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 \y^.tXJi..,J.,.^tU.A-' , C/J/-^i.A.^ 
 
 Q 
 
 CASE OF 
 
 ^ 
 
 ^^t%n%m\ fenittious 2ln»^ww 
 
 (IDIOPATHIC OF ADDISON.j 
 
 BV 
 
 WILLIAM G A R I) N E R. M . D 
 
 Pk ..fisou OF Medical .InmspiiuDBNOH, 
 McGiLL Univehsity ; 
 
 WILLIAM OSLER. M.I).. L.R.C.P. Lc.ni>., 
 
 FiioPKssoB OF Institutes ok Medicine, 
 McGiLi, Univeubity. 
 
 RepTinted Jrom Canada Medical and Suugical JoiniNAL, March, 1877. 
 
 Irtotttral : 
 
 PRINTEO AT rilK "(JAZETTE" PUINI'ING HOUSE. 
 
:^k : 
 
 m- \ 
 
 'Aj.^, 
 
T 
 
 CASE OF 
 
 |}i'(iiji'c$$iirt |li>i*aifr(ri($ %imm 
 
 (IDIOPATHIC OF ADDISOxV.) 
 
 nv 
 
 WILLIAM G A R D x\ E R , M . D . , 
 
 PROPESson OF Medical Juiiisr-.-DEN-CE. 
 McGiLi, UxivKnsiTv ; 
 
 AND 
 
 WILLIAM OSLER, M.D., L.R.C.P. Lond., 
 
 Professor of Ixstitutes of Medicixe, 
 McGiLL Umveusity. 
 
 tlfprinled from Canada Medic ai, and Scrgical Jocrxal, March, 1877. 
 
 PRINTED At tllt<: "GAZETTE" PRIXTING HOUSE. 
 
" 
 
A CASE OF 
 
 PROGRESSIVE PERNICIOUS ANAEMIA. 
 
 (IDIOPATHIC OF ADDISON.) 
 
 The following case occurring in the practice of Dr. Gardner, 
 is recorded as a contribution to the literature of a disease, rare, 
 but by no means new, in any sense, concerning the pathology 
 of which we have still a good deal to learn, and concerning the 
 succesful treatment of which we as yet know nothing. 
 
 G. A., set. 52, a native of England, employed in a spike fac- 
 tory, first came under observation on the 5th November, 1876. 
 He is a thin, spare, moderately well-built man of average 
 stature, and with gray hair and beard. 
 
 He is one of a large family, all of whom, except some who 
 died in infancy, are now alive, liis mother was very subject to 
 diarrhoea. All of the family have had at one time or another 
 serious illnesses, which, however, in their nature, have no 
 bearing on the present case. Two or three members of the 
 family have had a tendency to bleeding at the nose. 
 
DnS. QARDNEIl i OSLER. 
 
 At tlic age of between six and seven, shortly after coming to 
 Canada, he had a long illness of live or six months duration, 
 the nature of which, beyond the fact that it was attended with 
 fever of remittent type, could not bo ascertained. After 
 recovering from this illness, he contiuiicd to bo very healthy 
 <and active, suffering from little except somewhat frequent, slight, 
 nnd easily-controlled bleedings from the nose. lie never had 
 liad free bleeding from slight wounds. lie was, however, subject 
 to occasional attacks of diarrhoea. During the last few years 
 he had occasional attacks of lumbago, and pains in some of his 
 joints. None of these complaints prevented him for more than 
 a few days from continuing his employment, which, until within 
 some months previous to his ^ ing laid up, involved a great deal 
 of muscular exertion. 
 
 About five years ago he lost, within three months, the only 
 two sons of his family, and his friends assert that, although he 
 did not display much emotion, he took the bereavement very 
 much to heart, and that since then his health has greatly failed, 
 that in particular he has become weaker and lost colour. 
 
 Nearly two years ago this became so decided, that his friends 
 induced him to go away for change of air. He accordingly 
 went to Toronto on a visit to a sister. During the first few days 
 he felt better, but after exposure to cold and wet he was seized 
 with an illness, setting in with rigors, and attended with cough, 
 bloody sputa, and delirium. This illness lasted a fortnight, 
 and was called by his medical attendant congestion of the lungs. 
 
 Ever since this illness he has been gradually growing paler 
 and weaker, and liable during the summers, especially that of 
 1876, to frequent diarrhoea, never very severe, but rather 
 constctnt. lie would often have in the morning one or two loose 
 motions, and during the day have no further trouble from it. 
 
 The symptoms of which he specially complained were 
 weakness, attacks of shortness of breath, when he walked 
 in the cold air, especially if he faced a wind, and diarrhoea — 
 five or six motions in each twenty-four hours. Notwithstand- 
 ing these symptoms he bad been attending regularly to his 
 occupation, which, however, did not involve much muscular 
 
PROGRESSIVE PERNICIOUS ANAEMIA. 
 
 3 
 
 exertion. At this time the most striking feature of liis case was 
 a remarkable waxy pallor of the skin and mucous membranes, 
 and a pearly appearance of the white of the eyes. lie is some- 
 what deaf; this he attributes to his occupation in a noisy 
 workshop. 
 
 Pulse rather more frequent than normal ; temperature normal. 
 Appetite by his own account and that of his friends, is good — 
 he is able to cat meat ; suffers no distress after food. Sleeps 
 very soundly, and sleeps a great deal, much more than previous 
 to the failure of his health. If he sits down and is let alone 
 he is sure to go asleep. Is compelled to be up two or three 
 times each night to make water. Urine very highly coloured ; 
 (juantity in twenty-four hours thirty-four to forty ounces ; 
 specific gravity varied from 1012 to 1016 at difl'ercnt times ; 
 no albumen ; no sugar ; no bile pigment ; no tube casts. 
 
 Complains of some numbness of his fingers, hands and fore- 
 arms ; has difficulty in buttoning his clothes, or in using his 
 tools. Complains of a throbbing, rushing sensation in his temples. 
 Says that he has suffered from decided diarruoca for rather more 
 than a month, but the number of motions in each twenty four hours 
 has not exceeded five or six. They have been painless and free 
 from blood. Physical examination of the chest reveals nothing 
 abnormal. The superficial cardiac dulness is normal in extent ; 
 the apex-beat natural in position ; heart-sounds not specially 
 changed — the first sound perhaps less accentuated than normal. 
 There is a distinct bruit in the vessels of the neck and upper 
 part of the chest. 
 
 The spleen is normal in size, or at all events not enlarged ; 
 the hver not enlarged. 
 
 The most careful examination reveals nowhere any pigmenta- 
 tion or bronzins; of the skin. There is not the sliditest evidence 
 of enlargement of any of the superficial lymphatic glands. The 
 symptom of which he complained most was the shortness of breath, 
 which, as already mentioned, came on when he attempted 
 to walk facing a wind, and was so urgent as to compel him to 
 stop for a minute or two till he recovered his breath. 
 
DRS. GARDNER 4 OSLER. 
 
 The liq. fcrri pernitrati3 was prescribed in doses of fifteen 
 minims in a wine glassful of water three times a day, and also a 
 diet from which vegetables and fruits were to be excluded. At 
 the end of a week ho returned to say that his diarrhoea had 
 almost ceased, and that he fancied himself a little better. As 
 on the previous occasion, he had walked from his house — fully 
 three-quarters of a mile. There was no other change to note 
 in the symptoms. 
 
 He continued to come regularly at intervals of a week for 
 the next three weeks. During this time the diarrhoea had 
 entirely left him ; he was, he said, eating fairly, yet he was 
 growing steadily Aveaker. The numbness of the fingers, hands 
 and forearms was more marked, the difficulty in buttoning 
 his clothes greater, the throbbing and rushing sensations in the 
 head more distressing and the drowsiness more troublesome. A 
 loud systolic bruit, much intensified by exertion, had developed 
 in the region of the heart, loudest at the base, but heard also at 
 the apex. The murmur in the vessels of the neck had become 
 exceedingly loud. 
 
 At this time there was no oedema of face or ankles. The 
 attacks of dyspnoea had been much mitigated by wearing a 
 respirator over the mouth on going into the cold air. 
 
 He continued to take the pernitrate of iron during the first 
 three weeks, but the only effect noticed from its use, if, indeed, 
 it deserves the credit, was the cessation of the diarrhoea. The 
 ammonio-citrate was then given instead for the next two weeks, 
 but without the least benefit. Cod liver oil was next prescribed, 
 but it disagreed so markedly that it was discontinued at once. 
 He had not been seen for a fortnight, when, on the 29th Decem- 
 ber, a message was received asking that he should be seen at 
 his house. There was little change to note in his condition, other 
 than an intensification of the symptoms previously noted. The 
 pallor was more intense, the weakness greater, the drowsiness and 
 deafness more marked, but in addition there was slight oedema 
 of tJie ankles and eyelids. Vallet's pills were now prescribed 
 and taken for a week, but without the slightest benefit, as he 
 continued to grow steadily weaker and worse, being scarcely 
 
■^1^^F^^^^^!"^P— S?5 
 
 PUOORESSIVE PERNICIOUS ANjEMIA. 5 
 
 able to leave his bed. On the evening of the 11th January of 
 the present yoar, an urgent message to see him was received. 
 On reaching his house it was found thut on being assisted out of 
 bed to make water, he had had an attack, apparently syncopal in 
 its nature, and that at times, especially ffhen left to himself, he 
 was rambling and incoherent. He, however, answered questions 
 correctly. He was very restless; pulse 110, temperature 102". 
 He had also been vomiting. 
 
 Jan. 12th. — Noon — Temperature has fallen to 101'^. Other 
 symptoms as at last report. Dr. Howard, Professor of Medi- 
 cine, McGill University, saw him in consultation at this visit, 
 and fully concurred in the diagnosis. 
 
 At 10 p. m. the pulse was 105 and the temperature 97-5° 
 Retention of urine, requiring the use of the catheter. Urine 
 very high-colored, red-brown, acidity normal, no albumen, sugar 
 or bile-pigment ; specific gravity, 1016. 
 
 Jan. Vdth.—\1 a. m.— Pulse 98, temperature, ^I'Z^. Not 
 so restless, still incoherent ; vomits everything ; catheter has 
 to be introduced regularly. 
 Jan. lAth. — Died at 3 a. m. 
 
 The blood examined during life presented the following 
 appearances in a specimen obtained, in a capillary tube, fifteen 
 hours before death, and examined without the addition of any 
 reagent, 30" after withdrawal. (Ilartnack, No. 9 im. and 
 Oc. 3.) 
 
 About one-half of the red blood corpuscles run together to 
 form rouleaux. The majority of them appear of large size, but 
 do not present the characteristic round contours of these bodies ; 
 many are ovoid, others lozenge-shaped, or of various forms, with 
 irregular projections and processes. Isolated corpuscles look 
 of the natural pale yellow colour, but the alternating light and 
 dark centre with the change of focus is not so distinct as usual. 
 On touching the top cover and causing them to roll over, many 
 do not present the biconcave appearance, but look thin and flat- 
 tened out. A limited number are crenated. In each field 
 certain small round red corpuscles are seen, sometimes as 
 many as six or eight. They are spheres, not biconcave, of 
 
6 
 
 DBS. GARDNEa & OSLER. 
 
 a pale yellow colour, occasionallj crcnated or irregular in form. 
 
 The measurements of some of the coloured elements are given 
 below (Hartnack No. IG im. ), from which an accurate idea i» 
 obtained of the remarkable discrepancies in size. About forty 
 measurements were made of corpuscles taken at random in two 
 or three specimens obtained a few days before death. Of 
 these one was t-bVj" by Wr/', being somewhat elongated. 
 Five ranged from vAV' to ij-i'b", these being the extremes. In, 
 twenty-two the range was from ^oW iiaW" to In this group the 
 usual looking red disks occurred. In five the diameter varied 
 from between (toVo" and rnW' In five the diameter Avas less 
 than the boutt", the lowest being g,,W'- 
 
 Prolonged examination failed to discover a single nucleated 
 red corpuscle. 
 
 The colourless corpuscles did not appear relatively increased. 
 One or two were seen in each field of the No. 9 and 3. The mea- 
 surements in five corpuscles ranged from ^sW to n^W' They 
 were quite natural looking, and displayed a remarkable degree of 
 vitality. In a slide mounted and surrounded with parafiine at 
 1 P.M., the amoeboid movements were very active, the tempera- 
 ture of the room being about 60*.* At 7 P.M. the slide was 
 carried in the hand a distance of a quarter of a mile to the 
 house of a friend (temperature 14.2° F.), and the irregular 
 changes in outline were still observed, and continued until 
 8:40, when the observation was omitted. There was an entire? 
 absence of Schultze's granular masses. 
 
 Autopsy, — Thirty-two hours after death. 
 
 Body that of a well-built man of fair muscular development. 
 Hair grey. No emaciation ; panniculus adiposus well devel- 
 oped, especially over abdomen. Skin of extraordinary pallor,. 
 
 • It may be here mentioned that the statement of Ranvier, Traite 
 d'Hietologie (p. 210), that the amoeboid movements of white blood corpus- 
 cles do not go on at ordinary temperatures is incorrect. In University 
 sity College Laboratory, London, it was found on one occasion that the- 
 amoeboid movement contined in the colourless corpuscles twenty-four 
 hours after removal from the body. The blood was sealed in a capillary 
 tube, and remained at the ordinary temperature in the month of June. 
 
 W. 0.. 
 
 I 
 
I'ROGUESSIVE I'EllMCIOUH AN^^EMIA. 
 
 with sli^lit lemon tint, the shoulders marked with patches of 
 deeper yellow hue. A few old psoriasis spots seen in the 
 region of tlie elbows and knees. No petechiiie. Linese albicancuw 
 in the skin of groins, and upper and outer aspect of thighs, 
 and on the outer edge of anterior folds of axill;o. Fingers 
 slightly clubbed, and the nails of both hands markedly incur- 
 vated. lligor mortis moderately well marked. Post mortem 
 stains scarcely perceptible. No enlargement of the superfi- 
 cial lymphatic glands. No cadaveric odour. 
 
 Brain. — Not examined. 
 
 On making the preliminary incision a layer of deep yellow 
 fat, fully an inch in thickness, is cut through over the abdomen. 
 Muscles of the thorax of a remarkably liealthy red colour. 
 In the abdominal cavity the position of the viscera normal. 
 Omentum moderately fatty. In the thorax a considerable 
 amount of fat over the pericardium. The left pleural sac 
 contains twelve ounces of bloody, yellowish-tinged, serum. 
 A few strong adhesions posteriorly. In the right pleural sac 
 ten to twelve ounces of fluid of the same character. Adhesions 
 more numerous at apex and sides. 
 
 Pericardium. — Contains six drachms of a yellowish, bloody 
 serum. No ecchymoses on either leaf. 
 
 Heart. — Large, excessively flabby. Sub-pericardial fat 
 abundant about the base and in the anterior ventricular groove. 
 Patch of attrition over upper part of right ventricle in front, and 
 another behind, near the inferior vena cava. On opening the 
 heart in situ an ounce of blood, with one small coagulum, 
 in the cavities of the right side, and ten drachms in those 
 of the left. Organ flaccid, and walls collapsed when laid on 
 the table. Right auricle normal. Right ventricle somewhat 
 dilated, the endocardium stained by imbibition. Tricuspid 
 valves a little thiclcened and gelatinous at the edges ; orifice of 
 normal size. Pulmonary semi-lunar valves healthy, one seg- 
 ment fenestrated. Cavity of left ventricle large, walls of 
 normal thickness. Mitral valves quite healthy, a little stained ; 
 orifice of proper size. Aortic semi-lunar valves a little opaque ; 
 slight atheroma at their bases, and on the aorta opposite their 
 
8 
 
 DRS. GARDNER & OSLER. 
 
 free borders. Sinuses of Valsalva very distinct. Nothing 
 abnormal in the left auricle. Muscle substance of the organ 
 exceedingly pale, having a yellowish, faded-leaf apj carance, 
 especially marked in the -walls of the left ventricle. 
 
 Aorta. ; both arch and trunk of full size. Beyond the left 
 sub-clavian there is a flattened patch of atheroma, about the size 
 of a half-penny. 
 
 Lungs. — Deeply pigmented ; crepitant throughout ; lower 
 lobes ocdematous and dark in colour posteriorly. The mucous 
 membrane of the Trachea at the bifurcation, and extending 
 irregularly nearly to the larynx, is represented by a number of 
 bony plates, lying immediately upon the cartilages, which are 
 themselves very dense, and partially ossified. 
 
 Spleen. — Weight, six ounces ; soft and flabby. Capsule a 
 little opaque. On section, pulp soft, of a light brownish-red 
 colour. TrabecuUx; distinct. Malpighian corpuscles not evi- 
 dent. Very little blood in the organ ; none could be obtained 
 from the splenic vein. 
 
 Left Kidney. — Length, 5 ". Unusual amount of superficial 
 fat. Capsule loosely attached, and on removal leaves a very 
 anaemic-looking organ. No atrophy of the cortex, which is 
 pale and bloodless. Pyramids, except at the bases, also pale. 
 Right Kidney^ 4J " long, dark red in colour, uniformly con- 
 gested, forming a striking contrast to the other. Capsule easily 
 detached ; stellate veins prominent. On section, both cortex 
 and medulla contain much blood. 
 
 Supra-renal Capsules. — The right is soft in the centre, and 
 somewhat larger than the left, but nothing unusual about 
 either. 
 
 Bladder. — Distended with pale urine. Mucous membrane 
 healthy looking. Prostate gland of full size. 
 
 Tonsils and glands at root of tongue not enlarged. Several 
 ecchymoses beneath the mucous membrane of the anterior wall 
 of the pharynx. (Esophagus presents nothing unusual ; a few 
 small extravasations are noticed near the cardia. 
 
 Mucous membrane of stomach pale, and at the cardiac end 
 thin ; at the pylorus it is thicker. Duodenum healthy ; common 
 
 
 ( 
 
PROGRESSIVE PERNICIOUS ANAEMIA. 
 
 9 
 
 'C 
 
 bile duct is pervious. Jejunum contains a quantity of dirty 
 yellow mucus. Mucous membrane is pale. In tbe ileum^ 
 Peyer's patclies are scarcely perceptible ; the solitary glands 
 towards the ileo-caccal valve are alone distinct. In the large 
 bowel the mucous membrane is ansemic. No ulceration. 
 Scybalse in transverse and descending colon. 
 
 Liver. — Rather small, of a light yellow colour, especially in 
 the left lobe. Capsule smooth. On section a small quantity of 
 liquid blood is seen in some of the hepatic veins. In places 
 there is a very slight injection of the intra-lobular veins, which 
 relieves the otherwise uniformly pale surface. 
 
 Gall-bladder. — Full of dark tarry bile. 
 
 Pancreas. — Looks healthy. 
 
 Abdominal blood-vessels almost entirely empty. No blood 
 in inferior vena cava or aorta. Intima of both healthy-looking. 
 TiioraciG Duct pervious throughout. Mesenteric and retro- 
 peritoneal lymphatic glands small, the former unusually so, 
 requiring considerable searching to obtain any. The amount 
 of blood in the body appeared remarkably diminished, and it 
 was only by pressing along the limbs that sufficient could be 
 obtained from the veins to fill a small homoeopathic phial. 
 
 Piece of the sternum, the upper half of right fibula, the 
 inner third of left clavicle, half a rib, and one of the last dorsal 
 vertebrae were removed for the examination of the marrow. 
 Blood was collected from the heart, and junction of left jugular 
 vein with the sub-cl avian. 
 
 A striking feature in the autopsy is the extreme anaemia of 
 the organs, their almost entire bloodlessness, and consequent 
 pallor, the right kidney excepted 
 
 HISTOLOGICAL EXAMINATION. 
 
 The blood taken from heart and veins shows the same gene- 
 ral characters noticed during life. Prolonged examination of 
 different specimens made for this special object resulted in the 
 detection of two nucleated red blood corpuscles. 
 
 Heart. — The fibres are in a condition of extreme fatty dego- 
 aeration, the striaj being obscured by the number of densely 
 
10 
 
 DRS. GARDNER .t OSLEU, 
 
 crowded droplets and fine molecular fat ; only hero and there a 
 fibre occurs in which the striae are faintly seen. In teased 
 preparations niimeroiis short bits occur, together with oil-drops 
 and granules of fatty matter. In places there appears to be a 
 good deal of interfibrillar connective tissue with fat cells. 
 
 Muscles of the Trunk. — The fibres of the thoracic muscles — 
 which were observed to be of such a natural appearance — 
 present no trace of fixtty degeneration. 
 
 Spleen. — The ordinary corpuscles of the pulp, together with 
 elongated, sometimes branched, cells of the retiform tissue are 
 the chief elements seen in teased specimens. The red corpus- 
 cles have lost their colouring matter. A few cells containing 
 red blood corpuscles are seen, but no nucleated red cells. 
 
 Kidney. — Teased preparations show the epithelium of the 
 tubules, both in the cortex and pyramids, covered with fatty 
 matter in the form of minute drops and fine granules ; nowhere, 
 not even in the large collecting tubes, are the cells distinct. 
 The Malpighian corpuscles also contain many granules and 
 small oil-drops, and the same exist abundantly in the field. 
 
 Liver. — Cells arc stuffed with oil-drops ; none noticed without 
 them, while in many the protoplasm and nucleus are entirely 
 obscured. Free fat exists infiltrated between the cells, and in 
 the field. In a few, bile pigment is seen. 
 
 Mesenteric Q-lands. — Teased portions present a large number 
 of perfectly normal-looking lymph corpuscles, among which the 
 connective tissue elements occur in the usual proportion. Many 
 of the smpll vessels and capillaries have their walls uniformly 
 studded with fat grains, and t iy be traced as dark branching 
 lines. In others, the deposition is not so extensive. 
 
 Nothing abnormal observed in the axillary lymphatic glands. 
 
 Medulla of Bones. — The marrow of all the bones examined — 
 sternum, rib, clavicle, vertebra, fibula — is of a dark violet-red 
 colour, thick, about the consistence and colour of the spleen 
 pulp in fever. In the clavicle it is more diffluent, of a lighter 
 red colour, and to the naked eye looks a little fatty — an appear- 
 ance not noticeable in the other lx)nes, not even in the shaft of 
 the fibula. 
 
PROaUESSIVE PERNICIOUS ANEMIA. 
 
 ID 
 
 On microscopical examination, the following elements were- 
 found : — 
 
 (1) Colourless corpuscles — marrow colls — of various size, 
 with granular protoplasm, and bold vesicular nuclei. The 
 greater number of these are larger than white blood corpuscles, 
 and usually have a single nucleus, sometimes two. Others are 
 smaller, more approaching the blood corpuscles in form, while 
 in all the specimens examined, small round cells, like ordinary 
 lymph corpuscles, are also found. The above represent the 
 common colourless elements found in marrow, and they form 
 the majority of the corpuscles in the field. In eight of the 
 larger cells the extremes of measurements were xTiVr" by thW 
 and ^iU" by r^W. 
 
 (2) Coloured blood corpuscles, of which two varieties are- 
 seen ; (rt ) ordinary biconcave disks, somewhat irregular in 
 shape, and often, as noticed in the blood during life, provided 
 with long processes. They are abundant, forming the large 
 proportion of coloured elements. In the fibula, sternum, and/ 
 rib the colouring matter is retained, while in the vertebra and 
 clavicle it has disappeared from most of the corpuscles, and they 
 are recognizable only as outlines, (i) Small round red cor- 
 puscles, non-nucleated, from one-quarter to one-half the size of 
 ordinary corpuscles, and similar in appearance to the small 
 forms seen in the blood. They occur most numerously in the 
 marrow of the fibula, where they form fully one-fourth of the 
 coloured corpuscles. In the sternum and ribs they are not sa 
 abundant, though occurring in each field. As described in the 
 blood itself, they do not appear to be biconcave disks, but 
 spheres. The colouration is quite as intense as in form a, and 
 a few were observed to be crenated. 
 
 (3) Nucleated red corpuscles, the " transitional " forms of 
 Neumann, which are numerous in the sternu;n and rib, less so in 
 the fibula, while in the clavicle and vertebra rhey occur scantily, 
 or, owing to the general decolourization of the red corpuscles 
 in these bones, are seen with difficulty. iVs shown by the 
 measurements given below,they are as a rule larger than ordinary- 
 blood corpuscles, but present, like them, a perfectly homogene- 
 
12 
 
 DRS. GARDNER & 03LER. 
 
 0U8 coloured stroma, in which a finely granular nucleus is 
 imbedded. They are spheres, not biconcave, as a rule round, 
 though frequently irregular in outhne, or with one end pointed 
 and prolonged. The intensity of the colouration in most cases 
 equalled that of the ordinary red corpuscles, in some instances 
 being deeper, in others not so marked. The nuclei arc either 
 round or elliptical, and occupy from one-quarter to one-half 
 of the body of the cell (see measurements). They are solid, 
 granular, and inside the corpuscle look coloured, though not so 
 deep as the surrounding substance. The presence of nucleolus 
 could not be determined, The position in the cells is variable ; 
 in specimens examined within a short time after the post-mortem 
 they appeared to be chiefly centric, but in preparations taken 
 the next day very many of them had become quite peripheral, 
 while others had protruded almost through the corpuscle, when 
 it could be clearly seen that the nucleus was colourless. In 
 several instances the nuclei are seen to bo entirely outside the 
 cells, though remaining attached to them. In this condition 
 they look not unlike the small lymphoid marrow cells, and it is 
 only the large size of the corpuscles to which they adhere, and 
 the fact that in the same field others may be seen half-way out, 
 that enables a correct opinion to be formed. In three or four 
 instances dumb-bell-shaped nuclei were noticed. Cells with two 
 nuclei were not uncommon, and instances with three and four 
 were observed. As remarked above, the nucleated red forms 
 are numerous in the sternum and rib, six to eight being seen 
 at once in the field of the No. 9 im. and 3, while in the fibula 
 not more than three or four were noticed in any single field. 
 In fifteen measurements of these forms, eleven were above 
 
 the 
 
 1 " • 
 
 to 7J » 
 
 five being t}i^". The following measurements are of 
 
 three corpuscles with their contained nuclei: — (1) -ryVr" by 
 tioxs" ; nucleus js'i/'by t,W- (2) Wot" by ^tiVt"; nucleus 55'^^" 
 hy ffo'o-o". (3) y-q'jt" by T-u'64 ; nucleus tvsV^" by ^^^W". A good 
 idea of the irregularity in outline of these corpuscles and the 
 slightly elliptical character of the nuclei may be gathered from 
 the above. 
 
 (4) Cells containing red blood corpuscles. These are very 
 
PROGRESS'IVB PERNICIOUS ANVEMIA. 
 
 15 
 
 abundant in tlio marrow of tho vertebra, three or four occur- 
 ring in the field at once, and containing from five to six red 
 corpuscles, the colour and outlines of which in most cases are 
 preserved. In tho sternum and rib they are not nearly so 
 numerous ; in the fibula and clavicle they were not observed. 
 
 (5) Myeloplaqucs, of which one or two only were met with in 
 the marrow of the sternum and nb. Neither in the shaft nor 
 epiphysis of the fibula could these forms be determined, 
 
 (6) Fat cells, which are present in marrow of the clr.vicle in 
 small numbers, absent in the sternum, vertebra and rib. In 
 marrow from the fibula an oil-drop is occasionally met with in 
 the field, but here also they are almost entirely absent. 
 
 (7) The octahedra crystals, first described by Charcot, and 
 which always occur iii the marrow from twelve to thirty-six 
 hours after death. 
 
 Remarks, — Apart from the clinical features and general 
 pathological appearances of the above case, which show it to be 
 an exceedingly typical one, there are two points of special 
 interest, viz., the apjcarance of the blood, and the condition of 
 the bone marrow, both of which are deserving of a few com- 
 ments. 
 
 Prof. Eichorst has drawn attention in a short note* to the 
 presence in the blood of paitients suffering with pernicious 
 anoemia of exceedingly small red corpuscles, which he regards, 
 as pathognomonic of the disease, and affording a valuable diag- 
 nostic sign, being present in all of his cases, seven in number. 
 The following are his own words : 
 
 " Some of the red globules are of normal size, but very pale 
 and have lost their tendency to form rouleaux, others scarcely 
 attain J the diameter of a normal, perfect corpuscle, so that they 
 look like small drops of fat tinged red, and have not their bicon- 
 cave appearance.'" Towards the latter stages of the disease 
 he states that they increase, so that before death they may equal 
 in number the common forms. 
 
 The histological examination, both before and after death, 
 
 • Centralblatt f. die. Med. Wissen. June 24th, 1876. 
 
14 
 
 URS. GARDNER k OSLKlt. 
 
 and tho measurements above given, show that in this instance 
 the blood did contain an unusual number of small coloured 
 elements, and is so far confirmatory of Eichorst's statement. 
 Though not abundant, they were quite numerous enough to 
 attract attention, and offered a striking contrast to the other 
 red corpuscles about them, many of which were large, flattened 
 out, and less biconcave than usual, A great variation in size 
 was noticed in all the specimens examined, and range as given 
 in the measurements, from i;,,W to ^i/o^" must be regarded as 
 very remarkable. That these tiny elements are red corpuscles 
 there can be no doubt, as with No. IG Hartnack (l-86th) they 
 appear homogeneous, of a pale yellow colour, and, like the larger 
 forms, are sometimes crenated. In the third case reported in 
 Dr. Howard's paper on the subject,* the blood of which one of 
 us (Dr. 0.) had an opportunity of examining in the spring of 
 1875, the note on the appearances of the blood is as follows : 
 " There is a somewhat unusual variation in size among the red 
 corpuscles, many of them scarcely measure the TuVoth part of 
 an inch in diameter. The white corpuscles also present slight 
 variations in size and are more granular than normal. Max 
 Schultze's granular masses are abundant." Cohnheim, in a case 
 -which will be more fully referred to hereafter, states that the 
 presence of the small blood corpuscles was established. Quinckef 
 also speaks of the inequalities in the size of the red blood cor- 
 puscles, many of which were small and round. In three of his 
 cases these smaller forms presented great irregularities in con- 
 tour. These are, I believe, the only positive observations on 
 this point. On the other hand, there is a note by Prof. Grainger 
 Stewart of Edinburgh, J in which he states, that the blood in two 
 -cases of pernicious anoemia, under treatment at the time, did 
 not present the small red corpuscles described by Eichorst. 
 Among recent cases in Avhich the blood was carefully examined. 
 
 • Read before the International Medical Congress at Philadelphia, and 
 being published in the forthcoming Report. 
 
 t "Volkmann's Sammluug Klinischer Vortrdge, No. 100., translated in 
 Medical Times and Gazette, Oct. 14th, 1876. 
 
 t Brit. Medical Journal, July 8tb, 1876. 
 
TttOdUKSSIVB PERNICIOIJH ANAEMIA. 
 
 15 
 
 and no mention mado cither of small forma or great variations 
 in size are those of Pepper,* Scheby-Buch,t Tyo Smith, J 
 Lepine.§ Bradford, || in his case, mado a most careful examin- 
 ation of the blood, and reports not much variation in size, but 
 that all are rather smaller than usual. In Ferrand's case^j 
 many of the red blood corpuscles were larger than normal, no 
 mention is made of any diminution in size. In Bradbury's 
 case** the red corpuscles were larger than normal, i)ale, and 
 exceedingly irregular in shape. No small forms were noticed. 
 Burgcrft f^id not notice any great variations in size, but a 
 peculiar paleness about them. ImmermannJJ makes no men- 
 tion of alterations in form or size in the red corpuscles. 
 
 The presence of very small red disks in healthy blood is not 
 common, still, one of us (Dr. 0.) has occasionally measured forms 
 not yij'ooth of an inch in diameter, both in his own and in the 
 blood of other quite healthy individuals. Laptschinsky§§ has 
 also found these small corpuscles in the blood of patients with 
 various febrile affections, and speaks of them as being numerous, 
 about :\ the size of ordinary red corpuscles, some having an 
 intensely red colour, whilst others are pale. In the blood from 
 the above reported case, drawn in capillary tubes, and not 
 examined until some hours after, many of the red corpuscles 
 appear as deeply coloured spheres, slightly smaller than natural. 
 This is a physical alteration, resulting apparently in a change 
 from a disk-shape to a sphere, with, perhaps, a condensation 
 of the corpuscle. These forms were not present in perfectly 
 fresh blood, but could be seen in the slide six or eight hours 
 
 * Amer. Journal of Med. Sciences, Oct. 1875. 
 t Deutchcs Archiv. f. Klin. Medicin, April, 1876. 
 :J: Virchow's Archiv. Bd. 65. lift. 4. Dec. 1875. 
 § Bulletin General de Therapcutique, 30 Jullict, 1876. 
 II Boston Medical and Surgical Journal, May, 1876. 
 ^ Bulletin General de Therapcutique, Dec. 15, 1876. 
 ** Brit. Medical Journal, Dec. 30, 1876. 
 ft Berliner Klin. Wochcnschrift, No. 33, 1876. 
 
 tt Ziemsscn's Handbuch der spcciellen Path, and Therrp. Cd. xiii. Art. 
 Tro. Pernic. Anaem., 1875. 
 §§ Centralblatt f. d. Med. Wissen. No. 42, 1874. 
 
16 
 
 DUS, OARUNER & OHLBll. 
 
 after mountin;^. It is intcr'stin,!:^ to remark witli rcfercnco 
 to the lar^^o corpuscles, tliat Ilriyem* states that (luring a long 
 course of iron — ;just such as this man had been suhjcctod to — 
 the red disks undergo an increase in volume. 
 
 Until wo possess more definite knowledge than wo do at pre- 
 sent of the variation in size of the red corpuscles in constitutional 
 and febrile diseases, it would bo hasty, from the limited number of 
 observations, to conclude that the presence of the small coloured 
 corpuscles is pathognomonic of, or even affords a positive diag- 
 nostic sign in, progressive pernicious anaemia. It remains for 
 subsciiucnt observers to note accurately the size of the red 
 corpuscles in this disease, and it will not bo long before wo are 
 in a position to arrive at a satisfactory conclusion on thi^ inter- 
 esting point. 
 
 In a disc .se like pernicious antemia, which after death is 
 is not characterized by any important lesion in the viscera 
 or glands, it was natural that attention should bo directed to the 
 bone marrow, a structure now ranked among the blood-forming 
 organs, and which in leukasmia, and pseudo-leuksemia (an;\;mia 
 lymphatica, or Ilodgkin's disease) has been found remarkably 
 altered, so much so that myelogenous forms of both have been 
 described. With the two affections just named the one in ques- 
 tion is closely allied, and in its clinical features almost identical. 
 From the splenic and lymphatic forms of both, it is distinguished 
 by the absence of enlargement of the spleen and lymphatic 
 glands, and additionally from leukncmia by the failure of any 
 increase in the white blood corpuscles. In those rare cases of 
 leukajmia, where the disease is confined to the bone marrow — 
 myelogenous form — the only distinguishing feature is the excess- 
 ive number of colourless corpuscles in the blood, with, perhaps, 
 tenderness over the affected bones (Hosier). Immermannf 
 quotes a case in illustration of this. In the still rarer cases of 
 myelogenous pscudo-leuknemia, where the affection is uncomplica- 
 ted with disease of the spleen or lymphatic glands, a differential 
 diagnosis would be impossible, (compare the remarkable cases 
 
 • Bulletin General de Therapeutique, Doc. I5th 1876. 
 t Loc. Cit.p. 651. 
 
I'unuuK.S'iN r, I'kknu.iols an.kmia. 
 
 ;;ivcn by Wood*). It is not to be wondcrcil at tliat some writers 
 ( Inuncrmaiin and Jaccoudf) should bint at the identity of the 
 two diseases, or that Pepper, encoura;^cd by the appearance 
 of the marrow in one of Lis cases, should state that progressive 
 pernicious anncmia was " moroly the simple mcdullnry form of 
 pseudo-leukiomia,* ' 
 
 The evidence of an imi)lication of the marrow in this disease 
 rests upon the following reports : the first case in which it was 
 examined -was one of Pepper's, in which the marrow of the 
 radius and sternum was " made up almost entirely of small 
 granular cells.'' Passing over a case observed by Fedo-I and 
 recorded as one of pernicious anicmia, but -which ought to be 
 regarded as a well-marked myelogenous pseudo-lcukocmia, the 
 next observation is by Schcby-Buch,§ in one of whose cases 
 the marrow of the radius was pale red in colour, and contained 
 numerous cells like white blood corpuscles, and very few red 
 corpuscles or fat cells. In Lcpine'.s|| case nothing unusual was 
 found. Burger^ states that there was no aftcction of the marrow 
 in his case. ]Jy far the most extended account of the changes 
 in the marrow in this disease is that given by Cohnhoira in a 
 letter to Virchow.** The following is a summary of the 
 appearances described : Marrow of all the bones intensely red ; 
 fat almost entirely absent. Microscopically there ^\-ere (1), 
 ordinary marrow cells of various sizes, some small and lymphoid 
 in character, others large and with vesicular nuelri : (2.) 
 coloured elements in almost ccpial number, of these the common, 
 biconcave, red blood corpuscles formed a decider minority, while 
 the number of red non-nucleated corpuscles of various dimen* 
 sions -was very evident. The smallest of those had the diameter 
 of normal red blood corpuscles, the largest were more than 
 
 ♦ Am. Journ. of Medical Sciences, Oct. 1371. 
 
 t Nouv. Diet, do Med. et de Cliirurg. Leucocythemic. 
 
 t Quoted in Contralblatt, f. die, Med. Wisson., Oi-t. KUli, 1.^7.*. 
 
 § Loc. cit, 
 
 II Loc, cit. 
 
 ^ Loc. cit. Xo. ,31, 187(1. 
 
 *' Vircliow. .^rchiv. lid. Ixviii, lift., 2. Oit. L'C, ISTU. 
 
 •» 
 
18 
 
 Dim. (JAFIDNER A OSLER. 
 
 double tlij slz3 of colourlc33 blood corpuscles, and between 
 them forms intermediate in size. (3.) Nucleated red cor- 
 puscles in great abundance, and of various sizes, tho majority 
 equalling in size the smaller of the true marrow cells. The 
 blood examined after death was also found to contain a few 
 of the nucleated red corpuscles. In Quincke's article no 
 details are given, and this part of the question is disposed 
 of with the remark : " The marrow of the bone showed 
 no abnormality." In Bradbury's case, the red marrow from 
 tho right tibia looked natural, and was made up almost entirely 
 of granular spheroidal cells, like white blood corpuscles. In 
 that from the sternum the cells were much larger, and red 
 globules more abundant. Coloured corpuscles were not 
 numerous. 
 
 These are the only facts for and against the view that perni- 
 cious anecniia is the medullary form of pscudo-leukocraia. The 
 general statement of Quincke, and the more definite ones of 
 Lopine and Burger, are not very satisfactory, as no details are 
 given ; still, they must be accepted as negative evidence. It may 
 be held with Bradbury* that tho changes in the marrow of the 
 sternum and radius in Pepper's case were scarcely sufficient to 
 indicate serious disease of that structure, as only the normal 
 elements were found, though in the radius in slightly increased 
 numbers, and the same may be said of Scheby-Buch's case. In 
 Cohnheim's case and our own the constitution of the medulla was 
 altered, and, in addition to ordinary marrow cells, it contained 
 lymphoid corpuscles, embryonal forms,! and red blood corpuscles 
 of various sizes. The detection, too, in both, of the embryonal 
 forms in the blood, though in quite insignificant numbers, places 
 them apart from the others ; and on these grounds they alone 
 are strictly comparable with myelogenous leukromia. Indeed, 
 the question at once arises whether we have not to do here with 
 
 * Loc Cit. 
 
 t In a recent note in the Arcbiv. f. Mikroscop. Anatomic, Bd. xii. p. 79G, 
 
 Keumann expresses a wish that the term " transitional," as applied to the 
 
 nucleated njd corpuscles, should bo dropped, as involving an hypothesis 
 
 about their origin, advanced rather too confidently by him. He would 
 
 substitute the term "embryon.nl" or •' developmontfll " form. 
 
I'ROURKSJSIVE I'ERXICIOL'S AN.EMIA. 
 
 10 
 
 an uucomplicutod case of medullary i)seudo-]ouki\}mia, similar to 
 one of those described by Wood*. A consideration of the 
 symptoms will not help us, and the remarkable admission must 
 be made, that while the ante-mortem diagnosis of pernicious 
 anaemia was correct, a post-mortem one of pseudo-loukaMniu 
 might be equally so. 
 
 The absence of those changes in the marrow in the cases of 
 Quincke, Lepine, and Burger proves that the disease in certain 
 cases is independent of any aftection of this structure ; and wo 
 must either regard implication of the marrow as an accidental 
 complication, having but little todoAvith the e use or progress of 
 the disease, or refer all cases in which it is met with to the cate- 
 gory of myelogenous affections. Can the state of the marrow bo 
 regarded as an accidental complication, a secondary change, 
 depending on tho grave constitutional disease ? Our knowledge 
 of tho condition of this tissue in disease is not at all complete, 
 and tho only observations at hand on the subject are the following : 
 
 Neumannf met with groat hyperplasia of the marrow in a case 
 of Addison's disease. 
 
 Wood, in a paper already referred to, says, that he has " made 
 a number of examinations of long bones taken from patients 
 dead of various chronic diseases, and never, except in a single 
 case, found any abundance of the leucocytes ;" and this was 
 probably a case of Icukccmia. 
 
 In 14 examinations made by Dr. Osier of the marrow of the 
 long bones, obtained chiefly from chronic Hospital cases, in 
 only one was there found hyperplasia and marked alteration in 
 its constitution ; and in this instance there is a strong proba- 
 bility of the case belonging to the group under consideration. 
 
 Altogether, the few fiicts we have are opposed to the view that 
 in chronic diseases, accompanied with anemia and wasting, 
 hyperplasia of the marrow of tho long bones occurs as a secon- 
 dary change. 
 
 Cohnheim^; writing to Virchow, on his case, says, ■• You will 
 
 * Loc. CIt. p. 293. 
 
 t Quoted in Quarterly Joiirn.'il of Microscopv, 1871. 
 
 i Loe. Cit. p 382. 
 
2U 
 
 DItS. aAUDNER i OSLEll. 
 
 certainly agree 'with mo in taking for granted that the above 
 described condition of the marrow stands in intimate connection 
 with the fatal disease of the patient. That in this affection 
 ( progressive peruieions antcmia) we have to deal Avith a ja-o- 
 found disturbance in the constitution of the blood all observers 
 are at one ; and, on the other hand, it can at present be no longer 
 doubtful that an important disease of the marrow must have 
 a serious influence on the composition of the blood." 
 
 With this statement Ave concur, and arc inclined to regard the 
 ali'oction of the marrow in our case as the fons et origo m<di. 
 
 Our bcjt thanks are due to Dr. Howard, of McGill University, 
 who in his lectures has long taught the existence of Addison's 
 idiopathic antcmia, and who kindly allowed us to have access to 
 the manuscript of his paper on the subject. 
 
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