND MALIGNANT DISEASE. structures, as in this case the sweat glands, aud that, the same causes may be at work on these cells which produce the other forms of naevi from which scarcely a person escapes. In conclusion. I should suggest that these tumours under discussion are naevi of the type endothelioma, and that, owing to a fattj^ change which occurs in the cells during their dissolution, a xanthoma-like condition is produced. The name Naevo-Xantho-Endotheliomata would describe them exactly. Lyniphangioendotheliomata. Analogous growths in the skin to those just described may be made up of lymphatic and not vascular endotheUal cells. The only difference between the two lesions is one of colour, the lyniphangioendotheliomata being colourless. Lyniphangioendotheliomata must not be confounded with lymphangiomata, any more than haemangioendotheliomata must be confounded with haemangiomata. Both haemangiomata and lymphangiomata are new growths of the vessels, in which the endothelial cells do not participate. Clinically, they are also very different ; the lesions are usually single, and much more pronounced, and they often cover a wide area. To the haemangiomata belong the so-called vascular naevi and port wine stains, which are usually present on the child when it is born, or appear soon afterwards. The lymphangiomata are much more rare, the}' usually appear later in life, the condition is usually called Lymphangmna circiunscriptum cutis. The whole lesion is usually about the size of the palm of the hand, and is made up of a series of what look like distinct vesicles. Each small lesion has a fluid content, but when punctured, it does not give rise to lymphorrhoea. This condition must not be confounded with Lymphangioma tuberosum multiplex, which is not a lymphangioma at all, but a swingoma, i.e., an epithelial new growth of the sweat ducts. Malignant and Intermediate Endotheliomata. The malignant melanoma bears the same relationship to the pigmented wart, as the maUgnant epithelioma does to the papilloma. That is to say, the mahgnant cells are recognised, not because they invade healthy tissue, a statement which is impossible to make in the case of the melanoma, but because the tumour cells vary very much in size, exhibit marked nuclear and nucleolar activity, and in both cases pseudo -parasitism of the nucleolus is discernible. I consider that the so-called malignant melanoma is exactly analogous to that case of malignant pigmented epitheUoma described in Chapter XLV, and from which Plates 43 and 44 are taken. In both instances, the type of malignancy is what might be called the pseudo-parasitic ROLE PLAYED BY ENDOTHELIAL CELL. 579 type, in contradistinction to that type in which the cells arc of a distinctly embryonic character — the embryonic type, or what I have described above as embryonic activity. The embryonic epithehal cell resembles very closely that cell which constitutes the basal layer of the epidermis, and of which the rodent ulcer consists, but what are exactly the characteristics of the embryonic endothelial cell, is not so certain. I am incUned to the view myself, that the embryonic endotheUal cell is a spindle cell, and that it gives rise on the one hand to endothelial cells, and on the other hand to connective-tissue cells which form the support of the endothelial cells, and ultimately become the walls of the vessels. If correct, an analogy would exist between the endothehal and connective-tissue cells such as exists between the epidermis and its appendages. The first section taken from Case 92 is made up of what I take to be embryonic endothelial cells, before they have become differentiated into endothelial cells and connective-tissue cells. This case I regard very nuich in the same light as I do a case of mixed epidermic and appendicular epithelioma. The spindle and round-celled sarcomata probably arise from the mature endothelial cells which have become apportioned to form connective-tissue cells, and those cells which form the walls of vessels. 1 Uima (1896), " Histopathology of the Dis. of the Skin." Trans, by Korman Walker. W. Clay. Edinburgh. 2 Kyrle (1913), " Archiv. f. Derm. u. Syph.," cxviii, 319. 3 Whitfield (1900), " Brit. Journ. o£ Derm.," xii, 267. * McDonagh (1912), " Brit. Journ. of Derm.," xxiv, 8.5. = Sachs (1903), " Archiv. f. Derm. u. Syph.," Ixvi, 101. « Bauer (189.5), " Virchow's Archiv.," oxlii, 407. ' Delbanco (1896), " Monat. f. prakt. Dermat.," xxii, 105. " Kromayer (1890), " Dermat. Zeitschr.," iii, 263. » Gilchrist (1899), " Journ. of Cutan. and Genito-Urinary Dis.," xvii, 117. 1" Audry (1900), " Monat. f. prakt. Dermat.," xxx, 409. CHAPTER XLVIII. THE ROLE PLAYED BY OTHER CELLS IN INFLAMMATION, AND THEIR PROBABLE RELATIONSHIP TO MALIGNANT DISEASE. Introduction. The other cells which we have to consider, are the polymorphonuclear leucocytes, the basophile leucocytes, the eosinophile leucocytes, and the connective-tissue cells. All these cells play a more or less insignificant part in chronic inflammation. They do not form growths of their own, with the exception of the connective-tissue cell, therefore no relationship exists between them and malignant disease. Phagocytosis. The mere fact that the polymorphonuclear leucocyte is not much in evidence in chronic inflammation, should go far to lessen the importance of phagocytosis, for surely, the more chronic the lesion, the greater the call upon the host's pro- tective capacity. Hence if phagocytosis is, as many observers assert, the host's chief means of ridding himself of the parasites, surely there should be m5T:iads of them in granulomata. In granulomata the polymorphonuclear leucocyte is outnumbered by the lymphocyte, in which is incorporated the host's main protective weapon. Phadenitis accompanying, 131. loss of surface corresponds with celMar infiltration in corium, 127. nature of, 120. Chancres, primary, necrosis of, 126, 128. of experimental syphilis, tendency to ulceration, 120. — ■ of tonsil, 164. ■ diagnosis from Vincent's an- gina, 164, 165. papulo-erosive and papulo-ulcera tive course of syphilis after, compared, 130. worst cases of syphilis arise from, 129. papulo-tJcerative, 129. simple, 130. removal of crust of ulcer before diagnosis, 130. phagedaenic, 126, 131. — — pseudo-membranous. 131. ■ secondary infection, 126. site of breaking down under trauma, 13. ulcerative stages, 126, 128. variation in, 11. See also Button chancre. Chemoceptor, definition of term, 283. Ghemotherapj', results, how obtained, 285. — ■ — Ehrlich's conception of, 283. Child, syphilitic, danger of producing, 261. negative Wassermann reaction in, becoming positive, 257. treatment advisable in parents after birth of, 257. Child-bearing period, positive Wassermann reaction in women indication for treatment throughout, 256. Children, healthy, of sj-philitic parents, 261. non-sj'philitic, births of, intervening be- tween those of syphilitic, 260. sj^hilitic, early death of, 260. Chloride content of syphiUtic and normal lymphatic glands, method of estimation, 87. Chlorine, monovalent element, 276. Chloro-lymphadenosis, 541. Chloromata, 541. Cholangitis, sj'philitic, 177. complicated by jaundice, 177. Cholesterol, addition to antigen, 73, 74. appearance in syphilitic parasites, 49. Choroid plexuses, epithelial cells of, constitu tion, 78. derivation of reagin from, 78. Choroiditis, congenital syphihtic, 273. syphilitic, 155, 156. retinitis associated ■with, 156. Chromatin, specific action of methyl green for, 30. Ciliary body, gumma of, rare, 155. Circumcision, reasons for performing, 461, 464, 470. Citron's method of preparing neutral emulsion, 338. INDEX. 597 Clavicles, osteoperiostitis of, 172. Clove oil, not to be used as clearing fluid in staining syphilitic organisms, 33. Cocci accompanying svphilitic parasites, result, 145. Coccidiosis avenf.rea, case of, 18. inclusion bodies in, 20. treatment, 19. histological examination of early papule, 19. Coitus inlerruptus, 480. urethritis due to, 417. Cold, formation of reagin increased !>y, 89. Cold applications in epididymitis, 402. Colles's law, explanation, 250. • validity of, 251. Colloid, use of term, 501. Colloidal particle increase of in antigen, 72. Colloidal particles larger in syphilitic than in normal sera, 84. of dyes, positively and negatively charged, 25. Colloidal solutions, decrease of surface tension, how produced, 96. Colloidal and non-colloidal bodies, efEect on serum reactions compared, 77. Colour test in diagnosis of syphilis, 69. Colpitis in women, 428. Complement, adsorption bv reagin explained, 95. ■ action of, destroyed bv deep anaesthesia, 65, 80. how increased, 81. • pure lecithin globulin on, 79. best obtained from guinea pig, 65. cellular origin, 84. destruction of. following by disappearance of oxydase reactions, 83. does not keep when diluted, 74. fixation of, haemolysis in test tubes in relation to, 67, 68. fixation test in gonorrhoea, 435, 442. identical with antibody, S3. with lipoid-globulin, 83. lipoid-globulin particles in normal serum probably consist of, 82. method of preservation, 80. most important factor in Wassermann reaction, 98. once destroyed cannot be renewed, 81. precipitation in dialysmg apparatus, result, 96. rapid disappearance when kept, 80. • relation to oxydases, 82, 83. standardised strength must be employed, 98. strength of, method of ascertaining, 66. substances destroying, 81. Complement, syphilitic serum giving positive nin-hydrin reaction in presence of, 96. thcrmolability of, 80, 81. Complement and antibody, chemically identical, 76. identity of, 82. — — fixation by Spirochaeta pallida in presence of antibody, 61. in Wassermann reaction, essentials for, 73. fixation test, 71. ■ demonstration of antibody by, 69. use of active sera in connection with, 76. molecules and reagin homologous, 90. precipitation of, 70. Condyloma acuniinaium, 467. Condyloma latum, 137. Condylomata, congenital syphilitic, 263. Condylomata lata around anus, 176. following use of salvarsan, 302. Congenital syphilis, treatment of, 326. Congo red, adsorption of, in different concen- trations, 26. Conjunctivitis, gonococcal, in adults, 420. in new-boni, 422. Coimective-tissue cell, 588. • • function of, 529. in which asexual spore cysts develop, how affected, 56. invasion in development of asexual stage of Leucocytozoon syphilidis, 127. proliferation of, 127. Constipation in sexual neurasthenia, 478, 481. Corium, cellular infiltration in, loss of surface of syphilitic sore corresponds with, 127. degeneration of, Icad.s to formation of pustule, 136. Corona, induration most marked when chancre situated in, 127. Cowperitis gonorrhoica, 388. Crystalline forms of plasma cell, 533. Cutireaction in diagnosis of syphilis, 113. • rationale of, 115, 116. sypliilitic, positive, 116, 117. • simulating syphilitic lesions, 110. Cycling, urethritis set up by, 416. Cystitis, gonorrhoea!, 377. gonorrhoica, 397. ■ syphilitic, 154. Cytorrhycles hds, 1. Dacryo-cystitis, syphilitic, 155. Dactylitis syphilitica, 266. Deaf-mutism, congenital syphilitic, 273. Deafness, following salvarsan, 309. syphilitic, 158. due to neuritis of auditory nerve, 159. of cranial nerves, 160. • early, 158. effect of treatment on, 160. INDEX. Deafness, syphilitic, in early syphilis, 158. late, 161. Death, enormous increase of Wassermann reaction in cerebro-spinal fluid just before, 192. Wassermann reaction positive in blood taken just before or after in non-syphilitic cases, 85, 86. Death agony, increase of total nitrogen in cerebro-spinal fluid during, 85. Deferentitis gonorrhoica, 400. Dejliivium capillilii, in congenital syphilis, 264. Degeneration, products of protein metabolism, 530. Dermatitis, seborrhoeic, mistaken for syphilitic rash, 263. Development, errors of, in relation to syphilis, 261 Dextrose, addition to borax methylene blue, 28. presumably absent in syphilitic bodies, 49. pseudo-chylous fluid with, reaction ob- tained under, 49. Diabetes insipidus, aberrant form of syphilis associated with, 15. association with congenital sj'philis, 17. ■ lesion in pituitary body in congenital sj^hilis, 272. Diagnosis, differential, Wassermann reaction in, 104. Dialysing apparatus, precipitation of comple- ment in, result, 96. Diday's irrigation in gonorrhoea, 383. Digestive system, disorders following salvarsan, 300. Digestive tract, congenital syphilitic disease of, 268. Diploii, gummatous osteomyelitis of, 171. Diplopia, complicating syphilitic cerebro-spinal meningitis, 234, 236. Distillation, methods of, 297. Doelfle, supposed pathogenic agent of syphilis, 1. Drugs in treatment of gonorrhoea, 383. used in treatment, methods of adminis- tering them, 337. Dubois's abscesses of th3Tiius, 270. Ducrey'a bacillus, 11, 358. types of, 366. Duodenum, syphilitic catarrh of, associated with catarrh of bile ducts, 176. Dupuytren's contraction and Induraiio penis plaslica, 474. Dydynski. See Halhau and Dydynski. Dyes, acid, fixed protoplasm stains best with, "31. • taken up by dead cells, 26. basic, destruction of affinity of Nissl bodies of nerve cells for, 26. Dyes, acid, taken up by living cells, 26. value for in vivo method, 29. colloidal, nature of, 25. electro-negative and electro-positive, several effects of kations and anions on adsorptive powers, 26. fixation of, accelerated by heat, 26. giving best results for staining in vivo, 27. positively and negatively charged col- loidal particles of, 25. sensitive to electrolytes in adsorptive capacity, 26. Ear, internal, congenital sj-philitie inflam- mation of, 273. Ehrlich, conception of chemotherapy, 283. steps leading to discovery of salvarsan by, 284. theories of, 347. toxic action of oxidation product of sal- varsan, 224, 225. Ejaculatio praecox, 480. Elastin, 530 Electrolytes, extraction from cells of syphihtic bodies, 41, 42. importance of, in staining processes, 26. presence of factor in preparation of histo- logical specimens, 26. sensitiveness of dyes to, in adsorptive capacity, 26. Electrolytic theory in staining of syphihtic organisms, 31. Elephantiasis following gumma, 146. ■ syphilis as cause of, 145, 146. Embryonic areas, appearance in organs in con- genital syphilis, 274. Emissions, nocturnal, 478. Emulsion, neutral, preparation of, 338 Encephalitis, congenital syphilitic degenerative, 271.272. degenerative, ameningeal form of, 317. of insane, lipoid cell degeneration in, 85. onset explained, 230. result of luetin reaction in, 114. Wassermann reaction in, 104. degenerative syphilitic, albumin and globulin content in, cerebro-spinal fluid in, 189. content of cerebro-spinal fluid in, 194, 195. diagnosis by Kaplan's goldsol curves, 196-198. from meningeal lesion by blood-cell counts in cerebro-.spinal fluid, 186. Wassermann reaction in cerebro- spinal fluid in, 196. haemorrhagic, 222. following salvarsan, 223. INDEX. 599 Encephalitis, haemorrhagic, occurring inde- pendently of salvarsan, 223, 224, 228. occurring seven years after infec- tion, 227. syphilitic, 184. treatment, 184. huemorrhagica, hopeless case, how saved, 226. Syphilitic, not preceded by vascular lesions of nervous system, 213. degenerative, 240. • anti-syphilitic treatment un- satisfactory, 241. • cause of death in, 212. • cerebral cortex analogous to degenerative myelitis of posterior cord, 217. • development of spirochaetae pro- nounced in, 212. • incurability, 212. inflammation of pia arachnoid in, 210. ■ meningeal, prognosis better than in ameningeal form, 240. path of infection in, 210. positive Wassermann reaction in blood in cases of, 218. preceded by vascular lesions of nervous system, 213. pupil anomalies less frequent in, 241. • site of morbid changes in, 210. non-degenerative, 214. • with late symptoms, treat- ment, 214. treatment of, 331, 333. Endarteritis, sj^hilitic, 239. obliterative, how set up, 123. Endocarditis, gonococcal, 414. Endometritis, gonococcal, 431. Endoscopic examination of urethra, 379. Endothelial cell, role of, in mflammation, 563. Endothelial cells, 527. condition in case of aberrant form of syphilis, 15, 16. containing circular masses, distinction from connective-tissue syphilitic bodies, 22. in cerebro-spinal fluid in sypliilific meningeal lesions, 186. in which asexual spore cysts develop, how affected, 56. invasion in development of asexual stage of Leiicoq/tozoon syphilidis, 127. Endothelioma, inflammatory, 563. Endotheliomata, malignant and intermediate, 578. new growth, 565. pigmented and non-pigmented, 566. Endotoxines, bacterial action of, 299. Endotoxines, bacteri:il action of, toxicity oi salvarsan increased by, 299. Encsol preparation, 351. Enzyme action, acceleration of, 286. Enzymes, oxidising action of, how increased, 286. Eosinophilc cell, 286. Eosinophile counts in sj-philis, 1.50, 151. Eosinophilc granules, nature and function, 286. Epididymitis, syphilitic, diagnosis from tuber- cular, 154. early, 154. vaccine treatment of, 403. Epididi/mitis gonorrhoica, 401, 453. Epilepsv, association with congenital S3rphilis, 272. ' following salvarsan, 300. Jacksonian, after salvarsan, 313. Epiphj'ses, enlargement of, before first year sign of congenital syphilis, 274. separation of, in Osleochondrilis syphi- Ulica, 265. • — ■ — pathological changes resulting in, 265. Epithelioma, malignant, 500, 538. prickle-celled, 510. malignant, 500. squamous-celled, 510. Epithelioma adenoides ci/slicnm, 511, 514. EpitheUomata, cutaneous, classification of, 509, 512. mUia present in, 515. Erythema induratum differentiation from gumma, 143. Erythema following salvarsan, 224. Erythema mvltiforme caused by syphilis, 142. Erythema nodosum, 425. caused by syphilis, 142. ■ syphililicnm, 147. Ervthemata, congenital syphilitic, nature of, 262. • toxic after salvarsan, 301. Eugenic Committee, aims of, 495. Eyes, congenital syi^hilitic diseases of, 273. gonorrhoeal diseases of, 420, 423. syphilis of, 155. Fallopian tubes, gonococcal infection of, 431. • Father and mother, syphilis in, relative im- portance, 250. Fathers, prospective, subjects of syphUis, drastic treatment necessary in, 256. Fatty acid emulsions in sera exhibit strong anti-complementary action, 90. mixtures, action on complement, 79. Fatty acids, 302. increase amino-acid content of syphilitic sera, 90. unsaturated, contained in envelope of Spirochaeta pallida, 61 600 INDEX. Females, congenital syphilitic iritis conimoner in, 273. Females and males, lymphocyte count in S3rphilis compared, 151. Ferments, lipoids carriers of, 286. oxydase, 287. Ferricyanide, ferric, action of amuio-acids on, 37. staining of sections of syphilitic bodies with, 35. Fertilisation, chemistry of, 17, 18. increase of acid in female cell during, 17. influence of salts on process of, 18. processes of, requirements, 17. Fever, intermittent in syphilitic cirrhosis of liver, 178. Fildes. See Mackintosh and FUdes. Filter-passer, syphiUtio virus not a, 1. Finger, chancre of. See Chancre, primary digital. Fingers, recurrent local asphyxia of, in reality syphilitic phlebitis, 150. Fischer's theory of structure of protein, 88. Fixing reagents, employed in staining syphilitic organisms, 31, 32. Foetus, macerated sj'philitic, abortion of, 260. Folliculilis gonorrhoica, 389. Foreskin, long, balanitis with, 464. tight, effects of, 467. Formalin, as fixing reagent in staining of syphihtic organisms, 32. cauterisation with, 433. effect on antigenic action, 72. in sera exhibits strong anti-complemen- tary action, 91. diminishes amino-acid content of syphi- litic sera, 91. Fornet and Schereschewsky, precipitation test, 69. Fracture, spontaneous, following syphilitic osteomyelitis, 172. Freezing pomt of syphilitic sera, 75. • • compared with that of normal sera, 75. French arsenical compounds, 282, 283. Fuohs-Rosenthal method of countmg blood- cells, 185. Furunculosis, following salvarsan injections, 301. Galaotosuria, alimentary in syphilitic hepatitis, 178. Galyl, 282. constitutional formula, 283. phosphorus in, 283. - treatment with, 347. Gamete, definition of, 10. — female, fertilisation by Spirochaeta pallida, 9. 10. Gametes, female, and forms of red blood cor- puscle, distmction between, 22. Gametocytes, definition of, 10. female, circular bodies in mflamcd tissue, resembling, 21. staining during impregnation, 58. male, richer in lecithin globulin than female, 57. male and female, development, 56. of Leucocytozoon syphilidis, 9. Gangrene of penis, 466. Gastric crises in degenerative myelitis, 176, 246. Generative organs, female, syphilis of, 255. granuloma of, 470, 499. Gengou. See Bordet and Gengou. Genito-urmary tract, male, syphilis of, 152. Giemsa's stain, 418. Glans penis. Lichen planus affecting, 143. ■ sores on frequently non-indurated, 127. Globulin, formation of pigment from, 507. importance to life, 52. in cerebro-spinal fluid, 187. decrease of, with negative Wasser- mann reaction, 191. existing in form of lipoid-globulin, 191. in degenerative syphilitic lesions, reason for greater amount, 191. reducing action, 191. tests for detection, 187, 188. • pure, isoelectric, 86. See also Albumin and globulin. Globulm complexes, 503. • increased in syphilitic sera, 92. — ■ — pyroninophile protein of syphilitic bodies a, 41. Globulin excretion in urine, effect of mercury upon, 152. lipoid complexes, 503. tost, failure after injection of serum, 347. Globulinuria in progressive late syphilitic nephritis, 153. — — - in late syphilis, 153. Glucosamine, absent in syphilitic bodies, 48. Glycosuria, intermittent in syphilitic pan- creatitis, 179. Gold suspension, colloidal, preparation of, 188. Goldsol curves, Kaplan's, in diagnosis of de- generative encephalitis from degenerative myelitis, 196-198. ■ of early syphilitic infection of nervous system, 205, 206. Goldsol indicator, 188. . reaction, 80. Lange's method for testing presence of globulin in cerebro-spinal fluid, 188. Gonargin, 442, 452. Gonococcal emulsions in complement fixation test, 442. INDEX. 601 Gonococcal warts, 467. Gionococcus, antigens from different strains of, 439. epithelial cells destructive to, 174. Gram's mctliod of staining, 371. fixation of complement, 440. incubation peroid, 373. methods of destruction of, 382. ■ Pappenheim's method of staining, 372. spread, of the organisms, staining metliods contrasted, 371. • V. Leszcznysky's method of staining, 372. Gonorrlioea, 371. acute, 378. ■ and marriage, 490. antiseptic applications in, 383. argyrol in treatment of, 384. • — — • artliritis complicating, 407, 454. Arthritis deformans following, 173. Ballenger's "sealing in" method, 384. bursitis complicating, 406. cardiac, 413. cavernitis complicating, 389. chronic, 378, 380. complement fixation test, 435. complications of, 388. due to spread b}' metastasis, 406. — — conjimctivitis complicating, 420, 422. Cowperitis complicating, 388. cystitis complicating, 397. — ■ — • deferentitis cora])licating, 400. endocarditis complicatmg, 414. epididymitis complicating, 401, 4.53. • folliculitis complicating, 389. hegonon in treatment of, 384. • Herpes genitalis following, 478. in women, 427, 430. manner of spread of the organisms, 373. • metritis and metrorrhagia following, 255. muscidar, 412. nervous system involved, 413. —— ocular, 42*0, 423. osseous, 412. paraurethritis complicating, 391. ■ — — pelvic, 432. perifolliculitis complicating, 389. proctitis complicating, 404. prophylaxis of, 382. — - — prostatitis complicating, 391. protargol in treatment of, 384. pyelitis complicating, 403. pyelonephritis complicating, 403. • — ■ — rashes in, 424. secondary infection in, 380. - symptoms of, 375, 382. tenosynovitis complicating, 406. treatment of, abortive, 384. drugs in, 383. hygienic, 382. Gonorrhoea, treatment of, in women, 432. ■ injections in, 383. lavage in, 385. local, 382. symptomatic, 382. urethral comj)lications, 390. vaccine, 411, 4.50. ureteritis complicating, 403. urethritis in, 37(i, 452. — ■ complications, 388. urinary conditions in, 377. vascular, 413. vesiculitis complicating, 399. Gonorrhoeal neurasthenia, 480. Gram's method of staining gonococcus, 371. Granoplasm, beliaviour of in presence of various acids, 39, 40. nature of, 38. Granules, inject ive, 4, 5. oxydase reactions of, 287. Oranuloma inguinale, 15. extracellular bodies in, 473. geographical distribution, 470. intracellular bodies in, 473. pathology of, 471. protozoal organism in, 472. Granuloma pudendi, 470, 471. Granuloniata, 499. Grey oil injections after salvarsan, effect on syphilitic deafness, 160. Group reactions, 117. Group specificity, definition and explanation, 285. Guanicaine, 352. Guinea-pig, complement best obtained from, 65. Gumma, cerebral, 230. diagnosis from female chancre, 254. differentiation of Erythema induratum from, 143. • — — elephantiasis following, 146. formation of, 140. following syphilitic invasion of artery, 123, 215. of bones, 26fi. of ciliary body rare, 155. of heart, 149. in His's bundle, 149. of iris, rare, 155. of liver, congenital varieties, 209. of testicle, l.')4. of tonsil, diagnosis from priman,' sore, 164, 165. Gumma cerebri, neo-salvarsan in, 330. Gummata, congenital, 263. in heart muscle, 267. content of cerebro-spinal fluid in, 195. may be of equal severity in both sexes, 257. 258. 602 INDEX. Gummata, treatment of, 330. Gummatous osteomyelitis, 170. Gummatous osteoperiostitis, 170. Gummatous ulceration of rectum, 177. Guyon's catheter in gonorrhoea, 383. Haemangioendotheliomata, examuiation of nodule, 569. microscopical examination of nodule, 571. pathology of, 568. Haematogeneous origin of syphilitic nervous lesions, 212, 213, 214. Haeraatoxylin, staining of syphilitic tissues in, 51. Haemocytometer, Thoma-Zeiss, 185. Haemoglobiuuria accompanying tertiary sy- philitic fever, 178. spasmodic, accompanying Raynaud's disease, 149. due to syphilis, 150. Hacmogregarine, infective granule of, 4. Haemolysis in test tubes in relation to fixation of complement, 67, 68. Haemolytic system and Abderhalden's test, analogy between method of action, 95. Haemopoetic system, sj^j)hilis of, 144. Haemosiderin, 507. Hair foUicules, 510, 522. Halbau and Dj'dynski, optic atrophy and sphincter (bladder) paralysis in congenital degenerative myelitis, 271. Hausmann, differential diagnosis between syphilis and other diseases of stomach, 175. Hazen, blood changes in sj^hilis, 150, 151. Head and face, asymmetry of, in congenital syphilis, 271. Headache, causes of, in syphilis, 238. following withdrawal of cerebro-spinal fluid, 183. Heart diseases, contraindicating salvarsan, 313. gonococcal infection of, 413. gumma of, 149. symptoms in dcgeneraf ive myelitis, 246. — ■ — syphilitic lesions of, 148. • early, diagnosis difficult, 148. late, 148. pulse rate in, 149. Heart-block, accompanying gumma of His' a bundle, 149. Heart muscle, congenital gummata in, 267. Heat, fixation of dyes accelerated by, 26. Heating, effect on syphilitic sera, 75. Heel, painful, 406. Hegonon in treatment of gonorrhoea, 384. Heidenhain, M., specification of methyl green for chromatin, 30. HeUer's test, 187, 205. Hemiplegia, early syphilitic, mode of onset, 213. frequent early symptom of syphilis, 210. syphilitic, 147, 239. Hemiplegia, syphilitic, early and late, differ- ences between, 240. transverse myelitis analogous to, 217. Henry, infective granule of hacmogregarine, 4,5. Hepatitis, interstitial sj'philitic, diffuse, 177. • , localised, 177, 178. interslUialis et gummosa, 269. syphilitic, signs of, 178. Herpes febrilis, 298. Herpes genitalis, 298. causes of, 470. causing sexual neurasthenia, 478, 481. diagnosis of, primary chancre from, 133. • — — site of, 469. Herpes iris, syphilitic, 162. zoster, 298. Herring's roe, action of reagents on, tested against action on nuclei of syphilitic bodies, 42, 43. Herxheimer's reaction, 303. Hip joints, both, Arthrijis deformans affecting, after gonorrhoea and sj'philis, 173. Hirsch's injection, 352. His's bundle, gumma of, 149. accompanied by heart block, 149. Histidine, test for, 46. Histone, 503. Hochsinger, congenital gummata of liver, 269. • national loss by ante-natal sypliilis, 250. Hodgkin's disease, 536, 540. histology of, 557. Hoffmann, cause of syphilis, 3. life-history of Spirocliaeta pallida, 4. See also MUldens and Hoffmann. Schaudinn and Hoffmann. Homy cysts, 516. Hospitals, special, abolition advocated, 497. Host, intermediate, not required by all proto- zoa, 24. Huge's fluid for bathing of spiroohaete films, 63. Hutchtuson, Sir J., congenital syphihtic iritis, 273. Hutchinsonian teeth, 264. in later life diagnostic of congenital syphilis, 274. and nodes on tibiae association with double interstitial peratitis, 273. Hutchinson's pill, 354. Hyaline degeneration, crystal formation in, 504. masses of plasma cells, 502. — ■ — plasma cell, 533. use of term, 501. Hydrarthrosis, chronic bilateral due to con- genital syphilis, 267. ■ supervening on osteochondritis, 266. Hydrocephalus in congenital syphilis, 266. congenital syphilitic, 271. INDEX. 6oa Hydrocephalus, congenital, in utero, 271. Hydrochloric acid content, decrease in syphilis of stomach, 175. Hydrochloride of salvarsan, formula, 277. Hydrolysis and precipitation, Abderhalden's test, process of, 96. Hi/drops arlicitli, 172, 408, 410. Hydroxyl groups of spirochaetae, 305. action of salvarsan on, 289. Hygiene, personal, and sexual neurasthenia, 479. " Hyperideal " potency and toxicity, 294. Hypersensitiveness theory of onset of cerebral syphilis, 230. Hypochondria, sexual, 482. " Ideal " potency and toxicity, 294. Idiocy, association with congenital syphilis, 272. Incidence of syphilis, statistics of, 496. Indian ink method of demonstrating Spirochaeia pallida when dead, 63. Induratio penis plastica, 474. complications of, 475. Infants, syphiUfic, born without positive Was- sermann reaction in mother, 250. — — - iiifection after birth, 2(30. original method of Wasser- mann's reaction, guide to, 257. ■ — • treatment during pregnancies follow- ing birth of, essential, 250. Infectivity, variable syphilitic, 488. Inflammation, reactionary, 303. ■ less severe .with neo-salvarsan, 319. relationship to cancer, 508. to mahgnant disease, 499. role of cells in causation, 580. of endothelial cell in, 563. • of epithelial cells in, 501. — of lymphocyte in, 526. of plasma cells in, 534. Injections of salvarsan and neo-salvarsan, pre- paration of, 337, 341, 344. of vaccine, 441, 443. Intestines, congenital gummatous ulceration of, 268. syphilis of, 176. • commoner m congenital than in acquired form, 176. Intramuscular injections of mercury, 350. of neo-salvarsan, 341. of salvarsan, 337. . — clinical course after, 339. Intrathecal injection of salvarsanised serum, 346. Intravenous injections of antimony, 349. of mercury, 349. of neo-salvarsan, 344. of salvarsan, 341. of vaccine, 443. Inunction, mercurial, 352. Iodide rash, differentiation from papulo- pustular sypliilide, 143. Iodides and mercury, supplementary to sal- varsan treatment of ssfphilis, 111. in Ulcus molle serpiginosum, 365. Iodine, stauiing of syphilitic bodies in, 50. treatment, 356. loha intramuscular injection, 338. lonisation in Ulcus molle, 368. Iris, gumma of, rare, 155. Iritis, congenital syphilitic, 273. commoner in females, 273. treatment, 273. gonococcal, 422. syphilitic, 155. — ■ — and gonococcal, compared, 155. effect of treatment upon, compared, 155. Iron, action on enzyme action in nuclear link, 286. staining of nuclei of syphilitic bodies for content in, 47. Iron hydroxide, without action on sera, 77. Izar. See Ascoli and Izar. Jacobsthal, optic sero-diagnosis of syphilis, 69. Jakob. See Weygandt and Jakob. Jaundice, complicating syphilitic cholangitis, 177. congenital syphilitic rare, 268. following injection of salvarsan, 295. Jelly method, Ross's application in study of life-history of Spirochaeia pallida, 5, 6. Jennings, phases in development of Spirochaeia pallida, 5. Jews, circumcision compulsorj' with, 464. Joints, gonococcal infection of, 407. Hydrops arliculi, 408, 410. syphilitic, becoming tilled with pus, 267. • See also Bones and joints. Kaolin, effect on sera, 77. Kaplan, amino-content of syphilitic sera, 87. Kaplan's Goldsol curves. See Goldsol curves. method for testing presence of protein in cerebro-spinal fluid, 189. Kaposi's axiom as to diagnostic sign of con- genital syphilis, 262. Kations, effects on adsorptive powers of electro- negative and electro-positive dyes, 26. Keratitis, congenital syphilitic, interstitial double, conditions associated with, 273. ■ • interstitial, in congenital sj^jhiUs, 156. • in later life, diagnostic of congenital syphilis, 274. Keralodermia blennorrhagica, 425. Kidneys, congenital syphilitic disease of, 270. diseases of, contraindicating salvarsan, 314. 604 INDEX. Kidneys, diseases of, formation of paramino- (C phenyl-arscnoxide, 225. Kieselguhr, action on sera, 77. Kieselsdure, without action on sera, 77. KJausner, precipitation test of, 69. Klingmtiller and Baermann, syphilitic virus not a filter passer, 1. Knee-jerk, loss of in degenerative myelitis, 247. Knee-joint, gonococcal infection of, 408, 410. Korte, de, cause of syphilis, 3. Kreibich. See Lipschiltz and Kreibich. Kryzsytolowicz and Siedlecki, life-history of Spirochaeta pallida. Laboratories, public, advocated, 497. Lallemand-Troussean bodies in prostatitis, 392. Lange. See Wassennann and Lange. Lange's method (Goldsol reaction) for testing presence of globulin ia oerebro-spinal fluid, 188. Lanugo hair follicles, 516, 522. Laryngeal crises in degenerative myelitis, 246. Lecitliin, importance to life, 52. in nerve tissue, 50. — — present in syphilitic parasite, 50. ■ — — production of, 53. Lecithin globulin, effect on reaction when added to normal serum, 80. on sera, normal and syphilitic, 79. • • male gametocyte richer than female in, 57. phases of Leiicocytozoon sypMlidis rich in, 78. — ■ — ■ precipitation necessary before extraction, of fluid, 80. pure action on complement, 79. Lecithm - globulin complex, phj'sical and chemical properties, 52. • — — resistance to putrefaction of fluids con- taining, 53. Lecithin-globulin compound, precipitation of, 52. relation of pseudo-globulin content to, 52. Lecithin-globulin envelope, 505. V. Leczcznysky's method of staining gonococcus, 372. Leprosy, positive Wassermann reaction in, 100. Leptomeningitis, gummatous diffuse, congenital syphilitic, 271. syphilitic, 238, 241. — content of cerebro-spinal fluid in, 194. • of brain and spinal cord, 207. Leucaemia ciUis, 545. lymphatic, 535. myeloid, 535. pseudo, 536, 542. Leucocyte, basophUe, 582. eosinophile, 587. polymorphonuclear, 582. Leucocytes, changes of, in sjiphilis, 150. neutrophile, in syphilis, effect of treat ment upon, 150. mononuclear, increase of, on invasion of body with syphilis, 83. large, spirochaetae developing in, richer in lipoid proteins, 57. polyjuorphonuclear, in cerebro-spinal fluid, in syphilitic infections, 185. sign of degeneracy, 435. and lymphocytes, ratio between, in syphilis, 150. Leucocytozoon, spiroohaetal phase of, 57. Leucoci/tozoon syphilidis, 98, 230, 473. — - — aberrant development, 11, 200. in sores, 127. action of salvarsan on, 278, 279. annihilation of, 120. arguments against, 23. asexual development sore formed by, 120. asexual stage, 9. mode of development, 127. biochemistry of, S3. chemistry of, 25-54. destroyed by saprophytic organisms, 123. development in asexual stage only, 12. of, protective response of host to, 129, 130. — Spirochaeta pallida in, 9. effect of entrance of male gamete into female cell, 17. extension of polar bodies after im- pregnation, 58. formation of protective cells by host after invasion by, 126. invasion of nervous system by, compared with systemic invasion, 202. lecithin present in, 50. life-cycle of, 8, 136, 278. life-history, 119. male phase, extra-cellular development, 214. male and female gametocytes of, 9. not pus producing, 252. ■ — ■ — order to which assigned, 10. phases of, 499. congenital syphilis, 275. in brains from cases of degenerative encephalitis, 212. in section, ready methods for differ- entiating between, 30. rich in lecithin globulin, 78. — ■ situation of, in brain, 210, 212. porportion of cases in which nervous system is invaded by, 201. pus not produced by, 141. reaches nervous system during stage of generalisation, 200. spores of, do not cause inflammation, 121. INDEX. 605 Leucocytozoon syphilidis, spores of, infective, agent of syphilis, 126. spread to nervous system, 219. sporozoite of, 8. Leucoderma colli in generalised syphilis in women, 255. Leucoderma siiphililicuvi, 137. sex incidence, 137, 138. Leucoplakia followed by, but not cause of carcinoma, 1(33. — - — following use of salvarsan, 302. origin of, 103. of tongue, causes of, 163. common in syphilis, 103. • — . conditions producing, 163. Levaditi, silver nitrate impregnation, method of, 2. Levaditi's silver nitrate method, Noguchi's modification, 63. Lice, haunts and treatment of, 476. Lichen planus, affecting glans penis, 143. following use of salvarsan, 302. Lightning pain in degenerative myelitis, 246. Lipoid, increase in late cases of syphilis, 84. substance in, producing antigenic action, 71. Lipoid cell degeneration, 85. Lipoid complex, elaborate, steps necessary for building up of, 55. Lipoid degeneration in syphilitic aortitis, 147. strong Wassermaim reaction accom- panying, 148. Lipoid-globulin, 500. breaking down of, 300. complement identical with, 83. globulin in oerebro-spinal fluid existing in form of, 191. homologous, formation of, how effected, 118. ■ identity of reagin with, 78, 79, 80. in syj)hilis, functions of, 78. globulin particles in excess in early stages, 01. lipoid particles more numerous in later stages, 01. in syphilitic serum, adsorptive capacity, 82. in urine, 153. insolubility of, 38. nature and distribution of, 508. • of serum protective substance against syphilis, 258. . of serum of women, relation to that of syphilitic sera, 258. • protective agency of, 217. protoplasm of plasma cells rich in, 286. . pure, isoelectric, 86. reagui in all cases of syphUis a, 61. . • richness of nerve tissue in, 214. Lipoid-globulin, specific, productive in host, 110, 117. specificity in, on what dependent, 258. vital part of, 83. cirrhosis of, .syphilitic, 177. how distinguished from alcoholic, 179. congenital miliary gummata of, 269. syphilitic alcoholic extract, best form of antigen, 65. disease of, 268. contraindicating salvarsan, 313. foetal, syphilitic use as antigen, 09. formation of blood by, capacity retained in congenital syphilis, 274. Spirochaeia pallida in, 269. syphilitic, diseases of, 177. early administration of neo-sal- varsan important in, 177. Lipoid-globulin complexes, 506, 531. mode of action, 83. molecules, effect of successive salvarsan injections on, 94. in serum of pregnant women, 95. lipoid portion greater in late cases of syphilis, 94. particles, complement, probably in normal serum, antibody in sypliilitic, 82. Lipoid nitrogen, estimation in syphUitic sera cannot be made, 84. Lipoid-protein content of Spirochaeia pallida, 57. Lipoid-proteins, adsorptive capacity, 86. • complexes, 287. nerve-cells rich in, 57. Lipoids, carriers, of ferments, 286. increase in cerebrospinal fluid ui syphi- litic cerebral disease of, 192. Lipschiitz, Ulcera pseudo-i^enerea, 254. and Kreibich, infective granules, 4. Lithium carbonate, action on nuclei of syphilitic bodies and on herring's roe compared, 44. Liver, acute j'cllow atroph}- of, syjjhilitic, 177. Look Hospital, London — treatment at, 498. Loeb, chemistry of fertilisation, 18. staining of fertilised ovum, 17. Louse, crab (Phthirius inguinalis), 470. Ludyl, 282. treatment with, 347. Luetin reaction, negative, in untreated cases of sjfphilis, 114. positive in cases of .syphilis after triat- ment, 114. results in degenerative encephalitis and myeUtis, 114. Lumbar puncture, relieving compression in syphilitic pachymeningitis, 224. Lumbar puncture needles, Barker's, 182. Lung tissue extract, in diagnosis of recurrent and congenital syphilis, 115. 606 INDEX. Lungs, congenital syphilitic disease of, 268. syphilitic disease of, areas affected, 167. diagnosis difficult, 167. • by X-rays, 168. — effect of salvarsan on, 168. special nature of, 168. Lupus vulgaris and syphilis, differentiation of facial scars arising from, 140. Lustgarten's bacillus, 1. Lymphadenitis accompan3ring intra-urethral chancre, 131. treatment of, 369. Lymphadenoma, 536. Lymphadenosis, 536. — ■ — ■ chronic, 540. inflammatory, 538. malignant, 539. Lymphangitis, occurrence after development of primary sore, 122. ^— of penis; 367, 368. — — • phagedaenio chancres unaccompanied by, 122. syphilitic, 144. — - — ■ causing oedema of skin of penis, 144. ■ late, 145. • with enlargement of scrotum, 145. LymphangioendotheMomata, 578. Lymphangioraata, 578. Lymphatic glands, degree of enlargement and lymphocyte count, 151. effect of presence of phagedaenio ulcers, 122. — ■ — enlarged protective capacity of host against parasite better, 144. enlargement of, 528, 537. after development of primary sore, hardness, in diagnosis of 122. and chancre, 125. in congenital syphilis, 273. in neck, enormous enlargement due to syphilitic invasion explained, 144. infected, removal discountenanced, 122. inguinal, changes in syphilis, 121. enlarged iris and infection, 132. large and soft, and small and hard, histo- logical findings compared, 130. — ■ lymphocytes manufactured in, position of, 151. removal of, 322. — - suppuration after svi^liilitie invasion, 145. syphilitic, enlarged, 144. hard and discrete, 144. — • — ■ — • impUcation greatest in neighbour- hood of primary sore, 144. • and normal, estimation of chloride content, 87. total infection after syphilitic invasion, 122. Lymphatic leucaemia, 535. Lymphatic system of peripheral nerves aspath of infection to central nervous system, 208. Lymphatic vessels, lymphocytic formation of, 527. Lymphocyte chart, prognosis of syphilis from, 151. Lymphocyte count and degree of enlargement of lymphatic glands, 151. in males and females compared in syphilis, 151. in syphilis, 150, 151. in severe and mild cases, compared, 150, 151. relative in negro and white man compared in syphilis, 150. Lymphocytes and polymorphonuclear leuco- cytes, ratio between in sypliiUs, 150. cell which delvelops from, 529. embryo, in cerebro-spuial fluid in syphi- litic degenerative lesions, 168, 187. formation in lymphatics, spleen and bone marrow, 537. function of, 529. in cerebro-spinal fluid, in syphilitic infec- tions, 185, 186. origin of, 187. in syphilis, effect of treatment upon, 150. manufactured in lymphatic glands, posi- tion of, 151. origin of, 526. part played in disease bj', 534. partial source of reagin in cerebro-spinal fluid, 193. reaching circulation, source of, 151. rCile of in sarcoma, 538. small, staining of, contrasted with that of nuclei of parasitic bodies, 41. and sporozoitic resemblance be- tween staining of, 41. — ■ — • source of protective substances in host against syphilis, 151. staining characters of, 528. Lymphocytic growth, 544. Lymphooytoma, cutaneous, very strong posi- tive Wassermann reaction in, 97. endothelial, 547. leucaemic and aleucaemic, cause of, 98. Lymphocytomata, 543. leucaemic and aleucaemic, syphilis cause- of, 151. of skin, 560. svpliilitic, occurrence of amphoteric sera in, 73. Lymphocytosis, cerebro-spinal fluid, 205. — — in syphilitic lesions, effect of treatment on, 187. Lymphodermia pemiciosa, 543, 555. Lymphogranulomatosis, 550, 553, 555. INDEX. 607 Lymphosarcomatosis, 545. Lyniphopoetic system, syphilis of, 144. Lysine, test for, 46. McDonagh's intravenous syringe, 343. Mackintosh and Fildes, hypersensitiveness theory of late syphilitic lesions of brain, 230. MoLeod and Soga, method for cultivation of spiroohaetae under anerobic conditions, 62. Maculae coeriileae, 476. Macule, syphilitic, 135. Maculo-papules, syphilitic, on trunk, leading to atrophy of skin, 138. Magnesium carbonate in balanitis, 467. Magnesium sulphate, action on nuclei of sj-philitio bodies and on herring's roe com- pared, 43. Malaria, positive Wassermann reaction in, 100. tertiary syphilitic fever diagnosed as, 178. transmission of, not comparable with that of syphilis, 24. Males and females, lymphocyte count in syphilis compared, 151. Malignancy, two kinds of, 524. Malignant disease, relationship of inflammation to, 499. n'lle of cells in causation, 580. theory as to origin, 98. Malthusian appliances, 495. Marriage and gonorrhoea, 490. syphilis and, 485, 490. time to elapse after infection, 487. when permissible to men, subjects of syphilis, 257. Massage of seminal vesicles, 400. Mast cell granules, nature and function, 206. Mast cells, 583. activity of, 587. granides, staining of, 584. relation to supply of pigments, 286. Masturbation, sexual neurasthenia caused bv, 478. Medulla, inflammatory involvement of, 171. 172. See also Osteomyelitis, syphilitic. Meier. See Porges and Meier. Meiostagmine reaction, 70. Meirowsky, characters of SjiirocJiaeta pallida, 2. use of extract of syphilitic lives in cuti- reaction of syphilis, 113. Melanoma, malignant, 578. Men, reason why syphilis less severe in women than in, 151. Men and women, difference between syphilis in, 257. no difference in primary lesions of sy- philis between, 257. Meniere's symptom complex, following syphilis, 161. Meningeal lesion, syphilitic, diagnosis from de- generative lesion, 186. Meninges, cerebral, topographical anatomy of, 210. path of invasion by syphilitic organisms, 210. syphilis of, curability, 212. syphilitic, infection of, spreading to nerve matter, 215, 217. inflammation of, followed by cranial nerve lesions, 211. lesions of, curability under pro- longed drastic treatment, 220. Meningitis, cerebral, syphilitic, 241. cerebro-spinal syphilitic, 241. blood in cerebro-spmal fluid in, 18S. spinal, syphilitic, 241. treatment of, 334. streptococcal, total nitrogen in cerebro- spinal fluid in, 192. syphilitic basal, case-history, 233, 234. death following second injection of salvarsan, 234. complications, 233. cerebro-spinal, case liistorics, 234. proportion of cases showing signs or symptoms of, 201. treatment of, 328. Wassermann reaction in, 104. tubercular, total nitrogen in cerebro- spinal fluid in, 192. Meningo-enccphalitis, acute, blood in cerebro- sjjinal fluid in, 185. inflammatory, reaction in, 318. syphilitic, 238. content of cerebro-spinal fluid in. 194. degenerative, periods of quiescence in, 222. development in eases of severest cutaneous maniJfestations, 203. diffuse, 238. localised, 239. symptoms, 239. treatment of, 330. Meningo-myeHtis, syphiUtic, 242. course of, 242. degenerative and non-degenerative often co-existent, 243. syphilitic, development of, in cases of severest cutaneous manifestations, 203. symptoms, 242. Mercurial inunction, 352. pEls, 354. stomatitis, 3.54. suppositories, 353. Mercurialism, 355. Mercuric chloride as fixing reagent in staining of syphilitic organisms, 32. 2 Q 608 INDEX. Mercury, action as catalyser, 290. effect on absolute and relative lympho- cyte count in syphilis, 151. — globulin excretion in urme, 152. of treatment with, 355. formation of antibodies not checked by, 141. — — • hastens disappearance of sj-mptoms of primary syphilis, 122. Herxheimer's reaction after, 303. in congenital syphilitic interstitial kera- titis, 273. in excess, syphilitic disease of bones and joints aggravated by, 169. in treatment of syphilis, influence on Wassermann reaction, 106, 107, 108, 110. internal treatment with, 353. intramu-scular injections of, 350. intravenous injections of, 349. no improvement under, in aberrant form of syphilis, 14. oral administration, effect on tongue, 163. prolonged administration after salvarsan injections in syphilis essential, 123. — • salvarsan not supiilemented by harmful, 123. treatment by checking production of antibodies, 219. — development of degenerative sy- philitic nervous lesions after, 219. — ■ — poh'neuritis following but not due to, 231. prolonged, after several injections of salvarsan, effects, 220. Mercury and iodides sujiplementary to sal- varsan treatment of syphilis. 111. and salvarsan combined, in treatment of syphiUtic optic neuritis, 1.57. ■ — effect on syphilitic neuritis of cranial nerves, 160. Merozoite, 19. definition of, 10. Merozoites, sexual, development of trophozoite into, 56. number, formed variable, 56. Metals, action on oxidising enzymes, 286. and non-metals, arsenic on border between, 277. Methyl green compared with pyronin, 30. — ■ — positively charged colloid, 20. specific action for chromatin, 30. — — staining action facilitated by anions, staining of syphilitic organisms with Methyl green and methylene blue, comparison between, 30. and pyronin. See Pappenheim's stain. Methylene blue and methyl green, comparison between, 30. See also Borax methylene blue. line 27. 31. Methylene red, staining of syphilitic organisms with, 31. use for obtaining in vivo, 28. Methylene stains, 502. Methylene violet, reduction sensitive dye, 31. ML'tritis following gonorrhoea, 255. syphilitic, question of, 255. Metrorrhagia following gonorrhoea, 255. Metrorrhagia neoiialortim, 270. Metschnikoft's ointment, 495. Michaelis, precipitation test, 69. Milia present in epitheliomata, 515. Milian, adrenalin as remedy against untoward symptoms of salvarsan, 226. Milky effusions, production of, 53. Millon's reagent, staining of syphilitic sections with, 38. Mole cells, 567. Moles, 565, 568. Molluscum contagiosum, 468, 499. Monoplegia, syphilitic, 147. Moolgavkar, phases in development of Spiro- chaela paUirIa, 5. Morpliology of little help in differentiation of bacilli, 60. Mother and father, syphilis in, relative import- ance, 250. Mothers, syphilitic infants born without posi- tive Wassermann reaction in, 250. treatment during whole of preg- nancy, result, 251. Mouneyrat, preparation of gahl and ludyl, 282." Mouth, mucous membranes of, syphilitic papules, erosions and ulcers of, 267. syphilis of, 162. Mucous membranes, congenital syphilitic dis- ease of, 267. Mtihlens and Hoffmann, cultivation of spiro- chaetae, 60. Muscles, gonococcal infection of, 412. injections into, advantages of intra- venous injections over, 345. Muscular pain following injection of salvarsan, 298. Mycosis fungoides, 543, 545, 550. classification of, 551. clinical characteristics, 552. histological characters of, 555, 557. Wassermann reaction in, 558. Myelitis, congenital syphilitic degenerative, 271. • symptoms, 271. degenerative, 480. result of luetin reaction in, 114. treatment of, 336. syphilitic, albumin and globulm content in cerebro-spinal fluid in, 189. content of cerebro-spinal fluid in, 190. INDEX. 609 Myelitis, degenerative, syphilitic, diagnosis by Kaplan's Goldsol curves, 19(5-198. ■ • gastric crises of, 170. meningeal, and ameningeal orm, 244, 245. Opthalmoplegia iiiienui, symp- tom of, 158. spontaneous cure of, 196. • ■ Wassermann reaction, 190. ■ syphilitic, degenerative, 244. ■ case with .symptoms of, result of treatment, 215. oerebro-spinal fluid in, 245. • in comiection with primary optic atrophy, 236, 237. — ■ incurability, 212. • involvement of cardiac sym- pathetic nerves in, 149. • — - — • not preceded by syphilitic lesions of nervous system, 213. of posterior part of the cord analogous to degenerative encephalitis of cerebral cortex, 217. ■ — ■ • phases of leucocytozoon found in brains from cases of, 212. preceded by vascular lesions of nervous system, 213. replaces terms of Tabes dor- salis or locomotor ataxv, 244. site of, 210. spontaneous cure, 222. symptoms, 245, 246, 247. VVassermann's reaction in, 245. haemorrhagic, 244. stages of, 244. positive Wassermann reaction in blood in cases of, 218. retinitis associated with, 156. transverse, analogous to hemiplegia, 217. transverse prodromal and sensory symp- toms, 243. Myeloid leucaemia, 535. Myers, amount of calcium in sera, 87. Myocarditis, diffuse syphiUtic, 148. syphiUtic, 267. — — ■ of left ventricle, 149. Naevi, 565, 568. Naevo-xantho-endotheliomata, 568, 573, 577. Naevus verrucosus, 572. Navy, dimmution of venereal diseases in, 495. Neck, lymphatic enlargement due to syphilitic invasion explained, 144. Necrosis, following injection of salvarsan, 340. Negro, total increase of leucocytes in, compared with that of white man, in syphilis, 150. Neo-salvarsan, 279. admuiLstration at early stages in syphi- litic diseases of liver, 177. Neo-salvarsan, advantage over salvarsan, 279. formula of, 279. formula when injected, 280. in syphilitic pancreatitis, 180. in treatment of syphilis, influence on Wassermann reaction, 106. inflammatory reaction less severe with, 319. injections of, effects of, 295. intervals in treatment, toxic symptoms after, 302. intramuscular mjection of, 341. intravenous injection of, 344. ■ reagent agaiiist Spirochaela pallida, 280. therapeutic action compared with that of salvarsan, 280. toxic action of, 301. toxicity and potency of, 294. Nephritis, balsamic, 382, 404. interstitial chronic, am\loid disease supervening upon, 153. usually symptom of genera- lised arterio-sclerosis, 153. congenital syphilitic, 270. syphilitic, early, rarity, 153. late, progressive, 153. Nerve, auditory, sj'philitic neuritis followed by deafness, 159. optic, atrophy of in congenital syphilitic degenerative myelitis, 271. ■ primary, in connection with degenerative myelitis, 236, 237. Nerve cells, derivation of reagui from, 78. medium for development of s\'philitic organisms, 221, 222. Nissl, bodies of, destruction of affinity for basic dyes, 26. rich in lipoid proteins, 57. Nerve lesions, syphilitic degenerative, effect of treatment on Wassermann reaction. 111. Wassermann reaction in, 104. Nerve matter, syphilitic hifection of meninges spreadmg to, 215, 217. Nerve roots, spinal, syphilitic inflammatory changes in perineural sheaths of, 207, 208. ■ Nerve tissue, lecithin in, 50. richness in lipoid globulins, 214. syphilitic affections of, dependence on primary venous lesions, 212. Nerves, cardiac, sympathetic, involvement in degenerative myelitis, 149. cranial, paralysis of, congenital syphilitic, 272. • syphilitic lesions of, 236. yield to early and adequate treatment, 211. neuritis, effect of treatment upon, 160. 2 Q 2 610 INDEX. Nerves, peripheral, lymphatic system of, as path of infection to nervous system, 208. ■ syphilis of, 231. ■ syphilitic inflammatory changes in connective tissue coverings of, 207, 208. lesions of, aifect both motor and sensory nerves, 211. Nervous system, arterial lesions, 201. diseases contraindioating salvarsan, 315. gonorrhoea of, 413. invasion by syphilitic organism, com- pared with systemic invasion, 202. lesions of, blood in cerebro-spinal fluid resulting from, 184. parasyphilitic affections, countries where rare, 229. why increasing, 230. progressive degenerative changes in, 158. proportion of cases in which syphilitic organism invades, 201. stage of syphilis during which leucocyto- zoon reaches, 200. stoppage of supply of antibodies, to, 219. syphilis of, 489. ^ biology, 200. clinical aspect, 231. early inspection, clinical evidence, before and after treatment, 202, 203. * • of early infection, pathological evi- dence, before and after treatment, 205, 206. inflammatory reaction, 307. nucleinate of soda ui, 357. treatment of, 328. Wassermann reaction in, 104. syphilitic invasion of percentage of cases attacked, 217. lesions of, classification, 207. — — degenerative, frequency in- creasing, 230. early vascular, 213. central, congenital syphilitic degenerative lesions, fatal, 274. diseases of, 271, 272. • degenerative syphilitic lesions fol- lowing treatment by mercury, 219. ■ haematogenous as distinguished from lymphogenous infection, 208. ■ mctaluetio lesions, avoidance of term, 216. sj'philitic degenerative lesions, de- velopment of, 221. diseases of, 216. how to avoid symptoms, 227. influence of treatment upon, 217. meningeal, 216. neurotropic origin, 228, 229. ■ no evidence of selective action of organisms, 230. Nervous system, central, syphihtic degenera- tive lesions, percentage in persons contract- ing syphilis, 228. . symptoms on the increase, 217. syphilitic invasion of, date of onset, "217. syphilitic lesions of compared with cutaneous lesions, 214, 215. factors influencing develop- ment, 220, 221. haematogeneous origin, 212, 213, 214. — • neither wholly degenerative nor wholly non-degenerative, 215. symptoms of, occurrence at early stage, 218. paths and sites of uifection, 207, 208. primary, 236. secondary origin, 232, 233. symptoms of, 218. Neurasthenia, gonorrhoea!, 480. sexual, causes of, 480. Herj^es genitalis causing, 478. prostatorrhoea in, 397. syphUitic, 480, 482. Neuritis, brachial, sj-philitic, 232. foUowtng salvarsan, 309. of spinal nerve roots, syphilitic, 232. optic, complicating syphilitic basal menin- gitis, 233, 234. • complicating syphilitic cerebro- spinal menmgitis, 234, 235, 236. in syphilitic meningo-encephalitis, 239. ■ syphilitic, 157. bilateral and unilateral, 157. treatment by salvarsan and mercury combined, 157. peripheral, 413. syiAilitic, 231, 481. Neuro-reourrences after salvarsan, 308. Neutral emulsion, preparation of, 338. New-born, gonococcal conjunctivitis in, 422. Nicolas (and others), experiments with glycerin extract of foetal syphilitic liver, 113. Nicol's prisms, appearance of syphilitic cells, under use of, 49. van Niessen, discovery of Syphilomyces by, 1. Nile blue sulphate, stauiing of syphilitic bodies with, 50. Ninhydrin inaction, positive, given by syphi- litic serum in presence of complement, 96. given by syphilitic serum with placental extract, 95. Xissl's bodies of nerve cells, destruction of affinity for basic dyes, 26. Nissl's granules, constitution of, 78. INDEX. 611 Nitrogen, increase in cerebro-spinal fluid during death agony, 85. in sypliilitic sera, 84. natural proteins in scrum only react with trace of, 88. time taken to give o(i, by various amino- derivatives, 87. total in cerebro-spinal fluid m disease, 192. relation to Wassermann reac- tion, 192, 193. in normal cerebro-spinal fluid, 192. valencies of, in relation to arsenic, 277. Nodules of Trichoe pithelioma papillosum, 515. Noguchi, cultivation of Spirochaeta pallida, 59, 60. preparation of luetin by, 113. Spirochaeta calligyriiiii, 60. Noguchi's moditication of Levaditi's silver nitrate method, 63. Noguchi's test for globulin in cerebro-spinal fluid, 188. Nonne, blood in cerebro-spinal fluid in case of syphilitic meningo-encephaUtis, 184. Nonne-Apelt's reaction, 187. Nose, perichondritis of, in acquired syphilis, 165. Notification of venereal diseases, 494. Nuclei, contents of, 286. Nuclein, transformation of, 505. Nucleinate of soda, injections of, 357. Nucleolus, description of, 50C. function of, 505. Nuoleo-protein, 45. of nucleus of syphilitic bodies, 42. protein radicle of, 45. Nucleus, accelerator of enzyme action in, 286. Oedema of skin of penis set up by syphilitic lymphangitis, 144. • toxic, after injection of salvarsan, 339. Oesophagus, syphilis of, 174. — recovery under treatment, 174. syphilitic stenosis of, 174. Oleic acid, action on complement, 79. Onychia, syphilitic, 264. Ophthalmoplegia, external, syphilitic, 158. ■ degenerative, 158. internal, syphilitic, 157, 158. significance of pin-point pupils in, 158. symptoms of degenerative myelitis, 158. •" syphilitic, 157, 158. Ophthalmoscope, in diagnosis of congenital syphilis, 274. Optic nerve, toxic action of atoxyl on, 281. Optic neuritis, after salvarsan, 309. Orchitis, sign of congenital syphilis, 274. Oriental sore, diagnosis, 143. Orr and Rows, path by which infection is carried to nervous system, 208, 209. Osteitis, syphilitic, inseparable from syphilitic periostitis, 170. • See also Osteoperiostitis, sy- philitic. Osteochondritis, syphilitic, hjdrarthrosis supervening on, 266. ■ syphilitica, 265, 266. • - — • incidence of, 265. Osteomyelitis, gummatous of dij^loe, 170, 171. — ■ — • syphilitic, diagnosis from syphilitic osteo- periostitis, 171. from tubercular form, 172. spontaneous fracture foUowmg, 172. Osteoperiostitis, syphilitic, 170, 260. diagnosis at sarcoma, 171. from syphiUtic osteomyelitis, 171. of clavicles, 172. • of flat bones, ] 70. of long bones, 170. effect of blood supply on, 171. Osteoporosis (syphilitic rarefaction of bones), 266. Ovum, staining of, during and after fertilisation, 18. Oxaluria, 378, 416. Oxidation and reduction, Unna's theory of, 31. Oxydase content and positivity of Wassermann reaction, no ratio between, 98. ferments, 287. reactions, disappearance upon destruction of complement, 83. in cerebro-spinal fluid, 192, 287. Oxydases, lipoid-globulin complexes, vehicles for oxydases, 82. relation of complement to, 82, 83. Oxygen, how conveyed to tissues, 286. necessary in fertilisation and develop- ment of zygote, 17. " Oxj'gen chain," links in, 286. nature of, 285. Oxygen ferments carried by lipoid -globulins in syphilis, 78. carriers of, 286. Pachymeningitis, gummatous diffuse, con- genital syphilitic, 271. gwnmosa, 238. haemorrhojica blood in cerebro-spinal fluid in, 185. inflammatory reaction in, 317. late symptoms of syphilis, 184. syphilitic, 237, 241. cause of persistent headache in later stages, 238. compression and unconsciousness relieved by lumbar puncture, 224. 612 INDEX. PachjTueningitis, syphilitic, content of cerebro- spinal tiuid in, 194. Pain in degenerative myelitis, 246. Palate, hard, syphilitic periostitis of, 165. perforation of, diagnostic of syphilis, 266. Pallidin, effect of injection of tuberculin in syphilitic subject followed by injection of, 117. lung extract used in diagnosis of syphilis, 115. Palms of hands, rash of congenital syphilis specially affects, 262. Pancreas, congenital s\'philitic disease of, 269, 270. syphilitic disease of, 179. Pancreatitis, syphilitic, 179. case-history, 179, 180. • treatment, 180. Pandy reaction for testing presence of protein in cerebro-spinal fluid, 189. Panosteitis, syphilitic, 171. Papilloma, types of, 510. Pappenheim, aleucaemia of, 536. • specific action of methyl green for chro- matin, 30. Pappenheim's method of staining gonococcus, 372. Pappenheim's stain, 531. use for syphilitic bodies, 31. use in preparation of sections of syphilitic organisms, 33, 34. Papular lesions, syphilitic, 137. Papule, chancres almost always commence at, 128. syphilitic, 135. degeneration with formation of crust, 136. retrogression of, 136. Papules, clmical appearance varies according to localisation, 138. — — mucous, syphilitic, 162. syphilitic, recurrent, scabbed, 139. Papule -pustular lesions, syphilitic, 137. Paraffin, use in preparation of sj^ihilitic speci- mens, 33. Paralysis, congenital syphilitic, 272. facial, imilateral syphilitic, 161. general, of insane, as Ij-niphogenous in- fection, 209. in degenerative myelitis, 245. Paramino-phenj-l-arsenoxide, formation of, in relation to kidney disease, 225. toxic action, 224, 225. Paraphimosis externa, 462. Paraphimosis interna, 462. Paraplegia, syphilitic, 243. See also Myelitis, transverse. Parasite, syphilitic, pyroninophile substance, and colloidal particles of pseudo-chylous iiuid, close resemblance between, 53. Parasites of cancer, so-called, description of, 506. Parasyjihilis, avoidance of terra, 216. Paraurethritis gonorrhoica, 391. Parents, syphilitic, healthy children by after proper treatment of, 261. treatment advisable after birth of syphi- litic child, 257. Parrot, congenital syphilitic enlargement of spleen, 270. gelatinous atrophy affecting skull bones, 266. Parrot's nodes, 266. Pediculus pubis, 476. Pemphigus, congenital syphilitic, fatal, 274. streptococcal, 263. syijhUitic, 263. syphiliticus neonatorum, 263. Penis, contiguous chancres on, 129. diseases of, 461, 464, 467. erections of, impaired, 480. gangrene of, 466. • Induratio jyetiis plastica, 474. locality of simple papulo-ulcerative chan- cre on, 130. lymphangitis of, 367, 368. oedema of skin of, set up by sj'philitic lymphangitis, 144. psoriasis affecting, 143. skin of, button-chancre on, 129. diffuse papular infiltration, 138. syphilitic eruption on, diffuse, papular, 145. See also CofOHn ; Glans penis. Pergenol, use of, 467. Perichondritis of nose in acquired syphilis, 165. Pericranitis, sj-philitic, 266. Perifolliculitis gonorrhoica, 389. Perihepatitis, syphilitic, 178. Periostitis, gonococcal, 412. syphilitic, 165. inseparable from syphilitic osteitis, 170. See also Osteoperiostitis, sy- philitic. of hard palate, 165. ossifjang, 266. Peripyle phlebitis syphilitica, 269. Peritoneum, syphilis of, 180. affecting tissue subjacent to, 176. Phagedaena, 362, 368. destruction of syphilitic organism by, 122. Phagocytosis, rule of, 367. in inflammation, 580. Phenyloxyacetic acid, arsenic derivative of formula, 284. Phimosis, accompanying primary sore in corona, 131. acquired, causes and treatment, 461. Phlebitis, gonococcal, 415. INDEX. 613 Phlebitis, syphilitic, 14(1. cases of, 146. recurrent local asphyxia of fingers in reality, 150. Phlegmonous arthritis, 409. Phosphaturia, 378, 410. Phorphorus, in galyl, 283. staining of nuclei of sypliilitic bodies for content in, 46, 47. Phthiriasis, treatment of, 477. Phihirius iitduinalis, 476. Pia-arachiioid, inflammation of, in degenerative encephalitis, 210. Pigment, formation from globulin, 507. production of, how effected, 286. protective mechanism, 286. Pigmented endotheliomata, 566. Pills, mercurial, 354. Pinkus, pseudo-leucaemia of, 536. Pituitary body, lesion in. Diabetes insipidus in congenital syphilis, 272. Pityriasis rosea, differentiation from syphilis, 142. Placental extract, factor in serum of pregnant women necessary to break down, 95. s\'philitic serum giving positive ninhydrin reaction with, 95. Plasma cell, chemistry and physico-chemistry, 285. crystalline forms of, 533. degenerate forms of, 532. function of, 532. nucleus of, behaviour on degeneration, 44. origm of, 529. protective against syphilitic organism, 285. Plasma cells, ballooned, 36. hyaline masses of, 502. See also A mi no- plasma cells. in cerebro-sptnal fluid in syphilitic de- generative lesions, 186, 187. part played in disease by, 534. protoplasm of, rich in lipoid-globulin, 286. Plasmosarconmtosis, 546. Plasmoma, syphilitic, histological appearances after salvarsan treatment, 93. Plastcin, 531. Pleuritis, syphilitic, 168. Pneumonia, syphilitic interstitial, 208. white, of Virchow, 268. Polar bodies, extension from Leucocytozoon syphilidis after impregnation, 58. PolJ^leu^itis, syphilitic, 231. following, but not due to mercurial treatment, 231. stage in whic^h met with, 232. Porges and Meier, precipitation test of, 69. Potassium iodide, internal administration in CB,se oi (.'occidiosis a venerea, 19. i Potassium permanganate, action of amino- acids on, 37. staining of sections of syphilitic bodies in, 35. Potency, relationship between toxicity and of salvarsan, 294. Precipitation and hydrolysis, Abderhalden's test, process of, 96. Precipitation test, in diagnosis of syphilis, 69. Precipitation theory of Wassermann reaction, 96. Pregnancies, first and last disastrous in syphi- litic parentage, 200. succeeding birth of syphilitic infant, treatment during essential, 250. Pregnancy, Abderhalden's test for, 94. date ijermitted for, after paternal syphilis, 257. repeated, effect on syphilis, 103. treatment of svphihtic mother during whole of, 251. Pregnant and syphilitic women, sera of close resemblance between, 95. Pressure, plus and minus, action upon sera, 76, 77. Preventive medicine and venereal disease, 493. Proctitis gonorrhoica, 404. Profeta's law, 251. Prognosis in congenital syphilis, 274. of syphilis from lymphocyte chart, 151. study of chancres a guide to, 129. Prostate, abscess of, 393. gonococcal infection of, 392, 396. Prostatitis, 379, 381. chronic symptoms of, 394. treatment of, 396. complicating gonorrhoea, 391. Prostatorrhoea, 397, 481. Prostato-urethritis, 380. treatment of, 395. Prostitutes, registration of, 494. Protagon, action on complement, 80. Protamine, 503. Protargol in treatment of gonorrhoea, 384. Protective substances becoming parasitic on host, 97. Protein, albumoses, degeneration products of, 88. examination of urine for, 152, 153. in cerebro-spinal fluid, 187. examination, 187. excess of, 191. influence of treatment on, 192. in urine in acute stage of syphilis, 152. of syphilitic bodies, 39. behaviour of in presence of various acids, 39, 40. insoluble in water, 39. pyroninophile, nature of, 40. 614 INDEX. Protein of syphilitic bodies. See also Pijro- ninophile substance. structure of Fischer's theory as to, 88. Protein metabolism, degeneration products of, 530. Proteins, derivatives of, strong reducing agents, 37. natural, in serum, only react with trace of nitrogen, 88. Protoplasm, fi.xed, amphoteric substance, 31. stains best with acid dyes, 31. in oxygen chain, 28(3. portion of syphilitic bodies, 38. Protozoa, intermediate host not required bv all, 2-t. V. Prowazek, life-history of Spirochaela pallida, Pruritis ani, 405. Pseudo-chylous fluid with dextrose, reaction obtained under, 49. Pseudo-globulin faction of serum, relation to lecithin globulin compound, 52. Pseudo-leucaemia, 536, 542. Pseudo-paralvsis, sign of congenital syphilis, 274. Pseudo-tabes, 243. Psoriasis, affecting penis, 143. differentiation from syphilis, 143. squamo-papularsyphilide resembling, 143. Public, instructions to, 497. Public health and venereal disease, 493. Pulse rate in syphilitic cardiac lesions, 149. Pupil anomalies in congenital syphilis, 272. — ■ meningo-myelitis, 242. in syphilitic mentngo-encephalitis, 238, 239. less frequent in degenerative ence- phalitis, 241. Pupils, pin-point significance in syphilitic Ophthalmoplegia interna, 158. Purpura in congenital syphilis, 264. Pus, not produced bv Leiicoci/tozoon syphilidis, 141, 252. produced by Ducrey's bacillus, 133. syphilitic jomt becoming filled with, 267. Pustule, svphiUtic, distmction from varicella, 136. Putrefaction, resistance of fluids containing lecithin-globulin complex to, 53. Pyelitis gonorrhoica, 403. Pyelonephritis gonorrhoica, 403. Pylorus, syphilis of, 174, 175. recovery from under salvarsan, 175. Pyogenic infections, diagnosis of extra-genital chancres from, 132. phagocytosis in, 581. Pyronin. formula of, 291. — — methyl green compared with, 30. stainmg action facilitated by anions, 27. staining of syphilitic bodies with, 31. Pyronin, staining with, 503. Pyronin and methyl green. See Pappenheim's stain. PjToninophile substances, 39, 40. nature of, 45. of syphilitic organisms, 31. staining of, 45. Rabbits, experimental sji^hilis in, condition of inguinal lymphatic glands, 120, 121. Rashes, gonococcal, 424. toxic, 425. RajTiaud's disease accompanied bj^ spasmodic haemoglobinuria, 149. association with syphilis, 149, 150. Reactionary inflammation, 303. Reactions to salvarsan, 299. Reagin, action of, 76. formation of, increased by cold, 89. identity with lipoid-globnlin, 78, 79, 80. in cerebro-spinal fluid invading blood, 193, 194. origin of, 78. source of, 193. in Wassermann reaction, source of, 151. lipoid-globultn in all cases of syphilis, 61. method of action, 86. nature of, 78. origin of, 78. reason for adsorption of complement by. 95. and complement molecules homologous, 96. Reagm molecule, action of salvarsan on, 93. injured by inactivation, 76. lipoid-globultn molecule in serum of pregnant women comparable to, 95. C[uestion of specific action, 94. Rectum, gonococcal infection of, 404. gummatous ulceration of, 177. syphilitic stricture of, 177. sex incidence, 177. Reduction and oxidation, Unna's theory of, 31. Relapsing fever, effect of salvarsan on, 5. Resorcinol solutions, use in preparation of specimens of s>-philitic organisms, 33. Retinitis, syphilitic, 156. associated with choroiditis, 156. associated with syphilitic myelitis, 156. Rhmoscleroma, aminoplasma cells met with in, 36. Rhouiberg's sign in degenerative myelitis, 247. Rickets and congenital syphilis, simulate one another, 266. Ricord's pill, 354. Rodent ulcer, 510, 514. Rongalit white, action of, 30. Roseola, congenital svphiUtic, practically un- known, 263. INDEX. 615 Roseola, syphilitie, 135. Ross, E. H., jelly-method of, .5, C. phases in development of SpirocJiaeta pallida, 5. Royal Commission, aims of, 400. " Saddle-nose," 267. Saline, dilution of syphilitic sera with. 74. injection after withdrawal of cerebro- spinal fluid, 183. Salpingitis, gonococcal, 431. Salts in normal serum, effect on Wassermann reaction, 86. influence on process of fertilisation, 18. Salvarsan, action of on, Leucocytozoon si/pltiliilis, 278. on lipoid-globulin in urme, 152. ■ on reagin molecule, 93. administration of, erythema following, 224. followed bj- haemorrhagic en- cephalitis, 223. hastens disappearance of symptoms of primary syphilis, 122. in .syphilis in several injections followed by mercury essential, 123. adrenalin in conjmiction with, 304. advantage of neo-salvarsan over, 279. arsenic of, 278. atoxyl and arsacetin more toxic than, 281. auditory lesions after. 309. blindness from use of, 483. blmdness not caused by, 157. chemistry of, 276. constitutional formula, 277. contraindications to, 312. • deaths from, 483. decreases clotting-time of syphilitic sera. 93. discovery of, steps leading to, 284. diseases following administration of, 300. effect on cerebro-spinal fluid, 205, 206, 207. on relapsing fever, 5. on syphilitic iritis, 155. on yaws, 5. upon neutrophiles and lymphocytes in sj'philis, 150. fatal cases following, 312. formation of antibodies checked by, 141. formula, when injected, 280. haemorrhagic, not due to salvarsan, 228. haemorrhagic encephalitis oecurrmg inde- pendently of, 224. Herxheimer's reaction after, 303. hydrochloride of, 277. in diagnosis of sypliilitic arthritis, 173. in pulmonary s^'jihilis, 108. in syphilis of pylorus, 175. Salvarsan in treatment of syphilis, influence on VVassermami reaction, 108, 109, 110, HI. must be supplemented by mercury and iodides, 111. increases amino-acid content of syphilitic sera, 93. influence on protein content in cerebro- spinal fluid, 192. on Wassermami reaction, ex- plained, 93. injections of, ill effects following, 295. jaundice following, 295. insufficient use of harmful, 123. intervals in treatment, toxic s^^nptoms after, 302. intramuscular injection of, 337. clinical course after, 339. intravenous injection of, 341. marriage permitted to men after treat- ment by, 257. neuro-recurrenoes after, 308. no improvement under in aberrant form of syphilis, 14, 15. not supplemented by mercurv, harmful, 123. optic lesions after, 309. original base substance of, 278. oxidation product, toxic action of, 224, 225. positively acting serum becoming nega- tive after injection of, 93. producing symptoms of cerebral com- pression, 1. properties of, 277. provocative injections of, 110. in women, 256. raises amino-acid content of syphilitic sera, 89. reagent against Spirochaeta pallida, 280. relationship between potency and toxicity, 294. second dose actmg as anaphylotoxine, 224, 225. second injection followed by death in case of basal meningitis, 234. sodium salt of, 277. successive injections of, effect on lipoid globulin molecules, 94. syphilitic anaemia due to, present rarity, 150. neuritis of cranial nerves following, 160. therapeutic action compared with that of salvarsan, 280. elaboration, 284. author's views on, 285. toxic manifestations in post-pure water days, 300. 616 INDEX. Salvarsan, toxic symptoms of, 226, 294, 298. toxicity increased by presence of patho- genic organisms, 299. treatment by, histological condition of syphilitic plasmoma after, 9.3. in several injections, and followed by prolonged mercury treatment, effects, 220. inadequate or spasmodic checking production of antibodies, 219. Wassermann reaction becomes increas- ingly positive only after first two or three injections of, 93. water question in preparation of, 295, 297. and grey oil injections, effect on syphilitic deafness, 160. and mercury combmed in treatment of syphilitic optic neuritis, 157. effect on syphilitic neuritis of cranial nerves, 100. See also Neo-salvarsan. Salvarsanised serum, intrathecal injection of, 346. Saprophytic organisms, leucocytozoon de- stroyed by, 123. Sarcoma, arishig in plasma cells, 546. diagnosis of syphilitic osteoperiostitis as, 171. part played by lymphocytes in, 538. Sarcomatosis cutis, 547. Scabies, differentiation from syphilis, 142, Schaudinn and Hoffmann, discovery of Spiro- chaeta pallida, 2. Schereschewsky, mixed cultivation of spiro- chaetae, 59. See also Fornet and Schereschewsky. Schmidt, pathlogical changes resulting in sepa- ration of epiphyses, 265. Sohiiffel, Peripylephlehitis syphilitica, 269. Schukowsky, Metrorrhagia neonatorum, 270. Sohiirmann, colour test of, 69. Sciatic nerve, syphilitic neuritis of, 231. Scrotum, enlargement in late syphilitic lym- phangitis, 145. Sebaceous adenoma, 518, 524. Self-abuse, sexual neurasthenia caused by, 478. Seminal vesicles, inflammation of, 399. massage of, 400. Sensitising process, changes produced by, 447. Sequeira, J. H., aberrant form of syphilis asso- ciated with Diabetes iiisijiidus, 15, 17. Sera, amphoteric, 73. action of on cells of syphilitic bodies, 44. pressure, plus and minus on, 76. active, use of, 257. Sera, antigonococcus, 445. " control," 439. effect on, by treatment with barium sul- phate, 78. fixation of complement, 438. immune horse and human, 445. sensitising process, 447. multiplication of bacteria in, precaution against, 45. normal, differentiation from syphilitic, difficulties in, 82. effect of lecithm-globulm on, 79. lipoid-globulin particles in, prob- ably complement, 82. surface tension in, 96. of pregnant and syphilitic women, close resemblance between, 95. of syphilitic non-pregnant women, be- haviour of, 258. syphilitic, active, 75. in connection with pure com- plement fixation test, 76. majority of positive reactions obtained from, 75, 76. amino-acid content, 87, 88. and Wassermann reaction, 92. diminution, 87, 88. increased by salvarsan, 93. • less in untreated cases, 88. • amount of calcium salts in, 87. clotting-time decreased by sal- varsan, 93. colloidal particles larger in. than in normal sera, 84. decrease of amino-nitrogen in, 92. differentiation from normal, 82. -; dilution with saline, 74. effect of lecithin-globulin on, 79. effect of temperature on, 74. on addition of amino-acids to, on Wassermann reaction, 92. of heating on, 75. freezing jioint of, 75. globulin complexes increased in, 92. increase of nitrogen in, 84. lipoid-globulin of related to that of serum in women, 258. lipoid-globulin particles in, become antibody, 82. lipoid nitrogen, estimation not pos- sible, 84. rapidity for clotting, 87. substances depressing, 90, 91. substances raising, 89, 90, 91. surface tension in, diminished, 96. how lowered, 78. INDEX. 617 Sera, syphilitic, time taken to become positive, 74. Sero-diagnosis, optic, of syphilis, fii). Serum diagnosis of syphilis. See W'assermann. reaction. inactivated, yielding more positive reac- tion than active serum, 76. increase of adsorptive capacity result, 97. of lipoid globulin in, 83. mode of existence of amino-acids in, 88. natural proteins in, only react with trace of nitrogen, 88. normal, salts in, effect on Wassermann reaction, 86. of pregnant woman, factor necessary to break down placental extract, 95. of women, protective substances in, 258. salvarsaniscdintrathecalinjcctions of, 346. in treatment of non-degenera- tive encephalitis, 214. syphilitic, addition of antigen to increases size of ultra-microscopic particles, 82. application of controls, 109. giving positive ninhydrin reaction with placental extract, 95. giving positive ninhydrin reaction in presence of complement, 96. inactivation of, 109. lipoid-globulin in adsorptive capa- city, 82. — positive becomes negative after in- jection of salvarsan, 93. testing of, 109. See also Lijioid-globulin of serum. Serum reactions, effect of colloidal and non- colloidal bodies on, 77. Sexual connection, date chancre, after, 125. Sexual desire, diminution generative myelitis, 247. Sexual function, 477. weakness in svphilitic meningo-myelitis, 242. Sexual neurasthenia, 478, 481. Sexual organs, female and congenital syphilitic diseases of, extreme rarity, 270. Sheep's red blood corpuscles, washing and dilution, 66. Shillitoe, greater development of degenera- tive lesions of syphilis, 230. Shoemakers, liability to osteo-periostitis of sternum, 172. Siedlecki. See Kryzszlalowicz and Siedlecki. Siegel, Cijtorrhyctes luis, I. Silver nitrate impregnation method, demon- stration of Spirochaela pallida by, 2. Silver nitrate method, Levaditi's, Koguchi's modification, for demonstration of S^iiro- chriela pallida, in section, 63, 64. of appearance of or loss of in de- Silver preparation, application to spirochaefal films, 63. Skin, aleucaemia of, 546. atroph^• of, set uj) by maeulo-papules on trunk, 138. blood supply of distribution, 141. diseases liable to be confused with syphilis, 412. epitheliomata of, classification of, 509, 512. inflammation of, relationship to malignant disease, 509. leucaemia of, .545. lymphocytomata of, 560. syphilitic infection of, compared with lesions of nervous system, 214, 215. manifestation in severest, 203. Skin eruptions, syphilitic, of generalisation stage, 134. polymorphic nature, 136. Skin lesions of congenital syphilis, 262. Skull bones, gelatinous atrophy affecting, 266. Smegma, origin of, 464. " Snuffles," 267. often due to simple catarrh, 274. Soda. See Niideinale. Sodium chloride solution, action on nuclei of syjAilitic bodies and on herring's roe com- pared, 42, 44. Sodium compound of salvarsan, basic or amphoteric on injection. 278. Sodium salt of salvarsan, formula, 277. Soft sore. See Ulcus molle. Soga. See McLeod and Soga. Soles of feet, rash in congenital syphilis specially affects, 262. Sore, primary, treatment of, 321. Sjnrmatoct/stitis gonorrhoica, 399. Spermatorrhoea, 481. Sphincter (bladder) paralysis in congenital syphilitic degenerative myelitis, 271. Spinal cord, blood-vessels of, 210. injections of salvarsanised serum into, 346. ■ syphilis of, cases diagnosed as, 215. treatment of, 334. syphilitic degenerative lesions occur in any part of, 217. diseases of, content of cerebro- spinal fluid in, 195, 196. lateral column lesions of, 211. lesions of, 210. ameningeal, 243. meningeal, 241. topographical anatomy of, 210. Spirochaela balanitidis, 5. Spirochaela calligi/riim, relation to Spirochaela calligyrum and UNIVERSITY OF CALIFORNIA LIBRARY Los Angeles This book is DUE on the last date stamped below. APR 9 1958 jipR 1 5 1964 lib, I APR 5 1371 l&,i<' vr ^P Q\oiM-ii^;i^w 9 £0 UB. m iw Form L9-50m-ll, '50 (2554)444 THE LTBRARY taOVERSITY ()/ C VLIFORMUi LOS ANGELES via iiiii.iiiiiiiijiiiiii D 000 129 112 9