Chapter LXII: Part 62

In Addison's monograph on the suprarenal capsules (1855) there is a brief but clear account of the disease, which he speaks of as follows: "For a long period I had from time to time met with a very remarkable form of general anæmia occurring without any discoverable cause whatever--cases in which there had been no previous loss of blood, no exhausting diarrhoea, no chlorosis, no purpura, no renal, splenic, miasmatic, glandular, strumous, or malignant disease. Accordingly, in speaking of this form of anæmia in clinical lectures, I, perhaps with little propriety, applied to it the term idiopathic, to distinguish it from cases in which there existed more or less evidence of some of the usual causes or concomitants of the anæmic state." As early as 1843 this acute observer had spoken in his clinics of this condition.[61]

[Footnote 61: McKenzie, S., _Lancet_, 1879, ii.]

{899} The physicians at Guy's appear to have been well acquainted with the disease, and in 1857 Wilks described cases under the heading "Idiopathic Fatty Degeneration." To the labors of Zurich professors we are indebted for much of our knowledge. That versatile clinicist Lebert, then at Zurich, published in 1853 cases of puerperal chlorosis, and we owe to him the excellent designation of essential as applied to these cases of anæmia (1858). It was in 1871-72 that the communications of Gusserow[62] and Biermer[63] aroused a very general interest in the disease. Gusserow's cases, like some of Channing's, were in connection with pregnancy. Biermer, thinking he was dealing with a previously unknown affection, gave it the name of progressive pernicious anæmia. In the past ten years the literature of this form of anæmia has enormously increased. In Germany, in addition to the articles in the encyclopædias (Ziemssen's, Eulenberg's) and innumerable contributions and dissertations, two important monographs have appeared by Müller (Zurich, 1877) and Eichorst (Leipzig, 1878). In France, Hayem, Lepine, and others have published important observations. In England, the Guy's Hospital physicians, Taylor and Pye-Smith, in the _Hospital Reports_ (1878-83) have fully established Addison's claim to having given a clear account of the disease. Important contributions have been made by Stephen Mackenzie, Coupland, Bramwell, Bradbury, and others. In this country Pepper in 1875 brought the disease to the notice of the profession and suggested the name anæmatosis. Howard (R. P.) of Montreal at the Centennial Medical Congress (1876) gave a full account of the affection, the existence of which he had long recognized and taught. Musser[64] has reviewed the American literature, and has given a tabular synopsis of 39 cases which have been recorded in this country.

[Footnote 62: _Archiv f. Gynäkologie_, ii.]

[Footnote 63: _Correspondenzblatt für Schweizerische Artze_, 1872.]

[Footnote 64: _Proceedings of Philadelphia County Med. Society_, 1885.]

ETIOLOGY.--The disease is widely distributed, and there are no special geographical influences. In Germany and certain of the Swiss cantons--Zurich particularly--the cases seem to occur more frequently than in England or America. In this country it can scarcely be called one of the rare diseases, although up to January, 1885, Musser[65] could collect only 39 cases. During ten years in Canada I saw 16 cases, most of them with colleagues at Montreal.

[Footnote 65: _Loc. cit._]

That bad hygienic conditions have much to do with the induction of the disease is shown by the records of Zurich and Berne, where the cases have been very numerous among the lower classes, who are hard worked, ill fed, and poorly housed. Possibly here other unknown causes may be at work, as the conditions which prevail in the Zurich canton are not unknown in other countries. In Ireland, where the peasants have poor food and wretched houses, the disease does not appear to be common. In the Montreal cases the subjects were chiefly of the upper or of the higher mechanic classes.

The age most subject to the disease is the adult period; cases are rare under twenty and over fifty. In Pye-Smith's table of 103 selected cases there were only 6 under fifteen years of age; 4 between fifteen and twenty; 29 between the twenty-first and thirtieth years; 26 cases between the thirty-first and fortieth years; 21 between the forty-first and fiftieth years; 13 between the fifty-first and sixtieth; and only 4 above sixty. The youngest case I have seen was in a girl of twenty, and oldest in a woman over sixty. The youngest case on record was at the fifth year.[66]

[Footnote 66: Quoted in _Am. Journ. Med. Sci._, Jan., 1885.]

Sex.--If we exclude all cases in women directly connected with the puerperal state, primary idiopathic anæmia is more frequent in men than in women. Of the 16 Montreal cases, 4 were dependent upon parturition, and of the remainder, 9 were in men and only 3 in women. But most of the {900} collected figures include the parturition cases, and the women are in excess; thus, of 93 cases from the Swiss clinics at Zurich and Berne, 67 were females. Eichorst's figures are 65 women and 30 men. Of 110 cases collected by Coupland, 56 were men and 54 women. In Pye-Smith's careful tabulation of 103 selected cases, 48 were men and 59 women.

As observed by Channing, Lebert, and Gusserow, pregnancy and parturition are important factors in the production of a grave form of anæmia. In the majority of cases the symptoms develop post-partum, often, but not necessarily, in consequence of loss of blood during delivery. Obstinate vomiting during pregnancy and prolonged lactation may bring about the same condition. Of 29 cases of this sort in Eichorst's table, in 19 the symptoms developed during pregnancy and in 10 after delivery.

Gastric and intestinal disturbance, dyspepsia, vomiting, and diarrhoea have occurred in a number of cases prior to the development of the anæmia.

In some instances loss of blood, chronic discharges, ulcers, or other sources of drain have been present.

In not a few cases there has been mental worry, grief, or fright. This has been specially noted by Wilks and Howard, and more recently by Curtin.[67] It does not seem probable that malaria has any predisposing influence.

[Footnote 67: "Nervous Shock as a Cause of Pernicious Anæmia," _Med. Times_, Philada., April 4, 1885.]

It is by no means always the ailing or delicate who are attacked; many of the cases have occurred in men previously strong and robust.

After excluding all these factors, which prevail in a considerable proportion, there still remain cases without, as Addison says, any discoverable cause whatever--cases to which in our present knowledge we may apply the term idiopathic. These may be primary, and the others, in which some one or other of the above-mentioned causes appears to have prevailed, secondary anæmias, the latter to be distinguished from a host of other sequential anæmias only by the fact of a progressive and pernicious course.

Of 91 observations collected by Eichorst, in 24 cases the disease appeared to have come on spontaneously, and 67 as the result of various causes: pregnancy and parturition, 29; digestive troubles, 24; loss of blood, etc., 7; bad hygienic conditions, 7.

SYMPTOMS.--The classical description of Addison must ever be quoted in this connection: "It makes its approach in so slow and insidious a manner that the patient can hardly fix a date to the earliest feeling of that languor which is shortly to become so extreme. The countenance gets pale, the whites of the eyes become pearly, the general frame flabby rather than wasted, the pulse perhaps large, but remarkably soft and compressible, and occasionally with a slight jerk, especially under the slightest excitement. There is an increasing indisposition to exertion, with an uncomfortable feeling of faintness or breathlessness in attempting it; the heart is readily made to palpitate; the whole surface of the body presents a blanched, smooth, and waxy appearance; the lips, gums, and tongue seem bloodless; the flabbiness of the solids increases; the appetite fails; extreme languor and faintness supervene; breathlessness and palpitations are produced by the most trifling exertion or emotion; some slight oedema is probably perceived about the ankles; the debility becomes extreme--the patient can no longer rise from his bed; the mind occasionally wanders; he falls into a prostrate and half-torpid state, and at length expires: nevertheless, to the very last, and after a sickness of several months' duration, the bulkiness of the general frame and the amount of obesity often present a most striking contrast to the failure and exhaustion observable in every other respect."[68]

[Footnote 68: Monograph on _Disease of Suprarenal Capsules_, p. 3.]

The mode of onset is variable: in many cases there are etiological {901} conditions, such as pregnancy, loss of blood, etc., which for weeks or months precede, and perhaps determine, the development of the anæmia. There may have been mental worry or shock, and after a prolonged period of ill-health the anæmic symptoms become marked. Failure of strength, lassitude and disinclination for exertion, with shortness of breath and palpitation and an increasing pallor, accompanied by headache, giddiness, and dyspepsia, are the symptoms for which the patient seeks advice.

The condition of the skin is remarkable in pronounced cases: the color is rarely a deep white or ashen, as in the pallor of fear or fainting or the bloodlessness from hemorrhage, but there is a peculiar lemon tint, a light straw-yellow or grayish-yellow color, which may be mistaken for a mild icterus. This is one of the most characteristic features of the disease.

The subcutaneous fat does not waste; on the contrary, the fatty panniculus may increase, and, as Addison remarked, there may be a bulkiness of the frame. Actual emaciation is very uncommon.

Slight oedema is present in the feet, particularly toward the close, and it may extend up the legs, but rarely reaches a high grade. Occasionally it may appear in the face and hands.

Cutaneous hemorrhages in the form of small petechiæ are liable to appear on the legs and arms, not often on the trunk.

The sweat secretion is not affected, but in several instances, as in other chronic affections where death is protracted, a cadaverous odor has been perceived from the skin or breath.

The blood, as expressed, often with difficulty, from the finger-tip, has not the rich color of health, but is pale, like a light claret. The corpuscles usually fill the drop, and we do not see, as in certain cachectic states, an extreme degree of hydræmia in which the red corpuscles do not entirely occupy the plasma. It is sometimes difficult to get a drop of blood from the finger-tip, and to do so the arm should hang by the side and may be squeezed from the shoulder downward to press the blood into the hand. The microscopical characters of the blood are as follows:

(1) The red cells present a great variation in size, and there can usually be seen _(a)_ large giant forms, the megalocytes measuring 8, 11, or even 15 mm.: these are not often very numerous, and may show irregular foldings at the edges; _(b)_ medium-sized disks, such as are usually found in the blood: these always predominate; _(c)_ small round cells, microcytes, 6, 4, or even 2 mm. in diameter, and of a deep color. They are rarely absent in typical cases, though varying in number at different periods. The color of the large and medium-sized corpuscles may be much less intense than normal.

(2) In addition to the variation in size, the corpuscles show a remarkable irregularity in form--an irregularity which, so far as my observation goes, is never met with to the same extent in other conditions. They may be elongated and rod-like, scarcely recognizable as blood-disks. Balloon and kidney shapes are common. One end of a corpuscle may retain its shape, while the other is extended as a pointed or blunt process. The normal concavity may be lost on one side and deepened on the other. Many of the large forms are longer than broad, often quite ovoid, and with sinuous margins. The microcytes are either globular or present a pit-like depression on one surface. To this condition of irregularity of the corpuscles in size and form Quincke has given the name poikilocytosis ([Greek: poikilos], variously shaped). It possibly depends on an altered state of the serum; I have failed to produce it with dilution. The corpuscles in the blood of idiopathic anæmia do not form such well-defined rouleaux as in health.

(3) The colorless corpuscles may be relatively increased, but are usually diminished to some extent. They present no very special changes in form or stricture. Larger forms may occasionally occur, but I have not noted their {902} presence, specially the cases in which the marrow was found red and lymphoid after death. In two cases the majority of the corpuscles at several observations were smaller than normal. The amoeboid movements are active.

(4) In only two instances, in the cases I have examined, were nucleated red corpuscles present, and these very scanty. They have been noted by several observers. Ehrlich states[69] that they are present in all cases.

[Footnote 69: _Berl. klin. Wochenschrift_, 1880.]

(5) Schultze's granule masses, composed of the hæmatoblasts or blood-plates, are either absent or very scanty. In some cases not a trace of them could be found, and in others they are less abundant than in health. In this respect the blood offers a marked contrast to that of various cachectic states, and also to leukemia, in which the masses are sometimes very numerous. Leube,[70] however, has recorded a case in which they were abundant.

[Footnote 70: _Ibid._, 1879.]

(6) The fibrinous network between the corpuscles is thin and indistinct. The Cercomonas globulus and Cercomonas navicala, described by Klebs[71] as occurring in pernicious anæmia, are possibly peculiar to Prague.

[Footnote 71: _Real Encyklopädie_, art. "Flagellata."]

The reduction in the number of the red corpuscles is the special feature of the disease, the diminution reaching far below that met with after the most severe hemorrhage. Instead of a corpuscular richness of 5,000,000 per cubic millimeter, the number may be reduced to one-quarter, or even one-tenth. In the more extreme anæmia from hemorrhage, in cancer or in phthisis, the reduction rarely reaches as low as 1,500,000, while this figure is common in pernicious anæmia, and in advanced cases may sink below 1,000,000, or even to 500,000. This latter figure is exceptional. In only 2 cases have I counted the number so low as this. In a case of Quincke's the red were reduced to 143,000 per c.m., and, strange to say, the man recovered. Great variations may occur from month to month in the course of the disease. An increase in the number is not always associated with an improvement in the patient's condition.

The hæmoglobin is also greatly reduced, but not in proportion to the reduction in the red corpuscles. The relative coloration of the corpuscles is increased, and this seems as marked a feature in pernicious anæmia as the relative reduction is in chlorosis.[72] Owing to the fact that the hæmoglobin value of individual corpuscles is increased, the anæmia is never quite so intense as the number of corpuscles would appear to indicate.

[Footnote 72: Laache, _Die Anämie_, Christiania, 1883; _Deutsche Medicin Wochenschrift_, 1884, No. 43.]

The circulatory system presents many symptoms of importance. When the patient is recumbent and at rest, the heart's action is quiet, but on exertion or excitement the action becomes rapid, and there are palpitation, fluttering, and sometimes painful sensations in the cardiac region. Stairs are particularly trying to these patients. There may be slight enlargement of the heart, indicated by an increased area of visible pulsation, and an impulse in the third or fourth left intercostal space, near the sternum, is frequently seen. The hæmic or functional murmurs are usually present, variable in intensity and site, most often heard at the base and in both aortic and pulmonary areas, but also at the apex. Indeed, their variability is often puzzling; sometimes it would seem that there might be a murmur at each orifice, at another limited only to one; and for the bruit to be present at one examination and absent at the next is not uncommon. In several of Eichorst's cases there was a variable diastolic murmur at apex or base.

The larger arteries pulsate visibly--so much so that at times it suggests the water-hammer pulsation of aortic insufficiency. The carotid pulsation may be most evident, and still more so in the abdominal aorta, the throbbing of which may be very distressing to the patient. A systolic arterial murmur may be heard in all the arteries. The pulse is soft, compressible, usually {903} rapid (80 to 100 or over), depending a good deal on the position and state of excitement. One is sometimes surprised in these cases to find a full and at the same time very soft pulse. It may be dicrotic.

The venous hum is well marked, and is rarely absent except after prolonged rest in bed, when both cardiac and venous murmurs may disappear, to return at once on making the patient stand up. Channing, in the paper already referred to, speaks of the thin, scanty state of the blood, and yet notes the prominent appearance of the veins beneath the skin, particularly about the hands and wrists.

Hemorrhages occur very frequently. Epistaxis is most common, and may have preceded for years the onset of the grave anæmia. It may recur repeatedly and be a source of constant drain, or ultimately be the cause of death. From other mucous surfaces bleeding is not so common. I have seen one case in which there were for months repeated small hemorrhages from the bowels, and bleeding from the gums has been observed in several cases. The petechiæ on the skin have already been referred to. Retinal hemorrhages, as first noticed by Biermer, are very common. They are numerous and small, scattered around the disk. They are not peculiar to any special form, but are liable to occur in severe anæmia from any cause.

Respiratory symptoms are not prominent: a short cough may be present, but the only special feature is the shortness of breath, which is often early and troublesome, and depends on the condition of the blood, not of the lungs. There may be a very distressing and persistent sense of insufficient aëration (Pepper). Toward the close hydrothorax may develop.

The gastro-intestinal system is in the majority of cases more or less deranged. Dyspepsia may precede for years the anæmia, and may persist throughout the illness. There is loss of appetite, amounting sometimes to a positive repulsion toward all forms of nutriment. Nausea and vomiting are rarely absent throughout the illness, and there are some cases in which the gastric symptoms are so marked as to suggest a primary stomach lesion as the atrophy to which Fenwick[73] has called attention, or even arouse a suspicion of cancer.

[Footnote 73: _Lancet_, 1877, ii.]

Diarrhoea is also a frequent symptom, and in some cases hastens the fatal result. There may be melæna, and in Müller's monograph a case is given in which leucin and tyrosin were found in the stools.

The urine is pale, acid, and of low specific gravity. Occasionally it becomes darker in color. The urea may be diminished, but it has been found increased in some cases by Quincke, Eichorst, and Laache. The uric acid is more commonly increased, and the phosphoric acid. The percentage of iron has been found larger than normal. Albumen is rarely found. Peptones, leucin, and tyrosin may be present (Laache). Blood does not often occur.

Fever is not a constant symptom; some cases run their course without any elevation, but there is usually slight febrile reaction of an irregular, remittent type, an evening elevation of two or three degrees, and a morning remission to the normal standard. There may be a week or ten days of fever, and then a long spell without any. Toward the close there is commonly an elevation, occasionally depression, of temperature, as in one case reported by Müller in which it sank to 24.8° C.

COURSE.--In the majority of cases the disease runs a steadily downward course, well indicated by the terms progressive and pernicious. In almost every case periods of temporary improvement occur. Recovery is possible, and Pye-Smith[74] gives a summary of 20 undoubted cases which got well. The lactation and parturition cases stand a better chance of recovery than others. {904} The average course of the affection is from six to twelve months; there are rapid cases in which a fatal termination may be reached in a few months, and there are others which drag on for two, or even three, years, periods of improvement alternating with relapses. Death is usually by asthenia. It may be hastened by hemorrhage from the nose or bowels or by persistent vomiting or diarrhoea.

[Footnote 74: _Guy's Hospital Reports_, 1883.]

MORBID ANATOMY.--The body is not often emaciated; usually, indeed, the panniculus adiposus is well developed. The peculiar lemon tint of the skin is present in the majority of cases, and there may be petechiæ. The voluntary muscles may appear normal, but are often of an intense flesh color, more like horse muscle. In six cases the words "rich red color" and "remarkably deep red color" occur in my notes. In other instances they are pale. When the cavities are opened the general pallor of all the organs is most striking. The serous surfaces are smooth and glistening, and occasionally present ecchymoses. The amount of fluid may be increased. The mucous membranes are pale; minute hemorrhages are not uncommon.

The heart is in many cases large and flabby, in others normal, and in a few undersized. The pericardial fluid may be in excess, and the subpericardial fat is often increased. The flaccid relaxed state of the walls is very noticeable, and on opening the chambers the amount of blood is always very slight. In one case I could only obtain two drachms from the right heart, and between three and four from the left. There may be small clots entangled with the chordæ tendineæ of the valves. The muscle-substance is pale, of a faded-leaf, light-yellow color, and beneath the endocardium, particularly of the left side and of the papillæ, there are flaky spots (tabby mottling) of fatty degeneration. The peculiarities of general fatty degeneration of the heart are nowhere better seen than in these cases. The valves and orifices are usually normal. The intima of the aorta may show fatty changes. The smaller arteries and veins contain most of the blood.

The lungs are crepitant, pale, with a slight bloody oedema at the bases. The fluid expressed has often a yellowish tinge. Exudation into the pleural cavities is common. The air-passages do not offer any special changes.

The liver is of normal size, pale and generally fatty, not invariably; in none of Eichorst's cases was this a marked feature. Quincke and others have found the amount of iron increased.

The mucous membrane of the gastro-intestinal tract is pale, covered with a thin mucus, and may present ecchymoses. Post-mortem solution of the gastric mucosa is common, and I have seen oedema of it. Fatty degeneration of the cells of the peptic tubules is common, and they may be in an atrophic state, as well described by Fenwick.[75] Ecchymoses of the small and large bowel are common; ulceration is rare. In a few instances the lymphatic elements of the mucosa have been found swollen. Extensive atrophy of the mucosa has been found associated with degeneration of the nerve-elements, but these changes, as shown by the observations of Nothnagel[76] and Schleimpflug,[77] are not uncommon in many other conditions.[78]

[Footnote 75: _Loc. cit._]

[Footnote 76: _Beiträge zur Phy. u. Path. des Darms_, Berlin, 1884.]

[Footnote 77: _Zeitsch. f. klin. Med._, ix., 1885.]

[Footnote 78: Sasaki, _Virchow's Archiv_, 96.]

The blood vascular organs have naturally received special attention. The spleen offers, as a rule, no important changes; the size is variable, rarely enlarged, occasionally reduced in size, but for the most part normal. The smallest I have seen was in one of Howard's cases, in which the organ weighed only one ounce and five drachms. In the 51 autopsies noted in Howard's paper the spleen was stated to be normal in 36 and enlarged in 13. Ten ounces is the heaviest I have seen. The spleen-tissue is moderately firm, of a light brown-red color. I have never noticed either the extreme softening of an acute splenic swelling or the hardness of chronic induration. {905} The histological characters present nothing special. Cells containing red corpuscles occur, but not in such numbers as in cases of acute splenic swelling from fever. I have seen the nucleated red corpuscles in several instances.

The lymph-glands are, as a rule, normal in size and appearance. In three instances I found them decidedly smaller than normal, and in two they had a rich deep-red color, and on section looked more like spleen-tissue than lymph-gland. Weigert has noted the same appearance.[79] In one of the cases there were nucleated red corpuscles in the glands, as has been observed by Rindfleisch in a case of rickets,[80] and more recently in tuberculosis.[81]

[Footnote 79: _Virchow's Archiv_, Bd. lxxix.]

[Footnote 80: _Archiv f. Mikros. anatomie_, Bd. xxiii.]

[Footnote 81: _Med. News_, xiv. No. 23.]

The fatty tissue of the long bones is in many instances replaced by a red marrow resembling that of the short bones of the adult and the entire osseous system of the infant. This was first noticed by Pepper in 1875,[82] and has since been frequently observed. The color is usually of a reddish-purple when fresh, becoming a bright red on exposure. Sometimes there is a grayish-red appearance. It may not be universally distributed in the long bones, and the change would appear to proceed from the trunk toward the periphery--a direction the reverse to that in which the red marrow of the child becomes fatty. In many cases the marrow has been found normal; in others, the change known as gelatinoid has been observed. In five Montreal cases I found the marrow of the long bones lymphoid, in one gelatinoid, and in two the long bones could not be examined. It must be borne in mind that the short and flat bones of the adult contain a red lymphoid marrow mixed with a variable amount of fat, in which nucleated red corpuscles can always be found.

[Footnote 82: _American Journal of Medical Sciences_, lxx.]

The brain and cord present an intensely anæmic appearance; the membranes are relaxed and oedematous, and petechiæ may exist. The convolutions are often wasted, and the amount of cerebro-spinal fluid increased. No important changes have been found in the substance.

The ganglia of the sympathetic system have been examined by Queckett in one of Addison's cases and found fatty. Wilks and others have found them normal. Brigidi[83] has described an increase in the interstitial tissue and pigmentation of the cells. In two instances I found nothing abnormal. Sasaki[84] has described marked degenerative changes in Auerbach's and Meissner's plexuses in two cases of pernicious anæmia.

[Footnote 83: _London Med. Record_, 1878.]

[Footnote 84: _Loc. cit._]

The kidneys are usually pale and without special change beyond the fatty degeneration. Quincke has found the amount of iron increased. The suprarenals have in several instances been found very small. The sexual organs show no constant changes.

PATHOLOGY.--Under the general subject of Anæmia the pathology has been discussed at sufficient length. After excluding pregnancy, parturition, lactation, and inanition cases, as partaking more of the characters of secondary anæmia, we can recognize three groups of cases: First, those in which the bone-marrow has been found extensively affected--cases of anæmia medullaris; second, cases in which a primary atrophic change in the mucous membrane of the stomach appears to have been the starting-point of the trouble; and, third, cases in which after death no special changes have been found sufficient to explain the anæmia. To the latter the term idiopathic is applicable, and possibly they may be instances of hæmophthisis due to increased destruction of the corpuscles from causes unknown at present.

DIAGNOSIS.--A case in which anæmia comes on without obvious cause and without enlargement of the spleen, and progressively increases in spite of remedies, diet, change of air, etc., may be regarded as one of an idiopathic or essential character. If the case goes on to a fatal termination, the designation of pernicious is appropriate. I would place some reliance on the {906} microscopical examination of the blood, and would consider the presence of microcytes with great irregularity in the ordinary red corpuscles strong confirmatory evidence. The absence of wasting, the peculiar lemon tint of the skin, the occurrence of epistaxis and retinal hemorrhages, would render a diagnosis certain.

In that class of cases so well described by Fenwick,[85] Nothnagel,[86] and Nolen,[87] in which there has been an interstitial inflammation of the gastric mucosa and atrophy of the glands, the question has not yet been decided how far this condition is to be considered causal, and how far a part of the general disturbance of nutrition. The clinical picture may be identical with that of idiopathic anæmia, and in some of the cases the gastric symptoms have been so marked that the relation of the atrophy and the anæmia has evidently been that of cause and effect. And yet in these cases there does not appear to be the pronounced emaciation of inanition anæmia. In other instances the diarrhoea and chronic intestinal trouble may, with or without gastric participation, bring about a similar condition.

[Footnote 85: _Loc. cit._]

[Footnote 86: _Deutsches Archiv f. klin. Med._, xxiv.]

[Footnote 87: _Centralblatt f. d. Med. Wissenschaft._, xx.]

Profound anæmia may arise during or after pregnancy, and a considerable proportion of the cases on record have been in this connection.

From ordinary cases of Hodgkin's disease, anæmia lymphatica, there could be no difficulty in making a diagnosis if the superficial glands were enlarged. In splenic anæmia, if the enlargement was not great, there might for a time be uncertainty, which the progressive increase of the organ would remove. Neither in anæmia splenica nor lymphatica are we so likely to meet with the microcytes or irregular corpuscles.

Chlorosis occurs chiefly in young girls, and is amenable to treatment.

From the various cachexias--malarial, syphilitic, metallic--the history will commonly afford grounds for a diagnosis, and in these states, as in latent cancer, the wasting is apt to be more pronounced than in essential anæmia. Cases of gastric cancer are occasionally met with which simulate closely pernicious anæmia, and the diagnosis may be doubtful for months.[88]

[Footnote 88: Richard Neale, _Practitioner_, 1883.]

The enteritis and hemorrhages caused by the presence of Anchylostoma duodenale in the intestines may produce an aggravated form of anæmia resembling closely the form under consideration. It prevails among the workers in mines and tunnels, hence the name miner's anæmia or anchylostomiasis. The diarrhoea and the detection of the ova or worms in the discharges would afford grounds for a diagnosis.[89]

[Footnote 89: _Trans. of the International Med. Congress_, London, 1881, vol. i. 437.]

The PROGNOSIS is unfavorable, particularly in those cases which have arisen without any cause or previous ill-health. In the cases arising from defective food, etc.--inanition anæmias--pregnancy, or lactation, the outlook is less grave. Of the 64 Zurich cases in Müller's monograph, 7 recovered, and of Quincke's 31 cases, 11 recovered. Pye-Smith gives a table of 20 recorded cases of recovery.[90] Great improvement may occur, or even recovery for a period of several years, after which the disease may recur and prove fatal. This was the history in a case under the care of Wilkins at the General Hospital, Montreal.

[Footnote 90: _Loc. cit._]

TREATMENT.--The designation pernicious applied by Biermer indicates the hopeless character of the disease in perhaps a majority of the cases; of late the records happily show a considerable percentage of recoveries. Thus, Pye-Smith has collected 20 cases in which convalescence was established after severe and profound anæmia, belonging undoubtedly to the class here considered. The intractable nature of a case and the resistance to ordinary treatment are points which may first suggest to the practitioner the fact that he is dealing with a something more than simple anæmia.

{907} Hygienic and dietetic regulations are of the first importance. Cases appear to have got well with change of air and a better diet after resisting all ordinary means. In other instances no benefit whatever has been derived from residence at the sea or in the mountains. As a rule, the cases are best treated at home. The greatest care must be exercised in the regulation of the diet, which should be light and nutritious. So long as the digestion keeps tolerably active there is hope: anorexia, vomiting, and other dyspeptic symptoms are among the most troublesome and serious features. The bitter tonics, hydrochloric acid, and pepsin may be administered. But the stomach may fail absolutely and reject even the smallest amount of liquid food, and rectal alimentation must be employed. The gastric symptoms have been specially marked in cases in which there has been found post-mortem atrophy of the peptic glands. In certain of these cases the problem of feeding will tax to the uttermost the resources of the physician. Rectal injections of blood (fresh or dried), as recommended by A. H. Smith, I have found beneficial in several cases. Intestinal symptoms--diarrhoea, flatulence, and in some cases melæna--call for treatment.

Of medicines, arsenic is the most important, and in the form of Fowler's solution should be employed in small and increasing doses. We are indebted to Bramwell[91] for pointing out the great value of this medicine, and in certain cases it acts almost as a specific. In 8 of the 20 cases of recovery noted by Pye-Smith the improvement seemed due to the arsenic. Padley[92] has collected in the literature 48 cases treated without arsenic, of which 42 were fatal, while of 22 cases treated by arsenic 16 recovered, 2 improved, and only 4 proved fatal. The testimony of recent observers is very strongly in favor of this drug as the most efficacious we possess in this grave disease. The use should be continued long after the convalescence is apparently established; indeed, it should be given at intervals for many months after recovery, as there are dangers of relapse. There are cases which are not benefited by arsenic, even when well borne. Finlay[93] has recently reported a case which was cured by iron after the failure of arsenic.

[Footnote 91: _Edinburgh Med. Journal_, 1877.]

[Footnote 92: _Lancet_, 1883, ii.]

[Footnote 93: _Lancet_, 1885, i.]

Iron, as a rule, seems quite useless in the majority of these cases. I have frequently seen the percentage of red corpuscles gradually sink under its administration, and then rise in a remarkable way when the arsenic was employed. This is in curious contrast to the effect of this drug in the various secondary anæmias and chlorosis in which it is rightly regarded as a specific. The cases which are benefited may have a different etiology, and where the arsenic does not succeed some form of iron should be given, as Finlay's case, just mentioned, shows that there are instances where it cures after the failure of the arsenic.

Broadbent advises the use of manganese when the anæmia is associated with uterine or menstrual trouble. Phosphorus has been extensively employed, and occasionally with benefit.

When all remedies have been tried in vain the question of transfusion of blood arises. As a substitute for the intravenous transfusion the blood has been injected into the peritoneum: this has been practised in Italy with success.[94] The subcutaneous injection has also been used, and lately the inhalation of a spray of blood has been recommended.[95] In four or five instances intravenous injection has succeeded, but in the majority of cases it has proved useless. Von Ott's[96] interesting researches show that the injected blood-corpuscles and albuminous materials always undergo destruction in the blood, and a 6/10 per cent. solution of common salt seems to answer just as well, and is much more available and less dangerous.

[Footnote 94: _Practitioner_, vol. xxxi.; Ponfick, _Berl. klin. Wochenschrift_, 1879.]

[Footnote 95: _Med. News_, 1885, i.]

[Footnote 96: _Virchow's Archiv_, Bd. xciii.]

{908} The injection of milk, as first practised in cholera by my preceptors, Bovell and Hodder[97] of Toronto, has also been employed in anæmia (Pepper, Wulfberg).

[Footnote 97: _Canadian Journal of Science_, 1854.]

LEUKÆMIA.

DEFINITION.--A disease characterized by a great and persistent increase of the colorless corpuscles of the blood, associated with enlargement of the spleen, lymphatic elements, and bone-marrow.

SYNONYM.--Leucocythemia (Bennett).

HISTORY.--Our knowledge of this affection dates from the description of two cases by Craigie and Bennett in the October number of the _Edinburgh Medical Journal_ for 1845. The altered state of the blood was thought to be due to the presence of pus--a suppuration of the blood. In the November number of Froriep's _Notizen_ for 1845, Virchow described a case in which the proportion between the red and white corpuscles seemed reversed, and the blood had in consequence a grayish-white appearance. He attributed the condition to an increase in the colorless corpuscles. A case of Rokitansky's is referred to in this article. In 1846, Fuller described a case before the Medico-Chirurgical Society of London, in which the increase in the colorless corpuscles was noted during life and after death.

In the August and September numbers of _Medicinische Zeitung des Vereins für Heilkunde_ (1846) Virchow reviewed these four cases, and insisted upon the fact that the colorless cells in the blood were not pus, and vindicated a place in pathology for the white blood-corpuscle. In the January number (1847) of the same journal he gives further cases of white blood which he had collected in the literature--cases of Bichat (1801), Velpeau (1827), Caventon (1828), Andral (1839), Barth (1834),[98] and several others--and discussed the conditions under which the colorless elements might increase and the relation of the spleen to the white cells. In the same year (1847), in the first volume of his _Archiv_, Virchow proposed the name leukæmia. Vogel in 1849 diagnosed a case during life.[99]

[Footnote 98: Donne (_Cours de Microscope_, 1844), who examined Barth's case, seems to have been the first to recognize that the colorless cells were blood- and not pus-corpuscles. See note by Gowers in _Lancet_, i., 1878.]

[Footnote 99: _Virchow's Archiv_, Bd. iii.]

Bennett in 1851 collected additional cases, and gave the name of leucocythemia to the disease, and in 1852 published a monograph entitled _Leucocythemia; or, White-celled Blood, in Relation to the Physiology and Pathology of the Lymph-gland System_. He claimed priority in the discovery of the condition, and for several years a lively paper war raged between the Edinburgh and the Berlin professors.

At this distance of time and place we can, now that the clouds of controversy have blown away, see the truth. Bennett certainly described cases before Virchow, but only in a manner similar to that in which Bichat, Velpeau, and others had previously done, and he distinctly stated his belief that the grayish-white color of the blood was due to pus. Virchow from the first grasped the idea that the altered state of the blood was due to an increase in the colorless cells, and he first suggested the relation between their increase and the condition of the spleen and lymph-glands, and he first gave a satisfactory name to the disease; so that, while acknowledging the great and valuable services of Bennett, we must, perforce, recognize the greater merit {909} of Virchow, and recognize his priority in the scientific description of the disease and in giving to it a suitable name. The further investigations of Virchow enabled a splenic and a lymphatic form to be recognized, and many years later Neumann[100] described the myelogenous variety.

[Footnote 100: _Archiv der Heilkunde_, Bd. xi.]

FORMS OF THE DISEASE.--According as the pathological changes are located in the spleen, lymph-glands, or marrow we speak of splenic, lymphatic, and medullary or myelogenous forms; but it is very exceptional for pure unmixed varieties to occur. More commonly, the spleen and marrow, or these with the lymph-glands, are involved. The disease may begin and make great progress in one of these regions, or be confined to it for months, before appearing elsewhere. The spleen is most often affected, and with it the marrow. According to many recent writers, the myelogenous form is the most general, and certainly the marrow is rarely found unchanged. The unmixed lymphatic variety is not of frequent occurrence. An intestinal form, characterized by swelling of the solitary and agminated lymph-glands and the general adenoid tissue of the bowel, has been described by Behier.[101] In a few instances the tonsillar and pharyngeal lymph-elements have been early, perhaps primarily affected, and Kaposi has recently recorded a case[102] under the name lymphoderma perniciosa, in which the lymphatic elements of the skin were first involved.

[Footnote 101: _L'Union médicale_, 1869.]

[Footnote 102: _Wiener Med. Jahrbücher_, 1885.]

ETIOLOGY.--We know scarcely anything of the causes of the disease, but it is usual to take into account certain factors which may possibly influence its production, such as climate and country, age, sex, etc.

Climate and Country.--The disease appears to be more common in temperate regions; not many instances are reported from the tropics. It does not appear to be often met with in India. It is, I think, more common in Europe than in this country. The determination of its prevalence is rendered difficult by the fact that many cases reported simply as enlarged spleen, without any examination of the blood, have possibly been leukæmia. It does not seem to be more common in the southern part of this continent.

Age.--No age appears exempt. Cases are recorded in infants of eight or ten weeks and in men of sixty-nine and seventy years of age. The youngest case I have seen was in a suckling of eight months. The majority of cases occur at the middle period of life, from thirty to forty. After the fiftieth year the cases diminish very much in number.

Sex.--Males are more prone to the affection than females, in the proportion of at least 2 to 1. Of 11 cases which I saw in Montreal, only 3 were in females; of 200 cases collected in the literature, 135 were in males and 65 in females (Birch-Hirschfeld[103]).

[Footnote 103: _Lehrbuch der Path. Anatomie_, 2te Auf., 1883.]

Social and sanitary conditions do not appear to have much influence, though the lower and middle classes furnish the majority of the cases. Mental worry and depression are specially mentioned as predisposing causes in some cases.

Previous Disease.--In women it has frequently been noticed that disturbance in the menstrual and sexual functions has preceded the onset of the disease. The climacteric period has the greatest number of cases, and in a few instances the disease had developed during pregnancy.

The hemorrhagic diathesis has been noted in many cases, and the patient may have been the subject of slight hemorrhages for years. In one case of Howard's[104] the lad had been subject to nose-bleeding as a child, and his mother and one sister had been much troubled in the same way.

[Footnote 104: _Montreal Gen. Hosp. Reports_, vol. i., 1880.]

Malaria.--On account of the frequency of chronic splenic tumor in malarial infection, inquiries are always carefully made in any suspected case as to the occurrence of intermittent fever. An intimate connection is believed by {910} certain writers to exist between the affections, and a few cases seem to have followed directly upon chronic malaria. In Mosler's statistics of 112 cases there were only 4 in which the sequence was well marked.[105] In Gowers' 150 cases there was a history of malaria in 30.[106] In the Montreal cases there was an account of malaria in 3 certainly--possibly in a fourth. In the reports of 33 American cases there were only 6 with a history of malarial attacks within twelve years from the date of the onset of leukæmia. Guiteras of Key West (now of Charleston, S.C.) states that it is a rare affection in the South. Schmidt of New Orleans writes me that it is not uncommon in Louisiana, but there are very few cases reported in Southern journals.

[Footnote 105: _Die Leukæmie_, Berlin, 1872.]

[Footnote 106: _Reynolds's System_, art. "Leucocythæmia."]

Syphilis appears to have been in a few cases closely connected with the onset of the disease.

Injury.--Many patients give an account of a blow or strain in lifting. In 3 cases which I have seen the patients laid great stress on this. One had received a kick in the side from a horse, and the two others had strained themselves in lifting. De Chapelle[107] has dealt specially with this feature in the etiology of the disease.

[Footnote 107: _De la Leukémie dans ses Rapports avec la Traumatisme_, Paris, 1881.]

Previously-existing splenic enlargement does not seem, as we might expect, to predispose to leukæmia. It is rare for a case of simple chronic hyperplasia of the spleen--from malaria, for instance--to terminate in leukæmia.

The disease occurs in the lower animals, and cases have been described in horses, dogs, oxen, cats, swine, dogs, and mice. The majority of cases have been in dogs.[108] A study of the comparative pathology of the disease has not thrown any light on the etiology.

[Footnote 108: Siedamgrotzky, _Ueber die Leukæmie bei den Hausthieren_, Leipzig, 1878; Bollinger, _Virchow's Archiv_, lix.; _London Med. Record_, vol. ii., 1874.]

SYMPTOMS.--A division of the disease into two or three stages has been made by some writers, but as no special regularity is observed in the sequence of events, we need only recognize a period of development, in which the disease gradually becomes established, and a final period of cachexia, when there are symptoms of profound blood-change and the viscera are involved.

The mode of onset is insidious. In the majority of cases there is failure in health and strength, and the patient seeks advice for progressive enlargement of the abdomen with dragging pain in the side, or for the shortness of breath, the enlarged lymph-glands, the pallor, or the various symptoms of anæmia, as headache, palpitation, and dizziness. Bleeding at the nose is common. Vomiting and diarrhoea may be early symptoms, and in a few cases oedema of the face and feet has been noted early in the disease. Occasionally the first symptoms to attract the attention of friends or physician are of a serious nature--a sudden hemorrhage, for example. In one of Howard's cases the lad had played lacrosse two days before the onset of the fatal hæmatemesis, and in another case, a girl, there was early and fatal hemorrhage from the stomach before the condition of splenic enlargement was suspected.

Digestive System.--Gastric symptoms are rarely absent in the form of oppression after eating, nausea, and vomiting; the latter may be an early and troublesome feature. The appetite is variable, and when the spleen is greatly enlarged the mechanical pressure is apt to cause uneasy feelings after eating.

Diarrhoea is common, and may come on very early in the disease (Case I.[109]), and it is a frequent cause of death. The stools are usually thin and catarrhal, not often dysenteric, but melæna occurs in many cases. The diarrhoea may be due to a dysenteric process in the colon (Case II.), and tenesmus may {911} be present. It has not been noted that the diarrhoea is more frequent when the lymph-glands of the intestines are involved.

[Footnote 109: These figures refer to Montreal cases, some of which I saw with my colleague, Palmer Howard, others with John Bell, Lachapelle, and G. T. Ross.]

The liver shows no alterations in the early stage, but as the disease advances it is almost invariably enlarged. Jaundice is not often present, but there may be recurrent attacks (Case II.), due either to catarrh of the ducts or to pressure of glands in the hilus. Ascites is a variable feature; a slight degree is not uncommon as part of a general dropsy dependent upon the blood-condition, but in some cases it is a prominent symptom and calls for frequent tappings (Case IX.). In some cases it is due to pressure of leukæmic growths in the branches of the portal vein or the liver, or of enlarged glands upon the trunk at the hilus. The ascites is not always hepatic; like the hæmatemesis and melæna, it may be of splenic origin and occur without any disturbance in the portal vein or liver. Leukæmic peritonitis has been met with.[110]

[Footnote 110: Willcocks, _Proceedings of Conn. Med. Soc._, 1874.]

Nervous System.--Headache, dizziness, and attacks of fainting are common, and due chiefly to the anæmia. In some cases the headache is severe and persistent. The intelligence is well preserved; only toward the close is there rambling delirium. Mental disturbance may occur, and in one case the patient committed suicide. Some writers speak of special sadness and moroseness. This I have never noticed; on the contrary, in most of the cases I have seen the patients seemed specially tranquil and resigned. Coma may come on suddenly from cerebral hemorrhage (Case X.).

Sleep is not usually disturbed; some patients doze incessantly.

Special Senses.--Weak vision is often complained of, due to the anæmia, sometimes to the leukæmic retinitis. Blindness rarely supervenes, even when the retinal changes are extensive. Marked intolerance of light may be present.

The condition of the retina is variable. There may be simply turbidity and swelling of the retina, with large and tortuous veins, or more commonly with the opacity there are hemorrhages, such as occur in profound anæmia from any cause. A peculiarity, however, of the extravasations in some cases of leukæmic retinitis is the appearance produced by the aggregation of colorless corpuscles, often in the centre of the hemorrhage, so that there is a yellow or white nucleus and a zone of red. The collections of colorless corpuscles may indeed have the characters of small leukæmic growths. In one case (XI.) throughout the retinæ were numerous small raised opaque white bodies one to two millimeters in diameter, some of them surrounded by rings of extravasation. There was no swelling of the disk.

Deafness has been frequently observed, and may appear early. It was specially noted in the cases of Edes,[111] Morrill,[112] Seguin,[113] and Pepper,[114] and DaCosta.[115] No satisfactory explanation has been given, and the suggestion that it is due to hemorrhage has not, so far as I know, been confirmed by autopsy. Noises in the ears may be very troublesome, and even be so bad as to disturb hearing and necessitate the writing of questions (Case XI.).

[Footnote 111: _Boston Med. and Surg. Journal_, 1871.]

[Footnote 112: _Loc. cit._]

[Footnote 113: _Archives of Scientific and Practical Medicine_, New York, 1873.]

[Footnote 114: _Med. and Surg. Reporter_, 1883, 48.]

[Footnote 115: _Ibid._, 1874.]

Blood-vascular System.--In a well-marked case the blood-drop squeezed from the finger-tip is more or less turbid, of a reddish-brown or in extreme cases chocolate-brown color.

The blood should be examined in a thin layer, and for this purpose it is better to take a small than a large drop. A rough estimation of the proportion of white corpuscles can be much better obtained when a uniform thin layer is beneath the top cover. The red corpuscles, as a rule, present no striking changes, no special alterations in size or shape. Microcytes are {912} occasionally seen, and now and then larger forms, but the extreme variations of pernicious anæmia are rarely met with. They are reduced in number, but not often to a great extent. A reduction below 2,000,000 to the cubic millimeter has been exceptional in cases which I have examined. In only one did the number sink to 1,500,000 per c.m. Laache[116] has noted a case in which, with enlargement of the spleen and a ratio of white to red of 1:17, the number of red corpuscles was little if at all reduced.

[Footnote 116: _Die Anämie_, Christiania, 1883.]

The colorless corpuscles are enormously increased. Instead of eight to ten millions per c.m., as in normal blood, they may reach 500,000 per c.m. or even 700,000 per c.m. The ratio of white to red cells may be 1:20, 1:10, 1:4, or they may even equal or exceed the red. Without a proper apparatus (Gowers, Malassez, or Zeiss) an accurate estimate is impossible, and it is chiefly upon the rough-and-ready method that the statements are made of the white exceeding the red in numbers. It is very seldom indeed that this is the case, and even in extreme leukæmia the ratio does not often reach 1:3 or 1:2. In none of my observations did the ratio rise to 1:1; the highest was 1:2. Cases are on record in which the white have exceeded the red: Sörensen's,[117] where the red per c.m. were 470,000 and the white 680,000, and in an interesting observation of Fleischer and Penzoldt,[118] as a mean of 57 accurate counts, the ratio of white to red was 115:100. The corpuscles have the natural grayish-white appearance of leucocytes, but differ in certain points from normal white blood-cells. The variations in size are greater: in normal blood only a few may be seen less than 1/2800 or 1/3000 of an inch, but in leukæmia on a single slide there may be colorless cells with the extreme measurements of 1/2000 and 1/3500. In ordinary cases we meet with--(1) cells of the average size, about 1/2800 of an inch in diameter, like normal corpuscles, with two or three nuclei and fine granular protoplasm; (2) smaller forms, 1/3000 of an inch and under, with single nuclei, resembling rather lymph-cells, and they were believed by Virchow to indicate special involvement of the lymph-glands, but they are present in all forms, though possibly more prevalent in the lymphatic variety; (3) large forms, 1/2000 to 1/1500 of an inch, with bold nuclei and bearing a close resemblance to the marrow-cells. They are not always present, and are believed to originate in the marrow.