FLeepeecy etheet ec GUS Gl L \9 D | > Qornell University Library Sthaca, Nem York BOUGHT WITH THE INCOME OF THE SAGE ENDOWMENT FUND THE GIFT OF HENRY W. SAGE 1891 | pceae Sern Unversty Ubray Hii 0 ENDOCRINE GLANDS AND THE SYMPATHETIC SYSTEM BY P. LEREBOULLET : P. HARVIER : H. CARRION A. G. GUILLAUME TRANSLATED BY F. RAOUL MASON, M.D. INSTRUCTOR IN PEDIATRICS NEW YORK POST-GRADUATE MEDICAL SCHOOL AND HOSPITAL; ASSISTANT ATTENDING PHYSICIAN WILLARD PARKER HOSPITAL; ASSISTANT PEDIATRIST NEW YORK‘ POST-GRADUATE MEDICAL SCHOOL AND HOSPITAL OUT-PATIENT DI PARTMENT ABSISTANT ATTENDING PHYSICIAN, BABIES’ WARD, NEW YORK POST GRADUATE MEDICAL SCHOOL AND HOSPITAL. WITH THE COLLABORATION OF DANIEL R. AYRES, A.B., M.D. ASSISTANT PROFESSOR OF GYNECOLOGY NEW YORK POST-GRADUATE MEDICAL SCHOOL AND HOSPITAL; ASSISTANT VISITING OBSTETRICIAN CITY HOSPITAL, NEW YORK PHILADELPHIA & LONDON J. B. LIPPINCOTT COMPANY & Sisees COPYRIGHT, 1922, BY J. B. LIPPINCOTT COMPANY PRINTED BY J. B. LIPPINCOTT COMPANY AT THE WASHINGTON SQUARE PRESS PHILADELPHIA, U. S. A. PREFACE TO THE AMERICAN EDITION There is no subject in medicine at the present time which has aroused such a widespread interest as endo- crinology. The reason for this is obvious. In practically every specialty, be it internal medicine, surgery, gyne- cology, neurology or pediatrics, our knowledge of this subject is increasing daily and finding new applications. At first our use of the endocrines was limited to such applications as thyroid in cretinism, or pituitrin to stim- ulate labor pains. We now know that there are numerous grades and varieties of disturbances of the glands of internal secretion giving rise to many troublesome symptoms and pathological conditions, which could not very well be relieved by our common therapeutic meas- ures. Many of these conditions are now amenable to treatment by means of glandular extracts. A few ex- amples are sufficient to illustrate this: The improvement of certain persistent cases of enuresis or what at one time seemed to be ordinary cases of epilepsy by means of pituitrin; the relief of asthenia following acute _infec- tions by the administration of suprarenalin; the benefit derived from thyroid, thymus, pituitary or ovarian ex- tracts in gynecological conditions; the variety of obscure skin conditions which have been cleared up by giving one or more of the glandular extracts, and many more could be added to this list. The remarkable feature of this method of treatment is that it can be both symptomatic and curative in its action. This does not mean of course that all body ailments can be treated by the administration of glandular extracts, but a great many can be helped. An understanding of iii iv PREFACE TO THE AMERICAN EDITION the subject is necessary and, as in other phases of med- icine a.proper diagnosis is important. We are all liable to become rather confused by the mass of new evidence brought forward constantly as well as by the extravagant claims of certain enthusiasts. The French have probably as a nation been more inter- ested in endocrinology than any other people and the names of Claude Bernard, Brown-Sequard, Charcot and, ‘more recently, Pierre Marie and Sergent are cldsely related to the history of this subject. The translator believes that the writers have condensed in this volume in a clear and sober manner our present-day knowledge of the endocrines without the addition of any fanciful theories. Very appropriately, the study of the sympathetic system has been included, as these two subjects are closely connected. While at first the study of the sympathetic system may seem rather tedious, the reader will be amply repaid for his effort, as this subject, on which so little has been written, enables us to gain a ‘better understanding of functional pathology. At the request of the authors this translation has adhered, as far as possible, to the original French text. When it seemed suitable, footnotes have been added with the collaboration of Dr. Ayres. Certain recent facts have been omitted as not having as yet been sufficiently con- trolled by unprejudiced observers. For instance, the lack of small quantities of iodine in the water or food supply as the probable etiological factor in colloidal goitre, or the selective action of quinine or its derivatives on the true sympathetic and its clinical application in certain cases of tachycardia. The translator wishes to express his thanks to the pub- lishers who have made this American edition possible. F. Raout Mason. CONTENTS INTRODUCTION GENERAL CONSIDERATIONS ON THE ENDOCRINE GLANDS AND THEIR PATHOLOGY. P. Leresovuttet I. NORMALgAND PATHOLOGICAL ANATOMY AND PHYSIOLOGY” OF T. ENDOCRINE GLANDS......000.00000 0.02 ccc cece cece 4 WHAT ARE THE ENDOCRINE GLANDS FOR..........00. 0c cee ceeeeeee 4 Ways OF STUDYING AND CLASSIFYING THE PRODUCTS OF INTERNAL CREO My oe che 88 kad BA 6G deeb ee ow RRO RS EEE Ons ROR SR 8 FUNcTIONAL DISTURBANCES. (INSUFFICIENCY, HYPERFUNCTION, ABERRA- TION OF FUNCTION, FUNCTIONAL GLANDULAR CORROLATION. Part PLAYED BY THE SYMPATHETIC).......... 0.000 ccce sec cceceeeeueecs 16 Il. THE CLINICAL ENDOCRINE SYNDROMES ....................... 25 Ill. GENERAL THERAPY OF DISEASE OF THE ENDOCRINES.......... 40 FEETIOLOGICAL TREATMENT... 0... ccc cet e eee ee ee nnnes 42 SURGICAL TREATMENT. .... 0.0006 eect cece eect n eee eeneeeeesane 43 TREATMENT WITH X-RAY .... 0.0.00 c cece cece cer ee eee tee eeeeaauve 45 ORGANO THERAPY S395) Bdthe eM eslawcas oteineen ves seen 4a eR ewe ae ce ae 47 PATHOLOGY OF THE ENDOCRINE GLANDS P. Harvier J. PATHOLOGY OF THE THYROID................. 0.0.2 cece eee eee 57 FUNCTIONS OF THE THYROID........00000 0000 c cece eect eeeeneaee 57 I. THYROID INSUFFICIENCY SYNDROMES........................ 60 ADUET MYXEDEMA, 606i scevecoee cde bp » ebas Quaid ane a edb bad 4a fenced eae 60 MyYxEDEMA IN CHILDHOOD............ 000002 eee BAAN pep re Cetin le aire ont 63 Poe? OPERATIVE MIXEUIMA. os12.4 ceed ens deemed Wi vies uwns dawaee ede 66 JENDEMIC MYXEDEMA OR CRETINISM. ... 0.0000 c cece e eee eee ee 67 ABORTIVE MYXEDEMA (CHRONIC MILD HYPOTHYROID'SM, SLIGHT THYROID IN- SUPRICIENGY, oisid,5.ds asia aesteintas Seaeh wea walommieaes P earkeba see nascent 67 TREATMENT OF MYXEDEMA AND OF THYROID INSUFFICIENCY. ...........-. 71 Il. THESYNDROMES OF HYPERFUNCTION OF THE THYROID....... 75 [XOPHTHALMIC‘GOITRE: 2 6 o poscivnea sees ne daga OondQids oagesag Oedlaes 75 THE VARIOUS BasEpOW’S DISEASE SYNDROMES............00.00 00 cueeee 89 HyPERTHYROIDISM SIMULATING BASEDOW’S DISEASE .............200005 91 TREATMENT OF EXOPHTHALMIC GOITRE AND HYPERTHYROIDISM .......... 92 THYROID INSTABILITY..00000 ccc ccc eee cence teen nee eee tener aes 96 AcuTE THYROIDITIS. TUBERCULOSIS AND SYPHILIS OF THE THYROID... 97 Vv vi CONTENTS PAGE Il. PATHOLOGY OF THE PARATHYROID GLANDS................. 102 FUNCTIONS OF THE PARATHYROIDS. 0.0.0.0... 00ce cceceseeeeceaceceuee 102 PARATHYROID SYNDROMES 1.0.0.0... ccc cece eee eeceneeneneneees 103 PARATHYROID INSUFFICIENCY AND TETANY... 0.00... cceeeceeceeceeeuce 103 PossIBLE PARATHYROID SYNDROMES. .......0.00. 0000 cseeecseueeeueeees 115 SUDDEN DEATH IN CHILDREN AND LESIONS OF THE PARATHYROIDS........... 116 Til. PATHOLOGY OF THE THYMUSG...............0.. 0 cc cece ee cee eee 117 FUNCTIONS OF THE THYMUS. 0... 0000 e ccc cence ence nent teennee 117 THYMIC SYNDROMES #2 ¢ 44655455424 g:@oRR PERE S EAMnaS CEES ERA rman 119 SYNDROMES OF THYMIC HYPERPLASIA... 00.0. cee eee cece teen ees 119 HYPERTROPHY OF THE THYMUS... 20.2... ceec cece cece eee ees ... 120 SUDDEN DEATH OF THYMIC ORIGIN... 00.000 ccc cece cece neue 123 HyYprrtTropuy OF THE THYMUS IN DISEASES OF THE ENDOCRINES.......... 126 SYMPTOMS OF APLASIA OF THE THYMUS. CONGENITAL TIIYMIC IDIOCY..... 127 PATHOLOGY OF THE ADRENALS FUNCTIONS OF THE ADRENALGLANDS,.......0 0c cece cece eee eee eeeenes 128 I. SYNDROMES OF ADRENAL INSUFFICIENCY..................002. 131 ADRENAL INSUFFICIENCY ......0 0000s cece eee cnet cee e ene e eee eenenas 132 ADDISON'S DISEASE ano ce eda ced oak aed cuimeeinad a anitcadten’y eu AaB BA ee OSs 143 Mino ADRENAL INSUPIICIENCY 2. ci ca a5 5 2600 055244 RH RER TERS ERE EL EES 152 II. SYNDROMES OF HYPERFUNCTION OF TITE ADRENAIS.......... 156 Il. ADRENAL TUMORS AND DYSTROPHIES OF ADRENAL ORIGIN... 161 GENITO-ADRENAL SYNDROME. .... 2.00000 e cece cece ene eee teens 162 PATHOLOGY OF THE PITUITARY FUNCTIONS OF THE PITUITARY»... 0. cece eee ccc e erence eee ee en tenes 170 Prrurrary SYNDROMES... 25 <2 2s44s05ee05 024 o¢00554 Seeewev sees che tee 172 AGROMBEGALT Aes siesssin ge ce.d 4: Citubecdecettaicd 0d tack FAG Reece adaware aia wien desde 172 GIGANTISM cess. tits det be ee an aalalan bAtoedea a A Wanderers ne Sanaa hauls 178 PITUITARY INFANTILISM 0.0.0.0. c ccc cece cee teen een eens 183 ADIPOSO-GENITALIS SYNDROME .......0 00.00: e eee e eee cece teen eee 185 PITUITARY GUYCOSURIAy ..0 eyo eae. ee dawn Loe enced aed aaleeeiey oh ease 188 PITUITARY POLYURIAs «626053252 20s CHAR ARREE AED BRS UES xs BHeeD Et ES 190 PITUITARY SYNDROMES AND TUMORS OF THE PITUITARY..............006 191 ABORTIVE PITUITARY SYNDROMES ... 00.0000. 2c cece eect e eee eee 196 PITUITARY SYNDROMES‘IN INFECTICNS........00-0 0000 cece cece cece ee eee 197 TREATMENT OF PITUITARY SYNDROMES... ......00. 00 cece cece een eens 197 PATHOLOGY OF THE PINEAL GLAND PINEAL SYNDROME. iis occ eae s nd chaea eee Be 6a 0d 44 See ENE Bese aS 201 PATHOLOGY OF THE TESTICLES FUNCTIONS OF THE TESTICLES. 0.0.0.0... 00sec cece eee cece teen e eee 208 I SYNDROMES OF TESTICULAR INSUFFICIENCY................... 212 212 GASTRETION Ras eee oahua a aindeees We Robe wed Fudan ey eeaieeeconmeion CONTENTS vii PAGE PATHOLOGY OF THE TESTICLES—Continued UNDESCENDED TESTICLES. 000.000... cece cece cece cette eee eeeteeeeuas 214 TESTICULAR INSUFFICIENCY DUE TO TOXIC OR INFECTIOUS LESIONS OF THE PE STI CUBS) 5 64.0. diancnors ai 6, ocak Anaad sod se Saigne G Meee SARUM Oa Soak aaNe eS 215 II. SYNDROMES OF HYPERORCHIDIA..........0..0 0.00. 0c cceceeeees 218 INDICATIONS FOR TESTICULAR ORGANO THERAPY..........0. cc ceeeeeeee 220 PATHOLOGY OF THE OVARIES FUNCTIONS OF THE OVARIES. 00.0.0... 0000 ccc cee cence sees eeeenaees 22) SYNDROMES OF OVARIAN INSUFFICIENCY At nwsea Wa Gy eR ae Ss 223 Post OPERATIVE OVARIAN INSUFFICIENCY.....0.0 0.000 0c e eee eeeeeeeeee 223 DisTURBANCES OF THE NORMAL MENOPAUSE...........000.000eeeeeeeee Q27 CONGENITAL OVARIAN INSUFFICIENCY... 00000000 c ccc e cece eevee ees 228 OVARIAN INSUFFICIENCY AT PUBERTY... 0000000000 cee cece eevee ee ees 228 ACQUIRED OVARIAN INSUFFICIENCY. ......000000000 cece cece eee eeees 229 THYROID OVARIAN INSUFFICIENCY... 20000000 ccc ccc cc ccc eee ee eee 230 TREATMENT OF OVARIAN INSUFFICIENCY 2.000000 00 ccc cece ee eee eee eee 231 SYNDROMES OF OVARIAN HYPERFUNCTION.................. 233 METRORRHAGIA OF PUBERTY. 0.000000 c cece ccc eee e ner eeene 234 METRORRHAGIA OF THE MENOPAUSE.......... 0000 cee cece eee eee eee 234 TREATMENT OF OVARIAN HYPERFUNCTION.........0 00000 e ecu ee euee 236 PATHOLOGY OF THE MAMMARY GLAND MAMMARY HYPERTROPHY AT PUBERTY IN WOMEN............0000 000005 239 MAMMARY HYPERTROPHY IN MAN... 2.0... cece eee cece e eee eens 241 PLURIGLANDULAR SYNDROMES..................... pcuaaastk ch Ma i PATHOLOGY OF THE SYMPATHETIC SYSTEM Part I. INTRODUCTION TO THE STUDY OF THE NERVOUS SYSTEM OF VEGETA- TIVE LIFE FROM AN ANATOMICAL AND PHYSIOLOGICAL POINT OF VIEW. A. C. GUILLAUME. THE SYMPATHETIC, CRANIO PELVIC SYSTEM, AUTONOMIC SYSTEM, ENDOCRINE GLANDS. : I. WHAT DO WE MEAN BY THE SYMPATHETIC SYSTEM............ 254 Il. THE ANATOMICAL VEGETATIVE NERVOUS UNITY.............. 263 Ill. THE COMPONENTS OF THESE SYSTEMG......................--. Q74, IV. ANATOMICAL AND PHYSIOLOGICAL DESCRIPTION OF THE VARIOUS “ELEMENTS ® 224: acai card ea cane nae ee head Saeed nade me 286 V. PHYSIO PHARMACOLOGICAL OPPOSITION OF THE TWO GREAT VEGETATIVE SYSTEMS) cscs acstonenes poeion tales et dm edbapeewsne 4 306 vill CONTENTS PAGH PATHOLOGY OF THE GREATER SYMPATHETIC P, Harvier PART II. I. HYPEREXCITABILITY SYNDROME OF THE VEGETATIVE NERVOUS SYSTEMS sisciccasev-ain easton etonuiaibig wail. 4 palualowed Bato ake 315 (SYMPATHICOTONIA AND PARASYMPATHICOTONIA OR VAGOTONIA) Il. REACTION OF THE VEGETATIVE NERVOUS SYSTEM IN THE COURSE OF DISEASE AND VISCERAL AFFECTIONS ............ 319 III. ENDOCRINE SYMPATHETIC SYNDROME........................ 324 IV. LOCALIZED SYMPATHETIC SYNDROMES................00000005 328 CERVICAL SYMPATHETIC SYNDROMES..........0 00000 ee eee e ects eee 328 MEDIASTINAL SYMPATHETIC SYNDROME......... 00000 ee eeecueeeeeeeee 335 ABDOMINAL SYMPATHETIC SYNDROME, .......0 000: cece cece cece en eeeeees 337 ORGANO THERAPY H. Carrion PHARMACOLOGICAL FACTS. PHYSIOLOGICAL BASIS OF ORGANG THERAPY........00005 ceeeeceeveeees 349 MOonEs OF ACTION OF ORGANO THERAPY ...........0020 ce cccueeeeeeuee 351 THE PREPARATION OF THE VARIOUS PRODUCTS USED IN ORGANO THERAPY... 357 THE ADMINISTRATION OF ORGANO THERAPEUTIC PRODUCTS............--5 360 GENERAL INDICATIONS FOR ORGANO THERAPY........00000c ec eeeeeeeeee 361 CONTRAINDICATIONS TO ORGANO THERAPY..........0 0c ec ecee cece eens 362 TECHNIQUE OF ORGANO THERAPY.......0. 02 cece c cece eet e ee ee ee eneee 863 Doss OF ORGANO THERAPEUTIC PRODUCTS......... 00000000 cece eeeeee 364 CERTAIN GENERALITIES ON THE CHIEF ORGANO THERAPEUTIC PRODUCTS... 365 INTRODUCTION GENERAL CONSIDERATIONS ON THE ENDO- CRINE GLANDS AND THEIR PATHOLOGY. By P. LEREBOULLET “Agregé” Professor of the faculty of medicine of Paris. Physician to the hospital for sick children. ENDOCRINE GLANDS AND THE SYMPATHETIC SYSTEM INTRODUCTION The importance of the endocrine glands, both in physi- ology and pathology becomes every day more evident. By means of anatomical and experimental researches on the one hand, and, from clinical, as well as therapeutical observations, on the other, it is possible to realize the primordial importance of these glands, however complex it may appear, and sufficient knowledge has been ob- tained to reach some practical medical conclusions. These are the conclusions which Dr. Harvier has re- viewed in this volume. In a series of clear and concise chapters he has brought up to date our knowledge of the endocrine glands and their pathology. Very rightly abstaining from all hazardous pathogenic theories, he has limited himself to review the various glands and after going over their physiological action, has described their functional disturbances and the diseases resulting | from these alterations. Before going over these analytical chapters it would perhaps not be amiss if we reviewed the trend of thought which at the present time directs the medical mind in the observation of endocrine pathology and described how our knowledge on the subject has slowly developed from the anatomical, physiological, clinical and therapeutical point of view. 3 4 ENDOCRINE GLANDS 1. NORMAL AND PATHOLOGICAL ANATOMY AND PHYSIOLOGY OF THE ENDOCRINE GLANDS. WHAT ARE THE ENDOCRINE GLANDS? They are the glands which pour out their secretions, not in extraneous places, like the cutaneous surface of the gastro intestinal tract, but in the body itself, that is, in - the blood stream. The notion that such glands existed (internal secretions), as opposed to the glands of external secretion has only been reached very slowly and it has nearly always been French scientists which have led the way. nies The founders of the theory of internal secretions were, Claude Bernard and Brown-Sequard. As has been shown by Gley, they had predecessors like Legallois and Bordeu. It was Claude Bernard in 1855 who discovered the glyco- genic function of the liver and who in this way placed the physiology of internal secretions on a firm foundation. In a series of investigations, between 1855 and 1867 he admitted that “the secretory cell attracts, creates, elab- orates in itself secretions which it pours out, either on the outside on the mucous membranes or directly into the blood stream. I have called those which are poured on the outside eaternal secretions and those which are poured into the organism itself internal secretions. The internal secretions are not as well known as the external secre- tions. I believe, however, that they definitely exist and we must consider the blood as the product of vascular blood organs. The glycogenic liver is a large blood organ, that is, a gland which has no external opening. From this organ arises the various sugar products found in the blood and perhaps certain albuminoid substances. There are, however, other blood organs such as, the spleen, the thyroid, the suprarenal capsules, the lymphatic glands, THE SYMPATHETIC SYSTEM 5 the function of which is not yet determined. However, these glands should be considered as playing a part in the regeneration of the blood plasma as well as in the forma- tion of white and red cells which float in this liquid.” The idea of internal secretions was clearly seen by Claude Bernard, but in his mind they were always limited to the composition of the blood and did not have the multiple conceptions we have of these to-day in modern physi- ology. For a long time the findings of Claude Bernard failed to make any impression on his contemporaries and they were not likened to those of Brown-Sequard on the physiology of the suprarenal capsules and the death of animals which had these capsules removed (1856) or to the work of Vulpin on the coloring matter of the medullary part of the suprarenal capsules (1856) and its passage into the suprarenal veins, or to the work of Schiff on the rela- tions of the spleen with the digestive functions of the pancreas. When Schiff in 1884 published his experiments on the effect of the removal of the thyroid in animals researches resulting from the work of the two surgeons, Reverdin and Kocher, on post-operative myxedema, he did not think of the possibility of internal secretions as established by Claude Bernard. It was Brown-Sequard in 1889 in his investigations of the therapeutic action of testicular fluid who understood the full value of the theory of internal secretions and who founded endocrinology. His original researches can pos- sibly be criticized ; they, however, contain the germ of all the ideas which have been used as a starting point on all the studies carried out during the last thirty years on internal secretions. While taking up again the idea of Claude Bernard on the action of glands without external secretions on the composition of the blood he showed that many organs secrete in the blood certain substances which 6 ENDOCRINE GLANDS have the ability to act selectively on certain organs, be they near or far away. “Each tissue and more generally each cell of the organism secretes of itself special products, or ferments, which are poured into the blood and which influence through the intermediary of this liquid, all the other cells, thus brought in contact with each other by a mechanism other than the nervous system.”” From this was born the idea of the action on various organs of ’ specific substances secreted in the blood and as a corollary this other fundamental notion of a functional corollation of the secretions. The subsequent researches of Brown- Sequard and of a number of physiologists and physicians showed, in spite of the poor result of testicular fluid, how valuable were these theories. Not only did it open a new path to experimental physiology, but it allowed new clinical interpretations and new therapeutic methods. Pathology very quickly came to the help of physiology and shed considerable light on the endocrine glands. The thyroid gland is the best known in this respect. The con- ception of myxedema was born from the observation of Gull, Ord and Charcot on senile myxedema, of Reverdin and Kocher on post operative m myxedema, of Bourneville on idiocy due to myxedema and infantile myxedema, and was made more comprehensive by the investigations of Vassale and Gley who caused the improvement of the severe symptoms resulting from the removal of the thy- roid by means of injections of thyroid extracts, and completed by those of Murray applying this method to the treatment of human myxedema. In this way the double conception that an insufficiency of the thyroid was responsible for this condition and it could be remedied by means of organotherapy was the result of the discoveries of Brown-Sequard. Shortly afterward the researches of Moussu and those THE SYMPATHETIC SYSTEM 7 of Gley on the parathyroid glands and the part they play in the production of tetany opened up a new chapter. A few years ago Morel in physiology and Harvier from an anatomical and clinical point of view brought this subject up to date. The suprarenal gland, of which already in 1856, Brown- Sequard had had a glimpse of its importance, is another example of the progress of endocrinology. The anatom- ical and clinical investigations of Addison’s disease had already shown the consequences of its insufficiency. Oliver and Schafer, Cybilski and Langlois showed the cardio-vascular action of the suprarenal extract and of the venous blood from the suprarenal gland. These researches were finally vindicated by the discovery of suprarenalin, the product of the secretions of this gland. Its hyper- tensive action has led to many important conclusions. We know the part which Josue applies to a hypersecretion of suprarenalin in the production of suprarenal atheroma. As has been pointed out by Sergent and many other clinicians, the part played by an insufficiency of the supra- renals in acute and chronic affections has been deter- mined, in those cases in which hypotension is a cardinal sign. The use of suprarenal extract has been considerably increased since these facts have been brought forward. If certain restrictions have been made by Gley from the’ point of view of physiology, the facts determined clinically and ‘therapeutically still remain true. The story of the investigation of the pancreas is just as rich in useful informations. In 1889-1890 Mering and Minkowski proved experimentally the part played by alterations of the pancreas in the etiology of diabetes, already clarified clinically by Lancereaux and it was shortly afterward that verifying and confirming this discovery, R. Lepine, Thiroloix and Hedon showed that 8 ENDOCRINE GLANDS in this case we were also dealing with an internal secre- tion of the pancreas. Shortly afterward the pathology of the pituitary gave a new example of the physiology and pathology of an internal secretion. The discovery of acromegalia by Pierre Marie was the first chapter of this pathology, which was made more complete by the study of gigantism, in- fantilism, certain adiposogenital syndromes and diabetes insipidus. The remarkable investigations of Harvey Cushing have helped to clarify the subject, both clinically and experimentally. We must, however, accept with reserve some of the facts, as it is possible that some of his theories may not be confirmed. The pituitary has be- come one of the most important and most interesting organs among the endocrine glands. From a therapeutic point of view pituitary organo therapy has been very effective, just as much as a symptomatic medication as in the case of substitute medication. The results are com- parable to those obtained in thyroid administration. These rapid historical considerations are sufficient to establish the significance of the initial observations of Brown-Sequard. Gradually, thanks to the parallel help of pathology and physiology, the notion of endocrinology has become more definite and this subject has now a justifiable place in the field of medicine. WAYS OF STUDYING AND CLASSIFYING THE PRODUCTS OF INTERNAL SECRETION. It is not sufficient to just say that the vascular blood glands have an internal secretion which have a part in the formation of the blood and act on other structures and organs. It is necessary to prove the reality of these se- cretions, by studying histologically the secretory function of the cells, determine chemically the nature of the sub- THE SYMPATHETIC SYSTEM 9 stance secreted, and what is more important, by means of physiological and experimental studies prove the action of these secretions. By these means is constituted a solid base for physiological, pathological and clinical deduc- tions. In this respect considerable progress has been made during the last few years, but there is still much to be done. The study of the pathological gland goes parallel with the study of the normal gland. The thyroid and the suprarenal are the best known from the histological and physiological point of view. They are also the two glands, among those of internal secretions, whose pathology is most definite. We are beginning to know the pituitary as regards to its histology and physiology and it is only since then that its pathology is better understood. It is to be hoped that further studies of the physiology and anatomy of the endocrines will be made, which will throw further light on their pathology. Already certain well-defined facts have been established. Tue Hisrotocicat Stupy of these glands has enabled us to examine how the glands work. Not only can we study the thyroid vesicles, for instance, and see how the gland secretes a colloidal substance, which is re-absorbed by the blood vessels surrounding the epithelum but we can, thanks to the modern methods, delicately stain the cellular protoplasm and see the glandular cell in activity. In the case of the liver, fill with glycogen, or suprarenalin, in the case of the medullary cells of the suprarenal capsule. In this respect, the researches of Henle are very suggestive. He has opposed the chromaf- fin, or suprarenalin cells to the cells with collesterin or nerve cells. Very significant are also the histological in- vestigations on the acidophils, basophils, cyanophils, chromophokes cells of the pituitary, notably the work done on the pars intermedia, at the junction of the anterior 10 ENDOCRINE GLANDS and posterior lobe. Where the colloidal glandular secretion accumulates and which allows us, if not to understand, at least to imagine what can be the function of this vascular nervous gland (Soyer). Histology is all the time bringing us new findings which can be utilized by the _ physician. By understanding the cellular mechanism of the endocrin secretions, it is possible to better understand the functional disturbances noticed clinically. It is thanks to histology, that by the microscopic study of the lesions of exophthalmicgoitreit is possible to invoke dysthyroidism as the cause of the symptoms and not a simple hyperfunction. Tue CHEMICAL Stupy by determining in these sub- stances, certain definite compounds, such as, suprarenalin, glycogen, cholesterin, etc., takes us one step further in the study of the glandular secretions. While we do not deny the progress made in this line during the last few years, we must admit that there is still much to be learned in this respect. How could it be otherwise, considering the com- plexity of the study of these secretions which can only be found either in the blood or in the cell itself as contrasted with the products of the glands of external secretion. It is this lack of chemical knowledge which makes our treat- ment with organo therapeutic products so empirical. We know the action of the total extract; sometimes we know the action of certain of the constituents, such as, suprare- nalin, but in the majority of cases the pharmacological study of the extract is impossible. In this respect it is — extraordinary how the thyroid secretions, so well known in their therapeutic effects, are so ill defined from a chemical point of view. It is to be hoped that the rapid progress of chemistry will soon overcome this deficiency. Already we know something of the secretion of the anterior lobe of the pituitary (tetheline), showing the part played by certain THE SYMPATHETIC SYSTEM 11 liquids of endocrine origin and the possibility of their use in therapeutics (Brailsford Robertson). Tue PuysioLocicaL Stupy of the internal secretions givesusmuch more definite knowledge than either histology or chemistry, but without these two it must remain incom- plete. We are able to study from it the specific action of substances extracted from a gland or from a vein afferent from this organ. By this method it has been possible to study the character of the venous blood of the suprarenals and obtain the characteristic cardio tonic action. In the majority of cases all that can be done is to study the action of extracts of organs. This is the method which has given the best results and from which organo therapy has been deducted. We must not, however, make statements too specific as regards these. Gley has shown how careful we have to be. The isolation of extracts of organs is always complex. What do these substances represent? Do they exist in the living organ; are they excreted in the venous blood? If so, are they excreted all at once or in small doses? The action of the extract cannot be the same as that of the blood coming from the veins of the organ and the pathol- ogist must be careful not to.make any rash deductions, basing his conclusions on the action of an organic extract and comparing it to certain symptoms noted in certain affections. We must also keep in mind the toxicity of extracts of organs. This toxicity varies according to the method of preparation and can become more important than the specific action of the extract of the organ. It is also probable that the various manipulations which are performed in order to lessen the toxicity, can also modify the action. It is possible that the administration of extracts of organs be followed by anaphylactic phenomena, since these extracts contain foreign proteins or inversely 12 ENDOCRINE GLANDS tachyphylaxis, that is, a rapid immunization against the toxic action of certain organs. This last suggestion, to which we are indebted to Champy and Gley, adds to the complexity of investigating the mode of action of extracts of organs. There are certain extracts which will only give a reaction when given in extra physiological doses, the doses used representing the total weight of the organs from which these extracts are obtained. This is the case of pituitrin which is used in relatively large doses and whose efficacious action cannot be contested. All these facts show how careful we must be in inter- preting the therapeutic results obtained, and, as Gley has said, “the real criterion of the function of an internal se- cretion is the presence of a specific product in the venous blood of a gland.” This criterion so far has only rarely been complied with. This does not mean that we must dismiss all the facts revealed by therapy and experimen- tal investigations on the extracts of these organs. It simply means that we must be very critical and not jump at conclusions. EXPERIMENTATION ON ANIMALS often have confirmed the observations obtained with the extracts. All that is necessary is to recall the results of experimental thyroid- ectomy and para thyroidectomy, of hypophysectomy, and castration to establish the fact that these glands play a physiological part in the organism and that alterations in these glands will result in pathological conditions, which we run across clinically. Tue Nature oF THESE SECRETIONS is still uncertain. It was admitted early by Gley and others that these glands produced substances having a specific action on other glands or tissues; iodothyrin for instance, which is secreted by the thyroid, has a direct action on meta- bolism, and its absence will cause disturbances in nu- THE SYMPATHETIC SYSTEM 13 trition. These substances of glandular origin, having a specific stimulating action have been called functional stimulants and were termed hormones by Starling in 1905. It is by the intermediary of these hormones that the functional corollation of chemical origin which was sus- pected by Claude Bernard, is accomplished, as dif- ferentiated from corollation of nervous origin, which has been known for a long time. But simply to know of the existence of hormones does not mean that we understand them well. The duodenal secretin stimulating the pan- creas is a certain type of hormone, the suprarenalin, a product of the chromaffin. cells of the suprarenals and other cells, has a stimulating act on the cardio vascular system and represent another type of hormone. It is also possible that iodothyrin really exists, although not isolated definitely and that it may have a stimulating metabolic effect on connective tissue. It is possible that there are other hormones of endocrin origin, but so far we know very little about them. Next to hormones, the endocrine glands secrete sub- stances which are not cellular stimulants but materials which they utilize. Glycogen of hepatic origin, the fats, are examples of nutritive substances utilized in the forma- tion of energy. Other substances must be used in the repair of the blood (specific proteins of the blood). Outside of these, those which are of most interest to the physician are those which help in the building up of tissues during the course of development of the organism; these are the morphogenetic substances. Physiology, anat- omy and clinical experience have shown the evidence of glands having a morphogenic action, such as, the inter- stitial gland of the testicle, the corpus luteum, the thy- roid, the pituitary. The substances secreted by these glands have a chemical morphological action, the study 14 ENDOCRINE GLANDS of numerous cases of infantilism is sufficient evidence of this. What are these substances? What is their mode of action? We do not know. These are the harmozones of Gley. (From the Greek I regulate, I direct). The study of growth and its disturbances have been revolutionized by these new ideas and it is to be hoped that in the future our knowledge on this subject will increase considerably. These chemical compounds which regulate development are among those whose action must be most carefully determined in order to use them therapeutically. The action of thyroid and pituitary organo therapy in a great many disturbances of growth shows what may be expected once our knowledge of the harmozones of the thyroid and the pituitary are better known. The recent investigations on the anterior lobe of the pituitary and the regulating action on growth by a substance, Tetheline, which can be extracted from this lobe is at least very suggestive (Brails- ford Robertson). The endocrine glands can, therefore, create, either nu- tritive substances, such as, sugar, hormones, specific cel- lular stimulants, such as, suprarenalin, harmozones or regulating substances and finally we can, following Gley, separate from the hormones, certain by-products or par hormones, such as, urea, the product of the change of toxic substances like ammonia or amino acids. It is also possible to place next to the hormones, substances which, instead of being stimulating, are depressing. These have been designated by Schafer under the name of Chalone (from the Greek I slow down). Perhaps this distinction is too absolute; one internal secretion can be, according to the case, either stimulating or depressing. The conception of the various glands of internal secre- tion must be well understood before going into the study of their pathology. It shows how complex is. the mechan- THE SYMPATHETIC SYSTEM 15 ism and how difficult it is to deduct an insufficiency or a hyperfunction from functional alterations. The com- plexity of the subject is made more pronounced by the fact that a multiple of causes can cause disturbances in the function of the endocrine glands and cause a multiple of secondary syndromes. These facts which I have just enumerated have en- larged our studies of endocrinology. Instead of limiting ourselves to the glands which were first considered as hav- ing only an internal secretion, such as, the thyroid, the pituitary, the adrenals, etc., it has spread to the thymus, to the spleen, the bone marrow which is not a glandular organ, but a blood and lymph forming organ. After all, have not all cells an internal secretion? And has not the adipose cell of connective tissue certain characteristics of a gland of internal secretion? The custom, however, is to limit the study of internal secretion pathology and phys- lology to certain glands and this custom is justifiable. For instance, in spite of the latest investigations on the liver, these have not been included in this volume, nor the relationship between disturbances of bone marrow and certain dystrophies (Hutinel). These do not belong to this subject. The glands which are studied from a functional and pathological point of view belong to a certain group having anatomical and physiological connections with the sympathetic, so that the study of sympathetic and its disturbances follows naturally that of the endocrine glands. It is not planned in this work to give the physiological history of these glands or to describe their histology or even to analyze their actions in detail. The aim is simply to describe some of their normal and pathological functions. Some of them have a double secretion, internal and ex- ternal, like the pancreas, the ovary and the testicle. Others have only one secretion, such as, the thyroid, the 16 ENDOCRINE GLANDS adrenals and finally, there are some whose secretions are still not well understood, such as, the pituitary, the para- thyroid, etc. Gradually our knowledge of all these glands has become broader and at the present time it is possible to give a fairly accurate description of their pathology and to give some general principle as to treatment. FUNCTIONAL DISTURBANCES. ’ Insufficiency. Hyperfunction. Aberration of Function. Functional Glandular Corrolation. Part Played by the Sympathetic. The destructive lesions being the easiest ones to inter- pret and the resulting conditions the easiest to appreciate and reproduce experimentally by the removal of the organ, it was the functional insufficiency of an organ which was first noticed. Insufficiency of the thyroid was spoken of when myxedema followed the removal of the thyroid, in- sufficiency of the adrenals when the destruction of the adrenals was noticed in Addison’s disease. Inversely it was noticed that in some cases there seemed to be exaggeration of function and that the symptoms noticed were the inverse of those observed in insufficiency. These cases were spoken of as hyperfunction; hyperfunction of the thyroid was opposed to hypothyroidism of myxedema, hyperfunction of the adrenals was suspected as a cause of hypertension, and inversely hypotension was suspected to be due to hypoadrenalism. Gradually it was found out, after many physiological and anatomical observations, that functional disturbances are not always as simple and aberration of function had to be added to the others. From a descriptive point of view it is very useful to make such a division. As soon as an endocrine gland is disturbed its function is altered, either there is an excess, a decrease or an aberration of the secretion; that is, in the case of the thyroid, hyperthyroidism, hypothyroidism, THE SYMPATHETIC SYSTEM 17 dysthyroidism. It is easy to see that the analysis of these disturbances is useful, even necessary in thyroidien organo therapy, efficacious in hypothyroidism, possibly detrimental in hyperthyroidism, and in case of dysthy- roidism some other therapeutic measure may be indicated. However, it is wise to avoid too rigid a classification. As the facts become better known, the notion of aberration of function becomes more important than pure hypo or hyperfunction. From a physiological point of view, Gley has recently shown what facts we have to meet when we speak of a simple functional insufficiency; for instance, when it is known how small a portion of thyroid or pan- creas it is essential to leave to prevent the accidents re- sulting from the total removal. Hypofunction has often been implicated without any demonstrable reason, even in cases where the alteration of the gland, the adrenal, for instance, would seem to result in a secretory deficiency. It has been demonstrated how small the quantity of suprarenalin secreted was to keep up the muscular tone, _ the researches of R. Porak, both clinical and experimental are very suggestive from this point of view. The reality of insufficiencies is, however, not in doubt, but they are possibly associated with other functional disturbances and other physiological modifications which seem to make their results more pronounced. Hyperfunction, associated with an endocrine hyperse- cretion, is more difficult to prove. Hyperfunction has been admitted to exist, basing ourselves on clinical and therapeutical facts, but has never been reproduced exper- imentally. The repeated injections of pituitrin have never caused the appearance of the symptoms of acro- meglia; in the same way, a true increase in the secretion of suprarenalin, in cases of arterial hypertension, has never been proved, and physiologically it is hard to conceive of 2 18 ENDOCRINE GLANDS suprarenalin being in the blood in excessive quantity with- out being destroyed and that a morbid syndrome would result from it. Two examples in endocrine pathology will do more to explain this than anything else. Exophthalmic goitre was for a long time considered as a manifestation of hyperthyroidism and opposed to myxedema. Facts have, however, been published making the interpretation for the first of hyperthyroidism and the second of myxedema very difficult. Since exophthalmic goitre has been studied more closely and that the lesions have been more care- fully investigated it has been recognized by Roussy and others, that therapeutic hyperthyroidism could not be compared to true Basedow’s disease and that the latter was a manifestation of dyshypertrophy of the thyroid, that is, an exaggerated and abnormal thyroid secretion. This idea is certainly the clearest of our present know- ledge on the subject. In the same way, acromegalia has been considered by some to be a manifestation of hyper- function. It is relatively frequent to see patients suf- fering from adiposo genitalis of the adult, (which has been blamed, not without reason, to an insufficiency of the pituitary) show evidences of acromegalia. I have person- ally seen two cases of this type. The possibility of a dyshyperplasia of the pituitary is best adapted to the facts and would explain the presence of some symptoms due to a functional deficiency with those of hyperfunction. The more we understand the syndromes associated with alterations of the endocrine glands, the more we see the complexity of their functional disturbances. Does this fact not also hold in disturbances of the liver and the kidney, which cannot all be brought back to an insuffi- ciency or a hyperfunction? It is, nevertheless necessary, be it only from a didactic point of view, to look at them from the triple point of view of insufficiency, hyper- THE SYMPATHETIC SYSTEM 19 function and aberration of function. Therapy brings other arguments in favor of. this classification and it is quite certain that organo therapy by modifying certain disturbances, in leaving alone or exaggerating others, can bring out a glandular insufficiency or inversely, a normal or exaggerated function. While still keeping in mind the importance of functional deviation it is always essential to determine if the symptoms observed in a patient are due to an insufficiency or are secondary to an excessive function. The classification followed by Dr. Harvier in the following chapters is a necessity, but it is well to understand that it is not absolute. * * * * Endocrine pathology appeared at first to be very simple; a certain gland seemed to be responsible for certain symp- toms: myxedema was a manifestation of the alteration of one gland only, the thyroid, Addison’s disease was due to changes in the adrenals and it was not necessary to invoke other endocrine lesions, acromegalia was due to a lesion of the pituitary. If this had been so in every case, the analy- sis of functional endocrine disturbances would have been easy. The notion of functional glandular corrolation, however, carried out through the blood stream or through the nervous system has complicated matters. The study of infantilism allows us to understand the consequences of this fact. I have previously referred among the endocrine secretions, to the presence of harmozones or morpho- genetic substances regulating growth. After the first investigations on hypothyroidism and the observations of Brissaud and Hertoghe, it seemed as if these substances came directly or indirectly from the thyroid and that modifications of these substances were the cause of most cases of lack of growth. Infantilism seemed to be due to hypothyroidism. 20 ENDOCRINE GLANDS It had, however, been previously shown that castration in man and in animals caused certain changes in the devel- opment of the skeleton, thus showing the influence of the genital glands. More recently this action was strikingly demonstrated by the influence of the pituitary in certain cases of infantilism, without there being any evidence of any thyroid disturbance. In studying thyroid or pituitary infantilism it was discovered that this was probably due to alterations of the sexual glands. It would seem, there- fore, that it was an alteration of the pituitary or of the thyroid, which caused a disturbance of function of other glands (the genital glands), resulting in infantilism; the expression, not of the disturbance of one gland only, but of a multitude of glands. We can sometimes wonder if there is not a pre-existence of an endocrine disturbance on another gland, if the initial alteration of this gland does not represent the whole evolution. It seems to be the case in the facts described by Gandy under the name of reversive infantilism and by Brissaud and Bauer under the name of late infantilism of adults; sometimes of thyroid, sometimes of pituitary origin. These cases are relatively numerous and the course of the lesions can be clearly followed; in those which I have observed, I have seen quite clearly the appearance of the pituitary lesion, with characteristic symptoms, notably ocular disturbances, and secondarily genital alterations followed by obesity and other changes. These facts, when the symptomatology is reconstructed, show the simultaneous existence of lesions of several endocrine glands. It is thus in a good many cases of sini- lism, of gerodermia, genito-dystrophy, etc. It is partic- ularly so in the very interesting cases analyzed by Claude, Gougerous and Sourdel under the name of pluriglandular syndromes. There is no question but that there are cases which clinically and anatomically show alterations of sev- THE SYMPATHETIC SYSTEM 21 eral endocrine glands: adrenal and thyroids, thyroid, pit-— uitary and testicle, ete. A classification based on such changes is, however, difficult to follow. There are certain conditions, such as, infantilism which I have just referred to, in which the lesion of one gland, the pituitary, for instance, seemed clearly to have pre- ceded that of the other glands. In some cases where the endocrine lesions occur simultaneously, the clinical symp- toms are so characteristic that there is no advantage to give it any other name. In other words, the knowledge of a pluriglandular involvement helps us to interpret certain clinical syndromes, and to determine what symptoms be- long to such or such a gland and, while keeping to the classical classification, treat these cases by means of mixed organo therapy so as to overcome these various syndromes. This idea helps us to better interpret and treat more efficaciously certain diseases, the nature of which is still rather indefinite. Take for instance, the obesity of the menopause, instead of being entirely dependent on the suppression of the ovarian function, it seems to be due to simultaneous alterations of the thyroid and the pituitary. Dercum’s disease is believed to be of thyroid and pituitary origin and the characteristic asthenia associated with this condition is believed to be due to the adrenals. Sclero- dermia is not due, as was believed for a time, to thyroid lesions. The adrenals, the pituitary and perhaps the ovary, seem to play a part in some of the symptoms of this disease and mixed organo therapy can do a great deal to relieve the condition. Diabetes often results from the simultaneous alteration of several glands outside of the liver and pancreas. While it is difficult to describe as yet the definite symptoms the pluriglandular syndromes, it is possible in certain well-defined diseases: obesity, diabetes, sclerodermia, genital dystrophy, etc., to bring 22 ENDOCRINE GLANDS out the multiple endocrine alterations and to use these facts for the basis of rational medication. ok * * ke OK If what I have just said has been understood, the follow- ing conclusions result: The functional disturbances re- sulting from endocrine alterations are complex and only rarely come down to the typical picture of insufficiency or hyperfunction; more often they can only be explained by an aberration of the endocrine secretion, be it exaggerated or deficient, having been modified in its usual characteristics and having a different physiological action. What makes these clinical findings more complicated is the fact that this functional aberration is transmitted by the blood and by the nerves on the function of other glands. In this way the clinical syndromes observed appear as the expression of polyglandular functional disturbances, while originally, due to one gland. The aim of the clinician is to try and determine what are the glandular disturbances in each syndrome and what is their subordination, while an appropriate organo therapy can very usefully modify these symptoms. One last factor comes into play which modifies the evolution of functional endocrine disturbances; that is the very frequent and very important disturbances of the sympathetic in the syndromes under observation. It is impossible to separate the study of the endocrine glands and the study of the sympathetic. It has been known for a long time the part played by it in cardio vascular mani- festations, thermic changes, vaso motor, pilo motor changes, etc....... all manifestations which are indicative to a more or less extensive degree of diseases of the endo- crines. It has been known for a long time, for instance, the part played by the stimulation of the sympathetic in Basedow’s disease and inversely, the majority of the signs THE SYMPATHETIC SYSTEM 23 of myxedema have their origin in alterations of the sym- pathetic, causing a decrease in its activity. Briquet, for instance believes that the chief function of the thyroid is to furnish a necessary stimulant to the sympathetic and a decrease in its function whether total, or partial, causes a decrease in this stimulation, whence myxedema. It is to this same sympathetic that is due the development of bones, growth, puberty, and it is the decrease of its stimu- lation, by a decrease in secretions from the thyroid, thy- mus, and other glands, that infantilism, and other dis- turbances of growth are due to (Briquet). The action of the sympathetic has also been suggested in many other conditions, notably in pigmentation of the skin (chiefly pigmentation due to Addison’s disease), in ichthyosis, in sclerodermia which Brissaud has for a long time considered as a disease of the sympathetic system, (be it due or not to endocrine disturbances). In the clinical field, therefore, these few examples are sufficient to show the influence of the sympathetic in the symptoms due to endocrine dis- turbances. The knowledge of relationship between the two for a long time was rather vague and indefinite. Dur- ing the last few years anatomists, physiologists and clini- cians have attempted to better understand and analyze disturbances of the sympathetic. They have shown how hard it was to dissociate the endocrine from the sympathet- ic system. An experimental example has been shown in the recent researches of Professor Roger on the relationship between the adrenal glands and the sympathetic, and inversely, the action of the sympathetic on their function. Histologically and embryologically a proof of this rela- tionship has been shown by investigation of the paragang- lia. Scattered throughout the abdominal sympathetic they play a complex and important part. They have, just as the adrenal medulla, chromaffin cells which secrete 24 ENDOCRINE GLANDS suprarenalin, and in spite of being mixed up with the nervous sympathetic system have, nevertheless, a certain epithelio-glandular nature. It is also well known that their origin is identical; the original undifferentiated cells become either sympatho- blasts, from which arise the sympathetic nerve cells or pheochromoblasts from which originate the adrenal or paraganglionic cells. The neuro chemical corrolation is here very evident, the activity of the paraganglionic cells is closely related to that of the adrenals. Clinically, numerous proofs of the close relationship between the sympathetic and the endocrines exist. Among the most characteristic examples is Basedow’s disease, in which the recent re- searches on disturbances of the sympathetic, by means of the oculo cardiac reflex have given very suggestive results. It has been established, in the course of the study of the endocrines, that adrenalin was sympathicotonic and played an important part in the physiological and pathological function of the nervous system of vegetative life, that adrenal choline, secreted in the cortex of the adrenals was antagonistic to suprarenalin and para-sympatheticotonic (or vagotonic), that idothyrin is sympathicotonic, etc... . it is, therefore, impossible to separate the study of the function of the endocrines with the function of the nervous system of vegetative life. To study the pathological functional endocrine syn- dromes, without simultaneously studying the disturbances of the sympathetic and, more generally, the nervous system of vegetative life would be arbitrary and _ in- complete. For this reason, the study of the sympathetic has been included in this volume. The chapters by Dr. Guillaume give an excellent anatomical introduction and the descriptions of Dr. Harvier give it a splendid starting point which will be of great help to the reader. THE SYMPATHETIC SYSTEM 25 II. THE CLINICAL ENDOCRINE SYNDROMES. Tn spite of the frequency of endocrine disturbances, very often their existence and significance is misunderstood. As time goes on, new methods spring up to help us locate and identify them. In these introductory pages, it is not amiss, after having shown the complexity of altered endecrine functions, to show the influence exerted by the sympathetic and to recall the facts which the clinician must base himself on, in order to reach a diagnosis and treat the case. We must keep in mind the various types of lesions which give rise to endocrine symptoms. Next to the cases with mild lesions, we have others which are quite severe. The clinical interpretation and therapeutic application of the facts must be very different. In certain cases there is a congenital lesion; for in- stance, when there is agenesis of the thyroid, resulting in myxedema or cretinism. More often we have to deal with acquired lesions: neoplasm or inflammations. The neo- plastic lesions may vary considerably; they may be benign without any other importance than their location, such as, the colloid goitres, certain adenomata of the pituitary or of the adrenals. They may be epithelial or sarcomatous lesions, as have been reported in the thyroid, the adrenals or the pituitary; to the symptoms associated with destruc- tion of the gland, may then be associated those resulting from hypertrophy of the affected organ. Furthermore, the malignant tumor may show signs of cachexia due to the secretions (certain cancers of the thyroid). The histological study of a great number of benign or severe tumors has shown the part played by the hyper- plasia of the organ, more often dyshyperplasia than true hyperplasia and the resulting abnormal secretion, 26 ENDOCRINE GLANDS certain cases of exophthalmos, or acromegalia, for instance in which the histological characteristics undoubtedly pointed to this. Certain facts resulting from cystic tu- mors at the level of the pituitary show the damage which can be made by a limited lesion, sufficient to disturb the function of a gland and cause the appearance of dwarfism as in the classical case of Souques and Stephen-Chauvet. But—and this is important in ordinary clinical work— the endocrine lesions are often simply inflammatory or specific. The study of thyroiditis, or suprarenalitis, associated with acute infections, such as, typhoid or scarlet fever has been reported quite frequently during the last few years. In the same way infectious diseases have a well-known action on the pituitary. These diseases cause, either cellular alterations, which result in acute or subacute symptoms or interstitial alterations causing chemical changes. It is mostly in tuberculous or syphil- itic lesions of the endocrine glands that the symptoms ap- pear most frequently and most characteristically. If lesions of the thyroid, the adrenals, the parathyroids, the pituitary do not respond to treatment and evolute rapidly, those due to lues, however, can be very satisfac- torily treated. The physician examining a patient with symptoms of endocrine disturbance should keep in mind the possibility of neoplasms, which cannot be cured and inflammations, or irritations by compression as in the case of bony lesions of the sella turcica. In taking the history it is well to remember the fre- quency of infections as an etiological factor in lesions of the endocrines. Here, as everywhere else, acquired or congenital syphilis plays an important part. Hereditary syphilis has often been found to be the cause of symptoms of endocrine disturbance. The same applies to acquired lues, be it in the case of myxedema, exophthalmic goitre, THE SYMPATHETIC SYSTEM Q7 infantilism or Addison’s disease. Frequently, it appears to be the essential cause of the appearance of the symp- toms. In certain cases the lesions produced are des- tructive, but in a great many, antisyphilitic treatment, combined with organo therapy, can cause remarkable changes, notably in syphilitic thyroiditis. In other cases tuberculosis is responsible for the symptoms and will cause the appearance of pluriglandular syndromes. Syphilis explains very often the influence of heredity, but there is also an endocrine heredity. This heredity has been noticed particularly in thyroid pathology; it can be direct. Families of myxedematous individuals have been reported (Brissaud), hereditary or family exophthalmic goitre has been studied. It can be more complex; a mother having Basedow’s disease can have children with myxe- dema. Similar findings have been made ‘in regard to the pituitary, the adrenals, the pancreas, etc. It is possible that the well known heredity of disturbances of nutrition. or obesity are due to hereditary endocrine disturbances. The study of patients with endocrine disturbances should, therefore, not only include the investigation of the family for any evidence of lues, but other infectious diseases which manifest themselves in the children as disturbances of the endocrines. Emotions may possibly play a part in the etiology of endocrine disturbances. This has been known for a long time in the case of exophthalmic goitre and the late war has verified the influence of severe emotions and fright on this disease. We know the action of emotions on menstruation (periods delayed or ahead of time), on breast feeding, certain disturbances related to the internal secretions of the ovary (frequency of Chlor- osis at Nancy-French Lorraine, during the years the town was bombarded, Etienne and Richard). A large series of experiments, notably those of Cannon 28 ENDOCRINE GLANDS and his co-workers, have shown the existence of a hyper- secretion of suprarenalin as a result of emotions. Changes in the adrenal secretion are liable to secondarily affect the secretion of the thyroid; these experiments have also shown a decrease in the secretion of suprarenalin by the inhibition of the gland in certain severe emotions. These facts, when related to clinical observations, allow us to agree with Laignel-Lavastine that emotions are liable to be the starting point of endocrine disturbances. What we know of the sympathetic and the part that it plays in the function of the vascular glands helps us further to under- stand this possible action. But as in all other cases in which emotions are blamed as a possible cause, the exact part played by them remains complex and hypothetical. It is often exaggerated and it is necessary in each case to deter- mine exactly the importance of the emotional element. _ THE EXAMINATION of patients suffering from Endocrine disturbances is taken up in the various chapters of this volume. Sometimes our attention is drawn by the alter- ation of the gland itself. The hypertrophy of the thyroid in certain cases of goitre makes us look for alterations of the gland. The absence of the testicle or their atrophy after mumps makes us look for bony changes or other signs associated with testicular insufficiency. The evidence of a cerebral tumor, associated with bitemporal symptomat- ic hemianopsia due to retro-chiasmic irritation, makes us think of a lesion of the pituitary causing the various symptoms associated with lesions of this gland. There are, therefore, two types of symptoms: signs of a tumor, or anatomical alterations of the endocrine glands, or of the surrounding tissues, causing secondarily symptoms of compression, or irritation and functional signs, showing the aberration of the secretions with exaggeration or decrease of the secretions. The first are usually easy to see, but THE SYMPATHETIC SYSTEM 29 may be absent when the second are present; these alone are sufficient to often suggest therapeutic intervention. The study of the thyroid shows numerous examples of this. The functional signs should always be looked for, whether the signs of ‘glandular anatomical disturbance are present or not. They seem to have a predilection for cer- tain systems. For instance, disturbances in growth, such as, dwarfism, gigantism, etc., are usually due to distur- bances of the sexual glands, the thyroid, the thymus, the pituitary. What I have previously said of the morpho- genic function of the endocrines, of their harmozones which regulate development, shows the primordial im- portance of disturbances of growth. It was believed, for a long time, that the thyroid alone was responsible for infantilism. We now know the part played by the pitui- tary, the thymus and possibly the pancreas. The part played by the pituitary and the thyroid on the genital glands and growth is well known. All disturbances of growth should suggest to the physician an investigation of the function of the endocrines. Outside of disturbances of growth, alterations of the bony tissues are often of endocrine origin. Acromegalia is an example of this, so is rickets, osteomalacia, and many other bony affections have been found to be of endocrine origin. Recently, Professor Hutinel has shown how the study of any dystrophy of the bones should suggest an investigation of the endocrine system. Articular alter- ations are sometimes related to a certain degree to endo- crine lesions; chronic rheumatism is often associated with thyroid insufficiency (Lancereaux, Paulesco, Souques and Sergent) and clinical investigations in some cases reveal the influence of the testicle, the ovary, the pituitary and other glands. Here again, we should not limit ourselves 30 ENDOCRINE GLANDS to the study of the endocrines and the possibility of ac- quired or congenital lues should be investigated. Disturbances of the genital organs, male or female, be they primary or secondary to a known endocrine lesion, should always lead to investigation of the possibility of the disturbance of some other endocrine gland. Precocious amenorrhea has often revealed an alteration of the thyroid or the pituitary. Impotence in the male, while it is often the result of some acquired testicular lesion is sometimes the sign of late infantilism of pituitary or thyroid origin. In the same way, the absence of develop- ment of the genitals in a young man is sometimes due to the thyroid or pituitary causes of infantilism. Inversely, hypersecretion of the ovary or hyperorchitis suggest adrenal or pituitary lesions and Harvier has brought to- gether the well-known facts of suprarenal virilism, hir- sutism or pituitary obesity with precocious development of the genital system. The various manifestations at the level of the skin or its derivatives is very important. Squamous skin, ichtyosis, wrinkled or senile skin, are symptoms of thy- roid insufficiency. Dryness of the skin, decreased or absent secretions have also been reported when there was a thyroid insufficiency. Attacks of sweating have inversely been noted in cases of hyperthyroidism. Pru- ritus, urticaria, circumscribed edema, certain eczemas are also manifestations of endocrine disturbances. Disturb- ances in the cutaneous pigmentation, and _ specially melanodermia are of great value as indicating some change in the adrenals. The loss of hairs, particularly the partial loss of the eyebrows has been given as an evi- dence of abortive myxedema (Leopold-Levi and Roth- child). This is also observed in certain affections of the pituitary. Inversely, we see an exaggeration of the de- THE SYMPATHETIC SYSTEM 31 velopment of hairs in certain cases of suprarenal virilism or hirsutism. ‘Teeth easily affected, or absent, belong to this same group of symptoms and in children the persistence of the milk teeth and the superposition of the two denti- tions is sometimes a sign of hypothyroidism as I have observed with Mrs. Long-Landry. The nails can be also’ altered striated, with many white marks, thin and easily breakable. The examination of the hairs, the nails, the teeth, added to that of the skin, is essential when- ever an endocrine lesion is suspected, particularly a thy- roid disturbance. Among the disturbances in nutrition which go hand in hand with changes of the skin and its derivatives, obesity, holds an important place as being one of the most fre- quent signs of endocrine disturbance. Be it associated or not with bone, genital or skin lesions, it has often been caused by an insufficiency of the thyroid. There are also more complex causes; that is, it may be due indirectly to an action on the genital glands by the thyroid. Next to the thyroid in frequency and possibly more often, the pituitary is involved. Occasionally the pineal and the adrenal glands are to blame. Certain syndromes, such as, Dercum’s disease appear distinctly as polyglandular syndromes, in which at least three glands are involved: ovary, thyroid and pituitary, and possibly, also the ad- renals. In all cases an endocrine disturbance should be suspected in cases of obesity, particularly if it shows evi- dence of partial obesity, be it painful or not. Obesity associated with thin limbs is very characteristic in certain adiposo genital syndromes of pituitary origin. Next to obesity, we must place diabetes mellitus, which often leads the way to the discovery of an endocrine disturbance. Next to pancreatic diabetes, clinically and experimentally, so clearly specific, there are diabetes due 32 ENDOCRINE GLANDS to thyroid disturbances. Glycosuria has frequently been noted during exophthalmic goitre. Other cases seem to bear some relation to disturbances of the pituitary, the occurrence of diabetes during acromegalia is not excep- tional; if at first the origin might be pressure on the floor of the third ventricle (Loed, Launois, Roy, Marcel Labbe), instead of a functional pituitary deviation, it is neverthe- less, occasionally a suggestive sign in divulging a pituitary lesion. Finally, adrenal diabetes has attracted consider- able attention and we recognize more and more the im- portance of this gland in the etiology of certain cases of glycosuria. The investigation of a possibility of glyco- suria, the appreciation of its degree and rythm can put us on the track of an endocrine disturbance. The relation of glycosuria to the injection of suprarenalin or pituitrin has suggested certain very interesting conclusions which in the future may be of considerable clinical importance. Diabetes insipidus, more so than diabetes mellitus, can have a clearly defined significance, and a series of recent studies has shown its value as an indicator of para or pituitary disease; the injection of thé extract of the pos- terior lobe of the pituitary will temporarily cause the polyuria to disappear in certain cases. Investigations should, however, be carried out on the possible influence of the nervous system, which has been brought out by the recent work of Camus and Rousey who were able to cause a polyuria by irritation of the floor of the 3rd ventricle. Intellectual and mental disorders should also be investi- gated. We have known for a long time that backward- ness, imbecility, idiocy, etc., have been recognized as be- ing the result of myxedematous hypothyroidism. This is also recognized as the cause of torpidity and sleepiness, mental instability and various psychoses occur quite often in Basedow’s disease. In the same manner, in acromegalia THE SYMPATHETIC SYSTEM 33 many cases have been reported suffering from melancho- lia, desire to commit suicide and, particularly, torpidity and mental confusion. Patients with Addison’s disease are sluggish; those with Dercum’s disease melancholic. Grouping together all these facts Laignel-Lavastine a few _ years ago was able to bring together the psychic disturb- ances and abnormality of the endocrines. These dis- turbances are, however, not sufficiently systematized to be as valuable indicators as changes in the skin, nutrition, etc. All that can be said at present is that in view of our ignorance of the cause of the development of certain in- tellectual changes, the investigation of disturbances of the endocrine may be of value. This is the case in the mental changes during puberty and the menopause and perhaps such an investigation may result in interesting therapeutic conclusions. Nervous symptoms; such as, epilepsy or tetany, are in certain cases indicative of endo- crine disturbances. Generalized tetany, as seen in infants, in pregnant women, and in adults, is probably an indica- tion of parathyroid deficiency, whether there is a de- ficiency of calcium or not. Another illustration of symptoms of endocrine origin can be found in cardio vascular symptoms. We have known for some time that hypotension and certain associated manifestations, such as, the white line of Sergent, have been considered as due to adrenal insufficiency. The prognosis of certain acute affections (scarlet fever, ty- phoid, etc.) has often seemed to depend on whether or not the adrenals were affected, so much so, that a real adrenal syndrome has been found in acute infections having as a starting point cardio vascular changes. Inversely, arterial hypertension seems in certain cases to be due to an in- crease in the adrenal secretion. Dr. Harvier has studied these various syndromes in this volume. We must, always 8 34 ENDOCRINE GLANDS be very careful in their interpretation, but it is certain that the investigation of the causes of disturbances in arterial pressure may be of value in endocrinology. It is not my intention to describe in this introduction all the symptoms and syndromes related to the pathology of the endocrines. Each day the list grows longer. Each organ of the body can furnish an example of it. Above everything else it is the disturbances affecting the mor- phology of the individual, by altering his nutritive 1eta- bolism, which have a diagnostic value, and it is, therefore, on these that we must insist. It goes without saying that a complete examination may reveal may others. Such an examination will bring out the whole syndrome of thy- roid insufficiency or hyperfunction. It will make the diagnosis of pituitary or adrenal lesions. Each gland has its own symptomatology and Dr. Harvier has very correctly insisted on these various suggestive syndromes. All do not have the same accuracy. For instance, the symptomatology of the thyroid is now very definite, thanks to the publications of Leopold-Levi and Rothchild, and is particularly easy to understand, due to the results of thyroid organo therapy. Pituitary symptomatology is beginning to be better known, but adrenal symptomatol- ogy has not yet been definitely defined. The respective parts played by the glandular and by the sympathetic nervous system disturbances are hard to judge even in cases of Addison’s disease. Arterial hypotension which invariably results in adrenal insufficiency can be due to so many different causes that alone it cannot be consid- ered as indicative of adrenal insufficiency. For this reason, it would be very important during acute or chronic diseases to have definite signs of the functional capacity of the various endocrine glands, to be able to have endocrine tests similar to those performed in pathological THE SYMPATHETIC SYSTEM 35 conditions of the kidney and liver. In the same way, it would be very useful to have various signs to enable us to define the intervention of the sympathetic nervous system in the symptomatology under observation. At the present time our observations are still very indefinite. It is only fair to say, however, that the injection of suprarenalin and of pituitrin (posterior lobe) has been tried lately and has often given very interesting results. Not only has the subcutaneous injection of suprarenalin cardio vascular effects, which have been known for many years, but it can, with or without the injection of sugar give a glycosuria more or less marked (Blum) accompanied by a hyperglycemia, the significance of which has been very much in dispute. Somewhat similar to this supra- renalin glycosuria is pituitary glycosuria which was dis- covered by H. Claude and A. Baudouin. They consider that glycosuria is a normal consequence of an intra- muscular injection of the posterior lobe of the pituitary, previously purified and the lipoids having been removed, provided it is followed by a meal containing sugar (pre- ferably one half hour afterwards); this glycosuria is noticed particularly in patients suffering from arthritis, is absent in tuberculous individuals and is more abundant than suprarenal glycosuria under similar conditions. To this glycosuria are added cardio vascular phenomena stud- ied by H. Claude, R. Porak and Routier and consist in more or less marked changes in the tension of the pulse. H. Claude, together with R. Porak, has recently tried to make biological tests of these re-actions of suprarenalin and pituitrin so as to be able to bring out lesions of these glands in mixed glandular syndromes. For instance, the glycosuria and cardio vascular re-actions, following the injection of pituitrin are absent in acromegalia. In patients with Basedow’s disease, the cardio vascular re-actions are 36 ENDOCRINE GLANDS exaggerated after the injection of suprarenalin or pituitrin. In thyroid insufficiency the glycosuria and the drop in systolic pressure are normal, but the acceleration of the pulse occurs instead of slowing. In patients with Addi- son’s disease there will be no glycosuria and the systolic pressure will rise instead of going down. Without doubt it is too early to deduct from these tests, definite conclusions. They are liable to occur in transi- tory endocrine disturbances after infectious diseases, for instance, without this being an indication of any perma- nent lesion of the gland. Nevertheless, they are liable to give us some idea of the endocrine equilibrium and when we understand these reactions better we probably will be able to refer to them clinically to help us in diagnosis. These tests, furthermore, bring out the intervention of the sympathetic. It is the stimulation of this system which after the injection of pituitrin inhibits the fixation of glucose by the liver, its stimulation seems to play a part in certain of the effects of suprarenalin. Lately, the in- jection of suprarenalin has been used as a method of show- ing up excitability of the sympathetic. Dr. Harvier has gone over in detail the various plans of this subject, partic- ularly those of Eppinger and Hess on the injection of suprarenalin on one side and atropin and pilocarpin on the other. The injection of suprarenalin is inactive in some, in others it causes an increase in the blood pressure; tachy- cardia, polyuria, glycosuria with or without the previous injection of glucose, dilatation of the pupil, etc. It stimu- lates the sympathetic and such individuals are called sympathicotonic. Pilocarpin inversely, in predisposed individuals, causes a marked tachycardia, sweating, salivation, nausea, vomiting, spasms of the intestines, colic and diarrhea. In others, it is without effect. It stimulates the vagus nerve in the first type of case, which THE SYMPATHETIC SYSTEM 37 is called vagotonic. In the same manner atropin paralyzes the vagus and in sympathicotonic individuals will cause a tachycardia, dilatation of the pupils, dryness of the mouth, ete. This division of patients into vagotonic and sympa- thicotonic has been further investigated during the last few years. The oculo cardiac reflex is a great aid in this respect. When positive, that is, when there is slowing of the pulse after ocular pressure, it indicates vagotonia; negative, that is, when there is an acceleration of the pulse is considered to be a sign of sympathicotonia. In spite of a certain reservation which we must make for this test it is, nevertheless, a very useful sign whenever we are investigating the sympathetic system. — The study of the sympathetic is extremely fruitful and complex and recent investigations indicate how much our knowledge is increasing every day. It is, however, dif- ficult to determine its limits. The nervous system of vegetative life can be affected in many ways, often by the intermediary of a gland of internal secretion. Actually, as Dr. Guillaume has described, it consists of the true sympathetic and the cranial and pelvic parasympathetic system. It is in the cranial parasympathetic that we must include the vegetative fibres annexed to the vagus which exert their action on the respiratory system, the gastro intestinal tract and its adnexa and the heart. It is by the intermediary of these fibres that the association reflex, such as, the oculo cardiac reflex occur.. It is also the case in these reflexes showing the connection between the nuclei of the vagus and the general sensory tracts or those showing the functional sympatehico-parasympathetic mechanism. These examples show how many symptoms can result from disturbances of the normal mechanism of the sympathetico-parasympathetic apparatus. In the 38 ENDOCRINE GLANDS cases in which the equilibrium between these two systems is normal there are some (among which are the vagotonics we have previously referred to) which show a hypertonia of the parasympathetic which is discussed by Dr. Harvier in this volume. They have a slow pulse, myosis, sunken eyes, are pale, have abundant and easy perspiration, hypersecretion of saliva, bronchial and intestinal secre- tions. Pilocarpin exaggerates these symptoms. The oculo cardiac reflex indicates a hypertonia of the vegeta- tive vagus system and numerous other symptoms also indicate this. Others have hypertonia of the sympathetic which manifests itself by protrusion of the eyeballs, mydriasis, warm skin, tachycardia, decrease in secretions, slowing down of digestion, contraction of the sphinxters resulting in constipation. Secondarily, the suprarenal and thyroid secretions are increased and cause various phenomena. These individuals react to certain pharma- cological substances, notably suprarenalin, which some- times brings out certain confuse symptoms. These two syndromes are, however, not always dis- sociated clinically. We can have a resulting syndrome of hyperactivity of the two systems, with neutralization in antagonistic territories corresponding to what Hess and Eppinger have described under the name of vagotonia. It is better defined, as suggested by Dr. Guillaume, under the name of neurotonia (meaning hyperneurotonia). This neurotonia syndrome groups together a number of sick people, nervous system invalids, which complain of gas- tric disorders, cardiac disturbances, and various symptoms of neurasthenia. The investigation of the various reflex reactions is a great help to prove the existence of this syndrome. The oculo cardiac reflex is positive; atropin, pilocarpin and suprarenalin cause suggestive symptoms in THE SYMPATHETIC SYSTEM 39 these subjects. To understand this syndrome all that is necessary is to notice the symptoms which accompany emotions; the emotional neuro vegetative phenomena being neurotonic. The patients, which Dupré had in mind when he studied the emotional constitution, certainly were neurotonic. In the gastric neurosis we also find many examples of neurotonic individuals; that is, disturbances due to modification of the two nervous systems of vege- tative life. We see without insisting further, the multiple clinical manifestations which may result from disturbances of the nervous system of vegetative life. These also result in re- actions far away; reflex, neuralgia, tonic disturbances, symptomatic visceral affections and many others. In spite of the many. new discoveries relating to the pathology of the sympathetic, its symptomatology is still extremely obscure. The conception of neurotonia and of the balance which normally exists between the sympa- thetic and parasympathetic system certainly helps us in analyzing clinical facts. These can still better be inter- preted, thanks to the various reactions we have mentioned (oculo cardiac reflex, atropin, pilocarpin or suprarenalin tests). It is to be hoped that in the near future the physio pathology of the sympathetic system and its symptomatology will be possible to study from a practical point of view. At the present time, we limit ourselves to the observation of the effect of certain endocrine disturbances on the func- tion of the sympathetic and parasympathetic and the no less definite action of these systems on the endocrine glands. We must, however, remember that there are direct con- nections between the endocrine glands without the inter- vention of the nervous system, so that functional alter-. 40 ENDOCRINE GLANDS ations of a gland may occur without the intervention of one of these systems.* From what I have just said we see that the clinical study of the patient allows us, by the investigation of a series of symptoms, to look out for the possibility of some endocrine alteration, to sometimes fix the chronology of the various accidents and to reach certain therapeutic conclusions. Very happily, the treatment of patients has very largely benefited by these progresses in clinical investigation. The conception of the part played by the sympathetic and the parasympathetic, is very important and there is no question but that many therapeutic effects are exerted by the intermediary of this nervous system. It is, therefore, to be hoped that the progress in endocrinology and the study of the sympathetic, will enable us to better under- stand the neuro glandular disturbances allowing us to appreciate better the therapeutic indications and the most efficacious method by which these can be employed. III. GENERAL THERAPY OF DISEASE OF THE ENDOCRINES. In the preceding chapters I have brought out the well- established action of certain glands in the etiology of certain definite diseases: the thyroid in myxedema and exophthalmic goitre, the pituitary in acromegalia, the adrenals in Addison’s disease. I have also shown, next to these fairly simple examples, others more complex, in 1]t is well to remember that the part played by the nervous system is much more extensive than is at present admitted in the production of symptoms which are be- lieved to be of endocrine origin. Recent experimental researches as well as anatomical and clinical observations seem to show that the symptoms, believed to be due to pitui- tary lesions (polyuria, adiposes, infantilism) can be produced by purely nervous lesions of the floor of the third ventricle (Camus and Roussy). A case of so-called pituitary infantilism, on which an autopsy was performed in front of the writer and Dr. Cathala and Mouzon, showed a normal pituitary,while there was a tumor of the third ventricle. It is therefore possible that endocrinology, while correct as a whole, may have to be . revised as to its details. THE SYMPATHETIC SYSTEM 41 which the action of the endocrine glands was exerted on other glands. Such is the case of infantilism which may result from the effects of the thyroid, or the pituitary on the genital organs. There are other cases in which several endocrine glands are simultaneously affected, bringing on pluri-glandular syndromes, the clinical explanation of which varies: obesity of the menopause, Dercum’s disease, sclerodermia, certain types of senilism or of genito- dystrophic gerodermia, are examples of these types of cases. Whether we are dealing with such cases or others apparently simpler, we must not forget the part played by the sympathetic nervous system, which is very evi- dent in certain diseases (Addison’s), but more obscure in others. Clinical investigation allows us to bring out certain alterations of the endocrine glands, but what is often not brought out is the nature of the functional glandular dis- turbance, which causes the symptomatology: insuf- ficiency, aberration, hyperfunction. I have already said how difficult it was to decide and how very careful we must be of our interpretations, always, however, remembering the importance of aberrations by insufficiency which are particularly efficaciously treated therapeutically. Finally, we must remember that in endocrine pathology, outside of new growths a large place must be kept for inflammation, and that rheumatism, tuberculosis and syphilis are often the cause. The pathology of the thyroid, of the pituitary and of the pancreas shows numerous examples of this. The possi- bility of a luetic infection must be remembered and may be very useful when the question of treatment comes up. Our therapeutics can be etiological and aim at treating the disease which has caused the inflammation of the endocrine glands. It can by radiology, or by surgical inter- 42 ENDOCRINE GLANDS vention attempt to act directly on the diseased gland. It can finally attempt to supplement or stimulate deficient functions, and more rarely inhibit them. I. ETIOLOGICAL TREATMENT. However logical this method may appear, it is only rarely indicated. Naturally, when lues is the etiological factor, antisyphilitic treatment should be attempted; while recommended in thyroid and pituitary affections it has, however, only a limited effect, limited by reason of the lesions which must be remedied. When destructible, it cannot, even when healed, bring back the regeneration of the organ; gumma of the thyroid, of the pituitary leave sclerous lesions, which are incompatible with a normal function of the gland. The treatment, moreover, cannot change certain lesions in the neighborhood, such as, alter- ation of the chiasma of the optic nerves which is so often noticed following affections of the pituitary. In spite of its limited effect, antiluetic treatment should always be attempted whenever a syphilitic origin is suspected, associated with organo therapy it seems to definitely help in improving the condition in many cases; its action has been noticed in certain cases of myxedema due to a thyroiditis of specific origin. It seems to act in the same way in certain syndromes of pituitary origin, if not on the pituitary lesion at least on the meningitis, which is often associated with it. In other cases anti-rheu atic treatment will be beneficial. Sodium salicylate has been specially recommended in exophthalmic goitre. It cer- tainly is a great help in many cases. Since Chibret and later Babinski have advised its use; it has been admin- istered in much larger doses and not simply as an anti- rheumatic agent. In the same manner quinine plays a part in endocrine therapy and we cannot say that its use THE SYMPATHETIC SYSTEM 43 should be limited only to cases of malaria. Tuberculosis sometimes causes endocrine manifestations and this fact may be of value in certain therapeutic indications. In spite of all this, etiology does not help us very much in the treatment of these patients and the knowledge that we are dealing with functional disturbances by deficiency or excess, which we must attempt to modify, has done much to bring about a marked improvement in the condition of our patients. Il. SURGICAL TREATMENT. Surgical interference is rarely indicated in endocrine pathology. There are, however, certain definite cases in which it is of great help. We have known for many years the surgery of the thyroid. At first, limited to simple goitre and tumors, it has now extended to exophthalmic goitre and if intervention is still often questionable, be- cause of the danger, it can be considered as rational in certain cases, as for instance, those recently studied by Roussy. ‘ The facts established show that while there is no question of the benefit of partial thyroidectomy in Base- dow’s disease, it has also its drawbacks. Thymectomy has also been performed with variable success, with or without thyroidectomy. In hypertrophy of the thymus in childhood, for a while surgery of the thymus became popular as a result of the investigations of Veau, but it is now limited to very rare cases. The surgery of the pituitary has been even more care- fully studied and we are still far from having perfected it. The recent investigations in France of Lecene, Toupet and Lenormant have shown that the pituitary could be reached through the nasal route and that its removal in man was possible. The results are, however, far from what was expected after the first few cases were pub- 44 ‘ENDOCRINE GLANDS lished. It seems as if this very dangerous intervention, which is advised in acromegalia and patients suffering from adiposo genitalis, is only indicated when, to the symptoms of pituitary disturbance, are added serious evidences of hypertension (headache, alteration of vision), and when the X-ray also shows a marked enlargement of the sella tursica. The removal of the pituitary is never complete; it is necessarily a partial operation and is purely palliative. It seems as if in certain cases all that is done is to decom- press the affected region. The recently published obser- vations of Lecene and Morax verify this hypothesis, as by causing a falling down of the deep wall of the sphenoidal sinus, that is, the floor of the sella tursica, without touch- ing the pituitary, Lecene was able to cause the disappear. ance of an adiposo genitalis syndrome, associated with marked signs of hypertension, notably ocular disturbances with changes in the disks, which were also improved by the operation. A simple decompression has occasionally given similar results. Pituitary surgery, therefore, is still a method only to be used exceptionally, and aims more to relieve hypertension than the pituitary lesion. However, the results of decompression of the sella tursica, as per- formed by Cushing and Lecene, show that this method might be used in certain cases. However limited at present is the surgery of the endo- crines, it is indicated in removable tumors, (certain thy- roid tumors for instance) or to modify the consequences of certain neoplasms which, as in the case of the pituitary, cause secondary symptoms by direct pressure or by hyper- tension. It cannot be said, however, that endocrine surgery is a method we can hope very much from in the future, since it can only act in tumors and their conse- quences. It cannot remedy a glandular deficiency, the usual result of an endocrine lesion. THE SYMPATHETIC SYSTEM . 45 Its usefulness in certain disorders of sympathetic origin is also limited. However interesting might be the inter- ventions attempted in the past by Jaboulay and Jennesco, of resection of the cervical sympathetic in exophthalmic goitre, less severe methods will probably give better results. Ill. TREATMENT WITH X-RAY. The glandular cells are susceptible to the X-rays and these can decrease their function. This is, however not, without certain drawbacks and a classical case hes shown the etiological influence of radiotherapy, directed against hypertrichosis, in producing manifestations of myxedema, previously modified by thyroidien organo therapy (Acch- iote). This is not an isolated case, and such facts sug- gested that these rays might be usefully employed in cases in which hyperfunction of certain glands was suspected. X-ray has been used for many years in the treatment of fibroma and it was believed that its action on the ovary by causing premature menopause, would modify this condition. This theory has been found to be incor- rect, for we know now that radiotherapy has a direct ac- tion on the fibromatous tissue. It is, nevertheless, true that X-ray causes a decrease, then a cessation of the periods and anatomically brings about a degeneration of the Graafian follicles, while in man it will stop the evolu- tion of the spermatozoa. The atrophic action of the X-rays has been tried on the thyroid, in cases of exophthalmic goitre and very variable results have been obtained. In 1911 P. Marie, Clunet and Raulot-Lapointe by using large doses of very hard rays, obtained remarkable results, as regards the con- stancy and regularity of the evolution of the phenomena observed. However, not all cases are improved and 46 ENDOCRINE GLANDS radiodermia, which is particularly liable to occur on the neck, is often an obstacle to the use of this type of treat- ment. For this reason, this procedure is not the method of choice; furthermore, hyperfunction is not the only cause of Basedow’s disease and the theory of dysthyroidism possibly explains some of the failures of the method. The pituitary seemed to be susceptible to the X-rays and Beclere has advocated its use in certain cases of acromegalia. The few cases in which improvement was observed allow us to believe that it may be possible to stop the early evolution of acromegalia and gigantism by rad- iation, and that it might also be possible to modify some of the symptoms of adiposo genitalis with ocular symp- toms. Unfortunately in such cases, there is such a mixture of symptoms of insufficiency and hyperfunction that we cannot expect much from radio therapy, which is, moreover, difficult to apply and if Beclere, Jaugeas and others have reported favorable results, here again, as in exophthalmic goitre, we must abstain from any premature conclusions. Zimmern and Cottenot have thought that the adrenals could be affected in a similar manner. They believed that hypertension is often of adrenal origin, and that radio therapy of the suprarenal capsule through the lumbar region might be beneficial. This method, while without any effect in cases of arteriosclerotic or albuminuric hyper- tension, seemed to have improved real cases of uncompli- cated hypertension and to have markedly reduced the arterial pressure. This method has been experimentally controlled by Zimmern and Cottenot, which has enabled them in dogs to cause destructive alteration of the medulla and of cortex of the adrenals. Here again, however, we are dealing with inconstant results which we must accept with considerable reserve. These examples to which we must add the thymus, very THE SYMPATHETIC SYSTEM Aq easily affected by radiology according to Regaud and Cremieux, show that this method can be of value in cer- tain cases of hypertension. This method should only be used as an adjunct to other procedures more liable to modify the glandular disturbances. It is to organo therapy that we must look in most cases as the method most liable to bring about results. IV. ORGANO THERAPY. This method is based on the use of the juices and ex- tracts of tissues and has as chief aim, to remedy the ab- sence or hypofunction of an organ, by means of extracts of similar organs taken from animals. The extracts of organs have been utilized since antiquity, but it is only since Brown-Sequard and the first investigations of the treatment of myxedema with thyroid extract that organo therapy has become of any real value. Dr. Carrion and Dr. Hallion have covered this subject very thoroughly in this volume, so that there is no necessity to go into any detail. Organo therapy can be accomplished in many ways. Milk and eggs can sometimes be considered as organo therapeutic products. In the same manner, certain prod- ucts, such as, bile, gastric juice, are often utilized; in other cases, the active principle isolated from a gland is used. The typical example of this being suprarenalin, but it is chiefly the organs themselves, either fresh, or their extracts, obtained in various ways which constitute the majority of organo therapeutic products. When we are using them, it is well to know what to expect of them and to be warned against certain errors in interpreting their action. Thyroid organo therapy, which is so remarkably efficacious in myxedema has allowed us 48 ENDOCRINE GLANDS to discover a triple action: substitute, homo stimulating and symptomatic. The substitute action consists in that the extract which is administered substitutes its action for that of the deficient organ. In congenital myxedema due to agenesis of the thyroid, the extract takes the place of the absent thyroid. The homo stimulating or auto restorative action is also easily understood; if the extract is administered when the gland is only partly destroyed it can help in the re- building of the organ and stimulate its function. This is so in quite a few cases of thyroid insufficiency. To these two modes of action which can be termed spe- cific, we can add a third which we must always keep in mind when we are watching the effect of organo therapy. An extract of an organ, like all other organic or mineral medication, has a pharmacodynamic action peculiar to it. As such it can be employed symptomatically to bring out new symptoms or suppress pathological ones; the pituitary furnishes an example of this type of action. We use pitui- trin to accelerate labor or to increase intestinal peristalsis. Basing himself on the symptomatic action of these extracts, Gley has very rightly criticized the conclusions which are reached on the action of certain extracts of organs. In spite of this, symptomatic organo therapy has a big field of action and thyroid extract in small doses has shown its value in a multitude of cases. It seems difficult, however, in the great majority of cases, not to believe in the substitute or homo stimulat- ing effect of organo therapy. The recent investigations of J. J. Huxley on the acceleration of growth by means of very small doses of thyroid to tadpoles, his investigations on the axolotl of the salamander under the influence of the same medication show how pronounced is the action of thyroid on the phenomenon of growth. This action THE SYMPATHETIC SYSTEM . 49 seems to be really a substitute one or even homo stimu- lating. In the same manner the very definite effect of pituitrin in diabetes insipidus cannot be considered as purely symptomatic. It only manifests itself in the case in which other signs point to a pituitary cause for the polyuria. In other cases there is absolutely no effect. It seems difficult in such cases not to believe that there is a specific action. In the same manner in suprarenal organo therapy the action is far from being purely symptomatic and predominately cardio vascular. In many cases the blood pressure is hardly affected and it is chiefly in the cases of suprarenal insufficiency that the changes are noticeable. In all the cases of endocrine disturbances, in which some of the symptoms are clearly due to glandular hypofunc- tion, substitute or homo stimulating organo therapy is therefore indicated. This is so in the case of thyroid medication in myxedema, suprarenalin in Addison’s di- sease or adrenal insufficiency and ovarian medication in natural or artificial menopause. Inversely, when hyperfunction or aberration of func- tion with exaggeration of secretion is suspected, such type of medication would be detrimental. We know, for instance, the bad effects of thyroid medication in exoph- thalmic goitre. We can, however, to a certain extent rely on inhibitive organo therapy. This is the method which has led Ballet and Enriquez to use the blood of de- thyroided animals on the treatment of exophthalmic goitre, or which we employ when we give pituitary extract in the same disease. As the physiological action of the various endocrine glands is better known and their inter- glandular relation is better understood, such type of organo therapy will be used more frequently, and will become more definite. Already the theory of glandular 4 50 ENDOCRINE GLANDS hormones has enabled us to understand how certain types of organo therapy exert a stimulating action on other glands than the ones injected. If the conception of Chalones suggested by Scheefer is ever proved; if it is ever established that certain endocrine glands, have under certain conditions an inhibitive effect on other glands, then the therapy of glandular hyperfunction or dyshyper- function will have made a great step forward. This chapter is, however, only at its beginning. There are cases, becoming more and more numerous, in which, organo therapy must be complex. I have already insisted too much on the importance of polyglandular syn- dromes and the frequency of a simultaneous alteration of several glands, to say more on this subject. We must oppose an associated organo therapy to multiple func- tional disturbances. In some cases, it is best to give each one for a certain period, in other cases the extracts of various glands should be given simultaneously. I find more and more, that I have to use preparations containing a combination of: thyroid, pituitary, ovarian and adrenal in varying proportions. When administered in syndromes, such as, Dercum’s disease, glandular obesity, sclerodermia, certain cases of infantilism, etc., these organo thera- peutical preparations seem to act very favorably. It even seems as if thyroid medication was better tolerated when combined with either adrenal or pituitary extract. When medication has to be carried out for a long period of time the association of these extracts is particularly indicated, We must finally remember that the good or bad results of organo therapy can occasionally help us in diagnosis; this has been established by Gilbert and Carnot. It is by means of this method that Leopold Levi and H. de Roth- schild have shown the numerous consequences of a mild thyroid insufficiency. It is, also, by this method that the THE SYMPATHETIC SYSTEM 51 part played by the liver and pancreas in the production of diabetes has been established by Gilbert. No doubt we must, as suggested by Gley, Camus and Rousey, make certain reservations on the significance of the results of therapeutic investigations by these extracts. It would however, be unfair not to believe that they have at least some value. Simple or complex organo therapy has lately given re- markable results, and each day we see new indications arising. It, however, necessitates a definite technique and careful watching. The many accidents resulting from excessive or irrational thyroid medication is well known; in the same manner suprarenal medication is not without its drawbacks. The various methods of administering these extracts either by mouth or subcutaneously, deserve a certain amount of study, but Dr. Carrion has covered this subject very carefully so that it is not necessary to go into details. All that I will say, is that at the present time, dried extracts are far superior to fresh ones, except in certain exceptional cases. We must remember that the preparation of these products is very delicate and for this reason only reliable products should be employed. The mode of administration, according to the extract employed, has a considerable importance. Oral adminis- tration is the simplest method, and in prescribing thyroid * or ovarian extract, no other way need be used. The con- stant results obtained by this method of administration has been proved in many cases. The report of Murray on a case of myxedema who was kept in good health for 28 years by the ingestion of thyroid extract by mouth shows this well. It is, however, evident that other products are less active when administered in this manner; certain - gastro intestinal juices seem to affect them, for instance, pancreatic extracts are affected by the gastric juice. 52 ENDOCRINE GLANDS Attempts have been made to get around this by surround- ing the extracts with gluten, wax or keratine, without however obtaining constant results. Rectal administra- tion has been advocated and it seems as if macerations of fresh organs (liver or pancreas) have a real activity. This method, however, cannot be used for constant medication. It is administered at bed time and laudanum is added to it so as to prevent its expulsion. Subcutaneous injection was for a long time believed to be impossible, because of the drawbacks resulting from the administration of albuminoid materials under the skin. We now know that we can administer under the skin, without any inconvenience, certain preparations, from which the lipoids have been removed and which have been sterilized. The thermostable substances which they con- tain, still retain a certain number of characteristics. If such a method is without value in the case of the thyroid, it is very useful in the administration of pituitrin or supraren- alin. In certain severe anemias, the extract of bone marrow seems to act very quickly and very definitely. It is, there- fore, not always advisable to abstain from administering endocrine products subcutaneously. The only method which should be avoided is the intravenous route which sometimes will cause severe accidents. In spite of this, it has occasionally been recommended to administer in- travenously the posterior lobe of the pituitary is hemop- tysis. I believe that it is safer not to do so. Organo therapy when properly administered has given remarkable results, providing it has been given regularly and over a long enough period. Too often the diagnosis of an endocrine lesion is associated with that of some organic lesion which cannot be cured or modified very much. Organo therapy, which is the treatment of func- tional disturbances, can ameliorate the symptoms. It can THE SYMPATHETIC SYSTEM 53 even modify them by changing the functional disturb- ances. Thyroid medication has shown this clearly. Perhaps less striking are the results of adrenal medications in diseases of the adrenal glands. Pituitary medication has also given excellent results. The action of mixed organo therapy has proved itself in many cases of poly- glaridular syndromes and the fact that the medication must be kept up is not an argument against the value of this type of treatment. It certainly is a fact that by this type of medication results are obtained which otherwise would be impossible. Unfortunately, the dose to use and the procedure to follow varies in every case. Due to the lack ‘of familiarity with the pathology of this subject, many physicians neglect cases which could be benefited by this mode of treatment. By explaining the pathology and showing the various therapeutic indications of endo- crinology, Dr. Harvier has enabled the physician to detect the various types of cases which might be helped by this form of treatment. THE PATHOLOGY OF THE ENDOCRINE GLANDS By Dr. P. Harvier Physician to the Paris Hospitals, PATHOLOGY OF THE THYROID. FUNCTION OF THE THYROID. The thyroid is a gland surrounded by a fibrous capsule from, which partitions arise which divide it in lobes. Each one of these lobes contains a series of closed vesicles, of various sizes, and without any excretory canal. The walls of the vesicles are lined with epithelium, made up of two types of cells: the main cells, which have a round nucleus with a clear protoplasm and colloidal cells, which are polymorphous, have an oval nucleus and a protoplasm filled with acidophil or basophil granulations. The cavity of the vesicle, oval, or spherical, contains a thick secretion, more or less yellow, which has been termed colloidal substance. The secretion of the thyroid is made up of several prod- ucts, the most important of which contains iodine. Chemists have extracted it from the colloid and Baumann has designated it under the name of Iodothyrin. We know to-day that Iodothyrin is only one of the compon- ents of the thyroid secretion and that it is furthermore an artificial product, not well defined, and made up of several compounds. According to Oswald, the colloid contains at least two substances: 1—A globulin or thyroglobulin which contains all the iodine of the gland as an organic compound and from which iodothyrin is derived; 2— A nucleo protein, which does not contain any iodine, but instead other minerals, phosphorus and arsenic in particular. Iodine when introduced into the organism is fixed by the thyroid. The quantity varies in each species and in each individual according to the food. It cannot be con- sidered as an index of the activity of the thyroid. 57 58 ENDOCRINE GLANDS The functions of the thyroid have been elucidated by the observation of the various phenomena following the extirpation of the thyroid and by the physiological effect of the thyroid extract and finally, by the results obtained by giving experimentally excessive doses of thyroid. I. PHENOMENA FOLLOWING THE REMOVAL OF THE THYROID. In animals thyroidectomy produces two _ types of phenomena: 1.—AcutE Symptoms which consist of post operative tetany and are due to the simultaneous extirpation of the parathyroid glands. 2.—CHRONIC SYMPTOMS are the only ones which are really due to thyroid insufficiency. They are particularly marked in the young during the stage of growth. The de- thyroided animals are small and deformed, as compared to the controls. Their skin is infiltrated with an indurated ‘edema; at the same time it becomes dry, wrinkled squamous, the hairs lose their brilliancy, and fall out. The growth of bone is stopped and the genital organs (testicle or ovary) become atrophic. These animals become sad, slow, apathetic and appear idiotic. These accidents occur the more rapidly if the animal is young. The thyroid gland, therefore, secretes a substance neces- sary to the organism; the absence causes the appearance of trophic symptoms. If in a dethyroided animal a graft of thyroid gland is made or it is given the extract of thy- roid, these accidents are avoided. II. PHYSIOLOGICAL ACTION OF THYROID EXTRACT. Thyroid extract has a very definite effect on the blood pressure, the cardiac rhythm and nutrition. Schaefer in THE SYMPATHETIC SYSTEM 59 1895 showed that the intra venous injection of thyroid extract caused a drop in the blood pressure. Heinatz noticed the marked acceleration of the heart and pulse following its injection. All the observations concerning the action of thyroid extract agree that there is a loss of weight following the injection of thyroid, even when the food is abundant and at the same time, there is an increase in diuresis, and of elimination of urea and nitrogen. Ill. EXPERIMENTAL HYPERTHYROIDISM. Ballet and Enriquez by having animals absorb large doses of thyroid were able to observe a syndrome of hyper- thyroidism characterized by tachycardia, fever, nervous disturbances (restlessness and tremor), followed by loss of weight and diarrhea. All these physiological and experimental facts allow us to interpret the various syndromes of hypersecretion, and insufficiency observed in man. CHAPTER I. I. THYROID INSUFFICIENCY SYNDROMES. An insufficiency in thyroid secretion results in a series of dystrophic conditions known under the name of myx- edema. 1, - ADULT MYXEDEMA. This condition was described by Gull (of London) in 1873 under the name of cretinism. It was studied by Ord who suggested the name of myxedema, then investigated in France by Morvan and by Charcot. It occurs between the ages of 30 and 60, more frequently in women than men, usually as a result, sometimes a long time afterwards, of some infectious disease; articular rheumatism, typhoid, scarlet fever, etc., which has af- fected the thyroid and altered its secretion. The condition begins very insidiously and is at first marked by fatigue, weakness, persistent anemia and a gradual intellectual stupor. It is finally characterized by three important symptoms: infilération of the tissues, atrophy of the thyroid and mental degeneration. ; 1.—INFILTRATION OF THE TissuES.—The appearance of the patient is typical. “‘ Considered as a whole, the face is large and round, resembling a full moon,” according to the descriptive report of Gull. “‘The lids are infiltrated and cover the eyes so that they appear smaller; the nose is enlarged, the lips thick and protruding, the forehead and the ears are wrinkled, the cheeks are puffed and flabby. This tumefaction of the face is associated with changes in the coloring; the skin has a yellow waxy pallor with a marked redness of the cheeks and a slight cyanosis 60 THE SYMPATHETIC SYSTEM 61 of the lips. These changes cause the face to appear de- formed and monstrous and give an appearance of stupidness which causes the condition to be characterized as cretinoid.’’ (Souques). Fia. 1.—Myxedema (Infroid collection). This infiltration is not only present in the face, but invades the whole body. The skin has a pale yellow ap- pearance. The supraclavicular, axillary and inguinal hollows are filled in. The limbs appear to be infiltrated with a hard elastic edema, which does not keep the impres- sion of the fingers. The hands and feet are enlarged and thickened and have a spade-like appearance. The fingers 62 ENDOCRINE GLANDS are thick, sausage shaped and cyanotic, and the patients have some difficulty in moving their limbs or performing delicate movements with their fingers. The skin is not only infiltrated but dry and coarse (whence the name of pachydermic cachexia suggested by Charcot). Sweating is abolished. The hairs become dry, break off and fall out in the temporal occipital regions. There is often a falling out of the eyebrows, eyelashes and hairs of the arm pit and pubis. The nails become fragile and striated longitudinally. Similar changes take place in the mucosa. The tongue thickens and moves with difficulty; the teeth loosen up in the tumefied gums; the voice becomes weak, due to the infiltration of the laryngeal mucosa. 2.—ATROPHY OF THE THyroip.—At the beginning it is possible to notice a transitory swelling of the thyroid preceding the atrophy. This occurs as a rule after a certain time. The infiltration of the tissues renders the palpation of the gland very difficult. 3.—MeEntTAL CHancses.—The patient with myxedema is in a state of stupor and apathy; he stays motionless and isolated, indifferent to all that is going on; he avoids moving and walks very slowly. He is incapable of keeping his attention on anything or to exercise his memory. He looks stupid and answers questions in a slow and monotonous voice. Some.cases have, an unconquerable desire to sleep and do so anywhere. 4.—SreconDARY Symptoms.—These patients complain all the time of being cold; in winter they stay near the fire covered with blankets and their feet on hot water bottles; in summer they wear an excessive amount of clothes and stay in the sun all the time. Their body temperature is lowered and can be below 36° centigrade. The heart sounds are muffled; the pulse is small and THE SYMPATHETIC SYSTEM 63 the blood pressure below normal. The reflexes are weak and the cutaneous sensation somewhat dulled. Nutrition is slowed down, although the digestive functions are normal and the appetite is good; these patients have a dislike for meat. The urines contain very little urea or uric acid. Genital disturbances are constant: in the male sexual frigidity is the rule. The majority of women with myxedema cease to menstruate; in some of them, however menstruation keeps up and an intercurrent pregnancy may bring about a temporary improvement of the symptoms of myxedema. The examination of the blood reveals a certain amount of anemia; decrease in the red cells, and in the percentage of hemoglobin. An increase in the diameter of the red cor- puscles and the presence of nucleated cells characteristic of the blood picture of children, is often noticed. (Vaquez). 2. MYXEDEMA IN CHILDHOOD. This disease was described by Bourneville in 1880 under the name of myxedematous idiocy, and can be congenital or acquired. 1.—ConcenitaL Myxrepema.—It becomes evident from birth or a few months afterwards. It is due nearly always to an absence of the thyroid. If the gland does exist it is only made up of pea-shaped nodules. We do not know in the majority of cases the cause of athyroidism: tuberculosis, alcoholism, syphilis in the parents are the only hereditary stigma which occasionally are found. The myxedematous new-born child shows a character- istic appearance, which enables us to make the diagnosis on first sight; the head is large, round, close to the shoulders; the forehead is low and narrow, the eyelids swollen, the nose short and broad, between two flabby 64 ENDOCRINE GLANDS cheeks. The lips are thick and droop. The tongue is enlarged, cyanotic and protrudes from the mouth, from which saliva drools all the time. The facial deformity gives an appearance of apathy and stupidity. The skin is pale yellow, thick and coarse to the feel. The thorax seems crushed between the large head and the prominent abdomen. The skin of the thorax shows the same characteristic pallor and thickening; it forms rolls and wrinkles in the flanks. The limbs seem enormous, especially at the level of the hands and feet which are thickened cyanotic and infiltrate with an indurated edema. The hairs are dry and break easily; the nails are striated and badly formed; the voice is hoarse and nasal. The examination of these patients reveals a defective nutrition and circulation; the pulse is small, imperceptible; the respiration short; the body temperature below normal: 35 or 36 degrees centigrade. Coming on at an age when the body is in process of growth and when the intellect is not yet developed, congenital myxedema causes a complete arrest of both physical and mental development; whence the two im- portant diagnostic signs: dwarfism and idiocy. The height and weight are much inferior to the normal; the first teeth appear late; the fontanels stay open until an advanced age. Idiocy is absolute: the child cannot stand or walk; he stays still in a chair and lets known by cries when he is hungry or thirsty. He is not able to feed himself. He is a plant, which simply breathes and digests. Very late he ‘finally learns to walk, but his movements are very slow. He never is able to learn to talk or write; all attempts to educate him are a failure. The evolution is very slow, without any spontaneous THE SYMPATHETIC SYSTEM 65 improvement. If the child reaches the age of puberty, the physiological changes of this period do not ap- pear; the genital organs stay infantile and the hairs do not grow either in the axilla or the pubis. These subjects Fic. 2.—Myxedematous dwarfism (Infroid collection). have a very poor resistance to infections and usually die of some intercurrent disease or of tuberculosis. It is very rare to see a case of congenital myxedema over 30 or 40. 2.—AcquIRED MyxreprEMa.—It occurs usually in the first part of childhood. The usual cause is some infectious thyroid lesion, secondary to measles, scarlet fever, broncho pneumonia, gastro enteritis, etc. (Roger and Garnier). 5 66 ENDOCRINE GLANDS The symptoms are the same as those of the congenital type, but less severe. The physical development is bet- ter and the mentality more advanced; dwarfism is less marked and the idiocy less absolute. As a general rule, the symptoms of myxedema are proportionally less pro- nounced as the disease occurs later in life. The skin is still thickened and infiltrated, but much less dry. The first teeth come out at the normal time, but the second crop does not appear or the teeth are badly developed. Growth is delayed, the height is below the normal for the age. Ossification is not completed. The mentality is not retarded as much and these individuals can be educated to a certain extent; motion is very slow and awkward, but they can make themselves understood and can obey a few simple commands. The low body temperature, the sensitiveness to cold are as appreciable as in the previous type. These children when untreated usually die early. 3. POST OPERATIVE MYXEDEMA. In 1882 J. Reverdin showed that the affection described by Gull in adults and by Bourneville in children, could occur in either case after a thyroidectomy for goitre. This was a very important discovery which led to the path- ogenic treatment of myxedema; thyroid organo therapy. The total extirpation of goitres or a total thyroid- ectomy causes in man, as well as in animals, two kinds of phenomena. 1.—AcutEe Symptoms which were studied under the name of acute post operative myxedema. These were in reality cases of tetany due to the simultaneous extirpation of the thyroid and parathyroids. 2.—Curonic Symproms.—These occur usually three or four months after the complete thyroidectomy (partial THE SYMPATHETIC SYSTEM 67 thyroidectomy only causes mild and very transitory symptoms). The clinical picture is identical to that of acquired myxedema of the adult; infiltration, anemia, loss of hairs, asthenia, with slowness and awkwardness, sleepi- ness, deterioration of mentality and low body temperature. In children the symptoms are more marked than in adults. The thyroidectomy brings on a complete stoppage in mental and physical growth, being the more marked as the subject has been operated on early in life. 3.—EnpEMic MyxepEMA or CreErtinism.— Cretinism is found in certain mountainous countries (Valois, Alps, Pyrenees) in children drinking water from certain springs, and is characterized by a physical and mental deterioration. This condition is so similar to the myxedematous idiocy that the only way it can be differentiated from it, is by the presence of a goitre. The latter develops as a rule around puberty and becomes enormous. It forms some- times a hard tumor, containing cartilagenous centres, at other times, soft or cystic tumors. In spite of the presence of the goitre the function of the thyroid is abolished. According to their mental state these cases are classified as complete cretins, in which walking can only be accom- plished on all fours and speech is replaced by noises and semi cretins and cretinoids in which speech is slow but who, however, are able to perform a few simple tasks. 4. ABORTIVE MYXEDEMA.—CHRONIC MILD HYPO- THYROIDISM.—SLIGHT THYROID INSUFFICIENCY. When lesions of the thyroid disturb, without abolishing the function of the gland, myxedema reveals itself in a series of types showing various grades of thyroid insufficiency. A. IN CHILDREN. Following an infectious disease, the child shows a retardation in development. The skin becomes thicker, 68 ENDOCRINE GLANDS but not as much as in typical myxedema. The face is slightly pale and puffy and the rest of the body shows a slight obesity which tends to hide the sexual characteristics. Young boys show excessive adiposity, most marked at the level of the hips and the breasts. Little girls show an ungraceful obesity: the breasts are invaded with fat, the abdomen bulges out, the skin forms pleats on the sides and on the abdomen. At a more advanced age thyroid deficiency causes myxedematous infantilism. This attenuated type of myxedema, described by Brissaud, is evidenced by the morphological signs of childhood after puberty. The face is round, the thorax is elongated and cylindrical, while the abdomen protrudes as in childhood. The limbs are rounded. The shape is feminine, the underlying muscles being hidden by an excessive amount of subcutaneous fat. The genital organs are rudimentary; the penis is small and short; the testicles are well formed, have descended, but are small. The hairs are few or even absent on the pubis, axilla and face. The voice remains high pitched; the larynx does not protrude. In the female, the pelvis and the breast do not develop. The vulva looks forward as in little girls and menstruation does not appear. X-ray of the skeleton shows a delay in the appearance of ossification points and persistence of cartilage outside of the normal limits. Adolescents are like big children, not only physically but mentally. They are emotional, easily frightened, without care and are very affected. All cases of infantilism are not myxedematous and this type must not be mistaken for the real infantilism of Lorain. The latter is characterized by a decrease in size. The morphology is, however, not that of a child. The features of the face are formed; the shoulders are large and proportional to the other parts of the body. The THE SYMPATHETIC SYSTEM 69 abdomen is not prominent; the musculature can be made out. The sexual organs, while reduced in volume, are harmonious with the rest of the organism. The cartilages are fixed. There is no mental backwardness. To give the description of Meige, these cases are miniature men. Baur has designated these cases under the name of cheti- vism. This description allows us to understand the difference between the infantilism of Brissaud and that of Lorain. B. IN ADULTS. The symptoms of abortive myxedema studied by Thibierege are even more marked than in childhood. The complexion is yellow; the eyelids are puffy, partic- ularly in the morning. The hair turns gray early and falls from the forehead and the top of the cranium. The eyebrows are scarce, the mustache is scanty, the beard grows unequally, the hands and feet show an indurated edema and appear swollen and often show signs of vaso motor disturbances: acrocyanosis, syndrome of Raynaud, etc. The skin of the extremities is dry, coarse, thick and scaly, sometimes having the appearance of ichthyosis. The individual has a tendency to obesity. The pulse is weak and the blood pressure is low. Hertoghe, then L. Levi and H. de Rothschild, have described a certain number of minor signs which are evidences of thyroid insufficiency. The most important are the following: 1.—Catoriric DisturBANces.—Cases of hypothy- roidism are very sensitive to cold. Not only do they have cold extremities, but they feel the desire to warm them- selves up and cover themselves excessively at night. Their body temperature is, moreover, often below normal. Sometimes towards 4 or 5 o’clock they have chills, partic- ularly in the region of the back (Hertoghe). 70 ENDOCRINE GLANDS 2.—Nervous DisturBaNncres.—These patients com- plain of a sensation of fatigue in the morning, and only begin to feel normal after having been up for several hours. They complain of frontal or occipital headaches, muscular and articular pains, vaguely called neuralgias and of indefi- nite etiology. In some there is a decrease of the memory and of physical activity, resembling neurasthenia or psychas- thenia. Others need considerable sleep and doze off after each meal. Some have a marked intellectual apathy. 3.—Eprema.—White, firm, indolent edema, independent of all cardiac or renal affection, occurring on the face (forehead, eyelids). Some women at the time of men- struation have a temporary swelling of the hands and feet and can only remove their rings with difficulty. 4.—DicEstivE Disorprers.—Outside of anorexia, a common symptom, there is often, in women, a persistent constipation with or without muco-membranous colitis. 5.—Piuiary DisturBances.—Early baldness, alopecia, associated with rarefication of the hairs of the outer part of the eyebrows are stigma of thyroid insufficiency. Cases of hypothyroidism are predisposed to a variety of morbid disturbances. Respiratory infections are frequent in these patients which often have hypertrophic tonsils, a red pharynx, retracted nasal fossea, due to thickening of the mucosa. They are subject to repeated sneezing (Hertoghe) to sore throat, colds in the head and bronchitis. Asthma, of nasal origin is often remarkably improved by thyroid organo therapy. Menstrual disturbances are nearly constant and show themselves at the time of the periods by real hemorrhages, others have painful menstruation accompanied by head- ache or excessive nervous irritability. The attacks of migraine also come on between the THE SYMPATHETIC SYSTEM 71 periods. Their thyroid etiology is proved by the fact that they are rapidly improved by thyroid medication and that an intercurrent pregnancy or the menopause causes them to disappear due to the overactivity of the thyroid during these periods of sexual life. Finally, many conditions have been found to be due to hypothyroidism, such as: urticaria, eczema, psoriasis, ete., chronic rheumatism under a variety of aspects even the progressive deforming type. These various manifestations due to thyroid insufficiency are found to be related to this condition, not so much by their clinical appearance as by the co-existence of various stigma of hypothyroidism. We are entitled to suspect hypothyroidism when after the examination of a patient several symptoms of hypothyroidism have been detected and to verify our diagnosis by a therapeutic test. We must not expect to find in one patient all the signs of hypothyroidism. Some patients only show a yellow skin and a slight infiltration of the tissues. Others are simply stout without any other signs. Furthermore, the physical stigma have a much more valuable diagnostic significance than have functional manifestations; such as, fatigue, headache, constipation. If we suspect such common symptoms to be all due to hypothyroidism, the majority of medical diseases would have to be treated by the administration of thyroid. TREATMENT OF MYXEDEMA AND OF THYROID INSUFFICIENCY. A. MYXEDEMA. We will only refer to thyroid gland grafts; the first attempts made in France were by Lannelongue and did not succeed. Kocher and Payr only obtained temporary 72 ENDOCRINE GLANDS results, because of the total resorption of the gland. In spite of a few successful cases reported by Charrin, Christiani, Gauthier, etc., who grafted in the subcutaneous cellular tissue small fragments of thyroid, the method has not become generalized. To-day, thyroid organo therapy is the only method employed. Orcano Tuerapeutic Propucts.—Thyroid is usu- ally administered by mouth as the dried extract, fresh gland or iodothyrin. a—The fresh gland is a very active medication, but can only be used absolutely fresh. Sheep’s gland is used, the average dose being between 1.5 grammes to 3 grammes in adults (or 1 or two lobes), 0.25 to 1.5 grammes in children. It is given raw, spread on toast or chopped up and mixed with milk, or slightly warmed up soup. In certain cases of congenital myxedema who swallow with difficulty, it is possible to administer thyroid, chopped up very finely, in an enema. b—The dried gland as a powder, prepared in a vacuum and in the cold is the best preparation to use, because of its ease of administration. The average dose is from 0.3 to 0.4 grammes. c—Iodothyrin is one of the active principles of the thyroid and is given in doses of 0.25 to 0.75 daily. METHOD OF ADMINISTERING THYROID MEDICATION. 1—It is first necessary to find out gradually the susceptibility of each patient and begin with small doses (14 of a lobe or 0.05 grammes of the dried powder in a child, 44 lobe or 0.1 grammes in an adult) and slowly increase the dose. THE SYMPATHETIC SYSTEM 73 2—The treatment may have to be kept up a few months, a few years and perhaps all the life of the pa- tient, if recurrences are to be avoided. In children just as large doses can be used as in adults, for observation has shown that they tolerate thyroid extract very easily. 3—Once the results are obtained, the treatment is to be discontinued. Smaller quantities are to be used, varying with each individual and the patient is advised to take the medication for three weeks and then abstain for one week, or again he may be told to take the medication one week and rest the next. RESULTS OF THE TREATMENT.—Thyroid medication is indicated in all the forms of myxedema. It will always bring about some improvement and may even cause a cure. The results are the more marked as the child is younger; the infiltration of the tissues decreases rapidly and a real physical transformation occurs. The skin loses its roughness, the hairs become less coarse and grow longer, the features become more refined. The weight decreases and the height increases. The intellect improves, follow- ing the physical transformation. The indications for treatment can be very easily regulated by the measure- ments. As soon as growth ceases and weight increases, the treatment is to be taken up again. In older children, the delayed growth is resumed under the influence of the treatment. Due to the persistence of cartilage, these individuals can still increase in size at an age when growth has ceased in normal subjects. They become susceptible of an elementary education and in a few months the changes may be complete. In adults the therapeutic results are less marked. 74 ENDOCRINE GLANDS B. THYROID INSUFFICIENCY. The majority of the symptoms and accidents due to hypothyroidism, obesity, migraine, menstrual disturb- ances, constipation, etc., are attenuated under the influence of organo therapy. In general, however, the improvement is only temporary and ceases after the sup- pression of the medication. In chronic rheumatism the results are proportionately more successful as the rheuma- tism is recent and the subject is young. The administration of thyroid in these cases is more difficult. All authorities agree on the necessity of slowly finding out by experimentation. Very small doses must be used at first (0.01, 0.025 milligrammes) as these doses will in some cases be sufficient to cause an improvement. If the improvement does not manifest itself, then larger doses are used, which in certain individuals might cause symptoms due to hyperthyroidism. It is also advisable to discontinue the treatment occasionally and have periods of treatment followed by rest periods, so as to avoid accumulative effects and intolerance. The good effects of organo therapy do not occur some- times for quite a long period of time. The treatment should, therefore, be continued in certain unimproved cases for several months or even years. ACCIDENTS OF THYROID MEDICATION.—SIGNS OF INTOLERANCE. The use of thyroid medication, because of its potency should be watched. The extract of thyroid has a definite action on the cardiac rythm and the arterial pressure. Experimentally, it causes an acceleration of the heart rate and a characteristic drop in blood pressure. Collapse THE SYMPATHETIC SYSTEM 75 and even sudden death have been reported following its use in individuals with degeneration of the myocardium or valvular lesions. It is, therefore, important to test out with small doses at the beginning of treatment. During the course of the treatment, the intolerance manifests itself by the following symptoms: Acceleration of the pulse, palpitations, heat waves, sweating, tremors, loss of weight, diarrhea. As soon as they appear the medication should be discontinued or at least consider- ably reduced. These symptoms of intolerance are more frequent in adults than in children. THE SYNDROMES OF HYPERFUNCTION OF THE THYROID. I. EXOPHTHALMIC GOITRE. Exophthalmic goitre is a disease characterized by the following signs: hypertrophy of the body of the thyroid, exophthalmos, tachycardia and tremors. To these are added a number of secondary signs, the majority of nervous origins, which give quite a peculiar appearance to this disease. It is also called Basedow’s disease in spite of the fact that this condition was first described by Flajani in Italy and afterwards by Parry and Graves in England. It occurs most often in women between the ages of 20 and 40, usually associated with a nervous stigma or an impressionable character. SYMPTOMS. They begin very slowly and very progressively. The first noticed are nervous manifestations. The patient becomes peculiar and irritable. Her immediate friends notice a change in the patient. She complains of waves 76 ENDOCRINE GLANDS of heat, flushes, palpitations, insomnia. On casual exam- ination a swelling of the thyroid is noticed and an acceleration of the pulse rate. Very often this condition is interpreted as hysteria or nervousness. Slowly the characteristic signs of the disease become prominent. 1.—TacuycarDIA.—This is a very important sign, as it appears early and is very constant. The patient com- plains after the slightest effort, or the least excitement, of palpitations, at first intermittent and in the end constant. During the day time they sometimes have a sensation of discomfort which is very painful; at night they com- plain of palpitations and sleep poorly. The pulse is rapid; 90 to 120 per minute. It is small, but generally regular, although in some cases it can be very variable. Following a slight effort or excitement, it will go up to 100, 150, or 180. This acceleration of the pulse occasionally occurs spontaneously and coincides with attacks of palpitation. Quite often there is a slight rise in blood pressure. The examination of the heart reveals an abnormal cardiac condition. The wall is pushed forcibly at the apex and can be easily palpated. Auscultation reveals a tachy- cardia, either simple or associated with extra cardiac murmurs. If organic murmurs are present, these are prob- ably due to some previous rheumatic endocarditis (Barie). 2.—Tue Goitre.—Very soon the volume of the thy- roid increases, obliges the patient to wear larger collars or a more opened waist. Sometimes under the influence of fatigue or menstruation it grows very rapidly and in the interval goes down slightly. At an advanced period the hypertrophy of the gland causes a deformity of the neck, generally asymetrical. The right lobe being nearly always the largest. The THE SYMPATHETIC SYSTEM 77 vessels of the neck pulsate and are plainly visible, this in contrast to the very small pulse (Graves). These pulsa- tions are limited to the carotids. Exophthalmic goitre is a vascular goitre. On palpation it is elastic and semi soft; occasionally it gives a sensation Fic. 3.—Exophthalmic goitre (Service of Dr. Florand). of a thrill or of expansion synchronus with the cardiac systole. On auscultation a hum is often heard, most pro- nounced in systole. Some patients tolerate this hypertrophy perfectly. Others have a painful contraction of the larynx. The recurrent laryngeal nerve can be compressed; in which case the voice becomes hoarse. 78 ENDOCRINE GLANDS 3.—EXOPHTHALMOS completes the picture. The eye- balls protrude, and the lids are wide open, giving an ex- pression of fright. In most cases it is symmetrical, but sometimes starts in one eye before becoming noticeable in the other. Very rarely it stays unilateral, coinciding with a thyroid hypertrophy on the same or opposite side. The protrusion of the eyes may become so prominent that the insertion of the anterio ocular muscles is visible, and interferes with the closure of the eyelids and exposes the cornea, to infection. Emotions, fatigue, menstruation, increase exophthalmos just as they do the goitre. As a rule the patients do not have any visual dis- turbances, except a certain difficulty in fixing objects or reading small print. The pupils are equal, usually with a slight mydriasis and react quickly to light and accommodation. Paralysis of any of the extrinsic muscles is exceptional. Next to ophthalmia we have a number of signs indicating an absence of coordination between the movements of the eyelids and those of the eyeball. They are as follows: 1.—Von Graefe’s Sign.—The movements of the lids lag behind those of the eyeball. When the patient looks downwards the superior eyelids do not follow it completely and the eyeball stays abnormally open. 2.—Boston’s Stgn.—The eyelids follow by jerks the ocular movements. 3.—Stellwag’s Sign.—When the lids try to close, the pupil hides under the superior lid instead of the latter coming down. 4.—Joffroy’s Sign.—The frontal muscle does not move when the patient looks upwards (due to lack of synergy between the movements of the frontal muscle and the levator palpebrarum), Other signs not as common: THE SYMPATHETIC SYSTEM 79 5.—Moebius’ Sign—The eyes converge with difficulty, due to paresis of the internal recti. 6.—Jellenick’s Sign.—Abnormal pigmentation of the eyelids and of the skin of the orbit. 4.—Tremor.—The last of the important diagnostic signs. It may be localized to the legs or generalized with predominance of the hands and head. The following are its characteristics: 1.—Fine tremor of small amplitude. 2.—Mlixed tremor both spontaneous and intentional, not modified by the will. 3.—Tremor increasing in intensity after fatigue and excitement. The tremor can be brought out in the following manner: 1.—At the level of the head by a piece of paper on the top of the head. 2.—Of the superior limbs by having the patient raise his hand as if taking an oath; the tremor does not stay local- ized to the fingers as do alcoholic tremors, but involves the hand, the muscles of the forearm and even in some cases the arm. 3.—At the level of the thorax, by placing a hand on each shoulder a continuous vibration may be elicited. 4.—Of the inferior limbs, the patient sitting down, with his feet resting, moves the tips of his toes (P. Marie). To these functional signs are added other symptoms which have not the same constancy or the same clinical value. The majority are indicative of a secretory dis- turbance of the thyroid or of some other gland of internal secretion. ‘They vary with each patient and affect dif- ferent systems. 1. NERVOUS DISTURBANCES. a.—Disturbances in motility. These consist of muscu- lar cramps, particularly in the calves of the legs, contrac- tures and even epileptiform attacks. 80 ENDOCRINE GLANDS When paralysis occurs, it usually is localized to the legs and at the beginning shows the characteristic of a para- plegic functional paralysis with sudden onset and with the retention of the reflexes and integrity of the sphincters (Paraplegia of Basedow’s disease described by Charcot). b.—Sensory disturbances. These vary; neuralgia in various localities (cervical, occipital and especially facial) or arthralgia simulating rheumatism. c.—Secretory and vaso motor disturbances. These are very common and very important; waves of heat, profuse sweating, generalized or localized to the neck, trunk, arms, etc; sensation of abnormal heat or thermophobia. The patients place themselves in a draft or sleep without any bed clothes in winter. d.—Dystrophic disturbances. These are present in certain subjects. In some cases there is a melanodermia resembling Addison’s disease, vitiligo, brown spots, edemas characterized by a thickening of the skin at the level of the neck and buttocks. e.—Psychic disturbances are nearly always present. Changes in character become more pronounced as the disease evolves. The patients are impatient, emotional, irascible; one minute sad, the other cheerful and become very unsociable because of their change of humor. In predisposed individuals these changes may result in a true psychosis, melancholia, mania, with hallucinations, or persecution, etc. Insomnia is frequent. This can be opposed to the sleepiness of myxedematous patients. /2, GASTRO INTESTINAL DISTURBANCES. The appetite varies, sometimes increased, at others decreased. The digestive functions may be normal. Occa- sionally, patients with Basedow’s disease have gastro intestinal crises, beginning and ending very suddenly THE SYMPATHETIC SYSTEM 81 and resembling tabes; ptyalism, gastric or abdominal crises with vomiting and attacks of diarrhea, containing mucus and bile and which exhaust the patient and are followed by a marked loss of weight. 3. RESPIRATORY DISTURBANCES. Outside of the rare cases in which a large goitre presses on the air passages and causes respiratory difficulties, certain individuals with only a small goitre, have a dry cough, coming on in paroxysms and spasmotic in character. The respiratory difficulty in some cases consists of a difficulty in dilating the thoracic cage and taking a deep breath (Bryson). 4. GENITAL DISTURBANCES. The genital disturbances are constant in Basedow’s disease. In man there is frigidity or impotence. In women the menses are irregular or may be absent and then re-appear. The breasts nearly always become atrophic. 5. URINARY DISTURBANCES. Polyuria occurs at intervals very much like the attacks of diarrhea. During the periods in which the goitre is growing rapidly albuminuria and even glycosuria can be noticed. This glycosuria seems to be the result of hyperthyroidism. 6. GENERAL SYMPTOMS. Fever is not exceptional in Basedow’s disease. It oc- curs at intervals and lasts for a variable length of time. The examination of the blood shows a leukopenia with lymphocytosis (Kocher). These blood changes are very constant and are also found in the abortive cases. 6 82 ENDOCRINE GLANDS é EVOLUTION. Basedow’s disease may evolute very quickly. It may develop after a fright. The sudden increase in the volume of the thyroid causes asphyxiating symptoms, associated with cyanosis suffocation, often made worse by an asso- ciated enlargement of the thymus. It may improve and be the starting point of a slow evoluting type of case. In the majority of cases the evolution lasts for years, and progresses by sudden periods of activity during which the chief symptoms increase in intensity and are separated by intervals of remission or even regression which last a variable length of time. The general health for a long time stays unimpaired. In spite of the fact that these patients have a good appe- tite, some of these patients lose weight for weeks or months at a time. These periodic spells of loss of weight occur without any apparent cause or after diarrhea; be- tween these periods they regain weight. In this manner, the evolution is very slow. Cure is very frequent. It may occur spontaneously, but in the majority of cases is rarely complete. The secondary symptoms decrease and may disappear, but exophthalmos, thyroid hypertrophy and _ tachycardia persist and recurrence is to be watched for. . In other cases, the condition grows worse after several exacerbation. The patient dies from tuberculosis, progressive cachexia or from cardiac complications. 1.—PLEURO-PULMONARY TUBERCULOSIS in one of its various forms is a frequent complication. 2.—Cacuexia characterizes certain cases. They have anorexia, incoercible vomiting, profuse diarrhea, albumi- nuria and in spite of the absence of any evidence of THE SYMPATHETIC SYSTEM 83 tuberculosis are reduced to skeletons. Some become cachectic in a few weeks without diarrhea and die of marasmus. 3.—Carpiac DistuRBANCES.—Certain cases of exoph- thalmic goitre have a marked paroxysmal tachycardia. Others, as a result of fatigue, have an acute dilatation of the heart, an extreme dyspnea and die of asphyxia. In others, cardiac insufficiency develops slowly: edema, oliguria, and albuminuria and symptoms of dilatation of the right heart with foci of pulmonary apoplexy showing the typical picture of progressive asystole. This has usually a valvular lesion as a starting point, resulting from a previous attack of rheumatism (Barie). CLINICAL FORMS. Exophthalmic goitre shows certain peculiarities. 1.—In Cuttpren.—The condition can be hereditary or familial. It is mostly found in girls. The symptoms are mild; the goitre is not very big; the exophthalmos not very pronounced or absent; the tremor less marked and sometimes resembles chorea. A cure is possible, but a recurrence must be watched for when the patient grows up. 2.—In Man.—When Basedow’s disease occurs in man, the nervous symptoms and in particular the psychic symptoms are very marked and appear long before any of the important diagnostic signs. The evolution is more rapid and the prognosis is bad (Pic and Bonnamour). 3.—In Pregnant WomeENn.—Pregnancy is rare in this condition, as exophthalmic goitre is often accompanied with atrophy or insufficiency of the ovary. Some cases, however, are able to have several pregnancies without any trouble. Furthermore, it may be a cause for improvement. In other cases, however, pregnancy occurring during the course of Basedow’s disease has very 84 ENDOCRINE GLANDS dangerous consequences. It causes abortion, hemorrhages and even cardio pulmonary complications which resemble the severe gravid cardiac accidents. 4.—AportivE Type.—Charcot and his pupils, Pierre Marie among these, have shown that next to the typical types of these affections mild or abortive cases exist. According to P. Marie, the fundamental symptom of Basedow’s disease is tachycardia, and goitre, exoph- thalmos and tremor may be missing. The abortive cases are characterized by tachycardia, either with exophthalmos without a goitre, or with a goitre and no exophthalmos, or finally alone. The vaso motor, nervous, psychic changes which accompany these mild cases are sufficient to relate it to exophthalmic goitre. Next to these mild cases, we must place various cardiac neurosis. In certain defectives, having no signs of Basedow’s disease, not even a goitre, fatigue or excite- ment cause palpitations and tachycardia, a cardio vascular and nervous instability and even a slight tremor. Certain cases of tachycardia, not well classified, occurring inter- mittently and in paroxysms, which we saw during the war were probably due to disturbances in the thyroid function. These cardiac neuroses are closely allied to attenuated cases of Basedow’s disease and there is no def- inite line of demarcation between them. 5.—AssociaTED Forms.—Basedow’s disease is liable to co-exist with different nervous affections of the nervous system: syringomyelia, epilepsy, general paresis and particularly tabes. In the latter case it is probably of luetic origin. Combinations with other glandular syndromes are very curious: acromegalia, gigantism, Addison’s disease, myx- edema, etc. The latter follows the goitre in certain cases fol- lowing radiotherapy or the two affections evolute together. THE SYMPATHETIC SYSTEM 85 Finally, exophthalmic goitre can exist with a number of diseases, the glandular origin of which is suspected but not proved; diabetes: (severe diabetes with abundant gly- cosuria), Dercum’s disease, paralysis agitans, sclerodermia, Raynaud’s disease, osteomalacia, tetany, myasthenia, etc. DIAGNos!s.! 1.—The diagnosis of typical Basedow’s disease is made; when the four cardinal symptoms have been observed; this is found only in this disease. If the exophthalmos is very mild and if the ocular symptoms consist simply in a certain fixity and peculiarity of the eye, bulbar tabes can simulate the syndrome of Basedow’s disease by ophthal- moplegia and tachycardia. The examination of the patient reveals, however, the presence of symptoms of tabes foreign to Basedow’s disease. A co-existence of the two diseases is however possible. 2.—In mild or abortive form the diagnosis is difficult. In these cases the tachycardia predominates and the other symptoms are practically absent. Certain cases of Basedow’s disease appear clinically to simulate tuber- culosis, cardiac diseases, or nervousness. a.—Pseudo tuberculosis, because they have a dry cough, a rapid pulse, diarrhea, sometimes fever and they lose weight. b.—Pseudo cardiac, because they complain of palpi- tations, and they have extra cardiac murmurs. Some have pain which simulates angina pectoris, others have paroxysms of tachycardia and palpitation resembling paroxysmal tachycardia. c.—Pseudo nervous, because they complain of a variety GOETCH TEST FOR HYPERTHYROIDISM. 1 The subcutaneous injection of % c.c. of 1-1000 adrenalin solution will cause a rise of blood pressure of over 10 mm. or an increase of pulse rate of over ten beats a minute. 86 ENDOCRINE GLANDS of symptoms; vaso motor, dyspeptic, etc., which add to their mental state. Their impressionability often leads us to suspect neuropathy or hysteria. The cardio vascular disturbances must be looked for carefully, the instability, the hyperexcitability of the pulse, which increases at the slightest effort should lead us to suspect a thyroid lesion. The therapeutic test may be of great help: antithyroid medication may improve the case while thyroid medication, even in small doses exag- gerates the symptoms of this morbid condition. ETIOLOGY. Basedow’s disease is often the late sequel of an infec- tious disease: an acute thyroiditis caused by typhoid fever, scarlet fever, mumps, particularly acute articular rheumatism. It can also be the result of a chronic tuber- culous or syphilitic thyroiditis. In certain cases it seems to be the result, as in some cases of diabetes, of a cranial trauma. It may begin very rapidly, following violent emotions, fright, moral shock, repeated and deep sorrows. Some cases of exophthalmic goitre appear without any apparent cause. , PATHOLOGICAL ANATOMY. There are no specific anatomical lesions of Basedow’s disease. The thyroid is increased in volume as a whole, the right lobe being usually larger than the other. The thyroid veins are dilated and filled with blood. The gland is of soft consistency, and of a dark brown color. When incised, it often contains cysts filled with colloidal substance. The histological lesion, according to the investigations of Callum, Roussy and Clunet, resemble the compensatory THE SYMPATHETIC SYSTEM 87 hypertrophy obtained experimentally after the removal of the greater part of the thyroid and show definitely a hyper- function of the gland: hypertrophy and parynchymatous hyperplasia with increased colloid secretion. The colloid is paler, less chromophilic and more friable than normally. The abnormal cellular proliferation is characterized by masses of eosinophils. The thyroid follicles are dilated and are shown surrounded by fibrous tissue, more or less abundant and containing lymphoid cells. Lesions of the cervical sympathetic are rare. In some cases the nerves are increased in volume and sclerosed; the inferior cervical ganglion contains atrophic cells, smothered by a proliferation of connective tissue. Lesions of the nervous system (bulb and cord) are ex- ceptional and when they do exist do not have any spe- cific appearance. It is quite common to see an increased activity of the thymus in cases of exophthalmic goitre.! PATHOGENESIS. In spite of numerous theories, the definite pathogenesis of Basedow’s disease is still undetermined. 1.—Nervous Turory.—The syndrome is produced by a lesion of the cervical sympathetic (Abadie). The stimulation of the sympathetic causes tachycardia, ex- ophthalmos, dilatation of the arteries of the thyroid. Secondarily, the thyroid hypertrophies and due to a functional hyperactivity, pours into the blood stream toxic substances which cause the secondary symptoms: tremor, diarrhea, loss of weight, etc. 2.—Tuyroip THrory.—(a) Hyperthyroidism. Base- dow’s disease is the result of a hyperthyroidism (theory of Moebius). Experimental, clinical and therapeutic obser- 1 This may account for the ovarian and genital atrophy, 88 ENDOCRINE GLANDS vations have shown the exaggeration of the thyroid secretion: the symptoms of myxedema characterized by atrophy of the gland are opposed to those of Basedow’s disease. Experimentally, the injection of excessive doses of thyroid extract reproduces in animals some of the symptoms of the disease: tachycardia, loss of weight, as Basedow’s disease is improved by anti thyroid medication. The following facts are, however, opposed to the con- ception of hyperthyroidism: myxedema may co-exist with Basedow’s disease. Gley has also shown that the serum of patients with Basedow’s disease has not the ex- perimental effects of the extracts of thyroid and that the intravenous injection of extract of exophthalmic goiter causes a decrease in the blood pressure, a decrease in’ the strength in the heart beat, just as would the extract of a simple goitre. (b) Dysthyroidism (theory of Gauthier and Charolles, then of Renaut and Joffroy, brought up to date by Gley and Iscovesco). The symptoms of exophthalmic goitre are brought about by a perversion of the thyroid secretion causing an accumulation in the blood of toxic substances, normally destroyed by the thyroid. Perhaps one of these substances, stimulating the sympathetic is normally fixed by the thyroid. The tachycardiac and the exophthalmos could be understood without a lesion of the sympathetic. 3.—PoLyGLANDULAR THEORY.—The disturbance in the thyroid secretion is not primary, but secondary to the functional alterations of another gland in synergy with the thyroid, whence the thyro-ovarian and thyropituitary theories. The thyro adrenal theory is upheld in Germany and in America, by Wilson. Hyperthyroidism causes a hyperfunction of the adrenals, which causes ahypersecretion of suprarenalin, a permanent stimulant of the sympathetic. THE SYMPATHETIC SYSTEM 89 II. THE VARIOUS BASEDOW’S DISEASE SYNDROMES. To the typical Basedow’s disease are related a number of clinical syndromes of various etiology. These syn- dromes are related to the existence of a goitre. They are also secondary to the ingestion of thyroid products or of iodides. They may also be of ovarian origin. 1. Pseudo EXOPHTHALMIC GOITRE.. Certain goitres compress the cervical sympathetic on one or both sides and cause an exophthalmia, associated with an acceleration of the heart without any other sign of Basedow’s disease. There are simple goitres which for years evolute without any disturbance; then under the influence of overwork or sorrows or following the administration of iodides, some- times even without any evident cause show evidence of Basedow’s.disease. In these cases not only is exophthal- mos and tachycardia noticed, but signs of thyroid intoxi- cation: tremors, vaso motor disturbances, psychic changes diarrhea, etc. These can be differentiated from the classical Basedow’s disease by the following characteristics: the goitre has been perfectly well tolerated for a number of years, the palpa- tion of the thyroid reveals at least in one of the lobes the presence of cartilagenous or fibrous masses, while true exophthalmic goitre is a soft goitre and is essentially vascular. Surgical treatment improves or cures these cases. Certain cases of cardiopathy, associated with goitre, can be classified very closely to Basedow’s disease. Some patients with a simple goitre show prominent cardiac symptoms; in some the symptoms are those of cardiac insufficiency, complicated with pulmonary stasis second- ary to pulmonary lesions of bronchitis with emphysema. 90 ENDOCRINE GLANDS They are found in cases of goitre in which the respiratory passages are compressed by the hypertrophied thyroid. In others, the cardiac manifestations are independent of all pulmonary affections. The goitre varies in size; in some cases it is even small, retro sternal and can be even overlooked, while the patient complains of violent palpi- tations, coming on spontaneously or after the slightest effort. The heart is enlarged and beats between 100 and 140 and becomes accelerated and arythmic at the slightest provocation. More dangerous symptoms, in particular pains simulating angina pectoris, sometimes occur. Asystole is the usual result of these cardiopathic goitres. Sometimes it is possible in these cases to note simultan- eously a slight exophthalmos and a peculiar brilliancy of the eyes. According to Kraus, the removal of the goiter causes the disappearance of these symptoms. For these reasons, these cases are considered as abortive cases of Basedow’s disease. Il, BASEDOW’S SYNDROME FOLLOWING THE INGESTION OF THYROID OR IODIDES. In patients taking an excessive quantity of thyroid or following a course of thyroid medication for too long a period of time (for instance in the treatment of myxedema, or for stout women to reduce without proper medical supervision) the syndrome of Basedow’s disease may appear more or less distinctly with tachycardia, exoph- thalmia, tremor, restlessness, nervosity, insomnia, etc. This syndrome is usually temporary and will disappear after the removal of the cause. Similar symptoms may be seen in patients with simple goitres which have been given iodides. 3. SYNDROME OF BasEDow’s DiIsEAsE oF OVARIAN Oricin. —In certain young girls at the time of puberty, THE SYMPATHETIC SYSTEM 91 in women at the time of the menopause, or after ovarectomy, the symptoms of Basedow’s disease, in general attenuated, will appear. They are characterized more by a brilliancy of the eyes than by a true exophthalmos, a swelling of the thyroid, an acceleration of the pulse, and tremor. Ovarian organo therapy cures or improves these cases. Ill. HYPERTHYROIDISM SIMULATING BASEDOW’S DISEASE. This bears the same relation to Basedow’s disease as slight hypothyroidism bears to myxedema. The women suffering from this affection have character- istic appearance: The eyes are bright, the thyroid is slightly enlarged, they complain of palpitations of the heart during the day or the night, which last a few minutes. These symptoms are usually accompanied by a sensation of strangulation or waves of heat, followed by sweating. These women are usually very active, and constantly want to be on the move. Some have an exaggerated emotion- ability. Others are irascible. This condition is con- genital and is more the normal condition of the patient than a disease. The symptoms of hyperthyroidism appear after sorrow, overwork, emotions or even slight annoyances. The palpitations increase in intensity and become painful and are accompanied by a sensation of constriction of the thorax and sometimes a fear of death. The nervous disturbances become exaggerated: tremor, insomnia, abnormal excitability. All these symptoms very closely resemble Basedow’s disease. Between Basedow’s disease and predisposition to Base- dow’s disease, characterized by cardio vascular instabil- ity and nervousness, we have no definite demarcation. 92 ENDOCRINE GLANDS TREATMENT OF EXOPHTHALMIC GOITRE AND HYPERTHYROIDISM. The proposed medications are numerous. After having described them, we will study their indications. I. HYGIENIC AND DIETETIC TREATMENT. A quiet life, without any emotions or fatigue, is essential to these cases. Absolute rest in some cases is sufficient to modify the tachycardia and the nervous symptoms. The seashore is unadvisable, while the mountains; at a low altitude, are better tolerated. A stay at some mineral spring is a useful adjunct to the treatment. The sedative springs of Bourbon Lancy and of Neris (in France) are the ones which seem to benefit the patients most. The food must be carefully watched: all stimulants, all toxic foods are to be avoided. It is advisable to weigh these patients, for a gain in weight is an indication of improvement. II. MEDICAL TREATMENT AND ORGANO THERAPY. 1.—Sodium salicylate, in doses of 2 to 3 grams daily for several weeks, improves and cures certain cases of exophthalmic goitre. 2.—Quinine sulphate in doses of 1 to 2 grams daily is given alone or associated with ergot as a vaso motor constrictor. 3.—Anti thyroid medication, based on the theory of hyperthyroidism was first utilized by Ballet and Enriquez. The idea is as follows: neutralize the excess of thyroid secretion by the use of the blood of animals, whose thyroid had been removed. (The preparation usually employed is Hematoethyroidine). According to Enriquez, the dose is as follows: 1 tea- spoonful at each meal for one week, the first week; 2 THE SYMPATHETIC SYSTEM 93 teaspoonfuls at each meal the second week, and 3 tea- spoonfuls the third week. After each three weeks of treatment, the patient is given one week of rest and in this manner the medication is kept up for three months. If after this period there is no improvement, the treatment can be discontinued. The results of this treatment are as follows: 80 per cent. of the cases are improved, 10 per cent. are cured and 10 per cent. are unimproved or made worse (Sainton). 4.—Thyro Toxin serotherapy has been tried chiefly in America and has not been used very much in France. The idea results of the discovery of the cyto toxic serums and consists in the destruction of the thyroid cells. Its preparation and application has not yet been definitely established. 5.—Thyroid Organo Therapy seems paradoxical in cases of hyperthyroidism. In the majority of cases it makes the symptoms worse. It is, however, indicated in the cases where the disease evolutes towards myxedema, or in cases of Basedow’s disease, which have not responded to anti thyroid medication, or in which symptoms of instability of the thyroid are present. Large doses are always to be avoided and even small doses must be used very carefully. 6.—Various Other Forms of Organo Therapy. Ovarian organo therapy is justified in the cases of Basedow’s disease associated with ovarian insufficiency. Thymus organo therapy, based on theoretical facts (hypertrophy of the thymus in Basedow’s disease) has given such variable results that its indications are very obscure and doubtful. Pituitary organo therapy advised by Renon, improves the tremor, the sweats, the tachycardia, the insomnia, and 94 . ENDOCRINE GLANDS sometimes the exophthalmos and would seem to act as symptomatic medication. Hallion has shown experimen- tally that the extract of pituitary has a vaso constrictor action on the thyroid. Claude has observed that the extract of pituitary slows down the heart in cases of Basedow’s disease and thinks that pituitary organo therapy has a favorable action on Basedow’s disease. Ill. TREATMENT WITH PHYSICAL AGENTS. Tepid hydrotherapy sometimes gives excellent results. Electricity has shown itself to be one of the best thera- peutic measures. Faradisation has a vaso constrictor effect and decreases the secretion of the gland. Galvani- zation has a sedative and calming action. To-day both methods are used. Radiotherapy was advocated first in America, then in France. It gives very variable results. Some are im- proved, others are not affected and we do not know why. It is usually the nervous and cardiac symptoms which are first improved. IV. SYMTOMATIC TREATMENT. The palpitations are attenuated by tincture of Stro- phanthus in rather large doses: 8 to 10 drops three times aday. Digitalis is indicated in cardiac insufficiency which complicates the disease. The tremor can be improved by Belladonna and Jusquiam. Scopolamin is a less easily used drug and must be watched carefully. The nervous disturbances are treated by sedative medications: bromides, valerian, antipyrin, aconite, etc. The general condition is often improved by arsenic, phosphates, ete. THE SYMPATHETIC SYSTEM 95 V. SURGICAL TREATMENT. 1.—Partial thyroidectomy, care being taken to leave untouched the parathyroids, to avoid tetany, and pre- serve enough of the gland to prevent myxedema is a commonly used method of treatment. 2.—Ligations of some of the blood vessels of the thyroid is considered by some to be the method of choice. 3.—Sympatheticectomy, advised by Jabouley, is practi- cally never used any more. THERAPEUTIC INDICATIONS. All the methods of treatment given are not exclusive and can be associated with advantage. 1.—In classical exophthalmic goitre etiological treat- ment should be attempted: specific medication in goitre of syphilitic origin; salicylates if the patient has had acute articular rheumatism. In the majority of cases all etiological indication is missing. ‘The patients are first put on a regime of abso- lute mental and physical rest, then antithyroid medica- tion is first tried. If the patient does not react to it, there is no use continuing the treatment too long. The electric treatment should next be tried, then radiotherapy associated with symptomatic medication or organo therapy, depending on the case. If medical treatment fails or makes the condition worse then surgical treatment is indicated. This is counter- indicated in the cachectic cases and those with cardiac insufficiency, however. In the acute form with rapid evolution which usually resists all medical treatment, thyroidectomy should be resorted to. 2—In goitres with symptoms of Basedow’s disease, some are improved by antithyroid medication, others by thyroid organo therapy given carefully and in small doses. 96 ENDOCRINE GLANDS If these medications do not give any results, then thyroi- dectomy is indicated. Radiotherapy is without any effect in these cases. 3.—The syndromes of Basedow’s disease occurring at puberty, the menopause or during pregnancy, should be treated with ovarian organo therapy. THYROID INSTABILITY. Thyroid instability (Levi) is characterized by a disequi- librium of the functions of the thyroid. It results in the association, in various proportions, of signs of hypo and hyperthyroidism. During the course of thyroid insufficiency, no matter what its degree may be, disturbances may be observed which are due to hyperfunction of the gland. Inversely, but not as frequently, in hyperthyroidism are seen symptoms associated to hypothyroidism. Some patients, for instance, show signs of hypothyroidism: constipa- tion, alopecia, low body temperature and of hyperthy- roidism: palpitations, insomnia, febril attacks, making one suspicious of a possible tuberculosis. Thyroid instability has not only a theoretical interest but is very important practically and upon it must depend the treatment employed. Thyroid medication will not only improve the symptoms of hypothyroidism, but also those of hyperthyroidism; for these can be considered more or less as a reaction. There is, therefore, a thyroid disequilibrium. Before administering thyroid to a patient with mani- festation of chronic arthritis of thyroid origin, for instance, it is necessary to study the function of the gland. L. Levi advises to write on either side of a line the signs of hypo or hyperthyroidism found in each patient and to study also the reactions of the patient to menstruation, and THE SYMPATHETIC SYSTEM 97 emotions. Those in which hyperthyroidism predominates can be given very small doses of thyroid or 0.005 milli- grams. ‘Those in which the signs of hypothyroidism seem to predominate can be given larger doses: 0.05 to 0.10 milligrams. In those in which neither of the two pre- dominate, intermediary doses are given: 0.025 milligrams. According to L. Levi, the reactions to this medication regulate the doses of thyrcid. It is easy to see how organo therapy, by using excessive doses, can overreach its objective and cause, in certain patients, the symptoms of hyperthyroidism. The symptoms of hyperthyroidism symmetrically opposed to hypothyroidism are schematized below to allow us to study the thyroid equilibrium in patients. HypPoTHYROIDISM HyprErTHYROIDISM Dull Expression. Exophthalmos, brilliant eyes. Thyroid net appreciable in size. | Hypertrophied thyroid. Fall of hair. Eyebrow sign. Hypertrichosis, often cf the eye- brows. Tendency to obesity. Loss of weight. Hypodermia. Hyperdermia, waves of heat. Tachycardia. Dry skin; transitory edema. Moist skin, excessive secretion of sweat. Sleepiness, apathy. Insomnia, nervosity, irritability, etc. Anorexia, constipation. Tendency to diarrhea. ACUTE THYROIDITIS, TUBERCULOSIS AND SYPHILIS OF THE THYROID. INFLAMMATION OF THE HrattHy Tuyror is called thyroiditis; that of an altered gland, strumitis. The latter is the most frequent of the two. Thyroiditis is observed most frequently in women be- tween 20 and 40. 7 98 ENDOCRINE GLANDS The causes are: traumatism, chilling, and particularly, infections; typhoid fever, pneumonia, septicemia, scarlet fever, diphtheria, erysipelas, influenza, malaria, mumps and acute articular rheumatism. In rheumatism the thyroid is very often affected (H. Vincent). The condition starts with a chill, headache, followed by a temperature and pains often very sharp radiating towards the ear, the neck, the shoulders and the back of the head. The patient usually takes the characteristic attitude of the head bent downwards with the chin in the hand. On examination a swelling of the thyroid is noticed together with some local temperature. Very quickly an intense dyspnea develops with attacks of choking, a paroxysmal cough, dysphagia and sometimes a complete aphonia. To these symptoms of compression are asso- ciated signs of hyperthyroidism; tachycardia, tremor, slight exophthalmos. The evolution varies. Resolution is the rule in mumps and influenza. Suppuration occurs most frequently after pneumonia, typhoid fever and purpural sepsis. The skin then adheres to the gland, becomes red and edematous, but fluctuation rarely occurs and puncture may be nega- tive due to the depth of the abscess. According to the nature of the causative factor pneumococcus, strepto- coccus or typhoid bacilli are found in the pus. Gangrene rarely results, but when it does occur it usually is fatal. The differential diagnosis is made between this con- dition and the tumefaction of the gland at puberty and during menstruation, which evolutes without fever; it also must be differentiated from adenitis and abscesses in the neighborhood of the gland and from neoplasms (sarcoma or carcinoma). THE SYMPATHETIC SYSTEM 99 The treatment consists in the application of warm compresses and leeches. Tracheotomy may be indicated in the cases of dyspnea and suffocation. Surgical inter- vention has to be resorted to in suppurative or gangrenous thyroiditis. * *k OF * TUBERCULOSIS OF THE THyroID is rare. For a long time is was believed that the thyroid tissue had a peculiar resistance to tubercle bacilli; as a matter of fact, like all vascular organs, it does not offer a favorable field to the development of the tubercle bacillus and the formation of tuberculous lesions. 1.—Mii1ary Tusercutosis.—Is the best known and most common type. It has no particular clinical interest and is usually found at autopsy as a secondary manifesta- tion of tuberculosis. 2.—Massive TuBERCULOSIS—of the thyroid is rare. It can be found in two different types of cases. (a) Tuberculous goitre, which gives rise to a hard thyroid tumor, which causes respiratory disturbances by pressure and which sometimes simulates thyroid goitre, because of the rapidity of its growth, so much so that the extirpation of the gland may be necessary. This form causes caseation: the gland is studded with large solitary tubercles fresh or broken down. (b) Cold abscess of the thyroid sometimes resembles a cystic goitre and may cause dysphagia, compress the larynx or the recurrent laryngeal nerve or the sympathetic. The patient can recover after incision and drainage. 3.—ScLERoUS TUBERCULOSIS OF THE 'THYROID—is found quite often in chronic tuberculosis (Roger and Gar- nier). The thyroid is atrophic, decreased in size and paler than normal. The connective tissue is considerably 100 ENDOCRINE GLANDS increased and is particularly abundant around the blood vessels and penetrates into the gland in various directions, giving it a lobulated appearance resembling the thyroid of a child. The vesicle presents a variety of changes: in certain places the colloid is decreased, in others there seems to be hyperplasia of the cells. Endo and periar- teritis is the rule, but there are no follicular lesions. Tubercle bacilli are not found; inoculation is negative. This thyroid sclerosis takes on the appearance of an ordi- nary inflammation. Clinically sclerous tuberculosis of the thyroid gives the symptoms of a latent atrophic sclerosis. In very rare cases it may become hypertrophic and give rise to a hard tumor, developing rapidly and causing pain and respira- tory disturbances. This is the so-called canceriform thyroiditis which simulates cancer. It may also cause a dysthyroiditis giving rise to abortive or typical symp- toms of Basedow’s disease. Laignel-Lavastine, Mantoux and Ramond have reported similar findings. The de- velopment of exophthalmic goitre on top of a tuberculosis of the gland are to-day well known. To the period of hyperthyroidism succeeds a period of hypothyroidism resulting in myxedema. * *F * KF * SYPHILIS OF THE THYROID is more common than is suspected. In children, hereditary syphilitic sclerosis is possible in a certain number of cases of myxedema, and specific treat- ment is indicated in these cases as well as organo therapy. Acquired syphilis is better known. During the second- ary stage can be observed temporary congestions of the thyroid. Tertiary thyroiditis or gumma of the thyroid THE SYMPATHETIC SYSTEM 101 are found nearly always in women with a small goitre which has not been detected. From a clinical point of view, syphilis of the thyroid causes either a myxedema or Basedow’s disease or a goitre simulating a cancer. Certain cases of conjugal or familial Basedow’s disease are due to syphilis (Schulman). It, therefore, plays an important part in the etiology of exophthalmic goitre. Mercurial or arsenical treatment can be employed indifferently. Iodides must be used with caution, although some of these cases will be greatly benefited by it. Estimation of the Basal Metabolism can be used as an index of the activity of the Thyroid. A Subnormal Basal Metabolism indicating Hypothyroidism, while an increase is evidence of overactivity of the gland. CHAPTER II. I. PATHOLOGY OF THE PARATHYROID GLANDS. FUNCTIONS OF THE PARATHYROIDS The parathyroid glands were discovered by Sabdstroem in 1880. They consist of two pairs of small glands, the size of a lentil, situated on either side of the thyroid. There are two superior parathyroids corresponding to the union of the upper and lower two thirds of each lobe of the thyroid (sometimes they are included in the thyroid itself) and two inferior parathyroids on the lateral sur- face of the gland, in the neighborhood of the inferior thyroid artery. It has the structure of a gland of internal secretion although different from the thyroid. It consists of rows of glandular cells in intimate contact with the blood and lymphatic capillaries. The product of their secretions is not yet well deter- mined. All that we know is that the parathyroid cells contain a colloidal substance; iodine, glycogen, and various fatty substances, the exact part played by them not having been yet determined. ' The parathyroid have certain peculiar physiological properties brought out at first by Gley and de Moussu and since then by other investigators. Their destruction in animals results in three types of disorders: nervous, toxic and trophic. 1.—NeErvovus DisorpEers.—In the cat or the dog, in which all the parathyroids have been removed, certain phenomena occur two to three days after the operation. The animal begins to shake, has muscular tremors and 102 THE SYMPATHETIC SYSTEM 103 contractures of the muscles of the feet, neck and from time to time generalized convulsions. The following days these phenomena become more frequent and more pro- nounced. It becomes impossible for the animal to stand up; it becomes cachectic and dies usually in from eight to ten days after the operation. The total extirpation of the parathyroids, therefore, brings on fatal symptoms of tetany. The experimental cases which do not follow this rule are explained by an incomplete removal or the existence of accessory glands and are proved by autopsy. 2.—Toxic DisturBANcEs.—The animal whose parathy- roid has been removed shows digestive disturbances (loss of appetite, dysphagia, intense thirst, abundant salivation, frequent vomiting), a rapid breathing, an increased heart rate; the excretion of urine is decreased, contains albumin and often sugar and diacetic acid. All these symptoms being signs of intoxication. 3.—Tropuic DisturRBANcES.—They are observed in young animals who have only had a partial parathyroi- dectomy; arrest of development, loss of hair, cutaneous ulcerations, dental changes, etc. Of all the disturbances, the first are the most important. The complete removal of these glands is incompatible with ‘life. It determines symptoms of neuro muscular hyper- excitability (contractures and convulsions), comparable to those observed in man during tetany. PARATHYROID SYNDROMES. I. PARATHYROID INSUFFICIENCY AND TETANY. Tetany is characterized by attacks of painful contrac- tures localized to certain muscles (usually those of the extremities) and more rarely generalized. This affection was first described by Dance then Tonnele 104 ENDOCRINE GLANDS and was considered for a long time to be of rheumatic origin or to be a variety of tetanus. It is following the experimental researches of Gley and Moussy in France, that certain clinicians, struck by the clinical resemblance between human tetany and the nervous phenomena observed in animals after the removal of the parathyroids, suggested that this disease might be the result of a dis- turbance of the function of the parathyroids. THE SYNDROME OF TETANY. Tetany must not be considered as an autonomous affection, but as a syndrome coming on under a variety of conditions and characterized on one side by contractures, on the other by a mechanical and electrical hyperexcita- bility of the nerves and muscles. A. ConTRaAcTuRES.—They are usually symmetrical and localized to the extremities. They are preceded by tingling and a sensation of falling asleep of the part which is some- what painful. It affects the muscles of the hands and feet. The hand can take one of two characteristic attitudes. It takes the shape of a cone due to the forced adduction of the thumb and all the other fingers pressed tightly against each other and in which the first phalynx is half flexed, while the other two are extended. In the cases in which the hand is cupped, it resembles the position of an obstetrician making an examination. Sometimes the thumb is flexed in the palm and completely covered by the other fingers, also flexed. The contrac- ture is sometimes so marked that the nails penetrate into the palm. The foot gives a similar deformity and was described by Escherisch under the name of carpo-pedal spasm: the - foot is in varus equinus; the planter surface is cupped and the toes are flexed. THE SYMPATHETIC SYSTEM 105 These contractures are painful, involuntary and resist all attempts to overcome them. They occur after a simple movement, a change of position or without any apparent cause. They can be brought out by Trousseau’s sign: a com- pression of the arm at the level of the median nerve or above the clavicle at the height of the brachial plexus, will cause a tingling sensation followed by a contracture. In some cases, these contractures become generalized and invade the upper limbs, the trunk. the legs, and the face. The hands become flexed at an acute angle to the wrists, the forearms on the arms; the latter are pressed tightly against the body. The legs are usually in exten- sion. In the face the contractures are manifested by trismus, spasm of the eyelids and a sardonic smile. The lips are pushed forwards and simulate the mouth of a fish. The contracture may involve the muscles of the pharynx (dysphagia) and the larynx (spasm of the glottis), the vesicle sphincter (retention of urine), etc. Its generali- zation resembles the clinical picture of tetanus. In certain abnormal cases the contracture stays localized to a group of muscles (muscles of one of the hands, for instance) or to one muscle (contracture of the thumb, spasm of the eyelids). The most important of these iso- lated contractures is that involving the muscles of the larynx. As has been shown by Bouchut, Laryngospasm is always a symptom of tetany. The spasm is then called phreno glottic. Laryngospasm is often seen in the tetany of infants. B. HyperexciTaBILity oF THE NERVES AND Mus- cLEs.—This can be brought out by means of mechani- cal or electrical stimulations. (a) The percussion of the facial nerve, done on the middle of a line between the external auditory canal and 106 ENDOCRINE GLANDS the labial commissure, causes a sudden contraction of the muscles of the commissure and those of the side of the nose, sometimes even one-half of the face. This is Chvostek’s sign. Weiss’s sign is analogous: percussion performed on the superior branch of the facial at the level of the external angle of the orbit causes a contraction of the frontal muscle and those of the eyelids. (b) Investigation of the electrical excitability gives the following reactions: 1.—Galvanic hyperexcitability of the nerves and muscles and the possibility of obtaining muscular con- tractures on the closure of the Cathode with a current of loss of 1 milliampere. This is what has been termed Erb’s sign. 2.—Hyperexcitability at the anodal opening current and predominence of the contraction on opening instead of a closing as normally occurs. 3.—Hyperexcitability at the Cathodal opening and the possibility of obtaining opening contractions with a current of less than five milliamperes. These reactions are characteristic of tetany. (c} Accessory Symptoms.—The reflexes are often exaggerated. Sensory disturbances are missing, except in very severe cases, which are accompanied by cramps and sharp stabbing pains. There are no sphincter disturb- ances outside of retention of urine from spasm of the sphincter. The temperature is usually normal except in very severe cases. The examination of the cerebro spinal fluid does not show any evidence of meningitis. In certain chronic cases vaso motor disturbances may occur: indurated edema of the back, of the hand, or of the foot, redness or cyanosis of the extremities, or of the face and during the attack trophic changes; falling out of the hairs, brittle nails, etc., as in experimental tetany. THE SYMPATHETIC SYSTEM 107 COURSE—DURATION—ENDING. In the mild cases the contractures stay localized to the ends of the upper extremities. They occur in attacks lasting anywhere from a few minutes to a few hours; rarely they may persist several days. A series of repeated attacks constitutes an attack of tetany; these attacks last on an average of about two weeks and end in recovery. Recurrences are, however, frequent. In the moderately severe cases, the contractures are more pronounced. They are often accompanied by a slight fever, general malaise and vaso motor disturbances, erythema and edema. They can become generalized and involve the muscles of the trunk and the face, simu- lating tetanus. In the severe cases, particularly in children, the con- tractures are accompanied by or alternate with tonic or clonic convulsions, followed by a coma and comparable to an epileptic attack. In all those types of cases, death may occur by asphyxia, due to spasm of the glottis and contracture of the respira- tory muscles (this is a real danger in infants), or by eclampsia during one of the epileptiform attacks. For this reason, the prognosis of tetany should always be guarded even in the mild cases. CLINICAL MANIFESTATIONS OF TETANY. I. SURGICAL TETANY OR POSTOPERATIVE TETANY. This was first observed by Nathan Weiss in 1880 following the removal of a goitre. It was described by J. L. and A. Reverdin and by Kocher. The disease manifests itself a few hours or a few days after intervention by a prickling sensation or stabbing pains in the limbs. Attacks of painful contractures 108 ENDOCRINE GLANDS occur, symmetrically localized to the fingers of the hand. This takes on the typical “obstetrical hand” appearance. These contractures may involve the feet or become gener- alized. The electric reaction shows a hyperexcitability and tetany. The mechanical hyperexcitability of the nerves is easily brought out by the Trousseau and Chvostek signs. The attacks, sometimes short, sometimes long, re-occur after a certain interval. They are often accom- panied by fever, acceleration of the pulse, intense dyspnea, salivation and vomiting. All of which are toxic symptoms similar to those seen in experimental tetany. Post operative tetany does not always manifest itself under this typical form. There are also convulsive forms (Fr. Hochwart) characterized by clonic or tonic con- vulsions and periods of quiescence. This condition sometimes gets well spontaneously and completely. It can also become chronic, the attacks occurring at long intervals, but persisting for years. . Kocher has observed it associated with myxedema. Some cases die, either as a result of spasm of the glottis or after a convulsion. II. MEDICAL OR SPONTANEOUS TETANY. This condition is seen: 1.—During the course of some cerebro spinal affection, especially in tuberculous meningitis, cerebro spinal menin- gitis, hemorrhages of the meninges, hydrocephalus, etc. In these cases tetany is only a nervous syndrome added to the primary infection. 2.—Following gastro intestinal disorders.—In children various gastro intestinal affections are often complicated by attacks of tetany. In adults, the most common cause is a gastric affection. Tetany is observed in the course of pyloric stenosis of ulcerative or neoplastic origin, following THE SYMPATHETIC SYSTEM 109 the vomiting, or when patients have used stomach lavage extensively. It may appear as localized contractures ,or generalized as epileptiform attacks, sometimes even it may take on a chronic appearance. Its prognosis is severe, particularly by reason of the lesions which bring it on. 3.—In the course of infectious diseases —Typhoid fever, dysentery, cholera, measles, influenza, diphtheria, etc.; these can become complicated by tetany. This condition is usually mild; nearly always gets well and does not re-occur. 4.—In various types of intoxications.—Toxic tetany are very rare. They have been reported in delirium tremens, chloroform poisoning and uremia. 5.—Alt various periods of the genital life of women.— Tetany is occasionally met with at puberty. Rebaud considers this as a premonitory sign of menstruation. It disappears once menstruation has become regularly estab- lished. It is also reported during pregnancy. It ceases usually towards the sixth month, but is a rather serious complication, for the attacks are usually painful and last a long time. It may also occur after delivery in nursing mothers. It always gets well, but a recurrence is possible during each pregnancy and each lactation period. Finally Delpech and Dalche have seen it at the beginning of the menopause. IpropaTuic TetTany.—lIt is most frequent during the first two years of life, but is sometimes observed in adults, usually in men between 16 and 25, nearly always in winter. Tetany of infants occurs during a variety of diseases: measles, broncho pneumonia, athrepsia, congenital syphi- lis, etc. Two diseases play a preponderant part in the causation of this disease: rickets and gastro enteritis. But tetany may occur in infants without rickets, without any gastro intestinal disorders, and without any other disease. 110 ENDOCRINE GLANDS DIAGNOSIS. The diagnosis of the tetany syndrome is very simple. There is no disease simulating tetany, when the latter is characterized by localized contractures of the extremities occurring at intervals. A differential diagnosis has only to be made in the chronic or generalized forms, in which the contractures last for a longer period of time. Tetanus is distinguished from it by the mode of onset of the contractures. The latter begins with the masseter muscles; trismus is an early sign, then comes dysphagia and then contractures of the back of the neck, trunk and extremities. In tetany trismus is missing or only appears late in the disease and the contractures begin with the upper limbs. The temperature is never as high as in tetanus: sweats are absent. 'Trousseau’s sign, Chvostek’s sign, and Erb’s sign are missing in tetanus. The contractures caused by encephalo medullary organic lesions are permanent and associated with exaggeration of the reflexes and motor paralysis, the spasm affects all the limbs and not only their extremities. Hysterical contractures have not the aspect of the evolution of tetany, and have none of the electrical or mechanical signs of the disease. Lumbar puncture enables us to differentiate sympto- matic tetany from meningeal affections. PATHOGENESIS. RELATION BETWEEN TETANY AND PARATHYROID INSUFFICIENCY. We do not yet know the anatomical lesions causing tetany. This disease, which has been believed to be due to rheumatism, a central nervous affection, is at present considered as the expression of a parathyroid insufficiency. THE SYMPATHETIC SYSTEM 111 Post operative tetany, described under the name of strumic tetany or acute post operative myxedema, is due, without a doubt, to destruction of the parathyroids in the course of partial or complete thyroidectomies. Can medical tetany be considered as a manifestation of parathyroid insufficiency? Pineles has shown the clinical identity of the different types of tetany. In all the cases of tetany, be they post operative, infantile, gravid or idiopathic, the chief signs of the syndrome are present: contractures, convulsions, hyperexcitability of the nerves, electrical reactions. Furthermore, experi- mental tetany shows very similar symptoms. In animals in which the parathyroids have been removed, not only are the severe symptoms present but also the electrical hyperexcitability of the nerves. (a) InrantTILE TreTany.—Many types of lesions of the parathyroids have been observed at autopsy of children having shown symptoms of tetany. The most frequent are hemorrhages in the glands. Described by Erdheim, they have been studied by Yanase, Harvier, Strada, Auerbach, etc. They can be seen with the naked eye when the lesions are extensive. When they are discrete they can only be seen under the microscope. They are rarely found in all the glands; in the majority — of cases only one or two glands are affected. The cause of these hemorrhages is unknown and their frequency very variable according to the writers. In certain cases, generalized or localized glandular sclerosis has been noticed; in others, simple anomalies of the parathyroids, either in size or the number of the glands. These various alterations, or anomalies, cannot be considered as the determining cause of tetany. They are also found in children who have never had any signs of tetany (Harvier, Auerbach, Strada). Furthermore, cer- 112 ENDOCRINE GLANDS tain observers have not found any lesions of the para- thyroids in children dying from tetany (Thiemisch, Ravenna, etc.). (b) MaternaL Tretany.—Vassale and his pupils have established in classical experiments the influence of preg- nancy and lactation on the appearance of symptoms of tetany. Animals having had a well tolerated partial parathyroidectomy (a state of relative parathyroid insufficiency), presented in a subsequent pregnancy a severe or fatal tetany. Lactation had an analogous effect. A few autopsies of pregnant women dying from the eclamptic form of tetany have shown the presence of anomalies on lesions of the parathyroids (Pepere, Haberfeld). Finally, Vassale claims to have obtained excellent results by parathyroid organo therapy in certain cases of tetany. These facts have allowed us to conclude that certain pregnant women have a latent or even relative parathyroid insufficiency, capable of becoming more pronounced dur- ing pregnancy (under the influence of some endogenous intoxication; hepatic insufficiency for instance), at time of delivery (due to extra muscular fatigue), and during lacta- tion (by depletion of minerals). The remarkable likeness between experimental parathyroid eclampsia of the preg- nant female and the spontaneous eclampsia of the pregnant woman have caused certain writers to believe, as does Vassale, that eclampsia is of parathyroid origin. This theory cannot be accepted without a certain reserve; it is very probable that all cases of eclampsia are not due to parathyroid insufficiency. (c) Gastro InTEsTINAL TreTANy.—It has not been possible to reproduce it experimentally. The anatomical reports on the condition of these glands in this type of tetany are rare and not very convincing. It is possible, furthermore, that the action of the toxic substances on the THE SYMPATHETIC SYSTEM 113 nervous system, resulting from pyloric stenosis or other intestinal affections, are sufficient to explain the tetany manifestations without it being necessary to invoke the action of the parathyroids. (d) The action of the parathyroids in the other types of cases is doubtful and questionable. Histological exami- nation in tetany of infectious origin in adults is missing. In a tuberculous woman, developing tetany, Carnot and Delion found a tuberculous caseation of one of the glands, but were unable to find some of the other parathyroids. Winternitz in 1905 published a similar report. When all is said, only the post operative forms of tetany can be considered unquestionably to be due to parathyroid insufficiency. Medical tetany, because of its’ similarity to surgical tetany, has a possible parathyroid etiology, but the anatomical reports and the results of organo therapy do not allow us yet to confirm this possibility in all the cases observed. How does parathyroid insufficiency determine tetany? Two theories are suggested: 1.—Catcium Turory.—The observations of Loeb, who in 1900 showed the relationship between neuro muscular hyperexcitability with a decrease in the calctum salts, then the experimental work of Frouin, Parhon and Urechie, showing that the absorption of calcium chloride after parathyroidectomy, prevented the appearance of the nervous symptoms, have led us to believe that para- thyroid insufficiency caused an excessive secretion of calcium. The parathyroid glands regulate the metabol- ism of calcium, just as the pancreas regulates that of glucose. They have an inhibitory action on the excretion of calcium. Tetany is a calcium diabetes. 2.—Toxic Turory.—According to Pfeiffer and Mayer, Berkeley and Beebe the accidents of tetany are of a toxic 8 114 ENDOCRINE GLANDS nature. They are produced by endogenous poisons nor+ mally destroyed by the glands or neutralized by their secretions. Among these poisons, the most important would be guanidine, one of the by-products of nitrogen metabolism (N. Paton and Findlay). TREATMENT. Post operative tetany necessitates a preventative and curative therapy. To avoid any accident the surgeons have devised various manners of performing thyroidectomy so as to avoid the parathyroids. The main idea consists in avoiding any manipulation in the neighborhood of the glands. When tetany does occur after removal of the thyroid, two types of medication can be given: 1.—Symptomatic Merpication.—Anti spasmotic (chlo- ral and bromides), calcium medication has given good results in the shape of the lactate or the chlorides (Mayo, Grath, Meltzer). The daily dose is from 2 to 6 grams. 2.—Sprciric Mepication.—This includes organo ther- apy and parathyroid grafts. The ingestion of fresh glands, or the injection of para- thyroid extracts have caused the various phenomena to disappear in the patients of Callum, Pool, Halsted, etc. We must, however, add that the majority of these cases only had had a partial removal of the parathyroids. The action of organo therapy is temporary and by preventing the various symptoms developing, allows a compensatory hypertrophy of the remaining glands until these are capable of carrying on their function. Parathyroid grafts have the advantage, when successful, of assuring permanently the glandular function. It un- fortunately has many technical difficulties. However, when during the course of a surgical operation, it is found THE SYMPATHETIC SYSTEM 115 that one or more of the parathyroids has been removed, auto graft should be done at once in the parenchyma of the thyroid, where it has a good chance to succeed. In the majority of cases, however, it is only performed after the appearance of the symptoms of tetany; auto graft is then impossible and specimens must be obtained from other individuals. As animal grafts do not succeed, they have to be obtained from individuals who have died in an accident or to remove one of the parathyroids in a patient who is operated upon for goitre. Human graft has been successful in the hands of Pool, Czerny, Kocher, etc. 3.—Symptomatic medical tetany disappears with their cause and their treatment is related to the primary disease: diphtheria antitoxin in diphtheria, tetanus antitoxin in tetanus, lumbar puncture in meningeal affections, etc. 4.—Idiopathic tetany is treated by tepid baths, seda- tives: bromides, chloral and calcium chloride. Parathyroid organo therapy is given under the form of a fluid extract, given in doses of from 60 to 100 drops daily, or the dried extract of ox or horse gland, given in doses of from 5 to 20 milligrams daily. Marinesco, Vassale, Zanfrognini, etc., have obtained good results with this in infantile and gravid tetany. The failures are, however more numerous than the successes. i II. POSSIBLE PARATHYROID SYNDROMES. So called essential epilepsy has been suggested as being of possible parathyroid etiology. Vassale, Parhon and Golstein have obtained favorable results in epilepsy with parathyroid medication. Claude, Schmiergeld and Schmorl have found at autopsies of epileptics numerous appreciable lesions of the parathyroids. Other glands, however, such as, the thyroid for instance, are affected just as frequently and the parathyroid theory of epilepsy is still to be proved. 116 ENDOCRINE GLANDS PARKINSON’S disease was considered by Lundborg in 1904 as a chronic syndrome of parathyroid insufficiency. Parathyroid organo therapy when it has been tried has however given very contradictory results and, further- more, the anatomical study of these glands in Parkinson’s disease has never shown constant lesions. J. Gauthier who has recently taken up this disease, as regards to its relation to endocrines, believes it to be due to a thyroid- parathyroid insufficiency. All these facts are hypothetical and very questionable. Ill, SUDDEN DEATH IN CHILDREN AND LESIONS OF THE PARATHYROIDS. The part played by the parathyroids in the pathogenesis of sudden death in children is still to be determined. We have, however, a few cases which help us to interpret it. One of these was reported by Triboulet, Ribadeau-Dumas and Harvier and occurred in a congenital syphilitic, one month old infant. Autopsy showed a variety of lesions of the blood organs: adrenals, pituitary, thyroid and parathyroids. The latter showed severe hemorrhages and contained trepenoma. Grosser and Berke found on post mortem examination of three infants, who died very suddenly, hemorrhages localized to all the parathyroids. It is, therefore, important in all autopsies of children dying very suddenly to examine parathyroid glands, as well as the other endocrines. CHAPTER III. I. PATHOLOGY OF THE THYMUS. FUNCTIONS OF THE THYMUS. The thymus in man consists of a cervical part, made up of two diverging cones, which are attached to the thyroid by fibrous tissue and are closely approximated to the brachio cephalic and jugular venous trunks and a medias- tinal part located between the chondro-sternal portion of the thoracic cage in front, and the pericardium and the large vessels at the base of the heart and the right ventricle in the back. In the child, the thymus is a reddish gland, of soft con- sistency, plastic, which moulds itself to the blood vessels, insinuates itself between them and comes in contact with the anterior surface of the trachea. It is not a definitely demarcated organ: at a certain time of life it atrophies, but does not, however, disappear completely. There is a fatty change in the gland, but glandular lobules still persist and in certain pathological conditions can regenerate. The time at which the thymus reaches its greatest period of development and the time at which it begins to atrophy is still unsettled. The French investigators give as the weight of the thymus the following figures: at birth 3 to 5 grams (Hutinel and Tixier, Cruchet); at one year from 5 to 8 grams (Marfan); between 3 and 4 years from 7 to 9 grams. According to some the regression begins at the age of two, for others at four. Hammer, and then Sury, by studying the weight of the thymus in individuals dying in accidents give very differ- ent figures: at birth the thymus weighs 13 grams; from 1 to 5 years of age about 22 grams; from 6 to 10 years 117 118 ENDOCRINE GLANDS about 26 grams and from 11 to 15, 37 grams on the average. According to these writers, the weights usually given are erroneous, due to the fact that various illnesses influence the weight of the gland. It quite rapidly becomes atrophic when the nutrition becomes deficient, in various types of infantile cachexia, and during acute infections: measles, scarlet fever, diphtheria, etc. The histological investigations of Roger and Ghika, of Lucien and Parisot have shown the frequency of thymus lesions in the young, indicating a marked degeneration of the gland. Next to the physiological evolution and parallel to it there exists a pathological evolution, which may affect the first. In spite of all this, it seems to be generally admitted that the normal involution of the thymus does not-begin until between the 10th and 15th year. Until puberty it grows regularly and then gradually regresses. The thymus is at the same time a lymphoid, blood forming and internal secretion organ, for its removal in animals causes a variety of symptoms. The functions of the thymus which up to the present time have been well established are: 1.—AcTION ON GROWTH AND DEVELOPMENT OF THE SKELETON.—This has been shown by the experiments of Tarulli, Lo Menace, Basch, Lucien, Parisot, and U. Seli. Animals in which the thymus was removed show a delay in growth, a reduction in height and volume of the bones. According to Basch, the bones are more flexible and trans- parent than normal, due to a decrease in the calcium content. According to Lucien, Parisot and U. Seli, however, the calcium content remains normal and the resistance of the bones is not decreased. The earlier the animal is operated upon, the more marked the delay in growth. There is practically no change if the animal has reached its normal growth. THE SYMPATHETIC SYSTEM 119 2.—AcTION oN GeNERAL Nutriti0N.—It is parallel to the preceding. After the removal of the thymus the weight curve decreases slowly in comparison to that of controls. 3.—ACTION OF THE GENITAL GLANDS.— The develop- ment of the ovary and testicle shows a marked delay after the removal of this gland. It seems as if there was a balance between the thymus and the genital organs and that the thymic involution begins at puberty at the time. when the genital glands become active.! In the castrated male animals, the thymus atrophies much later than in controls (Cazolari). 4.—AcTION ON THE BLoop PressurE.—Extracts of CEs thymus taken from children or animals, injected intra- venously cause a marked drop in the arterial pressure. This hypotensive action which also belongs to the extract of lymph glands, should not be looked on as the result of an internal secretion. In athrepsia, atrophy of the gland goes hand in hand with a decrease with its hypotensive properties (Lucien and Parisot). When all is said, there probably is an internal seein to the thymus, although we do not know of any specific substance in this gland; its constituents have not the appearance of a glandular epithelium, and the clinical suppression of the thymus does not cause a clinical syn- drome comparable to the removal of the thyroid or the parathyroids. le THYMIC SYNDROMES— a A. SYNDROMES OF THYMIC HYPERPLASIA. ys ET The thymus is affected by acute or chronic oe (Roger and Ghika), but this reaction is purely histological. There are no clinical evidences of this ‘Clinically the administration of thymus extract controls menorrhagia and metrorrhagia when due to functional hyper ovarian stimulation. In fact in cases of uterine bleeding of obscure origin thymus can be used as a therapeutic test. 120 ENDOCRINE GLANDS In certain cases, hyperplasia of the thymus causes in young infants a very definite clinical syndrome commonly known under the name of enlargement of the thymus. I. HYPERTROPHY OF THE THYMUS. SYMPTOMS. We will simply give the chief clinical findings. In its usual form, it is characterized by respiratory and circulatory disturbances. The child has a loud and harsh inspiration and expiration; inspiration is, however, the louder of the two. This is associated with a marked drawing in. Attacks of suffocation occur which may last from a few seconds to quite a long period of time, and in which asphyxia and even death may occur. During these attacks, and also during the interval, the veins of the neck are prominent and the face is cyanotic, showing a disturb- ance in circulation. These attacks come on without any apparent reason or after a fit of temper or tears. The drawing in of inspiration, the cyanosis and the inspiratory and expiratory rales are exaggerated in certain positions; such as, in the hyperextension of the head for instance. In other types of cases, the respiratory disturbances are not continuous. Periods of suffocation do occur, but in between respiration is normal. Percussion of the manubrium and the radioscopic examination of the mediastinum allow us to find the cause of these respiratory difficulties in a hypertrophy of the thymus and differentiate this condition from analogous conditions of childhood. In these cases the therapeutic indications may be Radiotherapy or partial removal of the thymus. ETIOLOGY. We do not know the causes of thymus hypertrophy. Marfan considers it as one of the forms of proliferation of THE SYMPATHETIC SYSTEM 121 the hemo lymphatic organs, due to infections or auto intoxication of infancy: syphilis and tuberculosis would seem to be the most important. The disease occurs often in association with rickets and enlargement of the spleen. Very often however, it is an isolated affection observed among apparently healthy children without any evidence of rickets or any other disease. PATHOLOGICAL ANATOMY. The weight of the thymus varies between 25 and 200 grams. The gland may keep its normal aspect; that is, simply enlarged. Sometimes it is red, congested, more resistant than normal and filled with fluid when incised. The histological examination then reveals the reactions to an infection of the thymus: lymphocytes replaced by mononuclears, polynuclears, myeclocytes, corpuscles of Hassal showing recent degenerations. The blood vessels are dilated, filled with red cells, the tissues sometimes con- tain hemorrhagic foci visible to the naked eye. PATHOGENESIS. How does a hypertrophy of the thymus cause respira- tory difficulties? The trachea is the first organ to which attention is drawn. Its compression has shown during life by means of the tracheoscope: Jackson noticed its flattening at the superior level of the thorax. The opera- tive observations in the course of thymedectomy and num- erous autopsies have shown the trachea bent, flattened and crushed. To see these changes at autopsy it is neces- sary to take certain precautions, as due to its elasticity, the trachea will take up its normal position again, as soon as the thorax is opened. _It is necessary to remove, as one mass, the thymus, the trachea and the large vessels and fix this mass in formaldehyde before studying the relation- 122 ENDOCRINE GLANDS ship of the different organs or, again, as advised by Marfan perform the autopsy in this region by following the opera- tive technique without opening the thoracic cage. The capsule of the thymus being incised, pressure is exerted on the lateral sides of the thorax and this will cause the thymus to rise above the manubrium. It then becomes easy to determine if it is exerting any pressure on the trachea. The question has come up as to how such a soft organ as the thymus could cause any effect on such a resistant organ as the trachea. This is due to the fact that the gland acts less by its weight than by its volume and this varies according to the circulatory conditions. The trachea can also be compressed indirectly by the inter- mediary of the large vessels at the base of the heart. In an observation of Barbier the right trachio cephalic arterial trunk deviated by the thymus had compressed and formed a groove in the trachea, which it com- presses directly. The large veins at the base of the neck can also be more and more flattened out by a hypertrophic thymus. Al- though this compression is hard to determine at autopsy it is very probable and such a theory alone could explain the cyanosis increased by extension of the head.