DISEASES OF THE BLOOD AND BLOOD-GLANDULAR SYSTEM.

BY WILLIAM OSLER, M.D.

INTRODUCTION.

The blood is a fluid tissue composed of cells floating in an albuminous plasma, and it differs from other tissues not less in the arrangement of its elements than in the activity of the changes which go on in it. It is the mart into which is poured from the alimentary canal the commodities needed in nutrition, and the elements of the body select from it the various materials which they require, giving in exchange those chemical combinations which result from the metabolism of the tissues. In spite of ceaseless changes, a uniformity of composition is one of the most striking features of the blood in health. This is maintained, as regards the constituents of the plasma, by the activity of the organs which regulate income and expenditure—the alimentary canal and liver on the one hand, and the kidneys, lungs, and skin on the other; while histological uniformity is maintained by the adenoid or cytogenous tissue throughout the body, the function of which is to replace the wornout blood-corpuscles.

The corpuscles form rather less than one-half by weight of the blood. The plasma contains about 90 per cent. of water, which holds in solution proteids in the form of serum, albumen, and the fibrin-forming factors; sugar in traces; creatin, hypoxanthin, and urea; various fatty bodies in small amount; salts, chiefly sodium; and gases. The corpuscles (red) consist of hæmoglobin (90 per cent.), proteid bodies, and traces of lecithin and cholesterin.

So far as we know at present of the function of these two portions of the blood, the plasma ministers to the general nutrition of the tissues, while the corpuscles (red) are chiefly concerned with respiratory processes, acting as the carriers of oxygen and carbonic oxide.

We shall first give a brief account of the histological characters of the blood, and of the relation of the groups of adenoid or cytogenous tissue to the corpuscles.

Two forms of corpuscles are usually described, but we can recognize four varieties of blood-corpuscles in the body: (1) red, (2) white, (3) nucleated red, and (4) the hæmatoblasts (Hayem), or blood-plates of Bizzozero.

(1) Red Corpuscles.—In each cubic millimeter of plasma there are about 5,000,000 red cells. The percentage may vary within health limits from 90 to 110. The corpuscles are circular, non-nucleated, biconcave disks, homogeneous, to ordinary inspection structureless, and consist of a colorless stroma which is possibly reticulated, and a red coloring matter, the hæmoglobin. In health they are tolerably uniform in size, about 7.9 µ¹ in diameter, or in English measurement ¹/3200 of an inch (Gulliver). Even in normal blood there may be slight variations in size between 6.5 µ and 8.5 µ, the average, according to Hayem, being 7.5 µ.

¹ µ is used to signify a micro-millimeter or ¹/1000 part of a millimeter.

(2) Colorless or white corpuscles, nucleated masses of protoplasm, with an average diameter of 10 µ, or about ¹/2500 of an inch. The majority have a finely granular protoplasm, but in a few the granules are coarse and do not completely fill the clear protoplasm. The ultimate structure is reticular (Heitzman). Erhlich² has shown by their varying reaction to eosin that there are chemical differences among the colorless cells quite unrecognizable by other means. In healthy blood they display active amoeboid changes at ordinary temperatures. Their protoplasm does not, as is commonly stated, rapidly disintegrate, but if kept at a medium temperature retains its vitality, as shown by movements, for hours. The number per cubic millimeter is from 8 to 15 millions, and the ratio to the red is variously computed as 1 to 300 or 1 to 500.

² Frerichs find Leyden's Archiv, Bd. i.

(3) Nucleated red corpuscles, which occur in the blood of the foetus and the infant, gradually diminishing until at the third or fourth year they disappear. In the adult they do not occur in the blood in health, but are normal constituents of the red marrow of the short bones. They measure from ¹/1500 to ¹/2000 of an inch, and are of somewhat variable intensity of color, often quite as deep as the ordinary red forms. There may be two or even three nuclei, not colored, grouped together, often eccentric, and in some instances protruding from the cell.

(4) The hæmatoblasts of Hayem, the blood-plates of Bizzozero, the elementary or intermediate corpuscles, are small discoid colorless corpuscles about 3 µ in diameter, and are normal constituents of healthy blood. When the blood is withdrawn, they aggregate together into irregular clumps or masses, which have long been known as Schultze's granule-masses. It can be readily demonstrated in new-born rats or kittens, in which these masses abound, that the corpuscles composing them are isolated in the vessels, and only run together when the blood is drawn. The statement is commonly made that the granule-masses of Schultze result from the disintegration of the white corpuscle (of the red, Erhlich), but half an hour's study of the question in a new-born rat will convince any competent histologist that we have here to do with a separate blood-element.³ It appears to have important relations with the production of fibrin.

³ Consult Proceedings Royal Society, 1874; Centralblatt f. d. Med. Wissenschaften; Medical News, 1882, 2; Bizzozero, Virchow's Archiv, Bd. xi.; Hayem, Recherches sur l'Anatomie normal et pathologique du Sang, Paris, 1878.

Of the origin and life-history of the red corpuscles during post-embryonic life we have still much to learn. They are stated to develop—

(1) From colorless corpuscles, the lymph-cells or leucocytes. In the lymph-glands, the Malpighian bodies of the spleen, in the thymus, or the adenoid tissue of the tonsil, of the lymph-elements in the intestines and other regions, colorless cells are constantly being manufactured, and the general belief has been since Hewson's time that the red corpuscles develop in some way or other from these leucocytes. How or where has not yet been settled. It does not apparently go on in the blood, or we should surely catch, in the many observations and with the excellent powers now in use, a glimpse of the birth of one of them. Some observers (Johnstone⁴) maintain that they develop from the granular protoplasm of the adenoid reticulum by a process of budding. This may be so, but we should expect to find the lymph in the efferent vessels and of the thoracic duct much more rich in red cells than is usually the case, and in specimens of healthy glands we should find young-looking elements such as he describes.

⁴ Seguin's Archiv, vol. vi.

(2) From the nucleated red corpuscles. In the embryo this undoubtedly takes place, and as the weeks of development proceed, the ordinary red forms gradually predominate. In the child the red nucleated cells disappear early, and are then found only in the red marrow. So far as my observations go,⁵ they apparently originate from colorless marrow-cells, which gradually become more homogeneous, and hæmoglobin develops in the protoplasm. The nucleus degenerates and disappears, when the cell has the appearance of an ordinary red disk. Rindfleisch thinks that the nucleus of the nucleated red is extruded in the development. It is possible that from these nucleated red corpuscles cells may originate in another way—viz. by budding. This I have seen and sketched in the marrow-cells,⁶ and Malassez has studied the same process.⁷ The gemmæ are small, and sprout from the protoplasm, not the nuclei, and when they break off they resemble the microcytes which occur so abundantly in certain anæmic states. Bizzozero⁸ holds that these nucleated red corpuscles are independent elements which do not develop from the colorless marrow-cells. They multiply by fission, and develop into the ordinary red forms with the disappearance of the nuclei. Several recent investigations support this view.⁹

⁵ Centralblatt f. d. Med. Wissensch., 1878.

⁶ Trans. Am. Ass. Ad. Science, 1882.

⁷ Archives de Physiologie, 1882.

⁸ Centralblatt f. d. Med. Wissenschaften, Bd. xix.

⁹ Fortschritte der Medicin, 1885, No. 1.

(3) Hayem believes that the red corpuscles develop from the small hæmatoblasts, but, so far as I know, his observations have never been confirmed. He states that in normal blood they occur in the proportion of about 1 to 20 red. In all states of blood reparation they increase greatly. He describes a hæmatoblastic crisis as occurring after hemorrhage, fevers, etc., when the number of these elements rapidly augments, and is succeeded by the addition of many small pale-red corpuscles, which he looks upon as intermediate between the hæmatoblasts and the ordinary red forms.

The colorless corpuscles are regarded as the direct offspring of the cells of the follicular cords in the lymph-glands and adenoid tissue, but whether by process of division of existing leucocytes or by sprouting from the endothelial places, or from the protoplasm in the fibres of the reticulum, remains to be settled.

The nucleated red corpuscles are in the healthy adult confined to red marrow, in which they probably develop from colorless cells, and may be regarded, as Neumann originally suggested, as transitional or intermediate forms between white and red cells. In anæmic states they may occur in the spleen and in the lymph-glands.

Of the origin of the hæmatoblasts or blood-plates we know absolutely nothing. They occur most abundantly under two most opposite conditions—in the young growing animal just entering upon life, and in the diseased, cachectic, wornout animal just preparing to abandon it.

Our knowledge of the relation of the cytogenetic organs to blood-formation may be thus briefly stated: The spleen certainly takes part in the development of colorless corpuscles, but its participation in red blood-formation is more doubtful. The nucleated red or embryonal forms do not occur, at least in any numbers, in health, though some observers have noted that after a repeated bleeding the organ was swollen and contained many such cells, as if it was the seat of an active development. Though the opinion prevails widely that the spleen is one of the important organs in the formation of red corpuscles, the evidence for this belief is of an exceedingly scanty nature.

The lymphatic glands and the adenoid tissue in other regions are the seats of constant production of colorless corpuscles, but of their relation to the red corpuscles there is the same lack of information as in the spleen. I do not know of any corroboration of the observation of Johnstone above mentioned, and in any case the number of red cells in the efferent vessels of a lymph-gland is so small—and indeed in the thoracic duct itself—that we cannot believe they are produced as red corpuscles in large numbers within the lymphatic system.

The red bone-marrow, as pointed out by Neumann¹⁰ and Bizzozero,¹¹ appears to be the seat of blood-formation, and in the adult body is the only region in which the embryonic or nucleated red cells are found. It is a tissue similar in many respects to the spleen, and, though confined to the short and flat bones, the total amount in the body is very considerable. In the young it also fills the long bones. The evidence of the development of red corpuscles in the marrow rests upon the constant presence of nucleated cells infiltrated with hæmoglobin, and of their fission. Forms undergoing the process of karyokinesis can be seen without difficulty. In excessive hemorrhage, natural or induced, it appears to undergo an active proliferation, and in the long bones a red marrow may replace the fatty tissue.

¹⁰ Centralblatt f. d. Med. Wissenschaften, 1868.

¹¹ Ibid., 1868.

The liver is doubtless the seat of blood-destruction, for the bile-pigments and leucocytes with red corpuscles in their interior have been found in its tissue. Nicolaides¹² has shown that in the blood of the hepatic vein there may be a reduction of from one million to one million and a half of red corpuscles per c.m. In the embryo Neumann¹³ has shown that it may be the seat of the production of corpuscles, but there is no satisfactory evidence that in the adult this ever takes place.

¹² Archives de Physiologie, 1882.

¹³ Archiv der Heilkunde, xv.

The remarkable rapidity with which, after a profuse bleeding, the normal proportion of red corpuscles is reached shows with what activity the development may proceed, and how favorable the conditions must be for their production. After the loss of a large quantity of blood the manufacture of new corpuscles may proceed at the rate of 30,000, 40,000, or even 50,000 a day.

What becomes of the red corpuscles? Here, again, is a question not satisfactorily settled. We do not know the average length of life of corpuscles. They are supposed to be short-lived—three weeks, according to Quincke. The need for their dissolution is assumed to provide pigment for the various secretions and tissues, and we occasionally see a few cells in the blood with a pallor which may be regarded as an indication of senility.

Positive evidence, however, of their destruction is afforded by the occurrence of the so-called corpuscles containing red corpuscles, which occur normally in red marrow and in the spleen, and under some circumstances in the lymphatic glands and liver. The red cells undergo gradual transformation into a yellow granular, and finally black, pigment. In normal spleen and marrow the numbers found are very variable; in fevers and cachectic states they may be in extraordinary numbers. Quincke and his pupil Peters¹⁴ have studied with great care this process of transformation of the red corpuscles and accumulation of the pigment in the cells of the marrow, spleen, liver, and lymph-glands, to which the term siderosis is applied. These pigment-granules are in the form of an iron albuminate, and are used in the development of new corpuscles. Thus, after repeated bleedings in animals, they may disappear completely in the restoration of the blood, while in animals into whose vessels blood has been transfused or injected subcutaneously the iron-containing cells in the various organs are very numerous, and even the cortical cells of the kidney contain numerous granules.

¹⁴ Deutsches Archiv f. klin. Med., Bds. xxv., xxvii., xxxii., xxxiii.

The amount of hæmoglobin in 100 grammes of healthy blood is 13.45 grm. (Preyer). Malassez estimated the quantity in a cubic millimeter of blood at between 0.125 and 0.134 milligramme, and, taking the corpuscular richness at from 4,000,000 to 4,600,000, he has estimated approximately the amount of hæmoglobin in each corpuscle.

PLETHORA.

General and persistent polyæmia or plethora has scarcely a place in recent pathology. Formerly it was thought that either from over-production or lowered expenditure the total amount of blood accumulated and filled the blood-vessels to an abnormal extent. The amount of blood undergoes, within limits, constant daily alterations, and after a full meal the vessels are in a state of plethora compared with their condition at the end of a ten hours' fast. If a plethysmograph could be devised to record graphically the variations in the total quantity of blood, each ingestion of food or drink into the vessels would be followed by a rise, and each interval by a gradual decline. So long as the organs of secretion and excretion are active the quantitative and qualitative condition of the blood is maintained at a tolerably uniform standard in each individual. At different periods of life the relation of blood-weight to body-weight varies. In the new-born the blood amounts to one-eighteenth part by weight of the body, while in the adult the average is from one-twelfth to one-fourteenth; so that in the infant there is a condition of comparative plethora. There are no reliable observations on the proportion of blood- to body-weight at respective ages, but there appears to be a reduction in old age. In women it is stated that just before each menstrual period there is a state of polyæmia.¹⁵

¹⁵ Mary Putnam Jacobi, The Question of Rest for Women, New York.

Worm-Müller¹⁶ and Cohnheim¹⁷ have made some very interesting experiments on this question of plethora. By transfusion in dogs a state of artificial plethora is readily established, and the animals stand the injection of as much as 10 or 12 per cent. of the body-weight of blood, above which quantity a fatal result ensues. After an injection of 20 or 30 per cent. of the total amount of blood, the superfluous plasma and corpuscles are got rid of in a few days, while with a larger injection of 60 to 80 per cent. it takes two or three weeks before the normal state is again reached. The albuminous and nitrogenous materials are largely got rid of by the urine, which increases rapidly in quantity and also in the amount of urea. The excess of corpuscles gradually disappears, and the hæmoglobin becomes deposited, as Quincke has shown, in the form of small granules in the cells of the liver, spleen, and bone-marrow.

¹⁶ Transfusion and Plethora, Christiania, 1875.

¹⁷ Allgemeine Pathologie, 2te Auflage.

In a similar way, it is reasonable to think that the body is quite capable of disposing of surplus albuminous materials in over-fed, lazy individuals with active digestion, whose red faces, full vessels, and bounding pulses give the impression of a distended circulatory system, and whom we term plethoric. Their appearance is the result rather of blood-distribution than of actual increase in the total volume, and there is no evidence that under any circumstances a rich and abundant diet without much exercise can permanently increase the amount of blood. It was formerly held that the healing of an old sore or the cessation of an accustomed discharge or loss of blood, by diminishing expenditure while the blood-making power was maintained, could induce plethora if no local disorder was excited "before the vessels in general reached a state of plethoric tension." Of such a condition, and of the plethora apocoptica that was thought to occur after the amputation of a limb, we do not hear much now, and the prevalent opinion of pathologists is expressed by Cohnheim, when he says "that, except as a transitory state, polyæmia does not occur under any circumstances." What, then, is the meaning of the full-blooded, rubicund condition which we see in some men, not necessarily large feeders, but often with vigorous active constitutions and perfect types of health? The appearance of plethora is caused chiefly by the distension of the superficial vessels; the circulation of the skin is remarkably active, particularly in the face, and it is probable that we have here to deal with local peculiarities of the vessels or of their innervation, and not with any general augmentation of the total blood-mass. It may be, however, that in such persons there is a plethora of certain of the constituents of the blood—viz. the red corpuscles—and there may be a state of polycythæmia rubra, as it has been called, in which the percentage of red cells is increased. In several such cases I have found, as has been previously noted, the number of red corpuscles considerably over the average. A relative increase in the number of red corpuscles also occurs in those sudden and excessive losses of fluid, as in cholera, in which the blood may become thick and sticky from the great reduction in the plasma, particularly of the water and salts—anhydræmia—or in cases in which the income of fluid is greatly restricted. Henry (F. P.) has recorded a case¹⁸ of stenosis of the cardia, in which, with great emaciation, the corpuscles per c.m. were 5,525,000.

¹⁸ Archives of Medicine, New York, vol. vii.

The condition known as hydræmic plethora develops whenever there is a great reduction in the number of corpuscles, as after a hemorrhage, or when the blood has been impoverished by long-standing suppuration, albuminuria, or in the growth of large tumors. So also when the secretion of urine is diminished, as in some cases of Bright's disease, and at the same time charged with albumen, the blood may become very watery; but in these states there is not an absolute increase in the entire blood, but only a relative excess of the water. Occasionally, this great excess can be noticed in the blood-drop as it comes from the finger-tip; the corpuscles do not fill the entire drop, and consequently leave irregular areas unoccupied by the red disks.

ANÆMIA.

A reduction in the amount of the blood or of its corpuscles occurs under a great variety of circumstances. Broadly speaking, we can recognize two great clinical and pathological groups of cases: I. Those induced by causes acting upon the blood itself; and, II. Those induced by disturbance in the functions of the blood-making organs.

I. Of causes acting directly upon the blood, we shall consider—

1st. Hemorrhage, traumatic or spontaneous. A high grade of anæmia may be quickly produced by loss of a large quantity of blood, and the reduction is in all the constituents; there is a true oligæmia. If the amount lost be excessive, death results from the diminution in the total volume of blood and general lowering of the arterial pressure. If the hemorrhage is sudden and profuse, as from a large vessel, the loss of four or five pounds of blood, or even less, may be sufficient to induce fatal syncope. In hemorrhage into the pleura or peritoneum from rupture of aneurisms, etc., it is rare to meet with more than three or four pounds of clot and serum; seven and a half pounds is the largest amount I know of shed into one of the cavities (pleura) by rupture of an aneurism. When the bleeding extends over several days, the amount lost may be very much greater. In cases of hæmophilia extraordinary accounts are given of the amount collected in the course of a few days. In a case of hæmoptysis a patient lost over ten pounds by measurement in one week, and then recovered from the immediate effects. After the most severe hemorrhages the reduction in the number of red corpuscles is not nearly so great as in forms of idiopathic anæmia. Thus in the case just mentioned at the termination of the week of bleeding there were 1,390,000 red corpuscles to the cubic millimeter. In any single bleeding a fatal result follows the loss of one-third or one-half of the total blood-volume. The process of regeneration of the blood goes on with astonishing rapidity, and in some bleeders a week or ten days will suffice to re-establish the normal amount. The restitution begins even during a hemorrhage by the absorption of lymph from the tissues under the lowered pressure in the vessels. The dryness and stickiness of the serous membranes after death from a profuse hemorrhage is usually very marked. The water and saline constituents of the blood are readily restored by absorption from the gastro-intestinal tract. The albuminous elements are also quickly renewed, but it may take weeks or months before the number of corpuscles reaches the normal standard. Indeed, this condition of oligocythæmia, as it is called, may persist, grow worse, and ultimately prove fatal. The microscopical characters of the blood after severe hemorrhage are not much changed, except as regards the white corpuscles, which are relatively increased, and the fibrin network, which is much less marked than in health. The white corpuscles may be very slightly reduced in number per cubic millimeter—a fact to be accounted for either by a relatively diminished loss during the bleeding, owing to their adhesiveness and wall-loving properties, or to a quick restitution from the lymph which is poured into the blood-stream. It has been observed both in dogs and men by Lyon¹⁹ that after a severe hemorrhage the number of red per cubic millimeter diminished for several days after the bleeding had been checked. How and where does the regeneration of red corpuscles take place after a severe hemorrhage? One would think that under these circumstances, if any, we should be able to get information which might be of service in determining the problem of blood-development; but, in spite of the numerous experiments on the subject, we are still far from a knowledge of full details. The observations of Neumann,²⁰ Litten and Orth,²¹ Bizzozero,²² Lepine,²³ and others appear to prove conclusively that the bone-marrow plays an important part in the formation of the new red disks, becoming lymphoid, losing its fat, and the nucleated red cells increase enormously. The same process has been observed in many cases in man. In a case of profuse metrorrhagia with profound anæmia Neumann²⁴ found the marrow in all the bones of a rich raspberry red, full of the nucleated forms, which were also very abundant in the blood, and more in the vena azygos than in the aorta. The evidence in favor of the active participation of the spleen is not so conclusive. Neumann²⁵ concludes that the spleen takes no share in the process, and holds that the nucleated red cells found in it are probably derived from the bone-marrow. Bizzozero, on the other hand, has found the spleen swollen and showing signs of lively blood-formation. He states that after removal of the spleen the restitution of the red corpuscles takes place much more slowly. Pouchet, on the contrary, says the regeneration goes on just as rapidly without the spleen. Of the action of the lymph-glands there is even less evidence. They have been found swollen, but in traumatic anæmia I do not know of any observations on their swelling and conversion into a red spleen-like tissue, such as have been found in some cases of idiopathic anæmia.

¹⁹ Of Norwich, Conn.: Virchow's Archiv, lxxxiv.

²⁰ Archiv der Heilkunde, Bd. x.; Frerichs and Leyden's Archiv, Bd. iii.

²¹ Berliner klin. Wochenschrift, 1877, li.

²² Centralblatt f. d. Med. Wissenschaften, 1879, xvi.

²³ Revue Mensuelle de Méd. et de Chirurg., 1877.

²⁴ Loc. cit.

²⁵ Loc. cit.

The microcytes which occur in numbers in blood in some cases of traumatic anæmia have been regarded as young developmental forms, but there is a great diversity of opinion as to their real nature, and their connection with productive blood-processes is somewhat doubtful.

Cohnheim suggests²⁶ that after a profuse hemorrhage the rapid consumption of red corpuscles may be reduced, in which case we need not suppose such an active development; but the fact noted by Lyon²⁷ and others of the increased reduction after a bleeding is against the view. In any case, if Quincke is right in assuming that the average life of a red corpuscle is only three or four weeks, what is the restitution of a couple of millions of corpuscles per cubic millimeter in comparison with the monthly renovation of the entire mass?

²⁶ Loc. cit.

²⁷ Loc. cit.

In the regeneration of the blood the development of the hæmoglobin does not keep pace with that of the corpuscles, so that they may, even when normal in amount, have a lowered hæmoglobin percentage, indicated under the microscope by a paleness in the cells.

2d. There is a large group of cases in which the anæmia is induced by a long-continued drain on the albuminous material of the blood—pus in a chronic suppuration, albumen in Bright's disease, prolonged lactation, etc. Rapidly-growing tumors act in the same way.

3d. The anæmia of inanition, brought about by defective food-supply or by conditions of the digestive organs which interfere with the proper reception and preparation of nourishment, as cancer of the gullet, chronic dyspepsia, etc. The reduction in the blood-mass may be extreme, but the plasma suffers proportionately more than the corpuscles, which even in the extreme wasting of cancer of the oesophagus may not be reduced more than one-half or three-fourths.

4th. Toxic anæmia, induced by the action of certain poisons in the blood, such as lead, mercury, and arsenic among inorganic substances, and the virus of syphilis and malaria among organic poisons. They act by increasing the rate of consumption of the red corpuscles, and the reduction may be considerable. The gradual impoverishment of the blood in pyrexia may be in part due to the toxic action of the fever-producing agent on the blood itself; but in this there is probably also disturbance of function in the blood-making organs.

The last three groups comprise what are known as secondary anæmias, and the condition of the blood is characterized by an increase in the water and diminution in the albuminous elements; the fibrin is often increased, and the network which separates, as seen under the microscope, is unusually dense; the white corpuscles are not much increased; there is rarely microcytosis or poikilocytosis; the reduction in the number of red corpuscles is not so great; hemorrhages do not often occur; when fever is present it is due to the disease or some complication, and is not the pyrexia of anæmia; and, lastly, they are more or less amenable to the action of iron and other remedies.

II. A consideration of the anæmias induced by disturbance in the blood-making organs themselves presents difficulties proportionate to our ignorance of the details of hæmatogenesis. We may regard, as above stated, the spleen, the general lymphatic tissue, and the marrow as the sites of production of corpuscles which are passed into the circulation fully formed. Certain of these organs—the spleen and marrow particularly—are also concerned with blood-destruction as well as blood-elaboration; but there is evidence to show²⁸ that they, to use an ordinary simile, consume their own smoke, using the waste products for the purpose of further manufacture. Looking now upon the hæmatogenetic tissues as a single organ scattered through the body, let us consider what general disturbances of function it may suffer comparable to those met with in other structures. We can evidently suppose the physiological activity to be diminished or increased, and we should expect to find corresponding to these changes equivalent alterations in the character of the blood. Unfortunately, our knowledge of the normal processes as they go on in these tissues is so scanty that it amounts to a discussion upon the disturbances of a function itself imperfectly understood.

²⁸ Quincke, quoted above.

With diminished functional activity in an organ we commonly meet with reduction in volume, the one depending on the other: now, the only instance in the blood-making organs in which a decrease in size and diminished functional activity go together is in the senile atrophy in which the spleen becomes small, the marrow more fatty, and the lymph-glands sclerotic, and in consequence the blood also is reduced in amount; but this is only a part of the general failure of nutrition in old age. Pathologically, there is no such well-recognized condition of uniform atrophy of spleen, lymph-gland, and bone-marrow, with a corresponding general reduction in the elements of the blood. Certain cases of idiopathic anæmia come close to it, in which these parts are wasted, but there are other differences which make the two conditions scarcely comparable. In fact, as we shall see, diminished activity in blood-making is usually associated with an increase in what we call hæmatogenetic tissues. Of increased functional activity in these parts we know very little, apart from the changes met with in cases of traumatic anæmia, in which the hyperplasia of the spleen and bone-marrow may be regarded as intimately connected with the rapid development of red corpuscles.

One fact is evident: that a progressive increase in the cytogenic tissues, local or general, is associated with disturbance in the process of blood-formation, and sooner or later induces anæmia. Thus, progressive enlargement of the spleen or of the lymph-glands or marked hyperplasia of the marrow, either singly or combined, is invariably accompanied with alteration in the characters of the blood. Even in those rare instances in which the lymphoid elements of the tonsils and fauces or of the gastro-intestinal canal are chiefly involved the same change may take place.

The nature of the process in the organs is of a hyperplastic character. In the spleen the pulp at first increases and the Malpighian bodies enlarge, but ultimately there is such a development of the fibrous reticulum that the consistence is greatly augmented and the organ becomes indurated. Histologically, there is very little distinction to be made between forms of chronic enlargement of this organ. In the lymph-glands there is increase in the cells; the tissue becomes more succulent, and is in a state of hyperplasia which may terminate in a great development of the fibrous elements, with induration. So also with the bone-marrow: in the short and flat bones, where in the adult a reddish or slightly fatty tissue exists, the fat disappears entirely, and the long bones, normally filled with yellow marrow, become occupied with a red-gray or greenish-gray cytogenous tissue not unlike spleen-pulp, and in many instances more consistent than the red marrow of early life.

A reduction in the number of red corpuscles is the chief and most constant change in the blood; anæmia seems to be the invariable result, whether the spleen, marrow, or lymph-glands are affected singly or together, and is the central feature in the entire group of cases. This diminution in the red cells may or may not be accompanied by an increase in the white corpuscles, which in some cases may be so striking as to be regarded as the special blood-change, and is, as a rule, permanent, though it may be a variable or even a transitory state.

The general and histological differences between forms of hypertrophy of these blood-making organs are exceedingly slight, and in their clinical features they present a large number of symptoms in common; indeed, we may say that all the important symptoms are present, whether the spleen is affected alone or with the lymph-glands and bone-marrow, or whether these parts are independently involved, and whether there is simple reduction in the red or with it an increase in the white corpuscles. Such common features are—the progressive anæmia with its group of circulatory symptoms; the irregular febrile reaction, essential fever of anæmia; the absence of marked emaciation; the tendency to effusions of serum; the progressive debility; the occurrence of hemorrhages; gastric and intestinal disturbances; and resistance to treatment.

The affections characterized pathologically and clinically by so many similar features are known and recognized as distinct diseases under the names leukæmia, Hodgkin's disease or pseudo-leukæmia, splenic anæmia, and idiopathic anæmia (some cases); and we shall now consider these a little more closely.

First, of the hyperplasias of the cytogenic tissues associated with simple anæmia. The various groups, spleen, lymph-glands, and marrow, may be involved singly or together; usually one is first affected, and the others, if at all, subsequently. Progressive enlargement of the spleen induces sooner or later anæmia, the anæmia splenica of Griesinger. These cases are by no means rare: certain of them represent the final stage of a malarial intoxication, but there are others in which the enlargement seems causeless. There may also be hyperplasia of the bone-marrow, less often of the lymph-glands. The anæmia may be profound, and the clinical picture is that mentioned above. Two cases of it under my care died of hæmatemesis. The diagnosis of this affection from splenic leukæmia rests solely on the microscopical examination of the blood. It is also classed as the splenic form of Hodgkin's disease or pseudo-leukæmia.

Primary enlargement of the lymph-glands with anæmia constitutes Hodgkin's disease or pseudo-leukæmia, in which there may be general hyperplasia of the lymphatic elements throughout the body, with nodular growths of adenoid tissue in other organs. The spleen and marrow are not often affected. Here, too, the diagnosis from lymphatic leukæmia rests with the microscope.

Is there a form of anæmia dependent upon hyperplasia of the bone-marrow—an anæmia medullaris? In 1875, Pepper and Tyson²⁹ found affection of the marrow in idiopathic anæmia, and Pepper suggested that this might be the starting-point of the disease, which could thus be regarded as a medullary form of pseudo-leukæmia. Cohnheim in 1876³⁰ described the same condition, and I had an opportunity of examining several cases.³¹ Granting that the marrow is a tissue which shares in the blood-making functions, it seemed reasonable to suppose that a general hyperplasia of its elements might disturb the processes of hæmatosis and produce anæmia, just as in hyperplasia of the spleen and lymph-glands. Two facts soon came to light which seem opposed to this explanation of the pathology of idiopathic anæmia. A hyperplasia of the marrow was found in cases of chronic disease with wasting, and cases of idiopathic anæmia were described in which the marrow was normal. The numerous observations of the past five or six years have not brought us nearer to a solution of the problem. The observations of Neumann,³² and those of Litten and Orth,³³ on the changes in the marrow in chronic diseases have been abundantly confirmed, and a red lymphoid marrow may be met with in various cachectic states. This, too, I have frequently seen, yet it is in my experience rare to find such marked, rich hyperplasia of the marrow, such an entire absence of fat, as in some cases of idiopathic anæmia. In 9 autopsies in typical cases at Montreal, not parturition cases, the marrow of the long bones was lymphoid and red in 6; in 1 it was not examined; in 1, which I did not see, the marrow was stated to be normal; and in 1, an old woman over sixty years of age, the marrow of the short bones was rich in lymphoid cells and nucleated red corpuscles, and the long bones contained a grayish gelatinoid—atrophic—marrow. It does not appear possible with our present knowledge to arrive at a satisfactory conclusion on this question. Some regard the marrow-change as the consequence, others as the cause, of the anæmia. Both Cohnheim³⁴ and Pye-Smith³⁵ regard those cases of idiopathic anæmia in which the marrow-changes are pronounced as cases of anæmia medullaris.

²⁹ American Journal Med. Sciences, 1875, ii.

³⁰ Virchow's Archiv, Bd. lxviii.

³¹ Centralblatt f. d. Med. Wissenschaften, 1877, Nos. 15 and 28; 1878, No. 26.

³² Berl. klin. Wochenschrift, 1877, xlvii.

³³ Ibid., 1877, li.

³⁴ Loc. cit., Bd. i. S. 467.

³⁵ Loc cit.

Next of the parallel series of hyperplasias of the blood-forming organs with anæmia, plus an increase of the colorless corpuscles—leukæmia. Here, too, we have the three forms—splenic, lymphatic, and medullary.

The splenic leukæmia is the most common, and in its general features is identical with splenic anæmia, the excess of white corpuscles being the only distinguishing feature. It is almost invariably associated with changes in the marrow.

The lymphatic leukæmia may arise in connection with hyperplasia of the lymph-glands or of the adenoid elements in the alimentary tract—tonsils and Peyer's glands. It is much less common than lymphatic anæmia or Hodgkin's disease, and there are not many uncomplicated cases on record. Apparently, a very limited bunch of glands—cervical—may induce the change in the blood.³⁶ Medullary changes are almost invariably associated with a great increase of colorless corpuscles in the blood, and a myelogenous form of leukæmia is now, owing chiefly to the investigations of Neumann, well established. Indeed, he would regard the change in this tissue as the primary and important, and those in the lymph-glands and spleen as secondary.

³⁶ Gowers, Reynolds's System of Medicine, art. "Leucocythæmia."

The hyperplasia, either lymphadenoid in character or pyoid, may result in the expansion and softening of the bones, with the production of irregular tumor-like masses.

We have, then, the following group of anæmias induced by a primary disturbance of function in the blood-making organs:

PRIMARY OR CYTOGENIC ANÆMIA.	Leucocytic	Splenic, Lymphatic, Medullary,	Leukæmia.
	Non-leucocytic	Splenic, Anæmia splenica. Lymphatic, Hodgkin's disease. Medullary, Idiopathic anæmia (certain cases).

There remain for consideration the relation of the tissue-change to the anæmia and the nature of the leucocytosis; but until the chief facts in the development of the corpuscles are thoroughly known we cannot expect a satisfactory solution of these problems.

The anæmia may be explained on the view of diminished production (anæmatosis) or increased consumption of the red corpuscles (hæmophthisis). We know nothing of the intimate processes connected with lessened production, but as anæmia so constantly accompanies the hyperplasia, we assume they are intimately connected with each other, and the diminution in the number of corpuscles in some way the result of disturbed functional activity in the blood-making organs. An increased consumption of corpuscles in anæmia is indicated by the presence in large numbers of cells containing red blood-corpuscles in the spleen and marrow, and occasionally in the lymph-glands; by the increased amount of iron which has been found in the liver; and in some cases by the deep color of the muscles and an intensification of the color of the urine. Either a failing production with normal rate of consumption, or a normal output with heightened destruction, would produce anæmia. Possibly, in some instances, both factors may prevail. Quincke's interesting observations³⁷ may enable us to determine the cases in which one or other has been dominant. Where there is great destruction we shall expect to find the granules of iron albuminate in the spleen, bone marrow, and liver-cells, possibly in the cells of the cortex of the kidneys, and the iron reaction should be present.

³⁷ Loc. cit.

The relation of the hyperplasia of the cytogenic tissues to the increase in the colorless corpuscles is even more obscure. A prime difficulty is the circumstance that apparently identical tissue-changes may be associated with either a leucocytic or non-leucocytic anæmia. The splenic hyperplasia of leukæmia and of anæmia splenica are histologically identical. The excess of white corpuscles may be due either to over-production or to failure in their transformation into red. That they develop in the hyperplastic spleen, marrow, and lymph-glands is not to be doubted, and it seems reasonable to attribute the excess to the hyperplasia. Their variable size, as spleen or lymph-glands are chiefly affected, was early observed by Virchow, and when the marrow is involved there may be many large leucocytes similar to the larger marrow-cells. Virchow's original explanation, that the excess of colorless cells was due to a failure in their transformation into red corpuscles, rests upon the presumption that such a transformation is the normal process—a view not fully established. If this is the case, we should expect to find some relation between the increase of the white and the decrease in the red, but this is not always constant; as a general rule, with a diminution of the white there is an increase in the red, but the red and the white cells may increase or diminish in numbers simultaneously, or, again, the leucocytes may be greatly reduced while the red corpuscles remain about stationary. Griesinger,³⁸ Biesiadecki,³⁹ and others regard the increase in leucocytes as a primary blood-change. Several recent French writers support this view, as Renant,⁴⁰ who believes that the unequal size of the leucocytes indicates their division in the blood, and Variot.⁴¹ One of the most interesting features in connection with an increase in the colorless cells is that it may be only transitory, and a case which clinically and pathologically may present the features of idiopathic anæmia to-day may to-morrow present the characters of leukæmia; a case of splenic anæmia may become one of splenic leukæmia, or vice versâ. Thus, in Litten's oft-quoted case—about which there can be no doubt⁴²—of acute anæmia of three weeks' duration, an enormous increase of colorless corpuscles took place, and finally a ratio of one white to four red was reached. Quite as interesting is the case of Fleischer and Penzoldt,⁴³ in which for eight months the patient presented the ordinary symptoms of anæmia lymphatica or Hodgkin's disease, and then, before death, the blood became intensely leukæmic, the ratio 1:9. Still more so as the case of Goodhart's,⁴⁴ in which, with an enlarged spleen and lymphoid growths in liver and kidneys, there were variations in the number of corpuscles every few days—at one time great excess of white, at another no increase whatever. Again, a case may early come under observation as one of leukæmia, with a ratio of 1:20 or 1:30, and in the course of a few months, with persistence or even aggravation of the general symptoms, the normal ratio of white to red may be reached. This was the history in one of the Montreal cases.⁴⁵

³⁸ Virch. Archiv, Bd. v.

³⁹ Wien. Med. Jahrbuch., 1876.

⁴⁰ Archives de Physiologie, 1881.

⁴¹ Thèse de Paris, 1882.

⁴² Berl. klin. Wochenschrift, 1877.

⁴³ Deutsches Archiv f. klin. Medicin, Bd. xxvi.

⁴⁴ Clin. Society's Transactions, London, 1877.

⁴⁵ Howard, Montreal General Hospital Reports, vol. i. p. 39.

It seems questionable whether such a variable feature as increase in the colorless corpuscles should be permitted to separate diseases which have all essential characters in common. We shall probably, however, continue for a long time to speak of these conditions as separate and distinct, but it is evident that as time goes on, and our knowledge of the diseases and of blood-development increases, the identity of many of them will be acknowledged, and we shall find that here, as so often the case in natural history, the multiplication of species has been the result of imperfect information, and that as points of resemblance in essential characters and development are studied minor differences disappear.

With reference to the general tissue-changes in anæmia there are two points of interest: The metabolism of the proteids is increased, as shown by the increased excretion of urea, and owing to defective exudation the decomposition of the fats is lessened; hence the retention of fat, or even increase, in anæmic persons. The influence of repeated small bleedings in hastening the fattening of cattle has been known since the time of Aristotle, and horse-dealers still affirm that there is nothing like bloodletting to put an animal into good condition.

CHLOROSIS

is a special form of anæmia distinguished by certain etiological and anatomical peculiarities. In the first place, it is a disease of the female sex; cases in the male are of extreme rarity. In the majority of instances it is associated with disturbed menstrual function or with the evolution of the reproductive organs at the period of puberty. Occasionally it occurs in pregnant women and in children. It is a common disease among the ill-fed, overworked young girls in large towns who are confined all day in close, badly-lighted rooms or who have to do much stair-climbing. Girls of the better classes are by no means exempt; indeed, some writers speak of it as specially prone to affect the higher ranks of life. Lack of proper exercise, good food, and fresh air, the mental stimulation of unhealthy literature, and masturbation, are important factors. Emotional and nervous symptoms may be prominent—so much so that the disease is regarded by some as a neurosis.

The anatomical peculiarities relate to the blood and circulatory system. There is anæmia, but the impoverishment is less in the number than in the corpuscular richness in hæmoglobin. This fact, first pointed out by Duncan,⁴⁶ has been abundantly confirmed. Thus, for example, in one case, with a globular richness of 85 per cent., the hæmoglobin was only 52 per cent., and in another, with 92 per cent. of red, the hæmoglobin percentage was as low as 64. The numerous investigations of the past few years⁴⁷ have, among other points, fully established this as perhaps one of the most striking features in chlorosis. The color-value of the individual corpuscle is very much reduced. Of 22 observations of Hayem, the average number of red corpuscles was 3,740,000, and the hæmoglobin reduced to about 50 per cent. In Laache's 13 cases the average percentage of corpuscles was 72, and of hæmoglobin 45. This author has pointed out that in certain cases with all the clinical symptoms of chlorosis well marked there may be very slight reduction in the corpuscles or hæmoglobin; and such he terms pseudo-chlorosis. The red corpuscles in chlorosis vary much in size. Very large forms—giant red cells—are common, and microcytes are sometimes to be seen; but there is not the extreme irregularity in size and outline of the blood in idiopathic anæmia. The presence of a large number of young, imperfectly-formed corpuscles, especially as regards the hæmoglobin, is the distinguishing feature of chlorotic blood. Hayem and Willcocks both regard the average corpuscular diameter to be lower than normal, though many large forms occur. The color of the red corpuscles is noticeably pale, and the marked deficiency in hæmoglobin can be observed in individual corpuscles as well as in the blood-mixture prepared for counting. Quinquaud found the serum normal in quality, but the solids were slightly reduced in amount. Hunt⁴⁸ has shown that there are peculiar inter-menstrual oscillations in the blood in chlorotics. There is usually a fall in numbers just before the flow, but the individual value remains good; subsequently the number rises, but the color-value is not maintained (Willcocks). Virchow⁴⁹ pointed out that in many cases of chlorosis there was a defective development of the circulatory system, either congenital or resulting in failure of the normal rate of growth; the parts remained infantile. The heart and arteries were small, the walls of the latter thin, and the calibre of the aorta narrowed. In some instances there was found a compensatory hypertrophy of the heart. Defective development of the uterus and ovaries has also been noted, but these changes on the part of the circulatory and generative organs are not constant features in chlorosis.

⁴⁶ Sitzungsbericht d. Kais. Akad. d. Wissenschaften zu Wien, 1867.

⁴⁷ Leichtenstern, Hæmoglobingehalt des Blutes, Leipzig, 1878; Hayem, Recherches sur l'Anatomie, etc. du Sang, 1878; Malassez, Archives de Physiologie, 1877; Moriez, La Chlorose, Paris, 1880; Laache, Die Anämie, Christiania, 1883; Willcocks, Practitioner, 1883.

⁴⁸ Lancet, ii., 1880.

⁴⁹ Ueber die Chlorose, etc., Berlin, 1872.

The SYMPTOMS of chlorosis are those of anæmia of moderate grade. As in idiopathic anæmia, the subcutaneous fat is in full, or even extra, amount. The complexion is most peculiar, neither the blanched aspect of hemorrhage nor the muddy pallor of grave anæmia; but there is a curious yellow-green tinge in marked cases which has given the name to the disease ([Greek: chlôros]), and also its popular designation, the green sickness. Breathlessness, palpitation, and tendency to fainting are due to the anæmia. Digestive troubles are also common, and the appetite is often depraved. There are venous and cardiac murmurs. The menstrual functions are almost always deranged, and there may be hysterical and nervous manifestations. Relapses are not uncommon. The intimate pathology of the disease is unknown. In its insidious onset, sometimes causeless, and in certain features of the blood-state, it resembles pernicious anæmia, but it differs from it in many essential particulars. The association with menstrual disorders, the hypoplasia of the circulatory and generative organs in some cases, the favorable course and response to suitable treatment, as well as the sex and period of life, are features peculiar to chlorosis. Then, again, the anæmia is not so intense, and the relation of the hæmoglobin is just the reverse; in chlorosis the individual corpuscles are deficient in hæmoglobin, while in idiopathic anæmia the reverse appears to be the case.

Some regard the blood circulatory and uterine condition as the expression of a congenital defect leading to the formation of a diathesis—and in certain cases this may be so—but some of the most marked cases I have seen have been in girls of healthy families, who after a healthy childhood developed chlorosis at puberty, from which, under suitable treatment, they recovered to become robust and vigorous women. The almost specific action of iron suggests failure of the digestion or assimilation of the minute traces of this substance which are contained in our ordinary foods, and from which the iron of the corpuscles must be derived. Zander⁵⁰ holds that it is largely due to a defect in the hydrochloric acid of the gastric juice, by which the iron-holding compounds are dissolved, and claims that in chlorosis the administration of this remedy after eating fulfils every indication and enables the iron in the foods to be converted into an absorbable compound.

⁵⁰ Virchow's Archiv, lxxxiv.

The condition of the blood-making organs themselves throw no light on the PATHOLOGY of the disease.

The TREATMENT of chlorosis requires special mention. Iron may be regarded as a specific when given in sufficient doses. I have found Blaud's formula, as given in Niemeyer's textbook (ferri sulph. potass. carb. et tart. aa ounce ss; tragacanth q. s. Make ninety-six pills. Two or three pills to be taken three times a day), the most satisfactory method of administering the drug. Under their use I have repeatedly seen the number of the red corpuscles per cubic millimeter double in a fortnight; and it is one of the most interesting therapeutic phenomena to watch with the hæmacytometer the progressive development and increase of red corpuscles under the influence of fifteen or twenty grains of iron daily. Other forms may be used—reduced iron, dialyzed, the lactate, the tinct. of the perchloride—and it does not really make much difference which form is employed so long as enough is administered. Dilute hydrochloric acids or the vegetable acids may be given, and special attention should be devoted to dietetic and hygienic regulations.

MELANÆMIA

is a condition characterized by an accumulation of granular pigment in the blood and various organs, particularly the spleen, liver, marrow, and brain. It is almost invariably associated with prolonged malarial infection, and the pigment results from the transformation of the hæmoglobin of the corpuscles, many of which undergo destruction as a direct consequence of the influence of marsh miasm. Very exceptionally, however, the dark particles are extraneous, and result from the passage of carbon-granules into the circulation in cases of intense anthracosis. Soyka⁵¹ met with a case of this kind in which the coal particles were distributed throughout the spleen, liver, and kidneys. In blood the pigment occurs either free in the form of fine granules or in cloud-like collections of various sizes and shapes, often surrounded by a hyaline margin, or it occurs enclosed in cells. The free pigment, not often met with, is either molecular or in the form of irregular particles which may equal a red corpuscle in size. Aggregations of the granules are not uncommon, forming various-sized masses which may be imbedded in a hyaline substance. More commonly the pigment is contained in cells, ordinary leucocytes or large flattened—endothelial—cells derived from the spleen or liver. The color varies from yellowish-brown to a deep black. Except during periods of intense malarial infection and in the most severe and chronic cases melanæmia is rarely observed. In most ordinary cases of intermittent one may seek in vain for the pigment-granules, and I have examined many chronic cases with well-marked ague-cake with negative results. In other instances the pigment is found during or after a paroxysm; and this is the period when an examination of the blood should be made. The greatest care and cleanliness should be exercised in obtaining the blood-drop; and it should be remembered that in some of the glass slips used for microscopic purposes irregular brownish flakes may occur which I have known to be mistaken for pigment.

⁵¹ Quoted by Hindenlang, Virchow's Archiv, lxxix.

The melanæmia is but the expression of extensive destruction of corpuscles and accumulation of pigment in the spleen, liver, and bone-marrow; and these organs in cases of fatal intermittent or remittent fevers may present important changes. In the spleen, which is usually enlarged and indurated, the pigment is chiefly in the vicinity of the arteries and veins, the tissues about which may be absolutely black, and in both stroma and pulp innumerable cells are found filled with blood-corpuscles and blood-pigment in all stages of transformation to melanin. The color of the organ may be of a deep reddish-brown, or in very chronic states gray or even a dark olive. In the liver the dark granules are chiefly at the periphery of the lobules, fixed within the connective-tissue elements and leucocytes, not in the liver-cells themselves. It may be abundant about the portal branches, staining the connective tissue of Glisson's sheath, and it is also met with in the vicinity of the hepatic veins. When much affected the liver may have a deep bronze tint. As Arnstein has shown,⁵² the bone-marrow may present similar changes and have a grayish-brown color. There may be deep pigmentation of peritoneum and omentum. The deposition of the granules in and about the vessels of the cortex cerebri may give a slate-gray color to the brain, or even a graphite tint in very severe cases. The capillaries have been found occluded with cells filled with the pigment-granules. The kidneys—particularly the Malpighian tufts—the mucous surfaces, and the skin may also be the seat of pigmentary deposition. These coarse changes in the organs in chronic malaria were known to the older writers, and in Bright's Medical Observations a beautiful representation is given of the condition of the brain. To American physicians, with their extensive experience of malarial fevers, these changes were well known, and Stewardson of the Pennsylvania Hospital gave an admirable description of them in 1841;⁵³ and from the same institution in 1868 came another important contribution to the subject by Meigs, Pepper, and Rhoads.⁵⁴ Meckel⁵⁵ and Virchow⁵⁶ gave the first satisfactory explanation of the discoloration, showing that it was due to pigment, which might also be free in the blood. Frerichs in his well-known work on the liver gave an exhaustive account of the coarse and microscopical appearances.

⁵² Virchow's Archiv, lxi.

⁵³ Am. Journal Medical Sciences.

⁵⁴ "On the Morphological Changes of the Blood in Malarial Fever," Penn. Hospital Reports, 1868.

⁵⁵ Deutsche Klinik, 1850.

⁵⁶ Virchow's Archiv, Bd. i.

There is still some difference of opinion as to the mode of origin of the pigment. Most writers hold that it results from the destruction of the red corpuscles in the spleen and liver, and from these situations the pigment gets into the blood; but more recently Arnstein⁵⁷ and Kelsch⁵⁸ have urged the view that the melanæmia is the primary process, the destruction of corpuscles going on in the blood itself, and the particles and coloring material taken up by the leucocytes are transformed into melanin, and then the cells collect in the spleen, liver, and bone-marrow, producing the condition of melanosis. It is probable that the older view is the true one, and we may regard the process as an exaggeration or intensification, under the stimulus of the malarial poison, of the normal process of blood-destruction which goes on in the spleen and bone-marrow, and under some circumstances in the liver and lymph-glands. We can often trace in the cells of these organs the stages of transformation from red corpuscles to melanin-granules, just as can be done in the tissues in the neighborhood of an extravasation, where also the process is chiefly intracellular (Langhans). On the other hand, in those very states in which the red corpuscles are destroyed in the blood and the hæmoglobin set free, we do not find melanæmia. It happens occasionally in fevers that we meet with colorless cells in the blood containing red blood-corpuscles, which in time would be transformed into pigment, but, so far as we know, such a condition has not been observed in the blood in malaria. The connection between the fever paroxysm and the appearance of the pigment in the blood depends, most likely, on changes in the volume of the organs under the influence of the fever, whereby cells containing the pigment are dislodged and get into the circulation. This explains, too, their rapid appearance in some cases with the onset of a paroxysm. No doubt, as Virchow originally taught and as well shown in Gussenbauer's⁵⁹ observations, the pigment may result from the diffusion of the coloring matter and gradual precipitation of it in the granular form within the protoplasm of colorless cells; but of the occurrence of such a process in the circulating blood in malaria we have no satisfactory evidence, and we incline to the belief that the melanosis of the organs is the primary condition, while the melanæmia is secondary and inconstant.

⁵⁷ Loc. cit., and ibid., lxxi.

⁵⁸ Archiv de Physiologie, 1875.

⁵⁹ Virchow's Archiv, lxiii.

Occasionally, in cases of extensive melano-sarcoma, pigment-granules may be found in the blood in large numbers, and even appear in the urine and be deposited in the organs and skin. In a few instances also free pigment has been observed in the blood in Addison's disease.

PROGRESSIVE PERNICIOUS ANÆMIA.

DEFINITION.—Extreme and progressive anæmia developing without evident or apparently adequate cause.

SYNONYMS.—Idiopathic anæmia (Addison); Essential anæmia (Lebert); Anæmatosis (Pepper).

HISTORY.—During the first two or three decades of this century cases of severe and fatal anæmia were noted by Andral and others, but the credit of having given the first accurate series of cases belongs to Walter Channing of Harvard, who in the New England Quarterly Journal of Medicine for 1842 published a paper entitled "Notes on Anhæmia, particularly in connection with the Puerperal State and with Functional Disease of the Uterus, with Cases."⁶⁰ Any one who reads this communication will be convinced that Channing's description, particularly of the seven cases occurring in the puerperal state, is that of the disease to which Gusserow and Biermer have more recently directed attention.

⁶⁰ My attention was accidentally called to Channing's observations in the Periscope of Hall's British-American Journal for 1845. Since then Musser, in the Med. News, Oct. 7, 1882, has given a valuable abstract of the paper.

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

⁶¹ McKenzie, S., Lancet, 1879, ii.

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 Gusserow⁶² and Biermer⁶³ 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. Musser⁶⁴ has reviewed the American literature, and has given a tabular synopsis of 39 cases which have been recorded in this country.

⁶² Archiv f. Gynäkologie, ii.

⁶³ Correspondenzblatt für Schweizerische Artze, 1872.

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, Musser⁶⁵ could collect only 39 cases. During ten years in Canada I saw 16 cases, most of them with colleagues at Montreal.

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

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 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.

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

⁶⁸ Monograph on Disease of Suprarenal Capsules, p. 3.

The mode of onset is variable: in many cases there are etiological 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 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 states⁶⁹ that they are present in all cases.

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.

⁷⁰ Ibid., 1879.

(6) The fibrinous network between the corpuscles is thin and indistinct. The Cercomonas globulus and Cercomonas navicala, described by Klebs⁷¹ as occurring in pernicious anæmia, are possibly peculiar to Prague.

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.

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 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 Fenwick⁷³ has called attention, or even arouse a suspicion of cancer.

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-Smith⁷⁴ gives a summary of 20 undoubted cases which got well. The lactation and parturition cases stand a better chance of recovery than others. 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.

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 Nothnagel⁷⁶ and Schleimpflug,⁷⁷ are not uncommon in many other conditions.⁷⁸

⁷⁵ Loc. cit.

⁷⁶ Beiträge zur Phy. u. Path. des Darms, Berlin, 1884.

⁷⁷ Zeitsch. f. klin. Med., ix., 1885.

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. 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

⁷⁹ Virchow's Archiv, Bd. lxxix.

⁸⁰ Archiv f. Mikros. anatomie, Bd. xxiii.

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.

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. Brigidi⁸³ has described an increase in the interstitial tissue and pigmentation of the cells. In two instances I found nothing abnormal. Sasaki⁸⁴ has described marked degenerative changes in Auerbach's and Meissner's plexuses in two cases of pernicious anæmia.

⁸³ London Med. Record, 1878.

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 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.

⁸⁵ Loc. cit.

⁸⁶ Deutsches Archiv f. klin. Med., xxiv.

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

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

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.

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.

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 Bramwell⁹¹ 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. Padley⁹² 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. Finlay⁹³ has recently reported a case which was cured by iron after the failure of arsenic.

⁹¹ Edinburgh Med. Journal, 1877.

⁹² Lancet, 1883, ii.

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's⁹⁶ 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.

⁹⁴ Practitioner, vol. xxxi.; Ponfick, Berl. klin. Wochenschrift, 1879.

⁹⁵ Med. News, 1885, i.

⁹⁶ Virchow's Archiv, Bd. xciii.

The injection of milk, as first practised in cholera by my preceptors, Bovell and Hodder⁹⁷ of Toronto, has also been employed in anæmia (Pepper, Wulfberg).

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

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.

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 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 Neumann¹⁰⁰ described the myelogenous variety.

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 case¹⁰² under the name lymphoderma perniciosa, in which the lymphatic elements of the skin were first involved.

¹⁰¹ L'Union médicale, 1869.

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-Hirschfeld¹⁰³).

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's¹⁰⁴ 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.

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 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.

¹⁰⁵ Die Leukæmie, Berlin, 1872.

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 Chapelle¹⁰⁷ has dealt specially with this feature in the etiology of the disease.

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.

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 be present. It has not been noted that the diarrhoea is more frequent when the lymph-glands of the intestines are involved.

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

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.).

¹¹¹ Boston Med. and Surg. Journal, 1871.

¹¹² Loc. cit.

¹¹³ Archives of Scientific and Practical Medicine, New York, 1873.

¹¹⁴ Med. and Surg. Reporter, 1883, 48.

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 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. Laache¹¹⁶ 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.

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.

¹¹⁷ Virchow-Hirsch's Jahresber., 1874.

¹¹⁸ Deutsches Archiv f. klin. Med., Bd. xxvi.

Cafavy states¹¹⁹ that the colorless corpuscles of leukæmia do not display active amoeboid changes, indicating thereby a diseased and enfeebled condition of protoplasm. I find a note made in Sanderson's laboratory in 1873 on the very sluggish and imperfect movements of the colorless corpuscles in a case of leukæmia in University College Hospital. In Case V. the note on one day is, "Active amoeboid changes," and in two other cases since Cafavy's paper I have seen the protoplasmic movements tolerably active, but not in all equally. Possibly the leucocytes from the marrow do not move so freely as the others; normal marrow-cells have very feeble amoeboid powers. Ehrlich¹²⁰ has observed that the number of leucocytes in leukæmic blood which contain granules reacting with eosin is very great, whereas in normal blood very few occur.

¹¹⁹ Lancet, ii., 1880.

¹²⁰ Zeitschrift f. klin. Med., Bd. i.

Nucleated red blood-corpuscles, such as occur in the blood of the foetus and in the red marrow of the adult, have been found in leukæmic blood by Klebs, Mosler, and others. I have observed them in four cases. They are scanty, usually isolated, rarely more than one or two in a field; often, indeed, many fields must be searched before finding one. On two occasions (Case IX.) they might be called numerous—three or four in each field of the No. 9 immersion lens.

Schultze's granule-masses, the aggregations of the discoid hæmatoblasts, are present in variable numbers, sometimes very numerous. I have examined slides in which they were absent. A curious mistake was made by a writer in the Lancet (1878, ii.) when he described these as a hitherto unnoticed feature of the blood in leukæmia.

The fibrin network which separates between the corpuscles is usually very thick and dense.

Peculiar crystals, elongated octahedra or spindles, of variable size and bright-white appearance, separate very commonly on a slide of leukæmic blood, particularly if kept surrounded with oil or paraffin for twenty-four hours. They are known as Charcot's crystals, and are identical with those which occur in the bone-marrow, in semen, and in sputum in some cases of bronchitic asthma. White of Boston described them well in 1859,¹²¹ and believed they were produced by the separation of a neutral principle which he named leukosin. I can confirm Zenker's observation,¹²² that they form sometimes in the colorless cells.

¹²¹ Boston Medical and Surg. Journal.

¹²² Deutsches Archiv f. klin. Med., xviii.

Leukæmic differs from ordinary blood, and from that of other anæmic or cachectic states, by the readiness with which the hæmoglobin crystallizes. Often if a slide is kept and prevented from evaporating by a rim of paraffin, beautiful plates of hæmoglobin will crystallize.

The pulse is always quickened—80 to 100, and in the final stages 110–130—usually soft and compressible, and not always small in volume. The heart's action is readily excited. A systolic murmur is not infrequent at the apex; basic hæmic murmurs are not so often heard as in anæmia, but a venous hum in the neck is generally present. The apex-beat of the heart may be pushed up an interspace by the enlarged spleen. Oedema of the ankles and feet from the feeble circulation is constantly met with, particularly toward the close, and there may be general anasarca. Effusion into the pleural cavities is not common.

Hemorrhages are among the most constant features of the disease, and may occur at any time, early or late, in the course. The tendency to bleeding is greater in this than in any of the allied affections. Epistaxis is the most frequent form, and may precede the development of the disease for months or years. Hæmatemesis may carry off a patient early (Case II.), or even before the nature of the trouble is suspected (Case VI.). Hemorrhage from the bowel is common. Hæmoptysis and hæmaturia are rare. Bleeding from the gums may be present (Cases V. and VII.). In women there may be profuse menstruation. Petechiæ on the skin are frequent; occasionally there are large extravasations beneath the skin or between the muscles. Hemorrhage into the brain may prove quickly fatal (Case X.), and the extravasations into the retinæ may impair vision.

The respiratory system offers few special symptoms. The shortness of breath on exertion is due in great part to the anæmia, and progressively increases with the advance of the disease. The free action of the diaphragm is hampered by the enlarged spleen. There may be cough from bronchitis, and toward the end signs of oedema at the bases of the lungs. Pneumonia is not uncommon as a final complication.

The temperature in the early stages presents very slight variations, but when the disease is advanced there is always fever of the remittent or of the continuous type. There is usually a morning remission, and an evening exacerbation which reaches 101° or 103°. Periods of pyrexia may alternate with prolonged intervals of freedom from fever. In some cases the febrile movement is very slight throughout the entire course.

Genito-urinary System.—The urine is usually normal in amount, pale, strongly acid, and its specific gravity above the normal. Considerable variations occur in individual cases. Sediments of lithates are very common. The urea presents no constant changes; sometimes it is increased, at others diminished, the quantity depending probably on the food and the presence or absence of fever. The quantity of uric acid excreted seems always to be increased, due either to a lessening of the oxidation processes in consequence of the reduced number of red corpuscles, or, as Salkowski suggests, it stands in relation to the existing splenic tumor; but observers have not found the amount proportionately increased in other forms of splenic enlargement, and the cause of the constant increase is still doubtful. Hypoxanthine, lactic, formic, acetic, and hippuric acids have been found, but their presence is neither constant nor apparently of special import. Albumen may be present. Sugar is rare. Hæmaturia, as before observed, very seldom occurs. Cystitis may arise and be troublesome (Case XI.).

A curious symptom in connection with the generative system is priapism, of which a number of cases have been recorded. Edes¹²³ narrates the case of a boy of fifteen in whom obstinate priapism was the first symptom. Longuet¹²⁴ reports a case of six weeks' duration. Saltzer¹²⁵ mentions five cases, in one of which the condition persisted for seven weeks, and Peabody¹²⁶ gives a case in which it lasted six weeks. It is not definitely settled whether the priapism is due to thrombosis in the corpora cavernosa or to irritation of the nervi errigentes.

¹²³ Boston Med. and Surg. Journ., 1871.

¹²⁴ Progrès méd., 1875.

¹²⁵ Berliner klin. Wochenschrift, 1879.

¹²⁶ New York Med. Journ., 1880, xxi.

In women there are the usual menstrual irregularities consequent upon a grave constitutional disease. Occasionally the flow is excessive; more commonly it is interrupted altogether.

Blood-glandular System.—Slow increase in the volume of the spleen, causing a sense of weight in the left hypochondrium, is an early symptom in many cases. Patients do not usually come under observation until the enlargement is established and the organ can be felt below the costal border. Pain and tenderness over the organ are very common, though sometimes it is painless throughout. Palpation often elicits a creaking fremitus due to the rubbing together of the adhesions. The gradual enlargement causes an evident increase of girth in the lower thoracic and upper abdominal zones, and marked prominence of the left hypochondrium. The tumor extends to the right and downward, and may occupy a large portion of the abdomen, extending even to the pelvis. When there is no ascites the edge can be easily felt with the anterior notch or notches. The pressure of a large spleen causes distress after a full meal, and by its mechanical effect may even compress the bowels and produce fatal obstruction.¹²⁷ The effect upon the heart and respiration has already been noticed. The adhesions may interfere with the depression of the organ during a deep inspiration. The size varies in an inexplicable way, considering the indurated fibroid nature of the enlargement. It may be perceptibly larger after a meal.¹²⁸ A hemorrhage or free diarrhoea may reduce the size very much, as in Morrill's case.¹²⁹ A murmur may occasionally be heard, and an enlarged spleen has been known to pulsate.¹³⁰

¹²⁷ Collins, Brit. Med. Journ., 1882, i.

¹²⁸ Johnson, Lancet, 1870, Jan.

¹²⁹ Bost. Med. Journ., 1877.

¹³⁰ Gerhardt, Zeitschrift f. klin. Medicin, Berlin, Bd. iv.

Lymphatic Glands.—In the great majority of cases the lymph-glands are but slightly if at all involved. Even when they are affected it is rare to see such large bunches as in Hodgkin's disease. When they are growing there may be pain and tenderness, and if large they may be a source of inconvenience, but severe pressure symptoms are not often witnessed. Enlargement of the glands in the superficial groups is readily detected, but the deep-seated collections in the mesentery and retro-peritoneum can rarely be palpated unless of considerable size. Mediastinal lymph-tumors in leukæmia are exceptional. In none of the cases I have seen were the lymph-glands greatly enlarged. It is stated that in children the lymphatic variety is more common than in adults.

There may be tenderness over the bones, and in rare instances swelling, but unless the tenderness is marked and accompanied by some local expansion or softening, we cannot determine positively the existence of the myelogenous variety. The sternum, ribs, and flat bones are most often affected, and there may be great irregularity and deformities, as in a case I saw with Riess of Berlin. It is well to bear in mind that in perhaps the majority of persons there is a tender spot upon the sternum which may cause marked wincing when touched firmly. No reliance should be placed upon tenderness without swelling or softening. Such tenderness may exist, and post-mortem the marrow be found normal;¹³¹ and, on the other hand, there may be extensive changes in the bone-marrow without any tenderness (Litten).

¹³¹ Deutsches Archiv f. klin. Med., xxvi.

MORBID ANATOMY.—There may be extreme wasting. Dropsy of the feet is common, and ascites may be present.

A noteworthy feature is the full amount of blood in the heart and blood-vessels, usually in the form of large coagula. In one case (XI.) the weight of clots alone in the heart-chambers, not including what came from the veins, was 620 grammes. The portal, cerebral, pulmonary, and subcutaneous vessels were also greatly distended with clots. The portal vein just above the union of the branches measured eleven centimeters in circumference.

The blood is usually clotted in the heart and vessels, and the aggregation of the colorless corpuscles densely infiltrating the fibrinous clots and the serum gives a pus-like appearance, so that it has not infrequently happened, as in Virchow's memorable case, that the observer on opening the right auricle believed for the moment that he had cut into an abscess. The leukæmic clots often have a peculiar greenish color, and resemble somewhat the fat of the turtle. Similar coagula may fill the veins of the brain and abdominal viscera. The tendency of the white corpuscles to aggregate together, and the subsidence of the red to the lower part of the heart-chambers and vessels, may give an appearance of more intense leukæmia than actually exists. The reaction of the blood is usually acid. The chemical constitution has been carefully studied, but with no very satisfactory results. Hypoxanthine, lactic acid, leucin, tyrosin, a mucin-like body, and a gelatinous substance have been described, but none of them may be regarded as characteristic of the disease. The octahedral crystals are thought by some to be tyrosin,¹³² but Schreiner¹³³ says they consist of the phosphate of an organic base, the composition of which is not yet settled.

¹³² Huber, Archiv der Heilkunde, Bd. xviii.

¹³³ Liebig's Annalen, cxciv.

The specific gravity of the blood is lowered, 1036 to 1049. The water is increased. The fibrin in many observations has also been found increased; 4.8 per 1000 was the average of ten observations by Bennett. The albumen and the salts have not often been estimated. The former is stated to be diminished. The fatty bodies have been found in excess of the normal quantities.

The heart is often pushed up by the large spleen; the pericardium, more rarely the endocardium, may present ecchymoses, and the fluid may be in excess. In a few instances leukæmic growths have been met with. The chambers are usually distended, the walls soft, and a moderate grade of fatty change is very common. No special alteration has been met with in the blood-vessels. I have seen extensive fatty degeneration of the intima and small arteries.

In the great majority of cases the spleen is increased in size, but the shape is retained. It is usually of a deep violet-red color, and strong adhesions may unite it to the abdominal wall, diaphragm, or stomach. The capsule may be greatly thickened, forming a firm fibro-cartilaginous investment. The vessels are enlarged, particularly the veins at the hilus. The weight may vary from two to eighteen pounds. The largest on record is given by Langley Browne¹³⁴—18½ pounds. Six or seven pounds is an average weight. The length may vary from seven to twenty inches, and the breadth eight to twelve. The organ is in a condition of chronic hyperplasia—hard, firm, cuts with resistance, and displays a uniform reddish-brown surface on which the trabeculæ are more or less prominent. There may be hemorrhages or infarcts, and it is not uncommon to see regions of yellow or rusty-brown staining, indicating where an extravasation had occurred. As a rule, no trace of the Malpighian bodies can be seen. Grayish-white, circumscribed lymphoid tumors may occur throughout the organ, contrasting strongly with the reddish-brown matrix. The process of gradual enlargement is a simple hyperplasia. In the early stage, not often seen, there is swelling of the pulp, increase in the cell-elements, without the firmness and induration of the fully-developed leukæmic organ. Rupture may occur at this period from the intense hyperæmia. The Malpighian bodies are enlarged and prominent by their grayish-white color. A gradual and progressive induration results from the increase in the adenoid network and the fibrous trabeculæ. A section shows the enormous development of the fibrous elements. The cells may be scanty, only two or three in meshes, or, indeed, the reticulum may be so close that only a single cell is enclosed. As a rule, the hyperplasia extends over the whole organ, and the Malpighian bodies become involved and lose their distinctness. In only one of the cases which I have examined were they at all prominent. Leukæmic new growths in the spleen are rare.

¹³⁴ Lancet, 1877, ii.

Uncomplicated cases of the lymphatic form are very uncommon: usually they enlarge with the spleen, and in the majority of instances the hypertrophy is not extensive, scarcely ever reaching the high grade seen in Hodgkin's disease. The groups of cervical, axillary, mesenteric, and inguinal are most frequently affected; the bronchial and mediastinal but rarely. The bunches of glands are not usually larger than walnuts, moderately soft, isolated, movable; large matted groups do not often occur. They may vary a good deal in size during the course of the disease, often diminishing notably before death. In chronic cases they may become very indurated. The leukæmic lymphadenitis is a simple hyperplasia, and the soft glands may look, on section, of a normal gray color or may have a deep gray-red appearance. Hemorrhages may occur, and twice I have seen the enlarged glands deeply hyperæmic. Histologically, the appearance is very like a normal gland, only the lymph-spaces are more closely packed. In the harder glands the fibrous reticulum is much increased, the capsule thickened, and the section more grayish in color. Caseation or suppuration rarely occurs, and invasion of contiguous parts is most exceptional.

The tonsils and the lymph-follicles of the tongue, pharynx, and mouth have been found much enlarged.

The bone-marrow is usually the seat of important changes, which in some cases appear early and persist as very prominent features of the disease. The most constant alteration is a uniform substitution of a grayish-red or gray-green puriform-looking tissue for the normal red and fatty marrow of the long and short bones. The entire medulla may resemble the consistent matter which forms the core of an abscess, and the term pyoid applied to this condition by German authors well expresses the general characters. More rarely the marrow has a reddish-brown hue. The difference depends largely on the number of colorless corpuscles, which in the pyoid form are enormously increased, and there are but few red cells. Ponfick has met with dark-red, dense hemorrhagic infarctions in leukæmic marrow. The condition of the bones is variable; usually, the compact and cancellated tissues appear normal, but the hard shell may be much thinned and expanded, the cancellæ widened, and the whole substance rendered spongy. In marked cases there may be localized swellings which are tender, and even yield, on firm pressure. The sternum and ribs are most frequently affected in this way. There are instances in which the bone-marrow has not been involved, and in one case there was osteo-sclerosis.¹³⁵ Histologically, the chief change is hyperplasia of the colorless marrow-cells, which in the pyoid variety compose the chief part of the tissue. They vary much in size and appearance. Three forms can usually be recognized: large granular cells with distinct nuclei; medium-sized cells, like colorless blood-corpuscles; and smaller forms, like lymph-cells, with large nuclei and a narrow zone of investing protoplasm. The red corpuscles and microcytes are in variable numbers. In one case the latter were very abundant. Nucleated red corpuscles are very constant elements. Corpuscles containing red blood-corpuscles are not so numerous as in ordinary red marrow, nor, as a rule, are the myeloplaques abundant. Charcot's crystals are always to be found—if not at first, when the marrow is quite fresh, certainly later, when decomposition has begun.

¹³⁵ Heuck, Virchow's Archiv, lxxviii.

The thymus is rarely affected, and even in children is not often swollen. A few cases of enlargement have been recorded.

The thyroid is even less frequently involved.

In one case the suprarenal capsules were large and swollen,¹³⁶ and in addition to the leukæmia there was bronzed skin. Hemorrhage, caseous degeneration, and in one instance rupture,¹³⁷ have been noted.

¹³⁶ Barclay, Lancet, 1863, i.

¹³⁷ Fleischer and Penzoldt, loc. cit.

In the digestive system the stomach rarely presents any changes other than catarrhal. Even when death has occurred from hæmatemesis the mucous membrane may be pale, without erosion, hemorrhage, or ulceration (Cases II. and VI.). In a few instances lymphatic growths have been described. In many cases the intestines have been the seat of leukæmic tumors which have originated in the solitary and agminated glands of Peyer. Occasionally the lymphoid infiltration is diffuse in the mucosa and not confined to the follicles. Ulceration may occur in the patches, and in a few cases the bowel lesions have been so pronounced that the term intestinal leukæmia seemed justifiable.¹³⁸ The cæcum and colon may also present these new growths, and in a few cases dysenteric processes have been observed (Case II.). The peritoneum has been found covered with small lymphoid growths. In Willcocks' case of lymphatic leukæmia¹³⁹ there were growths on the surface of the stomach and gastro-splenic omentum. Blood may be found in the cavity from rupture of the spleen. Ascitic fluid is common. Fibroid thickening, induration, and adhesions are very often met with, particularly in the neighborhood of the spleen.

¹³⁸ Behier, loc. cit.

¹³⁹ Loc. cit.

The liver is very commonly enlarged, pale, smooth, and retains the normal shape. It may be greatly increased in size, as in case of Walshe's, where it weighed 13½ pounds. The substance is usually firm, of a grayish-brown color, or even marbled. Two chief changes have been met with—a diffuse leukæmic infiltration and numerous small leukæmic tumors. The infiltration may be very slight, and not noticeable with the naked eye, or it may be in the form of irregular scattered areas of a yellowish-white appearance, not distinctly isolated, but merging into the hepatic tissue. When moderate, a section shows the columns of liver-cells to be separated by wide spaces occupied by leucocytes, which are partly within and partly outside of the capillaries. The accumulation of these elements produces atrophy of the liver-cells, and their aggregation and increase in certain regions produce the grayish-white areas, in the midst of which traces of liver-tissue may be found. The defined leukæmic growths are small, not often attaining a large size, and may resemble tubercles. They are usually situated in the interlobular tissue, and consist of lymphoid cells in a well-defined reticulum, and they possibly have a different origin from the diffuse infiltrations.

Fatty degeneration of the liver-cells is a very common change.

The respiratory system is not often the seat of important lesions. Lymphoid growths have been found in the mucous membrane of the trachea and bronchi, and occasionally in the lungs, in which situation they may closely resemble tubercles, but differ from them in not tending to caseate or soften. Oedema of the bases of the lung is almost always found. Many patients are carried off by a low pneumonia. The greenish leukæmic clots projecting from the cut ends of the vessels may give a very curious appearance to the section of the lung. The pleural surfaces may be the seat of lymphoid growths.

The kidneys are usually pale, often enlarged, and show signs of parenchymatous swelling. The capillaries, like those of the liver, may be distended with leucocytes, and leukæmic tumors may occur, generally situated in the cortex and ranging in size from a pea to a cherry. In none of the cases I have examined were there any special changes in these organs beyond slight enlargement and filling of the capillaries with leucocytes.

The generative organs are usually normal. No changes have been found to account for the persistent priapism met with in certain cases.

The meninges of the brain, the veins, and sinuses, are often filled with grayish clots. Occasionally meningitis has been found, with exudation of lymph. The small vessels of the brain may be plugged with leucocytes, forming thrombi, from which softening results. Cerebral hemorrhage may prove rapidly fatal. In Case X. of the Montreal series the patient died suddenly, and without any premonition, with a huge apoplexy of the ventricles and posterior part of the hemispheres.

Leukæmic growths in the skin have been described.

The leukæmic tumors demand further consideration. They are not common. In 10 of the 11 Montreal cases careful post-mortem examinations were made, and in not one were there definite new growths. In Case I. there was diffuse leukæmic infiltration of the liver, the histological characters of which were carefully studied. In the 157 cases collected by Gowers¹⁴⁰ there were only 13 instances of leukæmic nodules in the liver, and 10 in the kidneys. They are still more uncommon in the lungs. In the spleen—unlike this organ in Hodgkin's disease—they are very rarely seen. The nodules consist of leucocytes in a meshwork of delicate reticular tissue. Their mode of origin has been much discussed. There can be no doubt, I think, that they are new growths of lymphoid tissue of local origin. Possibly they start from accumulations of colorless corpuscles which pass out of the capillaries. In the infiltration of the liver one sees diffuse collections which resemble new growths, but which have evidently resulted from the aggregation in and outside of the capillaries of enormous numbers of leucocytes, which cause the atrophy of the cells of the organ. Doubtless, they multiply in loco by a process of fission, and these aggregations may themselves be foci for the origin and development of colorless cells which pass into the blood-current and augment the number.¹⁴¹ Quite recently Bizzozero has studied the development of these leukæmic new growths, and has shown clearly that the cells which compose them are in process of active fission.

¹⁴⁰ Loc. cit.

¹⁴¹ "On the Histology of Leucocythæmia," Canada Medical and Surgical Journal, 1876.

The COURSE OF THE DISEASE is slow and chronic, a matter of months and years. There are exceptional instances in which the disease has proved fatal in a few weeks; this occurs sometimes in children,¹⁴² but acute leukæmia is very rare. In a table of 63 cases collected by Gowers, in which the date of the first symptoms was fixed with tolerable accuracy, the duration was less than one year in 13 cases; from one to two years in 16; from two to three years in 19; from three to four years in 9; from 4 to 5 years in 3; and five years and upward in 3 cases. The course is rarely uniform, but periods of improvement occur in which the fever subsides, the painful sensations in the abdomen diminish, the appetite improves, and the spleen reduces in volume. Such intervals, corresponding to the administration of certain drugs, are apt to lead to therapeutic errors. A patient may sometimes get about for months, and even attend to a light business, with an enormous spleen and a ratio of white to red corpuscles of 1 to 6 (Case VIII.). Hemorrhages, high fever, profuse diarrhoea, and the occurrence of dropsy shorten the course. Toward the close there is great muscular debility, and usually a wandering delirium.

¹⁴² Golitzinsky, Jahrb. f. Kinderheilkunde, 1860–61.

In the majority of cases death is by asthenia—a gradually progressive weakness and ultimate failure of the heart. Diarrhoea and hemorrhage hasten the fatal result. A profuse hemorrhage may cut off a patient early or after the disease is well established. Cerebral hemorrhage was noticed in 6 of 60 cases in which Gowers was able to ascertain accurately the cause of death. A few are carried off by pleurisy or pneumonia or peritonitis after tapping.

Pyæmia and rupture of the spleen are mentioned as causes of death in some cases.

The DIAGNOSIS of leukæmia rests upon the determination of a great and persistent increase in the colorless elements of the blood. Cases of Hodgkin's disease and of splenic anæmia, almost identical in general features, can only be distinguished by an examination of the blood. I should say that in any case we can speak of the blood as leukæmia when the ratio of white to red cells falls below 1 to 50. Some writers hold that to determine leukæmia the ratio should be at least 1 to 20, but when the study of the variations in the proportion of the corpuscles in any case extends over weeks or months, we not uncommonly find that the ratio, which, at one observation may be 1 to 8, or 1 to 10, a week later may be 1 to 60 or 80, or even 150. Indeed, the state of the blood is a variable factor, and too close attention to it has diverted our minds from the broad features which this disease has in common with others. For practical clinical purposes we have to distinguish ordinary lieno-lymphatic leukæmia from—(1st) chronic malarial infection with splenic hypertrophy; (2d) from cases of non-malarial splenic enlargements with anæmia; (3d) from general lymphadenoma or Hodgkin's disease. The history in malarial cachexia, the absence of lymphatic enlargement, and the blood-condition will usually be sufficient for purposes of a diagnosis. Great increase in the white blood-corpuscles is not often seen in the chronic splenic tumor of malaria; indeed they may be much diminished in number. Toward the end in very chronic cases the clinical picture may be very similar: the large abdomen, possibly ascites, dropsy of the feet, and irregular fever may resemble closely splenic leukæmia, and the absence of an increase in the colorless corpuscles may be the only marked difference. From anæmia splenica there is still greater difficulty, and I have seen instances in which the absence of an excess of the colorless corpuscles in the blood formed the sole criterion: the hemorrhages, the dropsy of feet and abdomen, retinal extravasations, the general cachexia, and the fever were identical with those of leukæmia. Still greater may be the difficulty of separating certain cases of lymphatic leukæmia from general lymphadenoma or Hodgkin's disease; but in the latter affection the glandular enlargement is usually greater and altogether a more prominent feature, and the spleen is not so often increased in size. There may, however, be a considerable increase in the number of the white corpuscles, 1 to 150 or 1 to 100 red, and cases do occur which appear intermediate or transitional in character, and upon which judgment must be reserved until the progress of the case decides the question.

Pure cases of myelogenous leukæmia are almost unknown; if the osseous symptoms are not marked the course is very like that of pernicious anæmia. Indeed, there are two interesting cases on record in which the progressive anæmia seemed to pass into leukæmia. In Litten's case¹⁴³ the patient presented the symptoms of profound anæmia, and five days before death the blood became markedly leukæmic. There was no enlargement of spleen or lymph-glands, but the bone-marrow was intensely leukæmic—i.e. of the pyoid form. In the case reported by Leube and Fleischer¹⁴⁴ the patient, aged thirty, four months after her confinement became anæmic and the left leg was swollen. Though at first only anæmic, subsequently the ratio of white to red corpuscles rose to 1 in 10. Gangrene of the leg supervened, necessitating amputation, from the effects of which she died. There was no affection of spleen or lymph-glands, but the marrow was of the red lymphoid variety. A gastric ulcer was also present. This was no doubt a case of post-partum anæmia aggravated by the presence of ulcer of the stomach, and the great interest of the case lies in the transition of the anæmia into leukæmia.

¹⁴³ Berliner klin. Wochenschrift, 1877.

¹⁴⁴ Virchow's Archiv, lxxxiii.

There are certain general conditions, accompanied by an increase in the colorless corpuscles, which must be distinguished from leukæmia. In suppuration there may be marked leucocytosis; so also in cancer and protracted cachectic states, as phthisis. In cases with large cancerous masses about the stomach and omentum, or where, as occasionally happens in chronic phthisis, there is a greatly enlarged amyloid spleen, if the white blood-corpuscles are much increased, care may be necessary to escape a mistake in diagnosis. In diphtheria the colorless elements may be much increased. Bouchat says that in some instances there may be an acute leukæmia.¹⁴⁵ In puerperal fever also the condition of leucocytosis is not uncommon.

¹⁴⁵ Gazette des Hôpitaux, 1877.

The PROGNOSIS is in the highest degree unfavorable, and in those cases, few, indeed, in number, in which there were symptoms like leukæmia and which disappeared under treatment, the doubt remains whether they were true examples of the disease. When once established, the spleen and glands enlarged, the hemorrhages and dropsies present, and the blood condition marked, death is the only termination to be expected. Specially unfavorable signs are a tendency to hemorrhage, persistent diarrhoea, early dropsy, rapid increase in the splenic tumor, great excess of colorless corpuscles, and high fever. Temporary improvement may occur for weeks or even months, and the white blood-corpuscles reduce in number, but such breaks are usually transient.

TREATMENT.—If, as some writers hold, chronic malarial poisoning is an important factor in the induction of leukæmia, we should take special pains with patients so affected, and endeavor by the use of quinine and arsenic to free the system and reduce the volume of the spleen. There certainly may be danger of the development of leukæmia in any case of chronic splenic tumor, though my own experience has been that in these cases the production of anæmia of high grade, without increase in the white blood-corpuscles, is more common. It is a mistake to suppose that anæmia always accompanies chronic splenic enlargement: it may persist for years with a percentage of red corpuscles little if at all below normal, but grave anæmia or leukæmia are probabilities to be dreaded.

In an early stage, when the spleen is moderately enlarged, the lymph-glands scarcely swollen, and the leucocytosis not intense, there is a hope that by the persistent use of quinine, iron, and arsenic a cure may be effected; but when the disease is fully established and the leukæmia marked, a recovery is rarely if ever witnessed, and the treatment is largely palliative and symptomatic. To reduce the volume of the spleen various remedies are recommended, and so long as the organ is only moderately enlarged and hardened some of them may be beneficial. Quinine should be given a full and prolonged trial, as undoubtedly under its use the organ may reduce in size. As anæmia is almost always present, iron may be administered at the same time. That the quinine has any special influence over the production of the white corpuscles, as some think, I have not been able to satisfy myself. To be of use, it must be employed early and in large doses. Ergotin internally and by injection into the spleen has been recommended. I have not seen any permanent benefit from its use. Local measures, such as inunction of biniodide of mercury ointment over the spleen, the interrupted voltaic current, the application of cold, either ice or the cold douche, may be employed. Moderate reduction in the volume may be effected by these means—most effectually by the electricity and mercurial inunction.

Arsenic should always be given a trial, and pushed for several months in increasing doses. Several cases are reported in which the improvement lasted for many months. Direct injections into the spleen are also of service. Phosphorus, from which much was expected after the favorable reports of Broadbent and Wilson Fox, has not proved of much value. There are very curious remissions in the course of the disease which render therapeutical deductions somewhat fallacious. I have seen the most marked improvement occur without any special treatment: ascites and dyspnoea disappear, the white corpuscles decrease in number, and the patient from a bed-ridden, wretched condition get up, attend to light duties, and walk half a mile to hospital (Case IX.). In Case VIII. there were also during eighteen months remarkable variations, depending more on the state of the gastro-intestinal canal than the blood condition.

Transfusion has proved useless. Leukæmic blood to the amount of several ounces has been withdrawn and other healthy blood substituted.

Excision of the spleen has been frequently practised in leukæmia. Collier¹⁴⁶ gives a résumé of 16 cases, and concludes that it is a useless and unjustifiable operation, as all of them proved fatal. A successful case, however, is reported from Italy. If performed early, there is a possibility of success, but when the organ is enormously enlarged and the blood intensely leukæmic, the conditions are most unfavorable.

¹⁴⁶ Lancet, 1882, i.

Gastric symptoms and diarrhoea call for careful treatment, as the comfort of the patient depends largely on the condition of the primæ viæ. Hemorrhage is frequent, and is a dangerous symptom, particularly when it depends upon engorgement of the portal system, and calls for appropriate remedies. Purgatives are to be employed with caution. The dragging pain in the left hypochondrium, and the sense of weight and distension after eating, are very distressing, and the splenic pain may require sedatives. Inhalations of oxygen relieve the dyspnoea and have been found to check the progress of the disease.

HODGKIN'S DISEASE.

DEFINITION.—A disease characterized by progressive hyperplasia of the lymph-glands, sometimes also of the spleen, with anæmia and the development of secondary lymphatic growths in various parts of the body.

SYNONYMS.—Pseudo-leukæmia; General lymphadenoma; Malignant lymphoma (Billroth); Lympho-sarcoma (Virchow); Adénie (Trousseau); Desmoid carcinoma (Wagner); Anæmia lymphatica (Wilks); Lymphatic cachexia (Mursick); Adenoid disease (Southey).

HISTORY.—Morgagni and other writers mention cases of enlargement of the lymph-glands proving fatal, but Hodgkin of Guy's Hospital first called special attention to the subject in a paper before the Medico-chirurgical Society of London,¹⁴⁷ entitled "On Some Morbid Appearances of the Absorbent Glands and Spleen." Some of the cases then described were undoubtedly examples of scrofulous glands, but four at least were instances of the disease which now bears his name; and at the meeting of the London Pathological Society in 1878, when a discussion on lymphatic disease took place, Wilks exhibited the original specimens collected by Hodgkin. Other cases were recorded in England by several observers, and in 1856, Wilks¹⁴⁸ reported several examples of enlarged lymph-glands with growths in the spleen associated with anæmia, but without any leukæmia; and again in 1865 this observer published additional cases,¹⁴⁹ and gave the name of Hodgkin's disease to the affection characterized by enlargement of the lymph-glands, growths in the spleen and other organs, and anæmia. The cases and discussions contained in the Transactions of the Pathological Society of London and Gowers' exhaustive article in Reynolds's System of Medicine embrace the most valuable of the English contributions. In Germany, Virchow described the cases under the term lympho-sarcoma, and in his work on tumors gave a full account of the histology. Billroth gave the term malignant lymphoma to these growths to distinguish them from local non-infective lympho-sarcomas. Cohnheim and Wunderlich used the term pseudo-leukæmia to express the distinction between these cases and leukæmic enlargements.

¹⁴⁷ Transactions, vol. xvii., 1832.

¹⁴⁸ Guy's Hospital Reports, 3d Series, vol. ii.

¹⁴⁹ Ibid., vol. ix.

In France, Trousseau described it under the term adénie, and Ranvier used the term lymph-adénie. In America many cases have been described, and one of the first and fullest analyses of recorded observations is by J. H. Hutchinson in the Transactions of the College of Physicians of Philadelphia, Series 3, vol. i.

ETIOLOGY.—No satisfactory etiological relations have been determined in the disease.

Age has an important predisposing influence. The majority of the cases are young persons. In Gowers' table of 100 cases, 30 were under twenty years, 34 between twenty and forty, and 36 above forty. Most of the cases I have seen have been in young adults.

Sex has a still more marked influence; at least three-fourths of all cases are in males, the proportion being considerably higher than in leukæmia—75 per cent. in Gowers' tables, and 40 out of 58 in Hutchinson's tables.¹⁵⁰

¹⁵⁰ Loc. cit.

Heredity has in a few instances been adduced as a possible cause, but not, I think, on very reliable grounds. In two cases (II. and III.¹⁵¹) the patients were each a twin. It might be supposed that members of tuberculous families, or those who had suffered from scrofulous enlargements when young, would be more liable to the disease, but the cases in which such connection can be traced are very few in number.

¹⁵¹ These figures refer to cases of which I have notes.

Antecedent syphilis has been noted in a few instances.

Exposure, intemperance, bad food, etc. are possible predisposing causes.

Local irritation, which so often produces lymphatic swellings, appears to stand occasionally in causal connection with the development of general lymphadenoma. Trousseau lays particular stress upon this, and gives instances in which chronic irritation of the skin, otorrhoea, chronic nasal or pharyngeal catarrh, irritation of a decayed tooth, gave rise to local gland swelling which preceded the general development of the disease. But this is a comparatively rare affection, and think of the hundreds of instances met with of local lymphatic irritation!

SYMPTOMS.—Enlargement of the lymphatic glands in the neck, axillæ, or groins is the earliest symptom noticeable in the great majority of cases. This may be quite painless at first, and the patient seeks advice on account of the disfigurement or the inconvenience felt in adjusting the collar. Occasionally the anæmic and constitutional symptoms first attract attention. When the trouble begins in the deeper groups—bronchial, mesenteric, or retro-peritoneal—pressure effects are the first complaint, and there may be great obscurity and uncertainty about the nature of the case. Thus, the first symptom may be dyspnoea, with pain in the chest, or pain in the abdomen with swelling of the legs and shooting pains in the course of the nerves; or in rare cases symptoms of a totally different nature may be among the first to attract attention. Thus in J. H. Hutchinson's case there was paraplegia from pressure of a secondary growth, and the same was observed in a case which I dissected at the Montreal General Hospital (Case VI.). But such are very exceptional, and in the great majority swelling of the superficial glands is the earliest phenomenon. In rare instances the tonsils and pharyngeal adenoid tissue have been first affected.

Hemorrhage is not an early symptom. Epistaxis has been noted, but not with the frequency with which it occurs in leukæmia.

With the progressive enlargement of the glands the patient becomes anæmic, and finally cachexia is developed.

The Lymphatic System.—In an early stage it is difficult or impossible to distinguish the affection from syphilitic or scrofulous adenitis. The gradual increase in the size and the involvement of other groups, and the oncoming anæmia, will alone in certain cases render a decision possible. In the cervical group, in which the trouble usually begins, the chain of glands on one side becomes enlarged—perhaps only those just above the clavicle, or in some instances the posterior ones are also affected. They are isolated, movable, and not, as a rule, tender. Months, or even years (three years, Case VII.), may elapse before the enlargement becomes general or affects the other side. With their increase in size and number the separation between the glands, at first evident, disappears, and they form distinct groups or bunches. Thus the submaxillary set, those of the anterior triangle, and those of the posterior may form irregular aggregations of various sizes. Ultimately, huge tumors may develop which obliterate the neck, extending upon the shoulders and over the clavicles and sternum. When these grow inward, toward the trachea, great dyspnoea may be produced, and the pressure may be so extreme that tracheotomy must be performed.

The skin becomes involved, and ulcerates. Usually it is freely movable over the masses. The pharynx and oesophagus may be compressed, and occasionally the carotids. The submaxillary tumors may limit the movement of the jaws.

Next to the cervical, the axillary glands are most frequently involved. If small, no inconvenience is felt, but when large bunches occur there is great pain in moving the arms, and pressure upon the brachial or axillary veins may cause swelling of the limbs. The tumors may pass far out, almost to the nipple.

The inguinal glands are not so often involved. In only one of the ten cases which I have seen were they affected, but they may form large and even pendulous tumors, as well shown in the cases of Surgeon-Major Porter.¹⁵²

¹⁵² Figured in Path. Soc. Trans., xxix.

Of the internal glands, those of the thoracic cavity are most often attacked. The chain in the posterior mediastinum may be involved and surround the aorta or compress the gullet; or they may pass up the trachea to the neck, and involve the thyroid (Case V.). When the bronchial group is enlarged there are signs of pressure on the tubes, dyspnoeal attacks, and serious implication of the lung (Case VI.) In the mediastinum there may be large masses covering the aorta, extending over the pericardium, and producing bulging of the sternum and ribs, perhaps pulsation, and ultimately erosion of the bones and outward projection of the tumors (Cases II. and III.). There may be considerable pressure upon the veins and obstruction to the flow in the superior cava and jugulars.

In the abdomen the mesenteric glands are often affected, and if the belly-walls are thin can be readily felt. The continuous chain of retro-peritoneal glands may be greatly enlarged, and extend from the diaphragm into the pelvis, surrounding the aorta, cava, and nerves. When the patient is thin there may be no difficulty in detecting these, but when there is an enormously thick panniculus the diagnosis may be impossible, as in Case I., in which intense lumbar and sacral pain and swelling of the legs were the only symptoms. The matting of organs in the pelvis caused by these growths may be a source of great difficulty in the diagnosis, as in a case in which I saw an eminent and careful surgeon open the abdomen to extirpate a uterus for fibroids, and found general lympho-sarcoma of the retro-peritoneal and pelvic glands.

It is probably in connection with affection of the abdominal glands that the bronzing of the skin occurs which is mentioned in a few instances. It was well marked in Case IV. of my series.

The glands present great variations in the rate of growth and there may be fluctuations from month to month. They may diminish rapidly, and almost disappear from a region to develop again in a few weeks. The enlargements may diminish very much before death.

The spleen does not present the almost constant enlargement of leukæmia, and in the majority of cases cannot be felt below the ribs. Moderate hyperplasia is common, but I have never seen the large splenic tumor. In some instances it has been found extending into the umbilical region, and if there are secondary lymphoid growths the surface may be very irregular.

The thyroid may be enlarged; it was so in Cases II. and IV., and in Case V. the growth in the glands of the neck involved the right lobe.

The thymus has also been found affected; indeed, the disease may, according to Virchow, sometimes begin in the gland.

Blood and Circulation.—The blood presents the characters of anæmia, and as a rule the more advanced the glandular trouble the greater the impoverishment. The red corpuscles are reduced in numbers one-half or even three-fourths, but never, in my experience, to the extent in pernicious anæmia. The lowest number per cubic millimeter which I have counted was in Case II., when on one occasion the numbers sank to 2,100,000 per c.m. There may be most advanced disease without great anæmia. In one case (IV.) with enormous enlargement of the cervical and axillary gland there were 4,250,000 to the c.m., and during his three weeks' stay in the hospital the numbers were never much reduced. So also in Case III. there was not profound anæmia to within two months of the patient's death.

The red corpuscles are usually uniform in size. I have never seen extreme poikilocytosis, though occasionally the microcytes have been numerous. The colorless corpuscles are not greatly increased, although there may be moderate leucocytosis, as in Case IV., in which the ratio of white to red kept about 1:150. A condition of actual leukæmia may be induced. The corpuscles may be smaller than usual, and present the characters of the blood in lymphatic leukæmia. I have not met with nucleated red corpuscles in any of the cases which I have examined.

The granule-masses of Schultze are in variable numbers.

Cardiac weakness and palpitation are common, due chiefly to the anæmia. The mediastinal growths in some cases cause great embarrassment from pressure. Fatty heart-muscle is an almost constant sequence of the anæmia. The pulse is quickened—80–110, or, if much fever, 120–130. Hæmic murmurs may be heard at the base of the heart, and the venous hum at the root of the neck is often very distinct. Pressure of the tumors upon the nerves may influence the heart's action, and in one case in which sudden death took place it may have been due to interference with the innervation of the heart by pressure on the nerve-trunks.

Respiratory System.—Shortness of breath from the anæmia is common, particularly on exertion. When the tracheal and bronchial glands are affected urgent attacks of dyspnoea may occur and suffocation be induced. Pressure on the pneumogastric or recurrent laryngeal may cause hoarseness or aphonia. The gland-tumors may invade the lung, or there may be secondary growths. These are not usually large enough to induce symptoms. The shortness of breath may be caused by pleuritic effusion, which may be an early symptom and the one for which the patient is sent to hospital (Case X.). It is due to pressure on the azygos and intercostal veins.

Fever is observed in nearly all cases; even in the early stages slight elevation of temperature may be noted. When the disease is firmly established the fever is a marked feature. It may be of an irregular hectic type, with morning remissions—this is, I think, the most common—or it may be continuous, with an evening exacerbation. More rarely there are ague-like paroxysms, with rigor, hot and sweating stage (Case I.), and during these the fever may rise to 104° and glands may become more swollen. The range is never very great, rarely exceeding 103°.

Digestive System.—Difficulty in swallowing may result from the enlargement of the lymph-follicles at the base of the lungs and of the tonsils and pharyngeal adenoid tissue. This may be so great as to necessitate feeding with a tube. There may be early gastric trouble when the mesenteric and abdominal glands are first affected—dyspepsia, nausea, and vomiting. Secondary tumors of the stomach are not common. The loss of appetite and feeble digestion, prominent symptoms in so many cases, are largely due to the anæmia.

Diarrhoea is not met with so frequently as in leukæmia; it may come on toward the close and carry off the patient. New growths in the intestine may produce severe attacks and sometimes hemorrhage. Obstinate constipation may be the result of pressure.

The liver is rarely enlarged, and there are not often hepatic symptoms. The new growths do not produce irregularity in the enlargement. Pressure of enlarged glands at the hilus may cause jaundice and ascites.

Genito-urinary System.—The urine is usually clear and presents no striking changes. Reaction acid; albumen may be present. The testicles may be the seat of secondary growths.

Nervous System.—Headache, giddiness, and noises in the ear are common, and are dependent upon the anæmic state. Southey¹⁵³ has noticed delirium and coma in some cases.

¹⁵³ Barth. Hospital Reports, vol. ix.

Special Senses.—Deafness is not uncommon, caused by pressure of the large glands in the neck or by the growth of adenoid tissue about the pharynx, closing the Eustachian tube. Inequality of the pupils has been noted, from pressure of a gland on the sympathetic. Retinal hemorrhages are uncommon.

Skin.—There may be definite secondary lymphatic tumors apart from direct infiltration by continuity.¹⁵⁴ Bronzing may occur (Case IV.). Papular rashes may be very troublesome. Subcutaneous oedema of feet and eyelids may occur when the anæmia is very profound.

¹⁵⁴ Greenfield, Path. Soc., xxvii.

MORBID ANATOMY.—The Lymph-glands.—Virchow made the division into the hard and soft varieties, the difference depending on the proportion between the cells and the adenoid reticulum. Where the cells predominate the growth is soft—may be semi-fluctuating—but when the stroma is much hypertrophied the glands are hard, firm, and feel like organs in a state of chronic induration. The great majority of the cases are of the soft variety. When first affected the glands may be hard, and as the development proceeds become less consistent; but there are cases in which they maintain their firmness and solidity throughout.

When examined in the early stage the individual glands are more or less isolated, perhaps not larger than almonds or walnuts, adherent by their capsules, but readily separated and movable. Even when death has been caused, some groups may generally be found in this state, as it is rare for all to be equally developed. When advanced, the glands fuse together, distinction is lost between them, and the bunch may form a large tumor the size of an orange or even a cocoanut. When of moderate size the section may show normal-looking gland-substance, and the distinction between cortical and medullary portions may be well preserved. When much enlarged the section has usually a grayish-white appearance, smooth, and of variable consistence, either firm and dry or soft and juicy. The vascularity is not often marked, and extravasation and areas of congestion are not seen so frequently as in some actively-growing neoplasms of the lymph-glands.

The capsules are thinned, and may disappear in the fusion of contiguous glands, traces being seen on the section as strands of connective tissue. About large groups the capsular tissues may be much condensed, forming a very firm investment. The growth may perforate the capsule and invade contiguous parts—muscle, skin, or the solid organs.

The chief changes which the tumors may undergo are fibroid induration, suppuration, and caseation. The gradual increase of the stroma may give a high degree of density, and the gland on section may present a smooth, glistening appearance. Suppuration is most frequently seen when the growth reaches the skin; it may point and an abscess discharge. In the deep glands the formation of pus is not often met with. Caseation is extremely rare. Hemorrhages may take place from rupture of the thin-walled vessels.

The chief characters of the lesions in the different groups have been dealt with in the section on Symptoms. The superficial glands are most often attacked, and the cervical or axillary may form huge masses before there are any signs of internal trouble. The superficial and deep cervical groups may be uniformly affected, the muscles lifted and wasted, and vessels and trachea surrounded by a solid mass. Sometimes all distinction between the tissues is lost, and the carotids run in the midst of the new growth, which may extend far out beneath the trapezius and down into the chest or over the clavicle on to the outside. When the neck is not primarily affected the groups are more isolated, and can be traced as chains of enlarged glands along the trachea and the carotids continuous with those of the axillæ and mediastinum.

The axillary group is next involved in the order of frequency, and the masses when large grow out under the pectorals and back beneath the scapulæ and high into the fossa, compressing the axillary vessels and causing great swelling of the arm. In Case VII. the growth infiltrated the neighboring muscles and eroded the humerus and neck of the scapula, perforated the blade, and exuded on its outer surface. Though an enormous mass, the vessels were not infiltrated, and only moderately compressed. The inguinal glands when very large may obstruct the femoral artery and vein, and seriously interfere with the circulation in the legs.

Of the internal groups, those of the thorax are most often affected, and we may have the chain in the posterior mediastinum along the aorta and the sides of the trachea and gullet, and along them pass into the neck (Case V.), or the bronchial group may be primarily attacked, with the formation of a great bunch at the fork and numerous small masses along each bronchus at the root of the lung, which may be extensively involved (Case VI.); or those of the anterior mediastinum beneath the sternum may be affected, with the production of large masses extending over the pericardium and passing even to the diaphragm. In these cases bulging of the sternum and ribs, with erosion and perforation, may occur. In Case II. the sternum was completely destroyed to a level with the fourth rib. The heart may be pushed aside and the aorta and its branches completely surrounded by growths (Cases II. and VI.). It is remarkable in these cases that great vessels do not suffer more from compression. When the abdominal glands are involved, the retro-peritoneal are most frequently enlarged, and form a continuous chain from the diaphragm to the internal rings on either side of the aorta and its branches, extending into the pelvis. Pressure effects are not common, but they may compress the ureter, causing hydronephrosis, the sacral and lumbar nerves, the iliac veins, and, as in the case I mentioned, may adhere to the broad ligaments and uterus in such a way as to deceive the most skilled gynæcologist. The mesenteric glands may present slight enlargement, but in my experience they are but little affected, even when the retro-peritoneal are of large size. When the glands at the portal fissure are involved they may compress the vein and duct. Phelps of Chateaugay, N.Y., sent me a specimen in which the glands of this region formed two huge masses the size of cocoanuts, and, so far as I could ascertain, they were primary lympho-adenomatous growths. The possibility of ovarian disease had been discussed by several consultants.

The chief change is an increase of the cells with or without thickening of the reticulum. The cells correspond to ordinary lymph-corpuscles; some may be a little larger, with darker granules and more pronounced nuclei. Giant cells are frequently met with, more often in the small glands. I have not seen them in the large soft tumors. In the early stage there may be simple hyperplasia and the relations of the lymph-paths are maintained, but when the glands are much developed the normal arrangement is disturbed and they cannot be injected. The reticulum varies much; in the very soft form it is expanded and can scarcely be found; the substance may be semi-diffluent. The firmer the structure the more evident is it, and in the hard forms the network of fibres in whose meshes the cells are enclosed can be distinctly seen and by pencilling very clearly brought out. It is not merely a thickening of pre-existing fibres, but probably there is a new development of adenoid tissue. In some cases of advanced fibroid change very few cells can be seen. The vessels passing to the glands are sometimes dilated.

Spleen.—In about 75 per cent. this organ is hypertrophied or presents lymphoid growths (Gowers). The enlargement is not often great, rarely approximating the colossal size of the leukæmic organ. It is due to either simple hyperplasia or to the presence of the new growths, sometimes to both. In the 75 cases of enlarged spleen new growths occurred in 56 (Gowers). Of the 38 cases in Hutchinson's table, 27 presented the splenic tumors. These are grayish-white bodies, ranging in size from a small pea to a walnut or larger, scattered irregularly through the substance, usually rounded in outline, but in some instances irregularly shaped. They contrast by color strongly with the red spleen-pulp. The numbers may vary from one or two to many dozens, the spleen-substance being a mere remnant between them. These masses often resemble the lymph-glands in appearance and consistence. They are not encapsulated, but in immediate contact with the spleen-tissue. They originate from the Malpighian corpuscles, and may be regarded as the enlarged and developed lymph-elements in the spleen. The larger ones probably arise from the fusion of several small ones. When uniform in size and scattered throughout the organ, they may resemble coarse tubercles, but the absence of any caseation may serve to distinguish them. Their histological characters are those of the glands, lymph-corpuscles in a fibrous reticulum; the consistence depends on the preponderating element.

Amyloid degeneration was found by Gowers in two cases in the growths.

The thymus has been found involved in the mediastinal growths, and is occasionally affected primarily. The thyroid may be attacked by the cervical tumors.

The suprarenals may contain secondary growths. In Case VII. both were extensively involved.

The medulla of the long bones has been found converted into red lymphoid marrow, and in a few instances into the pyoid variety met with in leukæmia. It has been found normal in other cases.

Digestive System.—In the mouth and pharynx the lymphatic elements are very commonly affected when the cervical glands are enlarged, sometimes independently. The tonsils may form large masses, and with the follicles at the root of the tongue and at the pharynx produce great obstruction. Sloughing may occur. In the gullet and stomach secondary tumors have occasionally been seen. In Case VII. there was a flat elevated mass at the cardia beginning to ulcerate.

The small intestines may be extensively involved; the glands of Peyer enlarged and even ulcerated. In Case VII. there were over twenty ulcers in the jejunum and ileum, ranging in size from a split pea to a bean, edges elevated and indurated and the bases sloughing. The large intestines may be secondarily affected, the intertubular adenoid tissue be greatly developed and compress the crypts of Lieberkühn, and lead to thickening of the mucosa.

The liver is often enlarged, and presents scattered lymphoid tumors, rarely larger than a pea, of a white or yellow-white color, and may be readily mistaken for tubercles. They are most common beneath the capsule and in the interlobular tissue. A diffuse interacinous growth may also occur. Cirrhosis has been observed in the vicinity of the growths, and fatty degeneration.

The pancreas may be the seat of secondary masses.

Genito-urinary System.—The kidneys are very often the seat of new growths, usually small and of a character similar to those in the spleen and liver. When the disease is very rapid the tumors may be large and very vascular. The texture of the kidney is usually soft, and parenchymatous change is common. The testicles may also be the seat of adenoid growths; this was the case in one of Hodgkin's patients.

The Respiratory System.—Growths in the trachea are rare. The lungs are frequently affected, either by the direct invasion at the root from the bronchial glands (Case V.), or by numerous scattered nodules through the substance. They develop about the bronchi, and may reach the size of marbles. Intense bronchitis, oedema, and congestion may be secondary changes induced by pressure on the bronchi or trachea.

The serous membranes occasionally present lymphoid growths. Pleural effusion is not uncommon.

The heart presents no very constant changes. When the anæmia is profound it may be very fatty. It may be compressed by mediastinal growths, and has been found much atrophied. Lymphoid growths may occur in it.

The Nervous System.—The brain itself is rarely affected, but growths have been found in the dura mater. In Case VI. a secondary mass compressed the spinal cord, as in Hutchinson's case, producing paraplegia.

The skin may be the seat of adenoid growths, as in Greenfield's case.¹⁵⁵ The growing tumors may involve it (Case IV.), and ulceration may occur.

¹⁵⁵ Loc. cit.

COURSE, DURATION, AND TERMINATION.—Trousseau and other French writers have divided the disease into different stages—the latent and period of early development, the period of generalization, and the cachectic state; but the course of the disease is very variable, and depends much upon the position of the glandular enlargements, the rapidity of development of secondary growths, and also the constitutional peculiarities of the patient. Early and rapid growth in the mediastinal groups may produce pressure effects, and cause death before any marked anæmia—much less cachexia or the development of secondary masses in important organs, as the cord, may prove quickly fatal. In some cases the glandular enlargement rapidly spreads, and group after group is involved in the space of a few months; in others there may be hyperplasia of a single set, as the cervical on one side, for months, or even years, before the glands on the other side or in other regions become involved. The most acute cases may run a course in three or four months, the most chronic in as many years. Periods of quiescence are not uncommon, and the tumors may not only cease to grow, but actually diminish, or even disappear in a region, and this without any special treatment.

The mode of death is commonly by asthenia; cachexia is gradually developed, the anæmia becomes more profound, and finally, with local or even general dropsy, the end comes from heart failure. Very frequently the patient is cut off before grave constitutional disturbance is established, particularly by asphyxia from the pressure of enlarged glands on the trachea and bronchi or occlusion of the pharynx. Hemorrhage and diarrhoea, such common symptoms in leukæmia, are rarely seen. Coma has been the cause of death in a few cases. Oedema of the lungs, pneumonia, extensive pleuritic effusions, may hasten, and in some instances cause, the fatal result.

The DIAGNOSIS is in most cases easy; in others time alone will decide the true nature of the glandular enlargement. Of the chronic forms of adenitis which are liable to be confounded, the scrofulous is the most common. The points to be attended to in the diagnosis are—the age; scrofulous glands affecting chiefly the young and individuals presenting other signs of the so-called scrofulous habit, or there may be a well-marked family history of phthisis. In the question of age, however, it is to be remembered that there is a condition known as adult or senile scrofula, in which there may be general enlargement of the glands. Of all groups the cervical are most frequently involved in scrofula, and the submaxillary set more often than those of the anterior and posterior triangles, while in Hodgkin's disease the latter are usually affected first. The enlargement in scrofula is rapid at first, and may last for years in a group without extending; the bunches are often, even when small, welded together, and, most important of all, they tend to suppurate—a feature scarcely ever seen in true lymphadenosis. Size is an uncertain criterion. I have seen masses of scrofulous glands in the neck as large as two fists and without suppuration. A single large bunch in the neck, particularly if submaxillary, persisting for over a year or eighteen months without involvement, however slight, of the glands in the same or the opposite side or in the axillæ, is almost certainly not malignant lymphoma. On the other hand, a group of slowly-enlarging glands in the anterior cervical triangle, with gradual affection of those of the opposite side of the axillæ, particularly if in a person between twenty and thirty and becoming anæmic, would render the suspicion of Hodgkin's disease strongly probable.

In connection with this it may be mentioned that occasionally in acute phthisis there may be great swelling of the glands, from a growth of miliary tubercles in them. A case of the kind was admitted into my wards in the General Hospital, Montreal: a man aged twenty-four, with great swelling of the cervical glands in both sides, tonsillitis, and sloughing pharyngitis, irregular fever, and diarrhoea, and for a time the case was believed to be one of Hodgkin's disease.

PATHOLOGY.—Local benign lymphomata occur, identical in histological characters with the tumors of Hodgkin's disease, and differing only in the absence of any tendency to extend in the neighborhood or to generalize. They are not uncommon about the neck, may grow slowly, and last for years.

The lymphatic growths of leukæmia are not in any essential particular different from those of Hodgkin's disease, and the diagnosis rests upon the examination of the blood. There are, however, certain broad differences when any considerable number of cases of the two diseases are compared. Thus the lymphatic element in leukæmia is less pronounced, the splenic and medullary forms predominate; in Hodgkin's disease exactly the reverse prevails. It is rare in leukæmia for the internal glands to be much involved, and patients do not often die from the pressure effects of the tumors. The hemorrhages so common in leukæmia, and the diarrhoea, are rare symptoms. The bone-marrow is more generally affected, and, lastly, the tendency to generalize seems greater in the growths of Hodgkin's disease.

From other forms of malignant growths in the lymph-glands there may be difficulty in the diagnosis, and even a microscopical examination may not serve to make the distinction.

Thus there is a true lympho-sarcoma, a small-celled growth of the lymph-glands, which must be distinguished, though it is hard in some cases, from the general lymphadenoma. The distinctions laid down by some writers, such as a special tendency to attack contiguous parts, and a more general distribution of the metastatic growths, will not hold, as we have seen that cases of lymphadenosis or Hodgkin's disease may attack neighboring structures, and the secondary tumors, though preferably in lymphatic textures, may occur in every organ. In the retro-peritoneum, for example, true lympho-sarcoma is not uncommon, forming large tumors which may press forward the viscera and produce a very prominent mass in the abdomen. They are not uncommon in children, and with renal sarcomas make up three-fourths of the abdominal growths of early life. But they may occur in adults and attain large size, involving adjacent organs, such as the kidneys, or, as in a case I saw a short time since, grow into the colon and cause death by gradual hemorrhage. These are local growths as regards the lymphatic system, not involving distant glands, and not often, indeed, producing metastasis.

We may recognize in the lymphatic glands—1st, the local benign growth which seems nothing more than hypertrophy, lymphadenoma, and which may persist for years; 2d, a local malignant growth, lympho-sarcoma, which invades contiguous structures and may be followed by metastasis, but there is not general involvement of the lymphatic tissues; and 3d, there is a generalized lymphoma involving groups of glands in succession, and the adenoid tissue throughout the body, usually accompanied by anæmia alone, in which case we term it Hodgkin's disease—sometimes by an excess of colorless corpuscles as well, when we call the affection lymphatic leukæmia.

PROGNOSIS.—When established sufficiently to make a sure diagnosis, the prognosis is in the great majority of cases bad; true examples of the disease rarely if ever recover. A hopeful prognosis may be given in those cases in which only a few glands are involved, and where there is any suspicion of a scrofulous habit or where the enlargement has persisted for years without extending. The presence of profound anæmia, the existence of swelling in distant groups and in internal glands, are grave indications. High, irregular fever, rapid growth, and the development of cachexia are symptoms of the full establishment of the disease. The physician must not be deceived by intervals of improvement, with perhaps subsidence of the glandular swelling in places. Such breaks in the onward progress are not uncommon.

TREATMENT.—When small and localized, the question of the removal of the glands may be raised. If they persist after appropriate remedies, and if there is not grave anæmia, and other groups and the spleen are not affected, excision should certainly be performed. Circumscribed lymphadenoma, particularly of the neck, may exist for years before the glands in other regions become involved; and in such cases removal affords the best guarantee that the disease will not extend.

Local applications are of doubtful benefit. I have never seen any permanent improvement follow the persistent use of iodine, biniodide of mercury ointment, or friction with oil. Galvano-puncture has not been successful, and the same may be said of the various substances injected into the glands—iodine, arsenic, chromic acid, etc.

Internally, iodine and iodide of potassium have been extensively used, but without much benefit. Quinine, iron, and cod-liver oil are useful as tonics, but have no influence on the size of the tumors. Arsenic is the only medicine which has seemed to me of positive value, and under its use I have seen the gland-tumors decrease greatly in size. It should be given in increasing doses until some of the unpleasant effects of the drug are manifested, when a return should be made to a small dose, and again gradually increase. When well borne, large doses, 20 or 25 minims, of the liquor arsenicalis should be taken three times a day for many weeks. In two cases with moderate enlargement of the cervical and axillary glands the progress of the disease seemed arrested, and the glands certainly became smaller and softer. In the history of these cases the patients will often speak of changes in the volume of the gland quite uninfluenced by any treatment; and these fluctuations must be taken into account in estimating the value of a drug; but, making due allowance for this, the beneficial effects of the arsenic are unquestionable when given early in large doses and the administration kept up for months. Many recent writers have borne testimony to this, among them Karewski,¹⁵⁶ who reports three recoveries.

¹⁵⁶ Berl. klin. Wochenschrift, 1884, 17 and 18.

Phosphorus has been of service in the hands of Gowers and Broadbent, and when arsenic is not well borne it should be tried.

Change of air and scene has benefited some cases. The patient's strength must be supported by every possible means; fortunately, gastro-intestinal disturbance is not so marked as in leukæmia, and even with most extensive and progressive enlargement of many groups of glands the appetite may be good and the digestion excellent.

When the glands of the neck compress the trachea, or when the lymphoid elements of the tonsils and pharynx obstruct the orifice of the glottis, tracheotomy may be necessary.

HÆMOPHILIA.

DEFINITION.—An hereditary or congenital fault of constitution, characterized by a tendency to bleeding, spontaneous or traumatic, and often associated with swelling of the joints.

SYNONYMS.—Hæmatophilia; Hereditary hæmorrhage; Hæmorrhagic diathesis; Idiosyncrasia hæmorrhagica. Ger. Bluterkrankheit, Blutsucht; Fr. Hémophilie. The term bleeder is applied to a patient.

CLASSIFICATION.—In this article the congenital or hereditary disease will alone be considered, to the exclusion of cases of transient hemorrhagic diathesis, the hemorrhages of scurvy, fevers, anæmia, purpura simplex, and purpura hæmorrhagica.

HISTORY.—So far as is known, the classical writers make no mention of the disease, though in the Pharsalia of Lucan there is a passage, quoted by Legg,¹⁵⁷ which well describes the hemorrhagic diathesis. The first positive reference is in the writings of Alzaharvi, a physician of Cordova who died in 1107 A.D. A doubtful case is mentioned by Benedictus in 1539, who relates the history of a barber who bled to death from slight wounds of the nose caused by clipping the hairs. Hochstetter described a case in 1674 to which Virchow has called attention.¹⁵⁸ Legg¹⁵⁹ found a well-recorded case by Banyer in the Philosophical Transactions (1743). Fordyce in 1784 described a Northamptonshire family the members of which suffered from hemorrhages.¹⁶⁰ With brief references to the disease by two German writers in 1793 and 1798, these scanty materials comprise the facts known at the beginning of this century.

¹⁵⁷ Hæmophilia, London, 1872.

¹⁵⁸ Virchow's Archiv, Bd. xxviii.

¹⁵⁹ Loc. cit.

¹⁶⁰ Fragmenta Chirurgica et Medica, London, 1784.

To American physicians belongs the credit of the full recognition and description of the disease and the discovery of its remarkable hereditary nature.

Otto¹⁶¹ gave an account of a New England family members of which had been bleeders for several generations. He also referred to a Maryland family observed by Rush. Otto appears to have been the first to note the immunity of females in bleeder families, and their tendency to transmit the disposition. In the Philadelphia Medical Museum, vol. i., 1805, a letter of E. H. Smith is published, written in 1794, in which he gives an account of a boy affected with the disease. Hay¹⁶² reported the Appleton-Swain families of Reading—one of the most remarkable histories ever published of the disease. In 1817 the Buel Brothers described the Collins family,¹⁶³ and Coates¹⁶⁴ a family in Delaware county, Pa. Hughes¹⁶⁵ and Gould¹⁶⁶ also described notable examples. Holton, Harris, and Dunn have studied other American bleeder families, and a brief record of the local literature of the subject will be found at the end of this article.

¹⁶¹ Medical Repository, New York, 1803, vol. vi.

¹⁶² New England Medical Journal, 1813, vol. ii.

¹⁶³ Transactions of the Medical and Physical Society of New York, 1817.

¹⁶⁴ North American Medical and Surgical Journal, Philada., vol. vi., 1828.

¹⁶⁵ Transylvania Journal, 1831, vol. iv., and American Journal Med. Sciences, 1833, vol. xxi.

¹⁶⁶ Boston Medical and Surgical Journal, 1857.

In Germany, Nasse (1820), Rieken (1829), Schönlein, Canstatt, Wachsmuth, Lange, Virchow, and others added greatly to our knowledge of the disease. Grandidier published a monograph in 1855, a new edition of which in 1877¹⁶⁷ contains a most exhaustive account of the disease and a statistical résumé of all cases to date. In England the disease has not attracted much attention. Legg published an important monograph in 1872, and many papers of value are scattered through the Transactions and journals.

¹⁶⁷ Die Hämophilie, Leipzig, Zweite Auflage, 1877.

In France the articles in the encyclopedias and a few theses—of which Gavoy's (1861) and Simon's (1874) are the most important—comprise the chief literature.

ETIOLOGY.—The disposition is, in the majority of cases, hereditary, but there may be a spontaneous origin, the disease appearing in the child of a family in which no previous cases had occurred. Nothing is known of the conditions under which the disease may thus arise in a healthy stock. Many of such cases die early, but others live and may become the starting-points of new bleeder families. In the history of sixty families Grandidier¹⁶⁸ found statements of this mode of origin of the affection.

¹⁶⁸ Op. cit., p. 136.

The two most interesting features in the etiology relate to sex and heredity. The disease is much more common in males than females, the proportion being variously estimated at 11 to 1, or even 13 to 1. In 64 bleeder families, in 5 were sons and daughters alike affected; in 27 all the sons were bleeders; and in 6 of these there were no daughters.

There is no disease with so marked a tendency to transmission, and it may appear in four or five generations in succession. In the Appleton-Swain family of Reading, Mass., there have been cases since the early part of the last century, and F. F. Brown of that town writes me that cases still occur in the descendants.¹⁶⁹ Legg gives a chart of the Clitherow family, in which it has existed for the past two hundred years.¹⁷⁰

¹⁶⁹ The last case Brown has been able to ascertain was in a lad, Warren Coburn, aged seventeen, who died about twelve years ago. His mother's brother was a bleeder, and died of hemorrhage from a slight scalp wound after having been brought to death's door on three or four other occasions by trivial wounds. Mrs. Coburn was a daughter of Daniel Hart, whose wife was a Norton. Her mother was a Bacheller and a granddaughter of Oliver Appleton's daughter. This lad is an instance of the transmission of the disposition to the seventh generation within a period of two hundred years. Brown further states that there do not appear to be in the vicinity of Reading any Appleton or Swain families in which bleeders exist. As the tendency is chiefly transmitted through the female members of a family, who lose the patronymic by marriage, it is often difficult to trace the relationship. I think if we had fuller genealogical details we should find that several of the bleeder families now thought to be distinct belonged to the same stock.

¹⁷⁰ St. Barth. Hospital Reports, 1881.

In the celebrated bleeder families of Tenna, Switzerland, five generations have been affected. The modes of transmission are as follows: (1) Father to son, grandson, etc. This is rare, but instances are on record. (2) Father not a bleeder, but of bleeder stock, transmits the tendency to son—very uncommon. (3) Father to daughter, granddaughter, etc.—not common. The daughters of a bleeder are usually free, though their brothers may be affected. (4) Mother a bleeder, transmits to sons and daughters. (5) Mother not a bleeder, but daughter of one, transmits to her sons, the daughters remaining free, but their sons affected. This is the most common mode of inheritance. Atavism by transmission through the female line is almost the rule, and the daughters of a bleeder, though healthy and free from any tendency, are almost certain to transmit the disposition to their male offspring. The 657 cases analyzed by Grandidier occurred in two hundred families. The chief facts of heredity are well illustrated by the preceding chart of the Yeaton family, given by Gould in the Boston Medical and Surgical Journal, 1857.

The Anglo-Germanic nations appear especially prone to the disease. Of 194 families in Grandidier's table, 154 were of the Teutonic stock. Records of the disease among the Latin races are rare. Jews are probably not more liable than other people, but the rite of circumcision gives an unusual opportunity for its manifestation at an early age.

The age at which the bleeding tendency first appears was determined by Grandidier in 113 cases as follows: in 63 during the first year; in 17 during the second, and up to the end of the second year in 93. It is rare for the first manifestation to occur after the twelfth year, and there was only one case in which the first bleeding appeared after the fifteenth year.

The constitution and temperament of bleeders, about which the older writers had much to say, probably present no peculiar characteristics. Some persons claim to be able to recognize bleeders even before they have manifested any tendency to hemorrhage. They are usually fresh, healthy-looking persons, with fine, soft skins, through which the superficial veins may show with more than usual distinctness. A division of cases into erethetic and atonic forms has been made by Wachsmuth and Grandidier. The mental activity of bleeders has been noted to be above the average, due, doubtless, to the fact that the liability to bleed from slight blows and cuts has made sedentary and studious habits preferred to out-of-door employments and amusements.

Families in all conditions of life are affected. Much interest was excited in the disease in England from the fact that the late Prince Leopold was a sufferer.

Climate appears to have an influence in determining attacks. Cold, damp, changeable weather is favorable, while a residence in a warm, equable climate diminishes the tendency in a very marked manner. Some patients have an extraordinary susceptibility to changes in the weather.

All observers have noted the great fertility of bleeder families. Those first born seem less liable to bleed than subsequent ones.

SYMPTOMS.—The existence of the defect of constitution may not be suspected until an uncontrollable hemorrhage follows some trivial injury or operation, or a spontaneous bleeding may occur and present great or insuperable difficulties in its arrest. The symptoms usually occur in the first years of life, and in the great majority of cases, as mentioned above, the first bleeding occurs before the fifth year. The symptoms may be grouped under three divisions (Legg, Grandidier): external bleedings, spontaneous and traumatic; interstitial bleedings, petechiæ, and ecchymoses; and the joint affections. Legg recognizes three grades of the disease. The first and most severe is characterized by bleedings of every kind, external and internal, and by troublesome joint affections: this form is most often seen in men. The second grade is less severe; there are spontaneous hemorrhages from the mucous surfaces, but no traumatic bleeding or ecchymoses and no joint troubles: this form is most often seen in women. The third and lowest degree is when there is a tendency simply to ecchymoses; no dangerous bleedings occur: this form is often seen in members of bleeder families, and if in women the menstruation may be early and profuse.

External Bleedings.—The spontaneous bleedings may occur from the skin, the mucous, and in rare instances the serous, membranes. There are frequently preliminary symptoms—prodromata—such as flushing, fulness of the head, and throbbing of the arteries—signs of so-called plethora; often there is irritability of temper, but sometimes, in children, extra cheerfulness has been observed. The localities affected and the frequency are shown by the following analysis of 334 cases by Grandidier: Epistaxis, 169 times; from the mouth, 43; stomach, 15; bowels, 36; urethra, 16; lungs, 17; cerebral hemorrhage, 2; skin of head, 4; tongue and finger-tips, 4 each; tear-papilla, 3; eyelids, 2; external ear, 5; female generative organs, 10; ulcer of skin, 2; navel (long healed), 2. An odd situation for spontaneous bleeding is mentioned by Townsend,¹⁷¹ in which a child bled to death from the scrotum. In many cases these spontaneous hemorrhages prove fatal—most frequently the epistaxis. The traumatic bleeding may result from blows, cuts, scratches, etc., and the blood may be effused into the tissues or discharged externally. Fatal hemorrhages have occurred from the following wounds: blow on head, 11 times; slight scratches on skin or abrasion of dermis; laceration of the frænum of the lip, slight cut (two lines deep) in a duel wound; bite of the tongue (7 cases); fall on the mouth; blow on the nose; blow of a stone on the finger; cut in paring the nail; fall on the head with meningeal hemorrhage (2 cases, brothers); and rupture of the hymen on the wedding-night.

¹⁷¹ Boston Med. and Surg. Journal, lv.

After operations, trivial and severe, many fatal cases have occurred, and the statistics of the same author give the following: cutting of the frænum linguæ, 1; leeching, 5; venesection, 4; blister, 2; extraction of tooth, 12; circumcision, 8; cutting umbilical cord, 4; vaccination, 2; fistula, stone, ligation of carotid, of radial, of ulnar, of femoral arteries, amputation of arm and of thigh, 1 each; phimosis, 2. Leeching, extraction of teeth, and circumcision are most dangerous operations in bleeders.

The bleeding is always a capillary oozing, and the vessels are not seen. It may last for hours, or even many days and weeks, and the amount of blood lost may be enormous. Epistaxis may be fatal in twenty-four hours. In Coates' case a medical student lost half a gallon of blood in twenty-four hours, and in the ten days which the bleeding continued it was estimated that he lost about three gallons.

The healing of a wound in a bleeder may take place rapidly, either with or without suppuration. When the hemorrhage is large or prolonged, severe anæmia follows, from which, as a rule, the patients recover with remarkable rapidity.

The interstitial hemorrhages—petechiæ, ecchymoses, hæmatoma—may be spontaneous or the result of injuries. The petechiæ occur most frequently in the skin, particularly of parts distant from the heart—the legs and arms, less often the face. On the mucous and serous surfaces they are less common. They resemble ordinary purpuric spots, and crops may come out with symptoms of swelling and pain in the joints. Large extravasations—hæmatoma—are most frequently of traumatic origin and may follow the slightest blow, as in a case of Sir Wm. Jenner's, in which from the fall of a rubber ball on the thigh an enormous extravasation took place between the knee and trochanter.¹⁷² They are blue, black, or reddish-black at first, and in their absorption go through the various changes in color which we notice in a bruise. These blood-tumors may occasionally arise spontaneously.

¹⁷² Legg, etc., p. 68.

The arthritic affections in hæmophilia are very remarkable, and so common as to form prominent features in the disease. There may be simple pain in and about the joints, or swelling with redness and signs of intense inflammation. The attacks may come on suddenly with fever, resembling closely acute rheumatism. The large joints are usually affected, the knees most often, then the elbows, ankles, and shoulders. There may be repeated attacks, and at last great crippling and deformity. The small joints are rarely affected. In cold, damp weather the attacks are most common; occasionally they follow traumatism. In addition to the joint troubles, bleeders suffer much with irregular pains in the limbs, particularly during change of weather, or these pains with arthritis may usher in an attack of hemorrhage.

Many other irregular symptoms are described in the monographs, some of which have no intimate relation with the disease. The anæmia has, of course, all the features of the traumatic form. Digestive troubles, after the bleeding, are common, and are due to the anæmia. The Buel Brothers¹⁷³ mention that in two of their cases the patients showed a marked inclination to eat sand and earth. Children with the hemorrhagic tendency pass through the ordinary diseases of infancy like others. Whooping cough is very liable to cause epistaxis. Rheumatism and scrofula are said to be common in bleeder families.

¹⁷³ Op. cit.

The blood in bleeder cases is, as a rule, normal, so far as our present means of investigation enable us to decide. When a hemorrhage has continued for some time, it is thin and watery, but at the beginning of the bleeding the blood is usually rich in corpuscles and fibrin and coagulates firmly. The salts have been found increased in quantity. No change has been noted in the corpuscles, the number of which is stated by several observers to be increased. Prior to a hemorrhage there may be, according to some writers, a state of plethora or increase in the total quantity of blood, and the tolerance of the loss, so much greater in bleeders than in ordinary persons, is adduced in support of this view.

MORBID ANATOMY.—Not many changes other than those of profound anæmia have been found in the bodies of bleeders. An unusual thinness of the walls of the vessels, first noted by Bladgen in 1817,¹⁷⁴ has been met with in a number of cases; in a few instances hypertrophy of the heart; in others a rounded foetal shape of the organ. Within the past few years careful microscopical examination has been made of the tissues and blood-vessels of bleeders. Kidd¹⁷⁵ found degeneration of the muscle-fibres of the middle coat of the arteries, and the endothelium of the small arteries, veins, and capillaries was swollen, proliferated, and some of the small veins were blocked with the products. Legg¹⁷⁶ reports a case in which Klein made a most careful examination with negative results, and he stated that of six such examinations which had heretofore been made, in only one case (Kidd's) were important changes found. At the same meeting of the London Pathological Society, Theodore Ackland also reported a case with negative results as regards histological changes.

¹⁷⁴ Medico-Chirur. Transactions.

¹⁷⁵ Medico-Chirurgical Society's Transactions, vol. lxi.

¹⁷⁶ Lancet, Oct. 27, 1884.

The joint changes have been studied in a number of cases. Hemorrhage has been found in and about the capsule, and the acute swelling may be due largely to it, as was shown in Hutchinson's case,¹⁷⁷ in which he aspirated the joint. When it lasts any time, there is great staining of the cartilages and discoloration. There may be inflammation of the synovial fringes and erosion and destruction of the articular surfaces (Legg).

¹⁷⁷ Trans. State Med. Soc. N.Y., 1877.

The PATHOLOGY of the disease is unknown. No doubt two circumstances combine in hæmophilia—congenital fragibility of the vessels and a defect in coagulability of the blood—but whereon these depend we are as yet entirely ignorant. There is no evidence of the nature of the anatomical changes in the vessels which permits of their ready laceration, and none on the nature of the alteration of the blood which prevents the normal thrombus formation in a wound; and in the absence of information on these points theories must necessarily be unsatisfactory, and their discussion, in a work of this practical nature, profitless.

The DIAGNOSIS presents no difficulty in members of a bleeder family, in whom slight joint trouble and petechiæ are as much manifestations of the disease as the more severe hemorrhages. In a large majority of cases the tendency becomes manifest at an early date. The spontaneous umbilical hemorrhages of infants are, as a rule, to be excluded, being dependent upon, or associated with, jaundice or syphilis or a mycosis (Weigert¹⁷⁸). The hemorrhagic diathesis may develop in children or members of a healthy family and prove fatal, and the question in such cases always comes up, Are they instances of hæmophilia? There seems to be a desire to limit this term to cases of an hereditary nature only; but when a child shows a marked tendency to multiple hemorrhages, spontaneous or traumatic, which tendency persists and is not merely transitory, and particularly if there are joint troubles, I think that under these circumstances we have a genuine case of hæmophilia; and such a child, if he—it is more likely to be a male—survives and marries, may be the founder of a bleeder family. These are the congenital in contradistinction to the hereditary cases. In the histories of the bleeder families we frequently come back to the origin in a person born of a healthy stock in which there have been no hemorrhagic tendencies. On the other hand, single severe uncontrollable hemorrhages in children or adults are not to be ranked as hæmophilia unless there have been other features pointing to the existence of the diathesis. The literature abounds in cases of this kind, many of which are described as hæmophilia. In doubtful cases it is very difficult to decide, as in a case of Forscheimer brought before the Academy of Medicine of Cincinnati.¹⁷⁹ In the review of American literature we have excluded all cases in which the hereditary or congenital characters were not well marked.

¹⁷⁸ Cohnheim's Pathologie, i. 382.

¹⁷⁹ Cincinnati Lancet and Clinic, 1884.

It may be useful to put down here for the guidance of the practitioner the varieties of bleeding commonly met with, and which must not be confounded with hæmophilia:

(1) The umbilical hemorrhages of infants, due to jaundice or to syphilis hæmorrhagica neonatorum, etc.

(2) Purpura simplex, seen often in debilitated, rarely in healthy, children, usually confined to the legs, and in some cases I have seen it associated with rheumatic pains or swellings in the knees and ankles.

(3) Peliosis rheumatica, an affection which in the large interstitial hemorrhages and the joint swellings touches hæmophilia in a curious way. It too may show itself in several members of the same family.

(4) Purpura hæmorrhagica, Morbus maculosus Werlhöfii, a grave disease, characterized by extensive cutaneous ecchymoses, mucous hemorrhages, but not dependent on any local disease, or, so far as is known, on any specific poison. The bleedings in scurvy may be mentioned here, but there could be little difficulty in determining their nature.

(5) Infective purpura, due to the action of some specific poison—small-pox, measles, scarlet fever, cerebro-spinal fever, etc. The hemorrhages may be cutaneous and trivial, or may be in the most aggravated form of interstitial and mucous bleedings, as seen, for example, in black small-pox.

(6) Toxic purpura, as in snake-bites and many poisons, such as phosphorus.

(7) Simple hemorrhagic diathesis, under which may be included those cases in which, without any hereditary disposition or previous hemorrhagic history, there is a tendency to uncontrollable hemorrhage from a slight wound.

(8) Hæmatidrosis, bloody sweats, which occur usually in hysterical or epileptic females, and are in rare instances accompanied with mucous hemorrhages.

In considering the PROGNOSIS it is well to remember that the patients rarely die in the first bleeding. The younger the individual the worse is the outlook. As above stated, the attacks are most frequent under five years of age, and of 152 boys the subject of the disease, 81 died before the termination of the seventh year (Grandidier). Legg, however, states that it is rarely fatal in the first year. The longer a bleeder lives, the greater the chance of his outlasting the tendency; but that it may persist to the end of a long life, and then prove fatal, is shown by the case of old Oliver Appleton, the first recorded American bleeder, who died at an advanced age of hemorrhage from a bedsore and from the urethra. A bleeder may have years of existence, in which the tendency seems lessened or even absent. The prognosis is always worse in a boy than in a girl. In the latter menstruation is sometimes early and excessive, but, happily, in the female members of hæmophilic families neither this function nor the act of parturition bring with them special dangers.

TREATMENT.—The prophylaxis is all-important. The members of a bleeder family, particularly the boys, must be guarded from injury as much as possible, and operations of all kinds must be avoided, except when life itself is in jeopardy. The extraction of a tooth should be absolutely prohibited. Occupations must be sought which will give the least possible risk of injury. Daughters of bleeder families should not be permitted to marry, as it is through them that the tendency is chiefly propagated, and, even if not bleeders themselves, some of their male children are certain to be affected. The question of the marriage of male bleeders is more difficult to decide, but in any case where the tendency is marked it should be prohibited.

When an injury or wound has occurred, absolute rest, cleansing the wound, and compression should first be tried. If in a favorable locality pressure on the artery may be employed, failing in this, the various styptics may be used. In epistaxis, ice, tannin, and gallic acid may be tried before plugging.

Internally, ergot seems to have been of use in several cases. Otto¹⁸⁰ speaks of the value of sulphate of soda in purgative doses. The perchloride of iron, 30–40 minim doses, every two hours, is advised by Legg, with a purge of sulphate of soda if there is no bleeding from the bowels. Venesection has been resorted to in several instances. Transfusion has been employed, but without benefit. The diet should be light and supporting. After the attacks the patients should take iron and cod-liver oil until the health seems restored. When possible, a residence in the South during the winter is advisable, as most cases are aggravated by the cold weather, and in any case care must be taken to protect patients against cold and wet.

¹⁸⁰ Loc. cit.

The joint troubles must be treated on general principles.

AMERICAN LITERATURE OF HÆMOPHILIA.

Buel: Transact. of the Med.-Physic. Society of New York, vol. i., 1817; 1 F., 4 cases.

Coates: North Am. Med. and Surgical Journal, Philada., 1828, vi. p. 37; 1 F., 5 cases.

Dunn: Am. Journal Med. Sciences, 1883, vol. lxxxv. p. 68; 4 F.

Felt: History of Ipswich, 1834—Appleton family referred to.

Gould: Boston Med. and Surgical Journal, 1857, p. 500; 1 F., 11 cases.

Harris: Philada. Med. Times, 1872; 2 F., 7 cases.

Hay: New England Journal of Med. and Surgery, 1813, vol. ii. p. 221; 1 F., 15 or 16 cases (accurate number rather difficult to make out).

Holton: Am. Journal of Med. Sciences, April, 1874; 1 F., 7 cases.

Hughes: Transylvania Med. Journal, 1831, vol. iv. p. 518, and Am. Journal Med. Sciences, 1833, vol. xxi. p. 543; 1 F., many cases.

Hutchinson: Trans. State Med. Society of New York, 1877, p. 208.

Otto: Medical Repository, 1803, vol. vi.; 3 F., 8 cases.

Pepper: Philada. Med. Times, 1881, vol. xii. p. 109; 1 case—Lancaster county family described by Dunn.

Sewell: Med. Chronicle, Montreal, 1857, vol. iv.; 2 F., 4 or 5 cases.

Smith: Philadelphia Medical Museum, 1801, vol. i. p. 284.

Traneus: St. Louis Med. and Surgical Journal, 1870, p. 535; 1 F., 4 cases.

Townsend: Boston Med. and Surgical Journal, vol. lv. p. 447; 1 F., 3 cases.

ADDISON'S DISEASE.

DEFINITION.—A constitutional affection characterized by asthenia without emaciation, a depressed circulation, gastric irritability, and usually pigmentation of the skin. In the majority of cases it is associated with a fibro-caseous degeneration of the suprarenal capsules, and in many there are changes in the abdominal sympathetic system.

SYNONYMS.—Morbus Addisonii; Bronzed-skin disease. Fr. Maladie d'Addison, Maladie bronzée; Ger. Addisonische Krankheit.

HISTORY.—In the Halle Hospital Reports for 1823 Schötte describes a case, and one is also given by Bright in vol. ii. of his Medical Reports, 1831. A few other instances are also on record before 1855, when Addison published his monograph On the Constitutional and Local Effects of Disease of the Suprarenal Capsules, from which we may date our knowledge of the affection. Following close upon the work of Addison numerous observations were made in England, where the disease appears to be more common than elsewhere. Wilks of Guy's Hospital,¹⁸¹ and Greenhow of the Middlesex Hospital, may be mentioned among those who in England have specially studied the disease, and the latter published an important monograph in 1875.¹⁸² In France, besides numerous minor contributions, the exhaustive articles in the encyclopædias have been the most important publications. In Germany the monograph of Averbeck (1869) and the abstracts of Meissner in Schmidt's Jahrbücher may be specially mentioned. Virchow, Griesinger, Oppolzer, Bamberger, and others have made valuable contributions. Recently Burger¹⁸³ has published a small monograph. In other European centres contributions have been made, among which may be mentioned that of Schmidt of Amsterdam, who brought forward cases in support of the view that the disease was an affection of the sympathetic ganglion. In America the first cases were reported by Ranking¹⁸⁴ and Taylor.¹⁸⁵

¹⁸¹ In numerous communications in Guy's Hospital Reports and Trans. Path. Society.

¹⁸² "On Addison's Disease," Croonian Lectures.

¹⁸³ Die Nebeunieren und der Morbus Addison, Berlin, 1883.

¹⁸⁴ Am. Journ. Med. Sci., 1856.

¹⁸⁵ New York Med. Journal, 1856.

ETIOLOGY.—The causation of the disease is unknown. Cases are more frequent in hospital than in private practice. Males are more often attacked than females; the proportion in Jaccoud's table¹⁸⁶ is 79 to 48, and in Greenhow's¹⁸⁷ analysis of 183 good cases, 119 were males and 64 females. Under ten and over fifty years of age the disease is very uncommon; the majority of the cases occur between the twentieth and the fortieth year. Greenhow has called attention to the fact that in a number of instances the disease appears to have followed an injury, such as a blow upon the abdomen or back, and in several cases caries of the spine has preceded the attack. He refers also to the greater frequency of the disease in the laboring classes and those exposed to injury from over-exertion. The disease does not seem to be more prevalent among members of phthisical families, although the morbid process in the glands has been regarded as of a tuberculous nature, and it is common for other tuberculous lesions to occur in the course of the disease.

¹⁸⁶ Dictionnaire de Médecine.

¹⁸⁷ Op. cit.

The disease is rare in America—apparently much more so than in England.

SYMPTOMS.—In the words of Addison, the leading and characteristic symptoms are: "Anæmia, general languor and debility, remarkable feebleness of the heart's action, irritability of the stomach, and a peculiar change of color in the skin occurring in connection with a diseased condition of the suprarenal capsules."

Although, perhaps, not the most essential, the symptoms pertaining to the skin are in the majority of cases the most prominent, and have given rise to the names bronzed skin, melasma suprarenale, etc. which have been applied to the disease. A gradual increase in the pigment of the rete mucosum, either patchy or diffuse, causes a gradual discoloration, which may ultimately reach such a degree that a previously blonde individual may have the aspect of a Malay or a mulatto. The grades of coloration may range from a light yellow to a deep brown, or even black. In some instances there is a greenish-brown tinge, to which the term bronzed is peculiarly applicable. In typical cases it is diffuse over the whole surface, but as a rule deeper on exposed parts, face, neck, and hands, and also in those regions where the normal pigmentation is most intense, nipples, scrotum, and penis, or in the vicinity of cicatrices or regions of chronic irritation. It is usually first noticed on the face, either diffuse or in spots, and the extension may be rapid or gradual, in many instances not reaching a high grade and not becoming universal. It may be absent, and is not to be regarded—as was formerly the case—as an essential feature of the disease. Patches of leucoderma may occur in connection with the pigmentation, as beautifully delineated in Pl. xi. of Addison's monograph. The pigmentation is not confined to the skin, but may extend to the mucous surfaces—mouth, conjunctivæ, vagina. In the mouth the patches may be as dark as in the dog; they are usually scattered, often on the margins of the lips and on the edges and under surface of the tongue and on the cheeks. The conjunctivæ are less often affected. The vagina may be very deeply pigmented. An intensification of the choroidal pigment has been observed. In some cases a patchy pigmentation of the serous membranes has been found, and is figured in one of Addison's original plates, and pigmentation of the nails, hair, and teeth may also occur. A variation has been observed in the intensity of the coloration with the general health of the patient. The discoloration rarely precedes the general symptoms, but more usually follows the asthenia.

Some observers have noted a peculiar odor of the breath and from the skin, particularly during the last few days of life.

Anæmia of a moderate degree may exist, but it is not, as often stated, a constant symptom. Greenhow states that "there is no real anæmia, the blood being often rich in red corpuscles, even in excess, and there is no increase in the white." No special alterations in the appearance of the corpuscles have been noted. In some instances free pigment has been found.¹⁸⁸ In a case recently at the hospital of the University of Pennsylvania, Hughes found the number of red corpuscles over five millions per cubic millimeter, and there were free pigment-granules in the blood.

¹⁸⁸ Corput, Gazette hébdomadaire, 1863.

Hemorrhages are rare; extravasations into the retinæ have not, so far as I can ascertain, been observed, nor are there often the other common features of anæmia.

The pulse is frequent and small, the heart's action weak—sounds clear; a venous murmur may sometimes be heard. In some cases there appears to be a special enfeeblement of the heart and a liability to fainting attacks, and without any warning a fatal syncope may occur. Cold feet and hands result from the weak circulation, and may be a most annoying symptom.

Symptoms in connection with the respiratory system are not common. There may be dyspnoea, and the complication of phthisis may give rise to all the features of that disease. There may, however, be extensive lung trouble with but few symptoms. The temperature is rarely elevated, more often it is subnormal.

Gastric disturbances are very common—anorexia, nausea, vomiting—particularly toward the close, but they may be early and prominent features, persisting in spite of all remedies and proving the most formidable symptoms of the malady. They appear to be of nervous origin, and not referable to changes in the organ itself. It is doubtful if the case reported by Gilliam,¹⁸⁹ in which there was degeneration of the gastric mucosa, was Addison's disease. The state of the bowels is variable; constipation is more frequent than the normal condition. Diarrhoea is common, and may come on suddenly without obvious cause, and is a not infrequent cause of death.

¹⁸⁹ Phil. Med. and Surg. Reporter, xxiv.

The urine is usually pale, free from albumen, not often increased in amount. It is interesting to note, in connection with the involvement of the abdominal sympathetic, that in a few cases there has been polyuria. The nitrogenous elements may be greatly reduced, the urea to 13–20 grammes daily, and the amount of indican may be increased as much as 64–75 milligrammes in 1000 c.c. (Samuel). In one case Thudichum found the urinary pigments greatly reduced in amount, the uromelanin not amounting to more than one-twelfth the normal quantity. A recent observation of Nothnagel is of interest.¹⁹⁰ In a patient aged twenty, who had the typical symptoms of the disease for two years, death took place by coma and the condition of acetonuria was determined.

¹⁹⁰ Zeitschrift für klin. Med., Bd. ix.

The symptoms connected with the nervous system are the most prominent in the disease, and are more constant than the anæmia or the bronzing. The most marked is a depression and enfeeblement of the nervous forces, a profound asthenia out of all proportion to the general condition. The patients complain of a lack of energy, mental and bodily; the least exertion is an effort, and there is a feeling of tire and weariness with which the facial expression is quite in keeping. The fainting fits, giddiness, noises in the ears, may also be due to faulty innervation, as they occur in cases in which the anæmia is by no means advanced. Headache, lumbar and abdominal pains are frequent, and in a considerable proportion of cases there is tenderness on pressure in the lumbar region. With the advance of the disease the prostration becomes more marked, the patient remains in the recumbent posture, the voice gets weak and small, the intelligence dulled, and occasionally there is delirium. Head symptoms may suddenly supervene, and death by coma or convulsions cut short the progress even early in the disease (Pye-Smith). In Jaccoud's series convulsions were noted in 19 cases.

The disease may be said to be invariably fatal, but the course presents many variations. The majority of cases die within eighteen months of the first onset of the symptoms. B. Fenwick, in an analysis of 30 recent cases,¹⁹¹ calls attention to the fact that when bronzing does not occur the course is more rapid. Thus the average duration of the non-bronzed cases was only 4.8 months, while for bronzed ones it was 23.6 months. There are acute cases in which, with great weakness, vomiting, and diarrhoea, the fatal end may occur in a few weeks. Some of these rapid cases resemble typhus. Syncopal attacks, coma, or convulsions cut short not a few cases. In a few instances it is much prolonged—six years (Niemeyer) or even ten years (Greenhow). Whether recovery ever takes place is doubtful. Finney¹⁹² has reported an apparently genuine case which got well. Some French observers (Potain) think that recovery takes place more often than is supposed. Sir Wm. Gull mentioned a case of recovery.¹⁹³ Periods of improvement lasting many months may occur.

¹⁹¹ Path. Soc. Trans., vol. xxxiii., London.

¹⁹² Dublin Med. Journ., April, 1882.

¹⁹³ Int. Med. Congress (London) Transactions, vol. ii.

MORBID ANATOMY.—The panniculus adiposus and subperitoneal fat may be in normal quantity. There is rarely great emaciation, nor are the organs blanched and bloodless. The most constant lesion is in the suprarenal organs, which present a caseo-fibrous change, more rarely simple atrophy or other alterations. So frequent is the caseo-fibrous condition that some writers (Wilks) hold that it is the specific lesion of the disease. The organs are enlarged—may weigh several ounces each. The capsules are thickened, and may present caseous or even calcareous masses. The normal shape of the gland is lost, and it forms an irregular nodular mass closely adherent to contiguous parts—liver, kidney, and cava on the right side, kidney, spleen, and often pancreas, on the left. There is usually a good deal of fibrous thickening and matting in the vicinity, and the adhesions to adjacent structures may be very strong. The peritoneum often shows patches of fibroid induration. On section the diseased organ cuts with great resistance, and to the touch has an almost cartilaginous hardness. The exposed surface shows caseous masses of a yellow or grayish-white color, varying in size from a pea to a walnut, imbedded in a grayish semi-translucent fibrous tissue, pale when first cut, becoming reddish on exposure. These caseous masses may undergo softening or calcification, and pockets of pus are not uncommon. Definite small miliary granulations are not often seen, though nodular grayish-yellow bodies the size of small peas may occur. The strands of fibrous tissue which separate and enclose the caseous masses have often a very peculiar translucent, infiltrated appearance. When the cheesy lumps are small, the amount of this tissue is considerable and gives a remarkable character to the section. Wilks has described a case in which this tissue made up the entire mass. The substance of the gland is usually destroyed. The vessels and nerves can be traced to the organs where they become imbedded in the fibrous tissue.

Histologically, the soft translucent tissue consists chiefly of spindle-shaped fibre-cells, and in firmer older parts of ordinary fibrous stroma. In the immediate neighborhood of the cheesy masses there are round corpuscles—about the size of or a little larger than white blood-cells—imbedded in a fine reticulum of fibres. Giant-cells are sometimes found, but they have not been common elements in the specimens which I have examined. The caseous substance consists of granular débris in which the remains of cells and fibres can be seen. In coarse and microscopical features the lesion resembles closely local tubercular affections. The extension is by a small-celled growth, which gradually invades the adjacent parts, extending peripherally as the central portions caseate. Distinct miliary granulations are not often met with. The relation of this local growth to tuberculosis is a very interesting question. It is usually regarded as a scrofulous or tuberculous process, to which in its general features it quite conforms. I have been interested in ascertaining whether the bacillus tuberculosis existed or not in the local lesion. In Cohnheim's laboratory Karl Hüber kindly gave me an opportunity of examining the adrenals in two cases, in only one of which were the bacilli evident. Since then I have re-examined the fibro-caseous tissue in Ross's case,¹⁹⁴ which was a most typical one, the suprarenals alone involved, and in the recent case reported by Pepper,¹⁹⁵ and in neither have I been able to demonstrate bacilli. Future examinations must decide whether the local affection is inflammatory or whether it belongs to the infective granulomata.

¹⁹⁴ Can. Med. Assoc. Trans., vol. i., 1877.

¹⁹⁵ Phila. Med. Times, 1885.

That other alterations may occur in cases of Addison's disease appears well established, though some still regard the caseo-fibrous change essential and specific. Atrophy of one or both glands has been frequently seen. Jaccoud gives 7 cases in his tables. Good recent cases have been described by W. B. Hadden,¹⁹⁶ Hebb,¹⁹⁷ and Goodhart.¹⁹⁸ The atrophy is due to a chronic interstitial process similar to cirrhosis of the liver. Hadden¹⁹⁹ states that the lesion is identical with that in the thyroid gland in myxoedema.

¹⁹⁶ British Medical Journal, 1885.

¹⁹⁷ Lancet, 1883, i.

¹⁹⁸ Path. Soc. Trans., 1882.

¹⁹⁹ Loc. cit.

Absence of one or both the capsules has been noted by Legg, Spender, Borland²⁰⁰ and Hubbard.²⁰¹

²⁰⁰ Boston Med. and Surg. Journal, 1867.

²⁰¹ Proceedings of Conn. Med. Society, 1868–71.

Cancer of the adrenals, by no means uncommon as a secondary process, rarely produces any special symptoms; but there are cases which are difficult to exclude from the category of Addison's disease. Jaccoud gives several, and in the case of Edes, often quoted,²⁰² the asthenia and discoloration may have been due to the capsular affection, but there was also extensive peritoneal cancer.

²⁰² Boston Med. and Surg. Journal, 1878.

By far the most constant morbid change after that in the adrenals is a more or less widely distributed tuberculosis, particularly of the lungs. A very considerable proportion of the cases are complicated with chronic phthisis. Regarding the disease of the suprarenals as primary, the general tuberculous affection may be secondary; and it is just in these organs, as Weigert has shown, that the veins are apt to be perforated by tubercles and systemic infection induced. The retro-peritoneal and mesenteric lymph-glands may also be tuberculous. Ulcers of the ileum may occur, and swelling of Peyer's glands and the solitary elements in the bowels is very common. In Ross's case there were numerous lymphoid infiltrations of the mucosa of the stomach, chiefly about the pylorus and cardia. The changes in the skin are confined to an increase of the pigment in the cells of the rete mucosum, most pronounced in the deeper layers and in the deeper parts in the connective-tissue cells of the papillæ and subcutaneous tissues. The condition is not to be distinguished from a deeply-pigmented scrotum or from the dark skin of the negro. The pigment resembles the ordinary coloring matter of the skin, but is possibly different from it in containing no iron.²⁰³ Nothnagel has made²⁰⁴ an exceedingly interesting study of the pigmentation in Addison's disease, and concludes that it is identical in distribution with that in the skin of the dark races; that it does not originate in the cells of the rete mucosum, but is elaborated in deeper cells, about the vessels of the cornium, and transported by them to the more superficial layers—a mode which recent observations seem to show is the normal one; and, lastly, that it is a process induced through the nervous system in some way as yet unknown.

²⁰³ Arnold, Virchow's Archiv, xxxv.

²⁰⁴ Loc. cit., Bd. ix.

The spleen has been found enlarged. The thymus gland may also persist or be much larger than normal. In Ross's case it weighed six ounces. The heart and blood-vessels do not present any constant changes: the heart has been found small in some cases. Venous engorgement of the abdominal viscera has been noted in a few cases, but it is not a common feature. It was not present in two typical cases which I have examined.

In the nervous system the condition of the abdominal sympathetic has received special attention, and in a number of cases definite changes have been met with, chiefly of a sclerotic or chronic nature and intimately associated with the fibroid induration about the capsules. The nerve-cells of the semilunar ganglia are described as degenerated, deeply pigmented, and often present a new growth of connective tissue about and between the cells. There are at least thirty or more cases in which such alterations have been found. In some instances the medulla of the nerves passing from the ganglia has been found wasted and the fibres in a state of fatty degeneration. In some cases these parts have been found normal (Foa,²⁰⁵ Huber,²⁰⁶ Hebb,²⁰⁷ and Hadden²⁰⁸). In a most typical case under Ross at the Montreal General Hospital, I could find no differences in the cells and nerves, comparing them with those of a woman dead on the same day of heart disease. More recently, I have examined a case for Pepper in which the right semilunar ganglion was imbedded in the sclerotic tissue of the right adrenal; the nerve-cells were undergoing atrophy from compression; and there were fatty changes and degenerations in the nerves connected with this ganglion. The left was uninvolved, and the cells and fibres appeared normal.

²⁰⁵ Virchow-Hirsch, 1879.

²⁰⁶ Virchow's Archiv, 86.

²⁰⁷ Lancet, 1883, i.

²⁰⁸ Loc. cit.

Jacquet has described pigmentary changes in the ganglia of the cord as well as in those of the abdomen, and Guermonprez²⁰⁹ alterations in the brain similar to those of senile dementia. At the Congress in 1881 at London, Semmola of Naples showed a figure illustrative of degeneration of the ganglia of the abdomen, and also an infiltration of leucocytes in the neighborhood of the central canal of the cord, from a case of Addison's disease without affection of the adrenals.

²⁰⁹ Quoted by Burger, loc. cit.

PATHOLOGY.—The suprarenal organs are usually grouped with the blood-vascular organs. From the number of nerve-fibres—sympathetic, pneumogastric, and even phrenic—passing to the medullary part, and from the presence of cells resembling nerve-corpuscles, Leydig and others have thought that this portion belonged to the nervous system. We know absolutely nothing of their functions. They do not appear to be essential to life, but may be removed, crushed, or destroyed with impunity, though the operation is not without danger from their close proximity to important structures. They are sometimes congenitally absent. They are proportionately larger during foetal life, but they do not appear to atrophy as age advances; indeed, it would appear from the observation of Mattei (Jaccoud) that they augment in volume with increasing years. Their chemistry has attracted much attention. Vulpian has described a material which gives a green, blue, or black color with perchloride of iron, and with oxidizing substances a rose-red; and the same observer found also hippuric and taurocholic acids. Leucin, margarin, myeline (Segilsohn), and a special coloring matter (Arnold), have been described. Henle has pointed out that the central part in the horse became of a rich brown with bichromate of potash from the reduction of the brown oxide of chromium. MacMunn's²¹⁰ observations on the spectroscopic appearance of the pigment of the suprarenals point to these glands as in some way concerned with the transformation of the effete coloring matters of the body.

²¹⁰ Paper read before the Physiological Society of London, Journal of Am. Med. Assoc., 1885, March 21.

An immense number of experiments have been made with a view of ascertaining the function of these bodies, and extirpations, crushings, etc. have been made—among others by Brown-Séquard,²¹¹ Gratiolet,²¹² Phillipeaux,²¹³ Harley,²¹⁴ Nothnagel,²¹⁵ the general result of which appears to be that they are not important organs and that they have no influence in the production of pigment. Recently, Tizzoni²¹⁶ has stated—as Brown-Séquard had done—that pigmentation followed extirpation in the rabbit; but there is a large amount of negative evidence by most careful observers; as, for example, Nothnagel, who found no changes in 153 animals in which he had destroyed the suprarenals.

²¹¹ Archives générale, 1858.

²¹² Ibid., 1856, ii.

²¹³ Ibid., 1858.

²¹⁴ Med.-Chir. Review, vol. xxi.

²¹⁵ Zeitsch. f. klin. Med., Bd. i., 1879.

²¹⁶ Lancet, 1884, ii.

Various attempts have been made to explain the phenomena of the disease, to two or three of which we shall refer:

1st. That the disease is directly dependent upon destruction of the capsules and consequent abnegation of their functions. This was the view of Addison, and it appeared to be supported by the experiments of Brown-Séquard (performed shortly after the publication of Addison's memoir), who held that after extirpation of the glands pigment accumulated in the blood; which he explained on the supposition that their function was the disposal of a material in the blood readily converted into pigment. Subsequent experiments appear to have demonstrated conclusively that, like the spleen, the adrenals are not necessary to life, and that no important changes occur after their removal, or even after the induction of caseous and fibroid induration (Nothnagel). A much stronger argument against this view is found in the fact that cases have been reported in which the capsules presented little or no change.²¹⁷ Taylor²¹⁸ held that the pigmentation was induced by destruction of the cortical part of the organs, and the general nervous phenomena by involvement of the central part, which has such close relation with the nerve-structures. This view has again been advanced by B. Fenwick.²¹⁹

²¹⁷ Care must be exercised in the examination of apparently normal capsules. There may be extensive small-celled infiltration and destruction of the gland-elements without either reduction or increase in size.

²¹⁸ Loc. cit.

²¹⁹ Path. Soc. Trans., xxxiii., 1882.

2d. That it is an affection of the abdominal sympathetic system, induced, most commonly, by capsular disease, but also by other chronic affections which implicate the solar plexus and its ganglia. Addison hinted at this explanation, and had the ganglia examined in one of his cases, but Schmidt of Amsterdam (1859) was the first to point out the possible connection and to record a case. Many corroborative observations have since been made, and this view has the support of the leading authorities. The changes which have been met with are very varied—fibroid thickening of the sheaths with atrophy of the nerve-tubes, fatty degeneration and wasting, excessive pigmentation of the cells, myxomatous degeneration of the stroma of the semilunar ganglia, and in a few instances there have been changes in the spinal cord. The chronic caseo-fibrous process in the capsules seems specially prone to involve contiguous tissues, and the close proximity of the semilunar ganglia renders them more liable to be attacked by the sclerotic process than in other affections in the vicinity, such as aneurism or tumors. According to this view, the symptoms of Addison's disease are to be regarded as the expression of a severe nutrition disturbance caused by a morbid state of the sympathetic ganglia, or, as Semmola puts it, the entire affection, beginning with disturbance of digestion and running its course with asthenia, low temperature, and marked debility in the oxidation and nutritive processes, is a pathological demonstration of the physiological functions of the sympathetic ganglia. The pigmentation may have its origin in changes in the trophic nerves, and the pronounced debility is the outcome of the disturbed chemical activity in the tissue-elements. It is, in short, a disease of the nervous system of organic life. Greenhow, who is a strong advocate for this view, also thinks that the circulatory, respiratory, and digestive symptoms may in part be due to implication of the pneumogastrics, the peripheral branches of which are frequently involved in the thickened tissues about the capsules. The feeble action of the heart, small pulse, the nausea, vomiting, and the gasping respiration, may arise reflexly from irritation of these branches.

There are about thirty cases on record in which changes have been found in the sympathetic system. Riesel²²⁰ compares the symptoms of Addison's disease with those which follow extirpation of the semilunar ganglia in animals. There is a paralysis of the vaso-motor nerves of the abdominal viscera, induced either by degeneration of the ganglia or reflexly by irritation, and consequently the blood accumulates in these parts, and there is a corresponding spanæmia of other organs, which explains the weak circulation, anæmia and the heart symptoms, fainting, and loss of energy. Recently this theory has been advocated by F. P. Henry.²²¹

²²⁰ Deutsches Archiv f. klin. Med., Bd. vii.

²²¹ Philada. Med. Times, 1885, No. 452.

The occasional occurrence of pigmentation of the skin in abdominal tuberculosis, retro-peritoneal tumors, cancer of pancreas, and in uterine irritation lends support to this view.

The weak points of this view are—the doubtful nature of the changes in the ganglia and the nerves in many cases. Mere increase of the normal pigment, slight fatty degeneration or swelling, so often recorded, should not be regarded as important, for they occur under a variety of conditions. Of positive swelling and redness of the ganglia, fibroid atrophy with destruction of nerve-cells and degeneration of the nerve-fibres, there can be no doubt, but about less marked alterations opinions will differ whether they are truly morbid or not. The fact that in certain well-observed cases the ganglia and nerves were found normal is hard to reconcile with a theory that the disease is an affection of the abdominal sympathetic. Burger states²²² that there are nine cases in which changes could not be found, and there are the recent cases of Huber,²²³ Hebb,²²⁴ Foa,²²⁵ and Hadden.²²⁶

²²² Loc. cit.

²²³ Virchow's Archiv, Bd. lxxxviii.

²²⁴ Lancet, 1883.

²²⁵ Virchow-Hirsch, 1879.

²²⁶ Brit. Med. Journ., 1885, i.

Hale White's recent observations,²²⁷ as well as those of Saundby,²²⁸ on the histological changes in the sympathetic clearly show that many of the changes which have been described in cases of Addison's disease are common in other affections, and have probably no direct association with the characteristic symptoms of the malady.

²²⁷ Ibid.

²²⁸ Ibid., 1883, i.

Then, again, the absence of the characteristic symptoms of Addison's disease in so many cases in which the matting and implication of the nerves seems quite as great as in capsular disease. In aneurism of the abdominal aorta in the neighborhood of the coeliac axis the tissues in the vicinity may be indurated and cicatricial, the semilunar ganglia compressed, and the nerve-fibres atrophied, without bronzing and without the constitutional symptoms. Cases, too, of retro-peritoneal cancer rarely induce pigmentation, though in some instances—as in a case of Paget's (Geo.),²²⁹ in which there was extensive lymphadenosis with involvement of the abdominal sympathetic—the bronzing may be intense. Induration about the pancreas and stomach in cancer has induced the same change, and recently Jürgens has recorded a case of aneurism²³⁰ of the abdominal aorta with symptoms of Addison's disease and degeneration of the sympathetic nerves.

²²⁹ Lancet, 1879, i.

²³⁰ Berliner klin. Woch., March, 1885.

3d. That the essence of the disease is to be sought in some injurious agent—a poison introduced from without or possibly arising within the body as a result of faulty metabolism. There is not the slightest evidence for the existence of any such specific poison, which Averbeck, in his monograph, brings forward to account for the anæmia and the local disease in the capsules.

A more plausible theory, one closely related to the first one mentioned, is that the blood is gradually poisoned by the retention of some material the destruction or alteration of which it is the function of the adrenals to effect. The disease is in this view analogous to chronic uræmia.

The relation of affections of the thyroid gland to myxoedema and cretinism, and the experimental production of these conditions by the removal of the thyroid, have widened our view of the importance of the ductless glands. It is interesting to note the analogy between myxoedema and Addison's disease. In both there are distinct histological changes in the tissues—in one an increase in the mucin, in the other an increase in the pigment—and in both marked nervous phenomena: mental dulness, a progressive dementia in myxoedema, a profound asthenia in Addison's disease. We regarded the thyroid as unimportant to life until the experience of surgeons and extirpation in monkeys by Horsley demonstrated that abolition of its function was followed by a serious train of symptoms; and perhaps the experimental removal of the suprarenals in monkeys—so much more closely allied to man than the animals hitherto experimented upon—may demonstrate that these little bodies are also not without their influence upon health.

Although the view of disturbed innervation consequent upon involvement of the abdominal sympathetic meets the case, theoretically, better than any other, and is at present widely held, yet there are signs of a return to the old view of Addison, which has been so consistently advocated by Wilks.²³¹ The data are not yet forthcoming for a final decision of the question, but it is possible that future investigations may establish the truth of Addison's view, that suspension of the function of the glands is the essential factor in the causation of the disease. That the sympathetic may be normal in genuine cases, and again that all the symptoms of the disease may occur without affection of the adrenals, are, however, facts difficult to harmonize with either theory.

²³¹ Discussions at Pathological Society of London, session 1884–85.

DIAGNOSIS.—It is of the first importance to remember that an increase in the pigment of the skin is by no means confined to Addison's disease, and, on the other hand, that the constitutional symptoms may be present without a trace of bronzing; and in their absence a positive diagnosis cannot be made. The conditions which give rise to a deepening of the color of the skin are—(1) Abdominal growths, tubercle, cancer, lymphoma. The patches of pigmentation in such cases are usually scattered, most often about the face and forehead. Occasionally the pigmentation may be deep and extensive, as in one case I saw of abdominal tuberculosis believed to be Addison's disease. Guéneau de Mussey²³² has called special attention to the frequency of this complication in chronic tuberculous peritonitis. Pigmentation may also be on the mucous surfaces in these cases. (2) Pregnancy, in which the discoloration is usually limited to the face, the so-called masque des femmes enceinte, and which, it is to be remembered, does not always disappear with the pregnancy. Chronic uterine disease, especially fibro-myoma, is a very common cause of patchy melasma. (3) Hepatic disease, which may induce definite pigmentation as well as the yellow-brown color of jaundice. Overworked persons of constipated habit and sluggish livers may present a patchy staining about the face and forehead. (4) The vagabond's discoloration, caused by the irritation of lice and dirt, may reach a high grade, and has been mistaken in several instances for the pigmentation of Addison's disease. (5) In rare instances there may be deep discoloration of the skin in connection with melanotic cancer—so deep and general that it has been confounded with melasma suprarenale. Wagner,²³³ Wickham Legg,²³⁴ and Falls²³⁵ have described remarkable cases of the kind. The occurrence of melano-sarcoma of the choroid or skin should render the diagnosis in these cases easy enough, but if deep seated a difficulty might readily occur.

²³² Étude sur la Pigmentation de la Face dans la Tuberculose abdominaire, Paris, 1879.

²³³ Archiv der Heilkunde, Bd. v.

²³⁴ Path. Soc. Trans., London, vol. xxxv., 1884.

²³⁵ Philada. Med. Times, 1883.

It must be borne in mind that there are cases without bronzing, in which the profound asthenia and gastric symptoms are the prominent features, and, as mentioned above, these cases seem to run a very acute course. Indeed, they have been mistaken for typhus.

TREATMENT.—As cure is out of the question, the treatment is symptomatic and directed to the avoidance of certain perils associated with the disease. We have no means of checking the progress of the capsular affection. Pepper advises counter-irritation, and in the early stages the cautery may be used. Rest of mind and body must be enjoined, and the dangers of exertion and exhaustion set before the patient. Even in the early stage fatal syncope may occur.²³⁶ The sense of weakness and tire at times becomes greatly aggravated, and may deepen into attacks of the most profound asthenia, during which the patient should be strictly confined to bed. It is in these paroxysms that special dangers occur. General tonic measures must be employed for the support of the strength. When there is anæmia, iron may be given, and Greenhow speaks of the good effects of the citrate or perchloride given with glycerin. Arsenic, strychnia, phosphorus, have been found useful in individual cases. Galvanism has been used, but without much benefit. The paroxysms of profound asthenia call for stimulants—wine, brandy, and ammonia. The gastro-intestinal symptoms require the most careful treatment. Bismuth, hydrocyanic acid, creasote, soda-water, ice, and champagne will be found useful in allaying the vomiting and irritability of stomach, but in some cases these symptoms prove most intractable. Purgative medicines must be given with very great caution on account of the liability to profuse diarrhoea and serious collapse. The constipation, which may be obstinate, is best treated by mild enemata. The greatest care should be exercised in the diet, which should be plain and easily digested. Though the vomiting is not directly dependent upon the state of the stomach, yet indigestible food and irregularities in eating may induce the gastric attacks. When there is much irritability of the stomach the patients seem to do best on a strict milk diet.

²³⁶ Quite recently an active professional man consulted me for bronzing of the face and hands, and he had had one fainting spell. With the concurrence of Pepper he was advised to give up business for a year and live quietly abroad. His general condition was so good and the pigmentation so limited that there seemed just a possibility that it was not Addison's disease. He went home and prepared to follow out our advice, but a second sudden attack of syncope proved fatal.

OTHER DISEASES OF SUPRARENAL BODIES.

ANOMALIES.—There may be four glands, two on each side. More commonly, there are small supplementary organs—glandulæ succenturiatæ—situated in the neighborhood, seldom reaching the size of a pea. Grawitz has recently shown that many of the small adenomas of the kidney are in reality minute portions of suprarenal tissue which have become included in the course of the development of these organs. Fusion of the two glands has been observed (Klebs). They may be absent.²³⁷

²³⁷ Defect of adrenals is very rare. There are not a few observations in which it is stated that the right gland was absent. Now, if the examination is not made with care, and particularly if the liver is removed first, the right gland may be taken away with it closely lodged in the fossa suprarenalis, and so escape observation. Time and again have I directed the attention of the student making the autopsy to the right adrenal on the under surface of the liver.

It is curious how liable the suprarenals are to anomalies in position or form in connection with defective development of the brain and cord. In anencephalous monsters the glands may be absent or very small.²³⁸ In one instance I found them normal in size, but they were below, not above, the kidneys.

²³⁸ Lomer, Virchow's Archiv, Bd. xc.; Weigert, ibid., Bd. c.

ATROPHY.—Extreme wasting may be met with as an accidental circumstance: there may be only a trace of gland-tissue left. Several such specimens have been found in association with Addison's disease. There may be an interstitial growth of fibrous tissue, cirrhosis, with shrinking of the organ. More often the glands are larger and harder in connection with the cyanotic induration of heart disease. It is stated by some writers that the adrenals of the negro are larger than those of the European races—a statement which I have not been able to confirm in several observations.

APOPLEXY.—In the new-born and young children congestion is not infrequent. Hemorrhage into the central medullary substance is by no means uncommon, either on one side or bilateral. The amount may be considerable, and the glands greatly distended, forming large tumors.

INFLAMMATION.—Suppuration is rare except in connection with the caseo-fibrous change already described as specially associated with Addison's disease. Abscesses in the vicinity, as from caries of the spine, may involve one or both capsules.

DEGENERATIONS.—Fatty changes are very common, particularly in the cortical layer, which then has a light-yellow color, instead of the normal dark gray-red. Yellow oil-drops appear to be normal constituents of the cells of the cortex.

Amyloid degeneration may occur, but only in connection with similar changes in other organs. The glands are enlarged, very firm, and the medullary part translucent. The iodine reaction shows it to be limited to the fibrous septa and blood-vessels.

The brown pigment of the intermediate zone, zona reticularis, may be greatly increased. Normally in man, the amount is very variable, and the deeper color may be due to congestion of the blood-vessels.

CYSTS with serous or hemorrhagic contents are occasionally found, chiefly in the cortical part. They may be multiple. Hydatid cysts have been met with.

TUMORS are not very uncommon. Cancer may attack them primarily, but more often they are involved in secondary growths after carcinoma of stomach or other organs. They are not infrequently affected in cancer of the kidneys by direct extension of the growth. Sarcomas are also not uncommon, and may form large masses the size of the foetal head. They may be melanotic.

These varied pathological conditions are not usually associated with any special or distinctive symptoms, and in the great majority of cases have been unsuspected during life. The organs may be totally destroyed without inducing any of the phenomena of Addison's disease. In a few cases, however, bronzing of the skin has been met with.