STUDIES ON GANGLION CELLS. FROM THE PATHOLOGICAL LABORA- TORY OF THE ALUMNI OF THE COL- LEGE OF PHYSICIANS AND SURGEONS, COLUMBIA UNIVERSITY, NEW YORK. By JAMES EWING, A. M., M. D., Clark Fellow in Pathology. WITH SIX PLATES BY THE AUTHOR. State Hospitals Press, Utica, N. Y. 1899 Monograph Publications from the State Hospitals Press, Utica, N. Y. Correlation of Sciences in the Investi- gation of Nervous and Mental Diseases, Ira van Gieson. Price, $1.00 Studies on Ganglion Cells, James Ewing. Price, $i.jo Neuron Energy and its Psychomotor Manifestations, Ira van Gieson and Boris Sidis. Price, So.jo Notes on Criminal Anthropology and Bio-Sociology, Henry Lyle Winter. Price, So.jo A Series of Experiments with the Weigert Methods—With Special Reference for Use in Lower Brain Morphology, C. Judson Herrick. Price, So.jo 576.3-616.078 STUDIES ON GANGLION CELLS.* JAMES EWING, A. M., M. D., Clark Fellow in Pathology, College of Physicians and Surgeons, Columbia University, N. Y. INTRODUCTION. Up to a period dating about ten years ago, the knowl- edge of the pathology of the ganglion cell rested upon the study of tissues hardened usually in chromic acid, and stained by carmine or by Weigert's or Golgi's methods. A rather voluminous literature had accumulated referring to changes demonstrable by these methods, and many of the grosser alterations of the ganglion cells had been accurately described and their significance partially determined. In most of the acute and chronic diseases of the nervous system the condition of the nerve cells had been studied, often exhaustively, and in many diseases affecting other organs, especially the infectious diseases, the lesions in the cells of the central nervous system had been described * A preliminary communication on these studies was read before the New York Pathological Society, February 9th, 1898. V 2 STUDIES ON GANGLION CELLS. at some length. Thus we find in such descriptions the terms, granular and cloudy swelling; pigment degenera- tion; vacuolation; colloid degeneration; shrinkage; loss of nucleus, nucleolus, and processes; increased or dimin- ished staining capacity; rupture of cell body and processes; dilatation of pericellular lymph spaces, and infiltration of this space and of the cell body with small round cells. Based upon the observation of these grosser changes the knowledge of the pathology of the ganglion cell had been very widely extended, and successfully applied in the interpretation of morbid clinical phenomena. Yet in spite of the prodigious labor steadily devoted to the subject, it cannot be claimed that any systematic basis for the classification of pathological changes in ganglion cells had been elaborated. In fact it had never been determined whether many of the changes described were the result of vital or of cadaveric processes, while it was constantly acknowledged that the described alterations were probably preceded by less marked changes not then demonstrable. Further, it had long been apparent that existing tech- nical methods failed to reveal a whole series of more delicate cytological changes which must be supposed to result from the action of powerful nerve poisons, in acute intoxications and in diseases proving rapidly fatal with pronounced nervous symptoms. The histological struc- ture of the ganglion cell was practically inaccessible to the investigator, equipped with the ordinary methods for microscopical examination of tissues. The past decade, however, has witnessed the develop- ment of a method of cytological research which has greatly enlarged our conceptions of the structure of nerve cells, and is claimed to demonstrate those finer alterations of STUDIES ON GANGLION CELLS. 3 structure which have been obliterated by other technical procedures. To determine to some extent how far these claims are justified, to ascertain in what these finer cellular altera- tions consist, and what significance may be attached to their presence, have been the objects of the present study which has occupied the writer during the past two and one- half years. Incidentally, the results bear on the relation of the nervous system to general diseases. The work has consisted in the examination of the nervous system in various diseases, by means of Nissl's and related methods, and in some experimental studies. The full report of these studies necessitates a review of the present status of our knowledge of this method of cytological research and of the cellular changes which it demonstrates. Section I. TECHNICS. In 1885 Nissl1 called attention to the fact that chromium salts destroy the finer structure of nerve cells, while pre- serving the fibres, and that if we are to demonstrate the minute structure of the cell, other hardening agents must be used. For this purpose he recommended alcohol as a fixative fluid and magenta red, dahlia, and vesuvin as staining agents. The sections of the tissues thus hardened were to be heated moderately in any of the above dyes, decolorized in alcohol and anilin oil, cleared in benzine, and mounted in balsam. By careful comparison of nor- mal and pathological brains, Nissl claimed to demonstrate pathological changes in the cortical nerve cells which had hitherto escaped detection. In 18902 Nissl recommended the use of methylene blue in watery solution instead of the dyes formerly employed. 4 STUDIES ON GANGLION CELLS. Methylene blue had already been extensively used in blood technics by Ehrlich, and had been applied by him in 1886 in the form of intravenous injections to demon- strate some of the finer details of the structure of nerve cells and especially of nerve end-organs.4 From what we now know of the great variety of appear- ances presented by the anterior horn cells of the spinal cord in disease, it is not a matter of surprise that the early experience with this method led to much confusion. All grades of intensity of stain and apparent change in struc- ture were met with under apparently identical conditions, and seemed to be referable to imperfections in the new method. Chromatophilic cells were found side by side with chromatophobic cells, and in some regions all the cells might appear chromatophilic, or, again, chromato- phobic. It was hoped to avoid some of these irregularities by improvements in fixation and staining and in 18943 Nissl published a very complex procedure for the staining by methylene blue. The tissues, not longer than twenty hours post-mortem, were to be hardened in 96 per cent alcohol, an$ sectioned without being embedded in cel- loidin. To the methylene blue solution (3.75 parts per 1000 of distil, water) was added, at the suggestion of Frank, of Wiesbaden, 1.75 parts of Venetian soap, and in this solution the section was heated until bubbles were produced. They were then decolorized in anilin alcohol, (anilin oil 10, alcohol (96 per cent) 90), until the dye ceased to be extracted. They were then placed upon a glass slide, dried by blotting paper, treated with a few drops of oil cajeput, dried again, finally treated with a few drops of benzine, mounted in benzine colophonium and heated till all benzine was driven off. The benzine colophonium was made by dissolving colophonium in a STUDIES ON GANGLION CELLS. 5 sufficient amount of benzine and allowing the fluid to settle for 24 hours, when the supernatant portion became translucent. The rationale of this method has not, so far as the writer is aware, been set forth in any of Nissl's publica- tions. All of these modifications of the original method, especially the addition of an alkali in the form of soap, tend to give clearer differentiation of the chromatic bodies, while the above mounting medium was probably devised to prevent the fading commonly observed soon after mounting sections in balsam. In the hands of various investigators the original and perfected method of Nissl has been submitted to several modifications. Rehm5 recommends immediate fixation in strong alco- hol as the most generally applicable method for nervous tissues allowing by different staining methods the demon- stration of cellular and nuclear structure as well as of fibres. Decolorization in anilin alcohol he finds necessary only in old specimens in which it clears up the deeply blue stained globules of free myelin. In other cases he prefers strong alcohol which in his hands seem to give better differentiation between nerve and connective tissue cells, the former remaining dark blue, the latter assuming a greenish tinge after staining in methylene blue. For the complete differentiation of nerve and neuroglia cells he urges the use of a counterstain, viz.: 1 per cent ale. sol. of fuchsin, in which specimens remain fifteen minutes. The use of some similar acid counterstain has also the advan- tage of demonstrating the achromatic substance of the cell body. Lenhossek6 has secured satisfactory results by harden- ing specimens in 20 per cent formalin, followed by strong > 6 STUDIES ON GANGLION CELLS. alcohol. He prefers oil of cajeput as a clearing medium. Staining for five minutes without heat in a concentrated solution of thionin he has found to give very excellent results. Sections thus stained are to be washed in water, decolorized in anilin alcohol, cleared in oil of cajeput, passed rapidly through xylol, and mounted in damarlack or in balsam. He has also secured good demonstrations of chromatic bodies by the use of saffranin, fuchsin, dahlia, and ordinary Bohmer's hematoxylin. During the past three or four years much of the reported study of Nissl's stain has been made on tissues hardened by corrosive sublimate. This chemical has been used as a saturated sol. in water or in .6 per cent salt sol., or in the form of Lang's fluid: mercuric chlor., 5 grms.; sodium chlor., 6 grms; acetic acid, 5 grms.; aq., 100 grms. All of these solutions have been reported as fur- nishing very excellent results in cytological detail, and they have been claimed in some instances to have proven superior to alcohol. Flemming1 who actively supports the fibrillar theory of the structure of ganglion cells, hardens the tissues in sublimate and stains with Delafield's or Heidenhain's iron hematoxylin. Colucci8 obtains very handsome specimens by hardening in y2 per cent picric acid in water or in alcohol, or in picric acid and sublimate. Held9 secures very instructive pictures of the ganglion cells by staining with erythosin and methylene blue. The method is as follows: The specimens are fixed by preference in Van Gehuchten's solution. Alcohol abs., 60; chloroform, 30; ac. glac, 10; or in the following sol.: Sublimate, 1; acetone, 40; aq., 100. The sections are first stained in erythosin, 1; aq. dist., 150; ac, 2 gtt.; which is gently warmed one to two minutes. They are then washed in water and stained in a special sol. of STUDIES ON GANGLION CELLS. J methylene blue, composed of Nissl's fluid (usual formula) and 5 per cent watery sol. of acetone, each equal parts. In this dye they are warmed till the odor of acetone dis- appears, then decolorized in -jL- per cent sol. of alum till the sections are red; washed in water, dehydrated in alcohol, and cleared in oil of cajeput. By this method the body of the cell appears red, the chromatic masses blue; nuclear membrane red, nucleolus blue, secondary nucleoli violet. Savdovsky1 ° expresses preference for a modification of Nissl's method devised by himself. The specimens are hardened three days in 10 per cent formalin, followed by alcohol. The sections are stained 15 to 60 seconds in 1 per cent sol. methylene blue, or better in a sat. sol. of fuschin in 5 per cent carbolic acid. They are decolorized in 1 per cent acetic acid till the gray and white matter appear differentiated, and finally dehydrated in absolute alcohol. Smirnoff11 hardens the tissues in alcohol as usual, but stains 10 minutes to 24 hours in a solution of toluidine blue, 1 part, NaCl .75, water 98, decolorizing in sat. alco- holic solution of eosin, thereby staining the achromatic part of the cell body. Marina12 recommends the following mixture as a fix- ative for nervous tissues. Alcohol 96 per cent, 100 cc.; formol, 5 cc.; chromic acid, 10 cgm. The tissues should remain in this fluid, frequently renewed, for about one week, after which either Nissl's or Weigert's staining methods may be successfully applied. Graf13 recommends as a specially valuable fixative for cytological study, mixtures in equal parts of sat. sol. of picric acid in water, and of formalin 5, 10, or 15 per cent. In these fluids specimens should remain from one-half to two hours and then be washed and thoroughly hardened 8 STUDIES ON GANGLION CELLS. in alcohols 30-98 per cent. As stains he prefers Heiden- hain's iron hematoxylin and Bordeaux red. For the demonstration of fibrillar structure Graf recommends the following mixture: 4 vols, oxalic acid (8 per cent); 3 vols, alcohol (95 per cent); 3 vols, chromic acid, (1 per cent). In this fluid thin pieces of tissue should remain one-half to two hours, after which they are washed in water and alcohol. The sections are to be stained in iron- hem atoxylin. Cox14 recommends the following mixtures for the demonstration of the fibrils as well as of the chromatic bodies of ganglion cells: (1) Sublimate, sat. watery sol. 30 Osmic acid, 1 per cent 10 Acetic acid (glac.) 5 or (2) Sublimate, sat. watery sol. 15 Platinic chloride, 5 per cent 15 Osmic acid 10 Acetic-glac. 5 or (3) Sublimate, (sat. watery sol.) 30 Formalin, 10 Acetic acid, glac. 5 Specimens should remain in these fluids two to three days and be washed in 60 per cent alcohol. Sections may be stained in Delafield's hematoxylin, by Heidenhain's iron hematoxylin, or by a process specially devised by this author, of which details may be found in the original article. As a decolorizing fluid, Gothard16 recommends on various grounds the following mixture, which dissolves celloidin, decolorizes the achromatic substance perfectly, STUDIES ON GANGLION CELLS. 9 and sharply differentiates the chromatic structure: Creo- sote, 50 cc.; oil of cajeput, 40; xylol, 50; absolute alcohol, 160. Rossalimo and Murawjeff,16 recommend fixation in formalin both for Nissl's stain and for the demonstration of degenerative products of myelin. They prefer a 2-3 per cent solution for the first two days, replacing this with a 4 per cent sol. in which the tissues may remain indefin- itely, to be transferred at leisure to alcohol for complete hardening and embedding. In addition to many of the fixing agents thus far enumer- ated the writer has had satisfactory results from the use of a 5 per cent solution of formalin saturated with bichlo- ride. The addition of formalin greatly accelerates the penetration of bichloride, this mixture being quite as active in this respect as Lang's fluid. After the use of mixtures containing formalin, the cells will be found to stain darker than usual, and to require rather longer decolorization in alcohol. In specimens fixed by this agent, the chromatic network of the small cortical cells appears more distinct than after fixation by most other methods, and the usual tendency to fade has been entirely lacking in specimens now a year old. These effects may all be referable to the distinct action of for- malin as a mordant for basic dyes. Formalin alone in 10 per cent sol. has given very excel- lent results in the writer's experience. This fluid pene- trates with considerable rapidity, and shrinkage of the cell from subsequent hardening in alcohol has been almost entirely lacking. Thin sections are necessary when examining tissues hardened by this agent. In most of the later cases in the present series, Van Gehuchten's fluid was the hardening agent employed; IO STUDIES ON GANGLION CELLS. (absolute alcohol, 60; glac. acetic, 10; chloroform, 30); and the results were usually satisfactory. There are, however, objections to the use of such an acid as glacial acetic in the study of nerve cells, as this chemical penetrates in advance of the other ingredients of the mixture, and when used alone transforms nervous tissue into a swollen, gelatinous mass. A very short experience in the use of Nissl's stain fur- nishes convincing evidence that this field of pathological research is largely a study of microscopical technics. The » almost infinite variety of appearances presented by nerve cells treated by this method and its modifications, has left the subject, even after the labors of a decade, in a state of considerable confusion. We meet on the one hand with the denial by Trezebinski,17 Kronthal,18 Fisher,19 Held,9 and others that the chromatic masses, the principal ele- ment demonstrated by Nissl's method, exist as such in the living cell, these investigators claiming that they are the artificial products of fixative agents and cannot be seen in fresh specimens or in frozen sections. Held furnishes apparently undeniable proof that the minute structure of the chromatic bodies may be altered at will by varying the strength of the alcohol in which the tissues are fixed, and the same writer finds that chromic acid in 2 per cent solution precipitates the chromatic substance in finely granular condition, and in 1 per cent solution causes it to appear nearly homogeneous, while a solution of ammonium bichromate leaves it entirely homogeneous. These and similar observations indicate merely that the chromatic substance exists in the cell in fluid form, and while we are dealing in the hardened section with an arti- STUDIES ON GANGLION CELLS. II fact, it seems probable that it is an artifact that under uniform conditions will give a uniform appearance. It does not seem, therefore, to be a matter of prime impor- tance in the choice of a fixative agent, whether it fixes the chromatic substance in fine or coarse granules or in a homogeneous mass. A much more difficult question in technics is encount- ered in the diffuse dark blue stain presented by many cells after treatment with methylene blue and denominated by Nissl "the chromatophilic condition." It has been claimed by Flesch and Koneff20 that this quality is a normal char- acter of the cell, indicating a distinct physiological con- dition. Nissl81 very early and rightly, as it seems, concluded that this character is artificial, and is devoid of pathological significance, resulting from accidental and as yet undetermined effects of hardening agents or from post mortem change. In the writer's specimens prepared after hardening in Lang's fluid the chromatophilic cells were found in greater numbers than in those tissues hardened in alcohol, especially in the outer zones of the blocks of tissue. On various grounds it seemed probable that the acetic acid in Lang's fluid, which penetrates in advance of the bichloride, might be responsible for this peculiarity—a suspicion which was proved to be at least partially correct by the following experiment. A small segment of the medulla of a fresh case was subjected for 24 hours to the action of a 5 per cent sol. of acetic acid, as found in the composition of Lang's fluid, it was then hardened in alcohol, and sections 15^ in thickness were stained in the usual way. The cells without exception were found stained darkly and diffusely blue, separate chromatic bodies being distinguishable in a very few in- stances only. An adjoining segment from the same 12 STUDIES ON GANGLION CELLS. medulla hardened in alcohol gave very few chromatophilic cells. The writer, therefore, discarded the use of Lang's fluid as a fixative agent on account of the disturbing action of acetic acid. Incidentally, the result stands at variance with the statement that immersion in weak acids dissolves the chromatic bodies as reported by Eve,82 whose ex- periments, however, were conducted on sympathetic ganglion cells. The chromatophilic condition is however too frequent in occurrence and too irregular in distribution to be always referable to a uniform cause, such as the action of fixatives. Not rarely a markedly chromatophilic cell may be seen immediately adjoining a perfectly normal cell, and such a combination is difficult to understand, on the theory of irregular penetration of fixative agents or from the action of any abnormal chemical agent spontaneously produced in the tissue after death. In the study of post mortem and putrefactive changes, to be considered later, the writer finds no evidence that the chromatophilic condition may result from such pro- cesses. In fact, in fresh nerve tissues smeared, dried and stained on a glass slide, distinctly chromatophilic cells may be found. Turner,23 has also seen them in fresh specimens examined in Farrant's solution and stained with methylene blue. From a study of the conditions under which these chromatophilic, perfectly opaque and homogeneous cells are found, the writer has been convinced that two princi- pal factors are responsible for their production: (i) If the entire thickness of an ordinary section (15—20 jit) is occupied by a compact normal cell, which is imperfectly decolorized, that cell may appear homogeneous and very darkly stained. For the majority of cells seen in any STUDIES ON GANGLION CELLS. 13 particular section of tissue do not extend throughout the section, and it is usually possible to find in every section, no matter what its thickness, some portions of cells which are excessively thin and clear, while others are very dark. (2) When the chromatic bodies have been uniformly and minutely subdivided, it may be impossible, even in comparatively thin sections, to detect these result- ing granules and the cell if fully stained, and especially if somewhat shrunken, may appear very dark and homo- geneous. The writer has rarely encountered distinct examples of the chromatophilic state which could not be referred to one or both of the above conditions. (Cf. Heimann, loc. cit. p. 319) Kreyssig,84 Trezebinski,1' and Nissl,81 have noted that as a rule the chromatophilic cells are much shrunken, leaving wide pericellular lym- phatic spaces. The formation of vacuoles has long been recognized as one of the necessary imperfections in most methods of fixation of nerve cells. Kreyssig,2 4 observed vacuoles in the majority of normal ganglion cells preserved in Mueller's fluid. From observations of Trezebinski1'" and others it appears that vacuolation is more frequent after hardening in chromium salts than with other fixatives, but its occurrence in normal specimens after fixation in alcohol and bichloride has been repeatedly noted. Yet vacuolization in any marked degree is re- garded by most authorities as of distinct pathological significance. The complete, absence of vacuoles has been noted in ganglion cells examined in the fresh condition by Kreyssig,84 Trezebinski,17 and Held,9 with whose ob- servations the writer's experience accords. Held very graphically describes and depicts their formation in fresh ganglion cells on the addition of water to the crushed 14 STUDIES ON GANGLION CELLS. tissues. He finds that fine vacuoles first appear in and about the chromatic bodies, that they swell markedly on the addition of water, and that their size and contour in hard- ened specimens varies much with the different fixatives. The writer cannot agree with the statement often seen that vacuolation may be regarded as pathological only when it is found in advanced degree. Among the present cases, extreme vacuolation when found, was always plainly referable to post-mortem processes. The study of cadaveric changes in ganglion cells indicates that vacuoles are one of the most constant of post-mortem pro- ducts; and that they frequently form in considerable numbers and of large size within a few hours, often pre- ceding other post-mortem changes. Especially when the brain and meninges are cedematous, or when the patient has suffered from general sepsis, vacuolation of cells may be expected unless the tissues are fixed very shortly (one- half hr.) after death. The above observations, as well as the circumstances under which vacuoles are usually found in stained specimens, indicate that in the great majority of instances vacuolation of ganglion cells is a cadaveric or artificial product, and in any case with the present state of our knowledge is devoid of definite pathological significance. The practical indications for the avoidance of this arti- fact are, then, the rapid fixation of material as fresh as possible, by means of a rapidly penetrating fluid of high osmotic power. A saturated solution of bichloride in nor- mal salt solution recommends itself for this purpose and in the writer's hands has given results very little disturbed by vacuolation, but its slow penetration requires that thin pieces of tissue only should be used. Formalin is also very reliable in this respect. P STUDIES ON GANGLION CELLS. iS Under many conditions, the nucleoli of ganglion cells presents spherical transparent globules often projecting from the edges of the nucleolus and frequently spoken of as nucleolar vacuoles. It is doubtful if these appearances are to be regarded as of similar character with the vacuoles of the cytoplasm. It appears more probable that they represent subdivided portions of the acidophile substance normally found at the centre of the nucleolus. This appearance of the nucleolus was observed in some degree in all the cases of the present series, but the irregu- larity of its occurrence has made it impossible to draw any conclusions as to its real nature and significance. The shrinkage caused by strong alcohol is one of the chief objections to its use in the Nissl method. Many of the instances of the chromatophilic condition are doubtless referable to this action. The appearance of large pericel- lular lymph spaces about irregularly shrunken cells and of peculiar folds in the nuclear membrane are nearly con- stant artifacts resulting from this method of fixation. So constant is this result that Lenhossek,6 ° was led to believe in the normal existence of a considerable free space about the spinal ganglion cell, an artifact which he now largely avoids by perfect fixation of fresh specimens in sublimate i; acetic 40; aq. 100, as previously adopted by Flemming. This fluid may, therefore, be recommended as a fixative in this respect. One of the chief advantages of formalin as a fixative is the usual absence of shrunken cells in tissues hardened in this agent. Besides the examination of stained sections of hardened tissues, other methods of study deserve notice in this con- nection. 1 st. The staining of living nerve cells by the intravenous injection of methylene blue as introduced by Ehrlich,4 has demonstrated some of the finer details of i6 STUDIES ON GANGLION CELLS. the fibrillar structure of sympathetic nerve cells and of terminal end-organs, and the results of this method have important influence on the views now held as to the sig- nificance of the chromatic bodies demonstrated by other methods. 2d. The study of fresh portions of nervous tissue crushed under a cover glass and stained by methylene blue as practiced by Thanhofer,8 5 Kronthal,x 8 Held,9 Turner,2 3 and others, or spread on a slide, dried by heat, or teased in salt solution, has proven of similar import. Arnold86 macerates small pieces of the gray matter for 2 to 24 hours in 10 per cent sol. of K. I. to which a few drops of Tr. Iodine are added, and examines the fresh specimens stained by eosin. 3d. The pictures furnished by frozen sections stained without the action of any fixative agent cannot be ignored in discussing the structure of the living nerve cell. By far the clearest demonstration of the cyto-reticulum, of the relation of the so-called achromatic and chromatic structures of the cell, and of the structure of dendrites, secured by the writer, has been obtained in freshly and finely teased specimens of gray matter, fixed by heat and stained by methylene blue and erythrosin. This method cannot, however, be recommended for general purposes, as the large majority of cells are destroyed and the thicker portions of the cells, especially the perinuclear region, are usually found very dense and obscure. Summary. Fixation.—To summarize the observation on technics it may be said that alcohol 95 per cent to 97 per cent is most generally used as a fixative. Its superiority consists in its convenience and the compact appearance of the chromatic structures which it insures. Its great disadvantages are STUDIES ON GANGLION CELLS. I 7 the shrinkage of cells, which is usually very annoying, and its comparatively slow penetration. The writer believes that a saturated solution of bichlo- ride of mercury in . 6 per cent salt sol. is superior to alcohol for many of the purposes of Nissl's stain, and that a saturated solution of bichloride in 5 per cent formalin (or more) is superior for the demonstration of the chromatic network. Van Gehuchten's fluid, absolute alcohol, 60; chloroform, 30; ac, 10, is to be recommended for the study of a fibrillar structure of the cell. The writer is at present using formalin 10 per cent as the initial hardening agent. Its results with Nissl's stain are good, and Weigert's staining method may also be employed after such hardening, but not always with success. The fluid recommended by Marina,18 alcohol 96, ioocc.; formalin, 5 cc; chromic acid, 10 cgm., deserves trial, as it is said to permit of the use of several staining methods. More important than the choice of any particular fixative is the care in handling the tissues, and the exclusive de- pendence upon thin pieces of tissue, 1—2 mm., which can be rapidly penetrated by all agents. Embedding.—Very thin sections, 1 \i, must be cut in paraffin. Properly hardened tissues may be cut 3—5 \i, in celloidin, which is quite thin enough for most purposes. For permanent preservation, tissues embedded in paraffin are superior. Staining.—The writer has been unable to find any ad- vantage in the addition of soap or any other alkali to the simple 1 per cent solution of methylene blue in water; nor do any of the related dyes possess distinct advantage VOL. 1—no. 3—B i8 STUDIES ON GANGLION CELLS. over methylene blue. In decolorizing it is important that the alcohol last used should be entirely free from dissolved methylene blue. There appears to be no distinct advan- tage in the addition of anilin oil to the decolorizer. Erythrosin is superior to eosin as a counter-stain and should be used after the method devised by Held and pre- viously described. Heidenhain's hematoxylin is to be recommended for the demonstration of the fibrillar struc- ture of the cell. Oil of cajeput gives clearer demonstration of the chro- matic structures than any other clearing agent. Speci- mens hardened in fluids free from acids, cleared in this oil, and mounted in Canada balsam, do not fade seriously, at least within two years. Section II. HISTOLOGY. The Structure of the Chromatic Substance. The employment of Nissl's stain at once greatly en- larged the knowledge of the histology of the ganglion cells, and although the chromatic bodies had been pre- viously seen and described by Flemming21 in 1882 and were remarked simultaneously by Benda2 8 and Nissl1 in 1885, it was entirely owing to the excellence of the tech- nical methods devised by Nissl that this investigator was enabled in a comparatively short time to propose a new classification of nerve cells based upon the character of their chromatic substances. Nissl89 divides all nerve cells into two main divisions: 1 st. The small ganglion cells, karyochromes, of which the distinguishing characters and basic staining elements are STUDIES ON GANGLION CELLS. 19 to be found in the nucleus. 2d. The larger cells, somato- chromes, of which the distinguishing characters and chromatic substances are to be found in the body of the cell. In the first division he distinguishes: 1st, as karyo- chromes, those cells containing a small amount of chromatic substance about a rather small nucleus, as in the cells of the substantia gelatinosa of Rolando, and 2d, as cytochromes those cells whose nuclei never exceed in size the nuclei of neuroglia cells, as in the cells of the granular layer of the cerebellum. In the 2d division, somatochromes, are the majority of ganglionic cells, whose distinguishing characters are found in the chromatic substance of the cell body, and of which four main groups may be distinguished. 1 st. Archyochromes (archos, network) in which the chromatic substance is found about the nucleus in the form of a fine network, often producing a longitudinal striation, as in the pyramidal cells of the cerebral cortex. 2d. Stichochromes {stichos, spindle) in which the chromatic substance is found as a series of lenticular spindles or masses composed of fine granules arranged parallel to cellular and nuclear borders, as in the anterior horn cells of the spinal cord. 3d. Archystichochromes, of which the body shows a combination of the structures of the two preceding varieties, as do the cells of Purkinje. 4th. Gryochromes (gru, granule) in which the chro- matic element is in the form of granules irregularly placed throughout the cell body, but usually forming threads or heaps, as in the cells of the corp. striatum. All types of cells may show variations in the quantity and compactness of the chromatic substance. Those in 20 STUDIES ON GANGLION CELLS. which the chromatic bodies stain intensely with methy- lene blue are indicated as pyknomorphous; those which stain faintly, apyknomorphous; while the intermediate grades are denominated as parapyknomorphous. In the chromatophilic condition the cell appears shrunken, intensely stained and almost homogeneous, the outlines of nuclei and chromatic bodies being faintly or not at all visible. This condition Nissl regards in all cases an artifact. The classification of Nissl was proposed merely as a provisional plan for the description of ganglion cells and in spite of many practical and theoretical objections to it, has been widely adopted as a temporary convenience. The objection most powerfully urged against such an early attempt at classification is the fact that in only two types of cells has the finer structure been thoroughly investigated by this and complemental methods—namely the anterior horn cells of the spinal cord, and the cells of the posterior spinal ganglia. Benda30 urges against this classification the lack of purity in the type of cells, finding many transition forms between the various groups of Nissl and more reasonably the supposition that the chromatic masses are not pre- formed elements of the cell but depend in form upon other fixed constituents of the cytoplasm. These and other similar considerations have, however, proved inadequate criticisms against a classification based upon very distinct grosser morphological differences. The further attempt of Nissl34 to connect the various morphological characters of the cell with distinct physio- logical functions has been much less successful. In only one group of cells, the stichochromes of the anterior horn of the spinal cord and medulla, does it seem probable STUDIES ON GANGLION CELLS. 2 1 that a distinct function is indicated by a particular type of cell, and as the question is summarized by Van Gehuch- ten,31 the facts at present, while not in opposition to this view, are quite insufficient to be convincing. Van Gehuchten admits that the same type of cell under like conditions always presents the same structure, as in the cells of origin of all peripheral motor nerves, the cells of the spinal ganglia, the olfactory bulb, the cornu ammonis, etc. Colucci,3 8 distrusts this particular claim of Nissl on the general ground that the data are too few to warrant a classification based on one peculiarity of the cell, while ignoring its features demonstrable by other methods, such as that of Golgi. Lenhossek,33 regards the arrangement of chromatic substance in ganglion cells as a purely empirical fact with- out known significance, and holds that we cannot begin to classify nerve cells until we know how and why structural features stand in causal relation to functional qualities. A more concrete objection is urged by Benda,30 who finds that no nucleus is composed exclusively of one type of cell, while impurity in the type is very generally observed. To these and other similar criticisms Nissl34 replies that the undoubted existence of transition forms is no essential objection to his scheme of classification; that he does not claim to have settled the whole question of the relation of structure and function, but insists only that the stichochromes of the anterior horn represent typical motor cells. The strength of this position it is impossible to deny, but it remains for future investigations to determine how far this morphological criterion may be applied to other varieties of cells. 22 STUDIES ON GANGLION CELLS. As already stated, in only two types of cells has the minute structure. been thoroughly studied by Nissl's and supplemental methods—in the stichochromes of the anterior horn of the spinal cord and the cells of the spinal ganglia. Structure of the Anterior Horn Cells of the Spinal Cord. The anterior horn cells are bipolar or multipolar cells, which vary in diameter from 60 jit to 120 \i. Their most striking feature is the arrangement of the chromatic substance in the form of irregular masses, spindles, or large granules, which are found thickly and concentrically grouped about the nucleus, lying parallel to the cell bor- ders, and drawn out into thin rods in the dendrites. Dogiel35 alone has been able to trace the chromatic bodies into the axis cylinder process, which is generally regarded as being entirely free from chromatic substance, as first noted by Benda28 in 1885. At the bifurcation of pro- cesses is often to be found a distinct triangular mass of chro- matic granules called the bifurcation cone. Often a cres- centic mass is closely applied about a segment of the nuclear membrane, and is called by Nissl the "nuclear cap," a body > that is more uniform and distinct in the bipolar cells of the posterior horn of the spinal gray matter. In the spinal stichochromes and spinal ganglionic cells the point of origin of the axis-cylinder process is marked by a crescentic area devoid of chromatic bodies. This area is absent in the ganglionic cells of the retina (Dogiel36), in Purkinje cells, and in the cortical pyramidal cells. The Chromatic Bodies.—It has been generally accepted that the chromatic bodies are composed of a conglomera- tion of fine granules, although some writers have claimed STUDIES ON GANGLION CELLS. 23 that they were occasionally homogeneous. The researches of Held must be admitted to have definitely proven that, treated with the usual fixatives, alcohol, bichloride, etc., they are usually granular, the size of the granules varying with the fixatives employed. (See discussion on technics, page 265.) Both Held and Nissl agree that in some instances the thinnest sections fail to show any granular structure in the chromatic bodies. In this connection Nissl3 7 refers especially to the finely reticulated but not at all granular structures of these bodies in the motor cells of doves and some other animals. On the question of the state of the chromatic substance in the living cell, opinions have long been at variance. Kronthal,18 in 1890, examining freshly crushed specimens of spinal gray matter, dried and stained with methylene blue, failed to find any formed chromatic bodies, although the cells were otherwise well stained. Fisher19 also con- cluded that the chromatic bodies resulted from the action of fixing fluids, while the living protoplasm of cell is homogeneous. The studies of Held9 have furnished important evidence in regard to the condition of the chromatic substance in the living cell. Examining freshly crushed specimens he was unable to find any trace of chromatic bodies in the anterior horn cells of the rabbit. Continued observation showed the appearance of small vacuoles in the cell body and the gradual accumulation about them of fine granules. Cells in this stage fixed in strong alcohol, showed the vacuoles to be located in the centres of chromatic bodies, while the granules proved to be particles of chromatic substance. He therefore concludes that the bodies of Nissl are a precipitate from a previous fluid substance 0" 24 STUDIES ON GANGLION CELLS. which is thrown down by fixing agents. The fact that the chromatic bodies become slowly visible when fresh cells are treated with a weak solution of methylene blue he refers to a coagulating or fixing action of the methylene blue. In a later article he somewhat alters this view, stating that the chromatic bodies appear in the cell within one- half hour after death, without the use of fixing agents, from a process of coagulation occurring as a part of cadaveric changes. In cells, examined within three min- utes after death he was still unable to find any traces of formed chromatic elements. He finds that 80 per cent alcohol to which has been added -^ to \ per cent of NaOH fails to precipitate the chromatic substance, which is soluble in alkalies. After treatment with alkalized alcohol the chromatic bodies may still be precipitated by the action of weak acids (after Van Gehuchten's formula, absolute alcohol, 60; chloroform, 30; ac, 10). The cadaveric precipitation, occurring generally within 12 hours after death, Held refers to the acidity of the central gray matter, which has been shown by Gescheid- len38 to increase after death. The writer has repeated Held's experiments with the fresh anterior horn cells of the rabbit, and is convinced that the chromatic bodies are homogeneous in the natural state, that they make their appearance in finely granular form shortly after death and may be demonstrated by weak solutions of methylene blue, either in the moist con- dition, or in specimens teased after Kronthal's method, or in frozen sections. Held's studies seem to have proven that the chromatic substance is originally semi-fluid, but it does not appear that this fact interferes essentially with the present views STUDIES ON GANGLION CELLS. 25 as to the significance of this constituent of the cell. On the essential point as to the location of the chromatic sub- stance in the living cell, there is no evidence to show that it differs at all from the position in which it is found in stained sections. Moreover, there is no evidence to show that the chromatic substance, whatever its nature may be, is altered in any important respect during fixation, or that it does not pre-exist in some form as a separate constituent of the cell, or that demonstrable variations in its character are not significant of vital processes in cell body. Dogiel39 claims that the mere fact that the living proto- plasm of the cell is homogeneous is no proof that the chro- matic bodies do not exist as such in the natural state, as their refractive power may be the same as that of the cell protoplasm. In his hands a very weak solution of methy- lene blue in .6 per cent salt solution stains the chromatic bodies well in 5 to 8 minutes, and yet this fluid cannot be said to kill the cell in that time, or at least is not active enough to precipitate the chromatic substance, for cilia, and spermatozoa, and various living larvae, stain well but remain active for a long time in weak solutions of methy- lene blue. There remains to be mentioned in the structure of the chromatic bodies the presence of a ground-substance in which, according to most authorities, the fine granules appear to be embedded, after staining by erythrosin and methylene blue as recommended by Held. This ground- substance appears of a violet color, and where the chro- matic granules have been dissolved by alcohol, the ground-substance remains behind unaltered. Juliusberger4 ° demonstrates this substratum of the chromatic bodies by staining thin sections in iodine green 26 STUDIES ON GANGLION CELLS. and fuchsine, after which treatment it appears identical in color with the achromatic portion of the cell body. Van Gehuchten41 speaks of the chromatic substance as an incrustation on the achromatic reticulum, and identifies the substratum of the chromatic bodies with the achro- matic reticulum. The writer's study of cells which in pathological con- ditions have lost their chromatic bodies, especially as seen in freshly teased specimens dried and stained on a glass slide, led to the same opinion that Van Gehuchten holds. An interesting and important inquiry relates to some chemical properties of the chromatic substance. As above noted, Held succeeded in dissolving this substance by weak solutions of NaOH and by concentrated solutions of lithium carbonate, and showed that it is insoluble in weak and concentrated mineral acids, such as nitric, hydrochloric, and by acetic acid. Eve,22 on the contrary, found that when sympathetic nerve ganglia were left in weak acids before hardening, the chromatic bodies disappeared, the cell staining dif- fusely pale blue. There is no apparent explanation of these entirely opposite results. Repeating the experiments of Held, the writer was unable to destroy the chromatic bodies by treatment with several mineral and organic acids, although a raggedness of outline was observed after prolonged (12 hours) exposure to strong solutions. A sat. sol. of lith. carb. also, contrary to the results of Held, did not destroy or alter the chromatic bodies of the medul- lary cells, although the tissue swelled to twice its natural size in the course of an hour. A weak solution of ammonia, however, completely destroyed all trace of chromatic substance in portions of tissue immersed in this fluid for one hour. STUDIES ON GANGLION CELLS. 27 Held found that by treatment with pepsin in a sol. of HC1, at 400 C, the cell body is entirely dissolved, leaving the chromatic masses intact. Millon's reagent he finds to have no effect upon them. Submitted to Lilienfeld's and Monti's microchemical tests for phosphorus the chro- matic bodies reacted slightly, and Held concludes that the chromatic substance belongs to the nucleo-albumens. The microchemical reactions of this substance abundantly show that it is not identical with nuclear chromatin. Benda30 regards the chromatic granules as related to the basophilic granules of Ehrlich, a supposition combat- ted by Nissl, Colucci8 and Heimann,64 and readily dis- proven by treatment of sections by Ehrlich's dyes, toward which they do not behave as strictly basophilic bodies, but show characteristic amphophile tendencies. The Achromatic Portion of the Cell.—Two opposite views are at present actively supported in regard to the structure of the achromatic portion of the cell. The presence of fine fibrils passing diametrically through the cell, with numerous anastomoses, giving often a fine reticular appearance is maintained by Nissl,4 2 Becker,4 3 Benda,4 4 Flemming,4 5 Kronthal,J 8 Lugaro,4 6 Dehler,41 Dogiel,36, 39, and many others. Becker demonstrates these fibrillar structures by Wei- gert's copper and hematoxylin stain, Kronthaleby staining freshly crushed and dried specimens with methylene blue, Flemming by hardening in chromic acid in the chrom- osmic acetic acid mixture, or with sublimate, and staining with Heidenhain's or Delafield's hematoxylin. Dogiel stains the fresh sections with y1^—\ per cent sol. of methy- lene blue, having fixed the specimens at various|intervals in picrate of ammonia, and demonstrates structures that appear to escape other methods. 28 STUDIES ON GANGLION CELLS. On the other hand Lenhossek,48 Van Gehuchten,49 Cajal,s ° and Held,9 are equally confident that the fibrillar structures described by others are not true fibres but rows of fine granules which give the achromatic substance a reticular and spongy appearance. The latest studies of Held are most convincing of the correctness of this view and that the appearances seen after the cells have been hardened in various fixatives are indistinguishable from those described by Butschli in fluid albumen treated in the same manner. It seems possible, however, that Held, Lenhossek, and Cajal, are not discussing the fibrillar structures that are demon- strated by Dogiel in the retinal cells. At any rate it is at present impossible to determine which of the two views of the structure of the achromatic part of the cell is correct. The fibrillar theory is most generally accepted, but cannot be said to be the most thoroughly supported. That the achromatic portion of the cell is nevertheless concerned in the function of con- ducting impulses appears very probable from various theo- retical considerations, among which may be mentioned that the continuation of the axis cylinder process is ex- clusively with this portion of the cell, and that this process is usually composed entirely of achromatic substance, as determined by Simarro51 and Schaffer.58 In addition to the fibrils or granules composing the achromatic substance, other larger granules of somewhat similar staining reactions have been described by Benda,3 ° Becker,43 Levi,53 and others. It has been claimed by some that these granules represent the metabolic products of the cell (Becker) and that they are increased in number after fatigue of the cell. But little attention has thus far been paid either to the existence or the significance of these elements. STUDIES ON GANGLION CELLS. 29 It falls without the scope of this article to more than mention the nearly constant presence of yellowish granu- lar pigment in the adult ganglion cells. This pigment has been shown by Rosin54 to be related chemically to fat, usually staining black with osmic acid. The presence of this variety of pigment is probably always pathological. A second variety of granular pigment not at all related to the former is found in the cells of the spinal ganglia, sympathetic ganglia, loc. ceruleus, substantia nigra, etc The development and distribution of this form of pigment has been studied at some length by several writers, recently by Pilcz,55 but the relation of the masses and granules to the other elements of the cell still remains unknown. Nucleus.—The structure of the nucleus of the ganglion cell is rather incompletely shown by Nissl's method. Methylene blue demonstrates a large vesicular nucleus, with a distinct nuclear membrane, a large central nuceolus and occasionally one or more secondary nucleoli (Held), while its further structure is either entirely invisible or is indicated by a fine network of granules stretching from the nucleolus to the nuclear membrane. Some of the various counterstains used in connection with Nissl's method, as the erythrosin of Held, demonstrate the finer structures of the nucleus and their different microchemical reactions. The ammoniacal carmine solution recommended by Rehm5 as a counterstain with Nissl's method (carmine, i; liq. amm. caust., i; aq. ioo, stain 5 min. then decolorize five minutes in alcohol, 100, K N 03, 1), demonstrates in the centre of the nucleus a rose red mass, which this author seems to regard as a vacuole. With this distin- guishing test, he has never been able to find more than 30 STUDIES ON GANGLION CELLS. one nucleolus in the normal cell. The writer finds that the central acidophile portion of the nucleolus is brilliantly demonstrated in sublimate preparations by Ehrlich's tri- color fluid, after decolorization in alcohol, nor has he suc- ceeded in finding any such central body in the numerous granules resembling secondary nucleoli to be found in pathological specimens. According to Levi,56 all the true chromatin of the nucleus is concentrated in a series of granules lying along the edge of the nucleolus, while the rest of the nuclear network consists of linin. The writer's study of the structure of ganglion cells has led to conclusions which in one particular, namely, the re- lation of the chromatic bodies and reticulum to the achro- matic or acidophile reticulum are at variance with the views generally accepted. These conclusions are based upon the examination of ganglion cells in normal and pathological conditions, fixed in various fluids, principally Van Gehuchten's, stained in section by methylene blue and by erythrosin and methylene blue, and of freshly teased specimens fixed by heat and stained by the same fluids. In very thin sections of cells prepared as above, by the use of artificial light (32 candle power electric arc), by applying oil to the condenser as well as to the lens (Zeiss apochromatic y1^) very clear demonstrations of the cyto-reticulum are obtained. This reticulum is remarka- bly clear and the relations of the chromatic and achro- matic structures appear especially distinct in freshly teased specimens fixed by heat (1000 C, 5 min.) Under the above conditions it appears to the writer that the chromatic structures in the cerebral, spinal, and spinal STUDIES ON GANGLION CELLS. 31 ganglionic cells are always found in the form of a reticu- lum with nodal thickenings, which in the stichochromes, reach a considerable volume, covering often several adjoin- ing meshes of the network. The connecting threads of the chromatic reticulum are very delicate in the spinal stichochromes, Plate I, Fig. i; and spinal ganglionic cells Plate I, Fig. 4; and rather coarse in Purkinje cells, Plate I, Fig. 2. The presence of this chromatic network is more plainly shown in cells deficient in chromatic substance, in which the fading chromatic bodies may often be seen to resolve themselves into a uniform and delicate chromatic net- work. (Plate V, Figs. 1 and 2; Plate VI, Fig. 4). Moreover, a significant pathological lesion, it is believed, consists in partial or complete disintegration, apart from simple fading of nodal thickenings, of this chromatic reticulum. (Plate VI, Fig. 1). The chromatic bodies and network, as conclusively shown by Held, may appear granular or homogeneous, according to the methods of fixation employed. These conclusions have reference solely to the^morphology of the cell in hardened tissues and may have little or no bear- ing on the relations of the chromatic substance in the living cell. The results of the present study indicate also that the achromatic or acidophile reticulum depicted by Held is fully demonstrable in specimens stained by methylene blue alone, and is continuous and identical with the chro- matic reticulum which the writer has been discussing. Freshly teased specimens fixed by heat and stained by erythrosin and methylene blue are specially convincing of the correctness of this view. In such specimens of the normal human lumbar stichochromes the main dendrite 32 STUDIES ON GANGLION CELLS. and adjoining portion of the cell body, an area which may be conveniently termed the '-'■polar dendrite" may some- times be found drawn out into an extremely thin layer, and under these circumstances the relations of the chromatic and achromatic portion of the cell are remarkably distinct. Here a single reticulum is demonstrable, stainable alike by methylene blue or erythrosin, and when both dyes are used the thinner strands of the reticulum appear bright red while the nodal thickenings are blue. Moreover, the blue masses fade insensibly into the red and both are everywhere continuous. The meshes of the reticulum are either clear or contain isolated acidophile granules of the same char- acter as the substance ensheathing the dendrites and cell body and continuous with the axis cylinder process. These indications of the relation between the so-called chromatic and achromatic reticulum accord with the ob- servations made upon sections of hardened tissue stained by the same dyes. In regard to the strictly achromatic substance of the cell, specimens of the "polar dendrite" prepared as above, show the presence of a granular acidophile sub- stance ensheathing the dendrites, continued in a layer of varying thickness about most of the cell body, visible in many of the meshes of the reticulum, and composing ex- clusively the axis cylinder process. This substance appears to be identical with the '' axis cylinder geflechte " of Held, but the accompanying fibrils as well as the serial arrangement of the granules, beautifully shown in Held's drawings, were not visible in the writer's prepara- tions. This view of the structure of the body of the nerve cell appears to be identical in most particulars with that recently formulated by Van Gehuchten.41 The appearance in the writer's specimens, however, STUDIES ON GANGLION CELLS. 33 fully accord with the observations of Schiefferdecker,5 7 Dogiel,5 8 Held,9 and Apathy,5 9 that the dendrites con- tain a granular substance identical with that found in the axis cylinder process, a fact which strongly indicates that all these processes share the function of conducting impulses. Spinal Ganglion Cells. The cells of the human spinal ganglia have been exhaustively studied by Lenhossek,60 Held,9 Flemming,61 Nissl,68 Cox,63 and Heimann,64 from whose descriptions the following outlines have been extracted. These cells are of large size, 60-80 \i in diameter, at times reaching 120 \l. Each cell is surrounded by a connective tissue capsule, often very cellular, and lined by a layer of flat endothelial cells which Lenhossek regards as furnish- ing nutriment to the contained ganglion cell. The cap- sule, in the natural condition, is entirely filled by the nerve cell, but in most stained specimens shrinkage of the cell creates an artificial space within the capsule. The cells are unipolar, the process being attached to the body in a knob-like projection, marked off from the rest of the body, as a clear achromatic crescentic area. The chromatic substance usually appears in the form of rather small granules which are distinctly more numerous about the nucleus, but are wanting in a narrow zone adjacent to the nuclear membrane, in a narrow peripheral zone, and at the crescentic area giving origin to the single process. This type of spinal ganglion cells belongs to Nissl's class of gryochromes. Other less numerous cells contain larger chromatic masses, resembling in structure the spinal stichochromes, while Flemming has described a third class of cells of vol. 1—no. 3—c. 34 STUDIES ON GANGLION CELLS. moderate size, staining usually rather dark, and con- taining very coarse granules of chromatic substance. A considerable variation in staining quality may be noted in the cells of the spinal ganglionic cells, a feature referred by Lenhossek to the greater density of the protoplasm, especially of the smaller cells. Cox describes two main varieties of spinal ganglionic cells. One type contains large or small irregular chro- matic bodies without distinct concentric arrangement. The cells of this type may be either large or small. An- other type of cell contains large irregular chromatic masses in definite concentric arrangement. Heimann, in a recent study of the cells of the spinal ganglia in rabbits, especially of their reaction to various dyes, seems to identify the cyto-reticulum with a fibrillar structure. He finds that the chromatic bodies are not continuous with these "fibrils," and he speaks of but one type of cell. From the study of the cells of the spinal ganglion in the present cases, the writer was unable to find convincing evidence that these ganglia contain more than one dis- tinct variety of cell. (See Plate I, Fig. 4.) While the peculiarities of the chromatic bodies above detailed were noted in many instances, there were indications that these features depended upon physiological or pathological variations rather than upon distinct differences in normal histological structure. Various grades of pigment deposit, increasing with age, may be found, especially in the larger cells. The structure of the achromatic portion of the cell may be regarded as similar to that of the spinal sticho- chromes. STUDIES ON GANGLION CELLS. 35 The Sympathetic Ganglion Cell. The knowledge of the structure of the sympathetic ganglion cell has been contributed largely by Kolliker,6 5 Cajal,6 6 Retzius,6 7 Sala,6 8 Dogiel; 6 9 Vas,7 ° and Dehler.7» These studies refer only in part to the structure of the chromatic portion of the cell. Vas finds that chromatic substance is absent from the cell in the seven-months foetus, and that it makes its appearance about the ninth month. At n-12 years the sympathetic ganglion cell attains its full development, having greatly increased in size and in content of chro- matic substance. Dehler's studies refer to the sympathetic ganglion cells of the frog. These cells measure on the average 10 to 40 fi in diameter and present a great variety of forms determined by pressure of the rather dense connective tissue capsule of the ganglion in which they lie. They are surrounded by an endothelial sheath similar to that of the spinal ganglion cells. The chromatic substance appears in the form of granules or larger spindle-shaped masses, most abundant in the periphery of the cell and arranged concentrically, not about the nucleus, but around a certain point of the cell, or centrosome, which lies midway between the nucleus and the opposite pole of the cell. The large chromatic bodies lie at the periphery of the concentric rings and the finer granules at the centre. The nucleus may be encircled by one or more rows of large chromatic masses. In the centrosome are to be found a group of granular chromatic bodies staining deep black by Heidenhain's hematoxylin. Dehler follows the technical methods of Flemming, tracing fine fibrils entering the cell from the processes, but does not find that they are connected with the nucleus. 36 STUDIES ON GANGLION CELLS. The spiral fibres encircling the bodies of the sympathetic ganglion cells are not demonstrable by Nissl's method. The nuclei of the sympathetic ganglion cells are similar in all respects to those of the spinal ganglion cells. In most of the higher vertebrates, especially in young indi- viduals, double nuclei are frequently seen in these cells. Small chromatophilic cells are rather abundant in sym- pathetic ganglia. Dogiel employed the method of vital injection of methylene blue and his investigations were principally devoted to the course and relation of fibres and intra- cellular fibrils. According to Dogiel the chromatic masses are usually of moderate size, of oval or angular form, and stain with varying intensity by Dogiel's vital injection method. They are more numerous in central areas, sometimes project beyond the cell borders, are seen in dendrites and even in the crescentic area of origin of the axis cylinder process. By high powers these masses are seen to be composed of fine granules. The intermediate substance is for the most part unstained by methylene blue, but in it are seen a network of fine fibres. He finds a clear acidophile substance or groundwork about the dendrites and periphery of the cell body, similar to that in the axis cylinder process, and believes that the acidophile substance of the axis cylinder process and dendrites is continuous, running through the deeply stained portion of the cell. The Structure of Purkinje's Cells. According to Nissl these cells furnish the type of archystichochromes, their chromatic substance existing partly as large spindle-shaped masses, largest and most STUDIES ON GANGLION CELLS. 37 abundant about the periphery of the cell and encircling the nucleus, and partly also in the form of a fine network found throughout the cell body, but most evident near the origin of the dendrites. There seems to be considerable variation in the number and size of the chromatic masses of Purkinje's cells in apparently normal cases. In some of the writer's specimens these bodies appear as densely packed as, though rather smaller than, in the spinal stichochromes. The dendrites of Purkinje's cells contain comparatively few chromatic spindles, but at the bifurca- tion of processes, even to the third or fourth order, a group of small chromatic granules may sometimes be detected. The presence of several small vacuoles, or as seems more probable, of small highly refractive translu- cent achromatic bodies, sometimes seen in the spinal stichochromes, is in the writer's specimens, a specially prominent characteristic of the nucleoli of Purkinje's cells. The writer's sketch of a normal Purkinje's cell was made from a teased specimen dried and stained on a glass slide. The chromatic network and relation of chromatic bodies appear more distinct than in stained sections. (See Plate I, Fig. 2). Structure of Cerebral Cortical Cells. The majority of the smaller pyramidal cells of the cerebral cortex belong to the type of pure archyochromes, the chromatic substance being in the form of a fine net- work of granules, the meshes of which vary considerably in size. This network is traceable for some distance into the larger processes. In some cells the network is dis- tinctly thickened at nodal points, a feature that becomes so pronounced in the deeper layers as to place some of the medium sized pyramidal cells in the class of archysticho- chromes. 38 STUDIES ON GANGLION CELLS. The large ganglionic cells of the motor areas belong to the type of stichochromes, the chromatic bodies being- numerous and distinct. The size and number of chro- matic spindles in the dendrites is distinctly less in all cortical cells than in the spinal stichochromes. The Medullary Nuclei. The locus ceruleus and substantia nigra are composed largely of medium sized or large stichochromes in which are usually abundant masses of large pigment granules. When the deposit is moderate in amount the outline of the pigmented area may be distinctly marked off from the cytoplasm, in other cases the pigment is very abundant and distributed all through the cytoplasm, being thickly packed between the chromatic bodies. Throughout the gray matter of the floor of the fourth ventricle and along its walls, the predominating type of cell is unquestionably the stichochrome, but in addition to this type one meets constantly with cells of a different con- stitution, often apparently belonging to the cranial nerve nuclei. Many of them are, undoubtedly, archysticho- chromes. Van Gehuchten31 (p. 237) also depicts such cells in the nucleus of origin the motor oculi of the rabbit. The fact that the eighth nucleus contains largely typical stichochromes is tiardly in accord with the theory of Nissl's classification, as noted by Van Gehuchten, who suggests that these cells may be cells of origin for the post. long. fasciculus, (p. 241, loc cit.) The cells of the olivary bodies belong to the class of archystichochromes, the chromatic reticulum being rather coarse and nodal thickenings distinct. At an early period, usually before puberty, a considerable area of these cells is converted into an achromatic, highly refractive, slightly STUDIES ON GANGLION CELLS. 39 yellowish substance, much resembling the pigmented areas found in many cells and in which the persisting chromatic reticulum is usually very distinct. The cells of the external arcuate nucleus are of the type of archystichochromes, with rather delicate reticulum and large chromatic bodies. In the upper medulla the writer has met with a type of cell which has as yet escaped description, and of which a short reference may here be inserted. These cells are located externally to and above the locus ceruleus. They measure 40 to 70 \i in diameter, and are multipolar. They are very rich in chromatic substance, the structure of which constitutes the characteristic feature of the cell. Chromatic bodies are wanting, this substance being found in the form of a network of which the meshes are ex- tremely coarse and thick. The appearance of these cells is totally different from that of any other type seen in the human subject. At the same level of the medulla single or isolated groups of cells are found, which are identical in structure with those of the spinal ganglia. An exhaustive study of the normal histology of the cells of the medullary nuclei is a contribution urgently needed, before detailed pathological studies can be conducted with advantage. During the examination of the central nervous system of a child, seven years of age, dying from shock and hemorrhage, a number of interesting cytological features were observed which are probably characteristic of early life. The groups of cells in the medulla were much more compact than in the adult. Often four or five cells in 40 STUDIES ON GANGLION CELLS. section lay in immediate contact with each other, and some of these cells were distinctly united by broad pro- cesses. The chromatic bodies of the large stichochromes were large and extremely abundant. Different types of chromatic structure were more distinct than in the adult, and some groups of cells in the medulla which the writer has never encountered in the adult, presented the struc- ture of the sympathetic ganglion cells. In new born infants, many of the above peculiarities were noted, but the chromatic bodies at this period were usually very deficient in size and number. The chromatic masses of Purkinje's cells at birth appear to be, as a rule, extremely small and faint. Babes72 finds that the "Nissl bodies " are often limited to the perinuclear region, in the normal infant. Vas70 has found that the chromatic bodies are wanting in the sympathetic ganglion cells at the seventh month of foetal life, that they make their appearance in the form of small granules at the ninth month, and are not fully developed until the eleventh year. Eve13 also notes the absence of chromatic bodies in the ganglion cells in early fcetal life in the rabbit, finding that only the vagi nuclei in the embryo 2.5 cm. long contain distinct masses of chromatic substance. It falls without the scope of the present study to consider further these details of the histology of the medullary and higher ganglionic cells, but it is obvious that until a systematic study of this subject has been contributed, it must remain impossible to accurately interpret the variety of pathological appearances presented by the medullary nerve cells in early life. STUDIES ON GANGLION CELLS. 41 Section III. Physiological Condition of Ganglion Cells in the Central Nervous System. Considering the great variety of appearances of the chromatic structure of- ganglion cells demonstrated by Nissl's method, it is obviously important to know what digressions from the typical and normal aspect of these cells may be expected in the cord and brain of the average normal case. It is by no means easy to secure at post-mortem material from human subjects in which a fatal lesion has not seriously involved the central nervous system. The following cases are believed to partially meet these requirements: Case I.—Multiple Injuries, Hemorrhage, Shock.—Male, 14 years; previously healthy. Was struck by a locomotive, receiving internal injuries from which death resulted in three hours, from shock and hemorrage. There was no elevation of temperature, and the patient was conscious until a few moments before death. Autopsy six hours after death. The body of the first lumbar vertebra, the ramus and body of pubes, were fractured, and the tissues in each locality lacerated and infiltrated with blood. There were a few ounces of bloody fluid in the peritoneal cavity. The viscera were normal. Microscopical examination. Van Gehuchten's fluid. The lumbar cord was lacerated at the point of fracture and infiltrated with blood for some distance above and could not be used for the present purpose. In the cervical cordthe great majority of cells presented an abundance of well-formed compact chromatic masses. The chromatic network connecting these bodies was usually distinct. The nuclei and nucleoli were normal and centrally placed. In Clarke's column, one large cell presented marked central chromatolysis and eccentricity of nucleus. All other cells in several sections were normal. Immediately external to Clarke's column was a group of medium sized cells, seen in several sections, in which the 42 STUDIES ON GANGLION CELLS. perinuclear chromatic masses were moderately subdivided and the nuclei eccentric. In the medulla the majority of cells were perfectly nor- mal in appearance, but it was possible in nearly every section to find some abnormalities. All the cells of the nuc XII, appeared normal. Above this nucleus nearly all the larger stichochromes also appeared normal, although the chromatic bodies were very large and of irregular contour. On the other hand, in many of the smaller stichochromes, and in the cells of the other mixed types which are abundant in this region, a moderate subdivision of perinuclear chromatic masses was the rule. A considerable number of examples was seen of central chromatolysis with eccentricity of nucleus. Throughout the cortex, the appearance of the cells was more uniform. The chromatic bodies were almost invari- ably compact and regular. Sometimes they were defi- cient or subdivided in the perinuclear zone. In the archyochromes, attention was drawn to marked variation in the size of the meshes of the chromatic reticulum. Purkinje's cells were rich in chromatic bodies of rather small size and somewhat indistinct contour. The results of the examination of this instance were disappointing in the attempt to secure a case showing perfectly normal conditions throughout the central nerv- ous system, and the lesions found must be referred to the severe concussion of the injury, and to the fatal shock and hemorrhage following it. Barring the slight distortion of the chromatic bodies most evident in the medulla, and the changes in the single group of spinal cells, for which no explanation can be offered, the conditions found indicate a high development and uniform preservation of the chromatic structures in all regions, and to this extent the case serves its original purpose, indicating the physiological condition of the nervous system, in the young normal subject. Case II.—Dislocation of Cervical Vertebrce.—Male, 60 years; fell four stories through an elevator shaft and sus- tained various injuries. Brought to hospital unconscious, but soon became rational, although there were intervals of mild delirium during the night. There was a fracture of the right femur, and complete hemiplegia below the clavicles. The next morning the patient was entirely rational, and asserted that he felt comfortable. It was noticed that he turned his head to one side, immediately after which he was found dead. Temperature 101.40. STUDIES ON GANGLION CELLS. 43 Autopsy eight hours after death. There was a reduced dislocation of the third cervical vertebra and the cord at this point was crushed. There was a little fresh blood in the spinal canal and the cervical muscles were infiltrated with blood. The brain and medulla appeared normal. There was a very little extra- vasated blood in the gray matter of the cord, on either side of the crushed area. The viscera could not be examined. Microscopical examination. Formalin 10 per cent. In the cord, above the injured segments, the majority of cells showed extensive central chromatolysis, but many of the large stichochromes were intact. In a few cells "axonal degeneration " was noted. In the medulla, the cells of the XII nuc. were perfectly normal. In the cells of the superficial X nuc, there was an extensive deposit of yellowish granular pigment, but the remaining chromatic bodies were of normal appear- ance. The large stichochromes in the region of the nuc. ambiguus were intact. In the VIII nucleus nearty all the cells were extensively altered, the chromatic bodies being limited to the periph- ery, the perinuclear areas being occupied by finely subdivided and partly faded chromatic particles. The nuclei were often eccentric, and pigmentation was excessive. Apart from excessive pigmentation, and the resulting loss and displacement of chromatic bodies, no changes were noted in the III, IV, V, VI and VIIcranial nuclei. In a considerable number of deeper lying cells, in many groups not certainly identified with named nuclei, there was a moderate loss, of perinuclear chromatic bodies. In the motor cortex, the giant stichochromes showed ex- tensive pigment deposits, but no changes in the chromatic bodies. In the smaller cells throughout the cortex, the perinuclear areas were often deficient in chromatic sub- stance, and showed an early stage of pigment formation. Elsewhere the chromatic structures were intact. Pur- kinje's cells contained an abundance of chromatic bodies of somewhat smaller size than is usual. A very few of these cells were distinctly deficient in chromatic bodies. With the exceptions of the extensive pigment deposits, and of the distinct changes in the nuc. VIII, which latter the writer is unable to explain, the chromatic structures of the medullary and cortical cells were found in nearly normal condition, and the case appears to furnish a normal standard of comparison for subjects of this age. 44 STUDIES ON GANGLION CELLS. Some experimental studies may here be cited on the effects of traumatism and shock on the nerve cells. After inflicting a severe blow on the abdomen of rabbits, a traumatism proving fatal in from four hours to four days, Parascandolo74 found by Golgi's method a shrink- age of the cells and rupture of processes; by Marchi's method, degeneration of fibres of Lissauer's column, of the posterior roots, and often of the posterior tracts; by Nissl's method, a considerable variety of forms of chro- matolysis. Vacuolation was frequent, but any nuclear changes seen were of uncertain character. He thinks these cellular changes will explain many of the symptoms seen in shock from such injuries. Luzenberger75 describes a peculiar concentration of the chromatic substance at one pole of the cortical cell in animals killed by blows on the head. This lesion was limited to the areas most exposed to the traumatism. The observations of Babes72 also indicate that in the nervous system of the average adult subject the perma- nent effects of previous diseases may be found in the presence of a moderate number of altered cells. Clarke's column, the lateral portions of the anterior horns, and some medullary nuclei, he indicates as the regions most often containing such abnormal cells. In aged subjects he rather frequently finds cells that have lost their chromatic bodies, or have become atrophic, as well as those exhibit- ing extensive deposits of pigment. In young subjects with sound organs, such appearances are much rarer. In animals recovering from various infections he found, after several weeks, many more altered cells in the anterior horns than in control animals. STUDIES ON GANGLION CELLS. 45 Section IV. On Cadaveric Changes in Ganglion Cells. The writer in sudying the pathological changes in nerve cells in various diseases, was early impressed with the frequency of alteration, which was most naturally refer- able to post-mortem processes, and being unable to find at that time (1895) any adequate discussion of this branch of the subject, was compelled to make a preliminary study of cadaveric changes in the ganglion cell as demonstrated by Nissl's method. All that has been said in reference to the artifacts produced by fixing agents, is of course of equal import in connection with post-mortem changes. In the writer's experience it has often been impossible to distinguish the one from the other, principally when deal- ing with vacuolation and the chromatophilic condition. The course of post-mortem changes in the ganglion cell as revealed by previous methods has been rather imper- fectly described by several observers, and among these studies may be mentioned that of Schulz.7 6 Recently several studies on post-mortem alterations of the chro- matic substance of nerve cells have appeared. Colucci77 has considered in detail the cadaveric changes demon- strated by Nissl's method. He finds that while adult nervous tissue undergoes post-mortem changes more slowly than most other tissue, yet it does not, even under favorable conditions, enjoy freedom from cadaveric alter- ation longer than twenty hours. The dependent portions, especially the second and third temporal convolutions and the cerebellum are the first regions to lose consistency. Microscopically, cadaveric changes consist principally in: First.—Granular disintegration of the cell body, giving it a powdery aspect, or leaving it homogeneous and 46 STUDIES ON GANGLION CELLS. diffusely stained. All the elements of the cell are in- volved in this change, last of all the nucleus, and its prominent characteristic is the uniform involvement of the entire cell body with alterations in the form of the cell. Very early and characteristic changes are to be noticed in the second and fourth layers of cortical cells, while the larger pyramidal cells of the cortex and medulla are more resistant. The fibrillar or achromatic portion of the cell is more apt to show these changes than are the chromatic bodies. Second.—Colucci notes that various segments of the processes are apt to remain unstained and thus give a false appearance of fragmentation of these processes. Third.—Complete rupture of processes in various directions may occur in the course of cadaveric alteration. Fourth.—Black droplets may be demonstrated by Marchi's method, either in the processes or in the cell body, or the entire cell may appear jet black, as the result of post mortem changes. Neppi78 noted the course of cadaveric alteration in the spinal stichochromes of the dog. Within six hours after death he found these cells in normal condition. A faint areola about the nucleus was noted, the significance of which appeared uncertain. After 24 hours the chromatic substance appeared normal, but in some cells a slight nuclear chromatophilia was observed. After 48 hours there was a diffuse staining of the entire cell body, but the chromatic bodies appear well differentiated, although often very scarce in the protoplasmic processes. The outlines of the nucleus are less regular, and the karyo- plasm shows a light diffuse bluish stain. The nucleus may become eccentric. After 72 hours the changes of the last stage are moderately increased. After 96 hours the cell STUDIES ON GANGLION CELLS. 47 outlines are more ragged, the chromatic masses are very scarce in the processes, and in the cell body they stain very faintly. Sometimes the dark areola about the nucleus is much increased in extent. The outlines of the nucleus are irregular and indefinable. In general, Neppi finds that cadaveric processes lead to a gradual disintegration and fading of the chromatic bodies, accompanied by a shrinkage and chromatophilia of the nucleus. This cadaveric chromatolysis does not, in his opinion, greatly resemble the vital chromatolysis described in various pathological conditions. As the initial alteration he regards of first importance the diffuse staining of the karyoplasm. The irregularity in outline of the nucleus and the shrinkage of the cell body are the most reliable indices of post-mortem as distinguished from vital pathological alterations. Barbacci and Campacci79 report a systematic study of cadaveric changes in various parts of the nervous system of rabbits. They used the methods of Nissl, Golgi, and Marchi. Nissl's method revealed, as the initial change, a diminution in the staining capacity of the chromatophilic masses. This change is associated with an irregularity of these bodies, their borders becoming indistinct, and two or more often appearing to be fused together in a larger mass, or the bodies appear to be broken into irregular particles. Occasionally the peripheral masses are entirely bleached, while the perinuclear bodies remain intact. Small areas or the entire cell body are sometimes found homogeneous and deeply chromatophilic The granular disintegration of the chromatic masses often gives the cell body a characteristic pulverulent aspect. Vacuoles of various sizes are oftenjseen espe- cially when the protoplasm appears homogenous. Very 48 STUDIES ON GANGLION CELLS. frequently the protoplasm shows a characteristic reticular aspect, the meshes of the reticulum being of varying size and the threads coarsely granular. The irregularity in the size and shape of the meshes of this reticulum serves to distinguish this change from the vital and patho- logical formation of vacuoles which latter are always rounded and sharply limited. The authors believe that it is quite possible to mistake the initial stages of putrefac- tive changes for the peripheral chromatolysis so often attributed to pathological processes. The nuclei are sometimes found irregular in outline, sometimes swollen and homogeneous, but with very dis- tinct outlines. The intranuclear network is converted into a series of irregularly placed granules. In advanced stages the nucleus becomes shrunken, ragged, and often homogeneous and deeply stained. In very advanced stages of decomposition the nucleus is indistinguishable, although the nucleolus usually persists in some form. Alterations of the nucleolus are relatively late, in cadaveric processes, as observed by these authors. They consist chiefly in eccentricity or extrusion of the nucleolus, in various changes in its form, and, at advanced stages, in swelling and fragmentation. In all these phases there is a progressive loss of staining capacity. In Golgi's method the author describes principally a peculiar irregularity or erosion of protoplasmic processes, which they term the " stato torlato," and which they find to have no resem- blance whatever to the varicose atrophy or moniliform condition now generally regarded as of pathological import. The full report of their observations is to appear later. Levi80 finds that the first cadaveric changes appear in the cortical cells within 18 to 24 hours after death, in the STUDIES ON GANGLION CELLS. 49 spinal ganglia within ^6 to 48 hours, and in the cord within 60 hours. The cells first appear coarsely granular and more in- tensely stained than usual, while the nuclear membrane becomes indistinct. After this " hyperchromatic stage " the cell body takes on a violet tinge with methylene blue, becomes irregular in outline, while the nucleus loses its identity, the nucleolus only being distinguisable. His studies were upon the central nervous system of rabbits, removed after killing the animals by bleeding, and exposed to the air. The writer's observations on cadaveric changes in ganglion cells consist in the examination of the brains and cords of rabbits in successive stages of decomposition, and in the study of alterations noted in cases coming to the autopsy table in from one to forty-eight hours after death. In the course of these observations, the ordinary rules governing the course of post-mortem changes in the cada- ver were found to be fully illustrated. In warm, moist weather, advanced decomposition of the central nervous system was found in some cases within six to eight hours, while in the coldest winter weather, the tissues were apparently intact in the great majority of instances after 24 hours. The condition of the tissues before death as determined by the nature of terminal infections proved of very great influence on the rapidity of change immediately after death. Cases of septicaemia, pyaemia, peritonitis, and the infectious diseases, seemed to require that the tissues should be removed and placed in preservative fluids within two to four hours, if one hoped to avoid serious alterations in the finer structure of the cells. In a case of leukaemia terminating in infection by the bacillus VOL. I—NO. 3—D. 50 STUDIES ON GANGLION CELLS. aerogenes capsulatus, the most bizarre phases of post- mortem destruction, predominated by gas formation, were found in the brain and cord, although the autopsy was held in January, eight hours after death. It does not appear possible to state for all conditions any approximate period within which the cellular structure demonstrable by Nissl's stain may be affected by post- mortem alterations. As a rule, the writer would regard with suspicion any areas showing simply granular disintegration of the chromatic bodies and nuclear chromatophilia, the earliest post-mortem alterations, unless the tissues had been preserved within four to six hours, or in septic cases within two hours after death. In the brains of very young infants the change proceeds with surprising rapidity. After removal from the body, the brain and cord may be preserved without noticeable change for 26 to 48 hours longer, if kept in cold storage at 320 C. After four days' storage in this way, the brain from a case of eclampsia, showed only a slight increase in the diffuse staining of the nuclei and a slight dimness in outline of the cell body and chromatic masses, which could be referred to cadaveric processes. A series of observations undertaken for the study of post-mortem changes in the nerve cell consisted in the examination of the central nervous system of rabbits, which had been allowed to decompose in the air for from 48 to 72 hours. Under these conditions the changes seemed to follow a somewhat uniform course. The alter- ations observed appeared to fall into three distinct periods. The changes of the first period were well marked within 24 hours, and were characterized chiefly by a granular disintegration of the chromatic substance. This alteration STUDIES ON GANGLION CELLS. 5 I was most uniform and general in the cortical archyo- chromes which at this time showed an irregular network of larger, more distinct, deeply stained granules, replacing the normal fine granular chromatic network. The achro- matic substance at this stage appeared slightly clouded or displaced by vacuoles. The outlines of the cells remained intact. In the spinal stichochromes the outlines of the chromatic bodies were slightly irregular and indistinct and the granules larger. (Bichloride fixation). In the den- drites there was an irregular network of fine granules, and the chromatic spindles appeared more coarsely granular than in the fresh specimens treated by the same methods. In many instances the nuclei of the cortical cells showed a tendency to stain diffusely but this change was not pronounced. Characteristic changes early affect the nucleus. The first indication of post-mortem alteration of the nucleus is seen in a progressive clouding of the intranuclear network. This change usually begins about the nucleolus, of which the chromatin appears to diffuse along the intranuclear network producing a diffuse chromatophilia immediately around the nucleolus and extending a variable distance out toward the nuclear membrane. Plate III, Figs. 1-2. When decomposition is rapid all parts of the nuclear network may be simultaneously affected, and appear uniformly thickened and coarsely granular. Plate III, Fig- 3- In the second period, usually well marked at the end of 48 hours, the characteristic feature was the uniform cloud- ing of the nuclei of the cortical archyochromes. After 24 hours the outer zones of these nuclei were usually clear and retained their delicate intranuclear network. In the second period, the intranuclear network was no longer 52 STUDIES ON GANGLION CELLS. visible, and the nuclei almost without exception, appeared evenly and diffusely stained throughout. The nucleolus were sometimes almost invisible. This diffuse nuclear chromatophilia appears to spread from the nucleolus out- ward, as in many of the larger and less affected cells, nuclei were found showing all transitions from a narrow radiating chromatophilic zone about the nucleolus, charac- teristic of the first stage, to a dark discoloration of the entire nucleus. The granular disintegration of the chromatic substance advanced rapidly in this stage, especially in the archyo- chromes. The normal network was now replaced by an irregular deposit of large discreet granules, often partially grouped, and usually leaving a clear zone about the dis- colored nucleus. In many cells large and small clear vacuoles appeared, distorting the outlines of the cell body, and disturbing the position of the large granules. In the achromatic substance an increasing chromato- philic tendency was constantly noted. A characteristic change also belonging in its earlier stages to this period, was observed in the shrinkage of the dendrites which now became irregular in outline and staining qualities, and often followed a wavy or spiral course through the section. In the spinal stichochromes the nuclear changes were less marked, but the diffuse staining of the achromatic portion of the cell body and dendrites and the irregu- larity and coarse granulation of the chromatic bodies exceeded those of the first period. In some instances the granular disintegration of the chromatic structures proceeded much more rapidly and at the end of 24 to 36 hours the cell body presented an irregular network of large granules unevenly distributed over the cell STUDIES ON GANGLION CELLS. 53 and often found free in the pericellular lymph space. Plate III, Fig. 3. The third period was characterized by the growth of putrefactive bacteria in the finer capillaries and in the pericellular lymph spaces, by the disintegration of the cell body, and by the separation of dendrites. When bacteria begin to develop in the vicinity, the out- lines of the ganglion cells soon become irregular and broken. The perinuclear zone of vacuoles fuses with the large peripheral vacuoles, and these open into the peri- cellular lymph space often leaving the border of the cell to be indicated only by a single row of dark granules. The process continues until nothing is left of the cell except a dark nucleus with a narrow fringe of dark granules. All stages of shrinkage, rupture, and complete destruction of processes may be followed at this period. The appearance of the nuclei is very characteristic. They are usually diffusely and very darkly stained. The nucleoli usually are much reduced in size but are often surrounded by such a deeply stained area that the central nucleolar spot be- comes very indistinct. The nucleoli may also be numer- ously subdivided. A striking difference noted in the spinal stichochromes was the resistance offered by the chromatic bodies of these cells to the effects of bacterial invasion. In some instances the cell body was riddled with bacilli and the pericellular lymph space choked with them, while the chromatic masses still retained a distinct outline, un- diminished staining capacity, and showed only a moderate increase in the coarseness of their granules. Usually, however, the outlines of the chromatic bodies were irregu- lar and indistinct, and often they were completely broken up into coarse, dark granules. Throughout these periods 54 STUDIES ON GANGLION CELLS. the spinal cord proved more resistant to cadaveric de- composition than did the brain or medulla. The fact that Purkinje's cells followed closely the behavior of the other cortical cells rather than that of the anterior horn cells, indicates that the slower progress of change in the spinal cells is referable to local conditions under which these cells are found and not to structural differences. Possibly the smaller content in fluids and the more rapid dessication of the cord may account for some of these differences, yet they were well marked in specimens allowed to remain in the body, where dessication was impossible. Comparing cadaveric changes found in cases coming to autopsy, under diseased conditions, with the course of post- mortem processes in normal rabbits, much less uniformity was observed. Extreme differences were noted in the periods required for the development of cadaveric changes in the human subject, so that it is impossible to give any approximate number of hours within which the stages detailed above may be expected to appear. As before mentioned, the rapidity of the process depends upon the ordinary factors governing post-mortem changes, the most important of which seems to be the condition of blood and tissues at death, and next in importance the condition of the sur- rounding air. It was often observed that a lack of uniformity existed in the character of the changes, both in different portions of the cerebro-spinal axis and in the nuclei of the same segment of the medulla. Central nuclei were sometimes found more affected by cadaveric processes than were superficial groups of cells. STUDIES ON GANGLION CELLS. 55 Yet whatever period the changes might have reached it always seemed possible to distinguish with certainty between post-mortem and vital pathological processes, except when dealing with increased chromatophilia of the nuclei of cortical cells. The writer has found no evidence indicating that cada- veric changes can simulate the characteristic central chromatolysis so often described as a part of pathological changes. No post-mortem appearances were encountered resembling the conditions seen after insolation. Even in the granular disintegration of chromatic bodies the cada- veric change is distinguishable from the pathological by the large size (bichloride fixation) and density of stain of the resulting granules, and by the uniform involvement of the entire cell. In the spinal stichochromes of a rabbit dying soon after a subcutaneous injection of the poison of a water-moccasin, distortion and granular subdivision of the chromatic bodies was found closely resembling post-mortem disintegration, but distinguishable from it by other features in the cells and surrounding tissues. In regard to nuclear chromatophilia, the author is in- clined to believe that this particular cadaveric alteration is sometimes indistinguishable in itself from a pathological change sometimes observed. Recourse must then be had to evidence obtainable from the probable condition of the tissue and the other characters of the cells. In this connection may be mentioned some artificial changes probably referable to the traumatism applied during the removal of the brain or cord from the body. The layer of Purkinje cells may sometimes appear to be separated from the adjoining layer by a zone of tissue 56 STUDIES ON GANGLION CELLS. similar to the molecular layer. The writer has found this condition very marked in specimens rather roughly ex- tracted from the cranium and frequently handled, and has been unable to find it when the cerebellum was removed with extreme care and immediately hardened. It seems probable, that the rupture of dendrites much more frequently results from similar traumatism than from pathological processes. In some specimens, removed one hour after death, large radially striated or coarsely granular bodies staining densely blue, or sometimes purple, have been found, most abundantly in areas composed of nerve fibres but some- times occupying the centres of large ganglion cells, dis- tending the cell borders, pushing aside and compressing nuclei and chromatic bodies, or almost entirely obliterating all trace of the cell. These bodies have been described by some as droplets of myelin. They are more abundant in roughly handled tissues. No evidence was found to indicate that the position of the nucleus is materially altered during the earlier stages of post-mortem decomposition. Later extensive vacuola- tion may lead to partial eccentricity of the nucleus. Section V. Pathological Changes in Chromatic Structures. Having considered the technics of Nissl's method, the effects of reagents and of mechanical injury on the nerve cell, the normal histology of the ganglion cell in some regions, and the course and character of post-mortem changes, attention may now be turned to the pathological changes in the ganglion cell as demonstrated by this method. STUDIES ON GANGLION CELLS. 57 A.—On Changes in Ganglion Cells in Diseases of Nervous System. I.—Neuritis and Lesions of Nerve Trunks.—The early observations on pathological changes in ganglion cells revealed by Nissl's stain were largely limited to experi- mental lesions produced in animals, and it must be ad- mitted that the more definite facts now known regarding the significance of certain changes in the chromatic bodies have been derived from experimental pathology. Cellular Lesions Following Section of Nerve Trunks.— One line of experimentation rather fully studied has been the effects on the spinal cells of various lesions of their fibres. On this subject many previous investigators have described a variety of changes demonstrated by other methods, principally Marchi's, and leading in the most advanced stages to complete disappearance of the cell. These studies may be found reviewed in the article of Onufrowicz.8 ] Nissl83 observed that characteristic changes could be induced in the cells of the facial nucleus by tearing out the facial nerve trunk in rabbits. Within 24 hours after this procedure he found that the chromatic bodies of the affected cell, began to disappear in a small area of the cell body. After two days the chromatic masses through- out the entire cell began to break up into a number of fine pale granules. By the third day the same changes affected the chromatic spindles in some of the dendrites, while the achromatic part of the cell began to darken. On the fourth day, he noted progressing disintegration of the chromatic bodies and swelling and irregularity of outline in the cell body. On the sixth day the cell body was rounded and presented a uniformly dusty appear- ance, while the dendrites were usually invisible. The 58 STUDIES ON GANGLION CELLS. nucleus had now migrated to one side, often projecting beyond the cell. By the tenth day, the cells were reduced to irregular waxy-looking or slightly granular masses without nuclei or dendrites. These changes did not affect all the cells of the facial nucleus with equal rapidity, but, on the tenth day, all phases of the above alterations could be seen in different cells. Without the knowledge of Nissl's work, Onufrowicz followed the changes in the spinal cord resulting from section of the dorsal nerve trunks in cats, considering chiefly later stages of degeneration found six days after the operation. His observations confirm those of Nissl. The anterior horn cells of the affected side and some also of the opposite side were found to be homogeneous, swollen, and entirely devoid of chromatc bodies, or showing only a little granular detritus. Somewhat simular changes with a marked tendency in one case toward chromato- philia were found in the cells of the posterior and lateral horns and in Clarke's column. The nuclei of the cells were often found markedly eccentric and in various stages of degeneration. Marinesco83 slightly varied the procedure of Nissl, simply cutting the nerve trunk and observing the changes in the cells of origin. He describes two phases of degenera- tion in the nerve cell induced by section of the efferent trunk. First, there is, according to Marinesco, a loss of chromatic bodies as described by Nissl, beginning about the axis-cylinder process, and effected, as he believes, by a process of hydration. He also noted the eccentricity of the nucleus. Secondly, he finds a disintegration of the protoplasm of the cell body indicated by changes in the achromatic substance. Lugaro84 studied the effects of transverse section of the STUDIES ON GANGLION CELLS. 59 cord in rabbits, and found that all cells within two or three mm. above and below the point of section degenerated, and after a time disappeared. All the cells within four mm. of the point of section, except the anterior horn cells showed the characteristic chromatolysis with swelling and loss of processes as described by Nissl. He concludes, therefore, that the lesions of the cells are greater and earlier the more extensive the lesion of their processes. Lugaro also found that while section of the peripheral roots of the spinal ganglia induces changes which progress to the total destruction of the cell, section of the central roots usually leaves the cells in their normal condition. Savdovsky85 ligated the sciatic in rabbits and described the changes in the cells of origin present at the end of four to five days. These consisted in a loss of chromatic bodies at the periphery of the cell and atrophy of many of the angles, concentration of large chromatic masses about the nucleus, and eccentricity of the nucleus. Flatau8 6 also observed all grades of the lesions described by Nissl in the nuclei of origin of the oculo-motor nerve, after section of the nerve in cats. Charrin and Thomas87 found in the spinal cord of a guinea pig two months after a double amputation, the changes described by Nissl and others as resulting from section of nerves. After section of the brachial plexus in rabbits Colen- brander88 found extensive chromatolysis, eccentricity or loss of nucleus, loss of dendrites, and sometimes extreme swelling of the cell body. Marinesco8 9 verified the observations of Lugaro that sec- tion of the central roots of the spinal ganglia induced very slight changes in the cells of the ganglia, while the usual lesions rapidly followed sections of the peripheral root. 6o STUDIES ON GANGLION CELLS. Marinesco has also studied the regenerative changes in the cells of the twelfth nucleus 24 days after section of the hypoglossus. At.this period he finds that the cells are enlarged, that they stain very deeply from increase in the size of the chromatic bodies, that the nuclei remain eccen- tric, and that some cells become permanently atrophic. The new formation of chromatic bodies may begin in a central or peripheral ring or irregularly throughout the cell. Flemming,9 ° in an extended study by Nissl's method of the effects of section of nerve trunks on the cells of the spinal ganglia and cord, came to the following conclusions: (1) The cells of the spinal ganglia are affected earlier (4th to 7th day) than are the anterior horn cells of the cord, but after the fourth week, the changes advance more rapidly in the cord than in the ganglia. (2) One of the first changes is a shrinkage of the nucleus, often also of the nucleolus, and a lateral migration of the nucleus. (3) The chromatic bodies first appear to be concen- trated about the nucleus where they become reduced in size and number and break up into fine granules. Some remaining chromatic bodies may be increased in size. The most comprehensive description of the changes in ganglion cells following section of nerve trunks is given in a summary by Van Gehuchten.91 According to his observations the changes that follow in motor nerve cells affect the chromatic substance only, the underlying net- work remaining intact, the nucleus showing no degenera- tive characters, and the cell under favorable circumstances returning to its normal morphology. Such cells cannot be said to reach a condition of true degeneration. When, however, the peripheral roots of spinal ganglia STUDIES ON GANGLION CELLS. 61 are severed or ligated, the cells of these ganglia suffer changes affecting both the chromatic and achromatic sub- stance, and the changes go on to complete degeneration. The reason for this difference in the behavior of motor and spinal ganglionic cells is found in the anatomical relations of the cells. After ligation of the filaments of motor cells the nutrition of these cells is maintained by the trophic influence of adjoining neurons. After ligation of the peripheral filaments of the spinal ganglia these cells, according to Van Gehuchten, are entirely cut off from exciting impulses and completely degenerate. (See also Flatau86). It will be seen that there is not complete accord in the observations of Van Gehuchten and others, and that the facts observed do not fully bear out the very rational theories of Flatau and Van Gehuchten. Onuf and Marin- esco describe true degenerative changes in motor cells after section of nerve trunks. This entire subject requires complete readjustment on the basis of the more minute changes in the chromatic and achromatic structures following ligation of nerve trunks. The writer's sections of pathological material indicate beyond doubt that long established neuritis affecting motor nerves leads to true degeneration and destruction of the anterior horn cells of the spinal cord. The changes in the achromatic substance and loss of dendrites do not always follow immediately upon the lesion of the fibre, as, in the case of alcoholic neuritis, reported in detail later, the chromatic bodies were largely destroyed in some cells which still retained their cyto-reticulum. In others it was evident that all portions of the cell were affected, the 62 STUDIES ON GANGLION CELLS. normal cyto-reticulum was wanting, the achromatic sub- stance was coarsely granular, and the processes were shriveled or absent. It seems probable that the conclusions now warranted in reference to this subject are that after section of nerve trunks, some cells of origin proceed at once to degenerate and disappear, others merely lose their chromatic sub- stance for a time either to recover or later to pass into a further stage of degeneration. The determining influence in the fate of the cell may very well be the trophic im- pulses enjoyed by the cell, and the partial preservation of function. Origin of Changes Following Section of Nerve Trunks.— The results of section of nerve trunks on their cells of origin raises several questions of importance in the physi- ology and pathology of the ganglion cell. One very natural inquiry relates to the chain of events that leads to these alterations in the anterior horn cells after section of the anterior nerve roots. A more difficult problem is encountered when one endeavors to explain the absence of changes in the spinal ganglia after section of their cen- tral roots. Why should section of the peripheral roots of these ganglia induce lesions which are entirely absent after section of the central roots? Since any direct traumatism to the ganglion cell can hardly be assumed to follow section of nerve trunks, it is necessary to assume that the cellular changes result from a disturbance in the physiological functions of the cell. On this assumption there is not only good reason for accepting the belief in the unity of ganglion cell and peripheral process as embodied in the modern conception of the neuron, but there is also a full explanation of the changes observed in the anterior horn cells after section of STUDIES ON GANGLION CELLS. 63 the anterior nerve roots. Such a lesion of the roots by destroying the activity of the cell leads rapidly to changes in the nutrition of the cell which may, in the event of the lesion becoming permanent, progress to complete atrophy. A similar explanation applies to the restoration of the chromatic bodies after the physiological functions of the cell have been restored by union of the divided trunk, as observed by Savdovsky, Marinesco, etc. In the experiments of Lugaro, after a transverse section of the cord, no changes were found in the ganglion cells below this lesion, except throughout a narrow segment adjacent to the lesion. It would, therefore, appear that the voluntary control of the functions of the anterior horn cells may be inhibited without inducing morphological changes in these cells. Flatau, in discussing this subject, refers the absence of changes in such conditions to the continuance of the reflex activity of the cell, which of course is not annulled after section of the cord. It then appears that the persist- ence of reflex activity and presence of peripheral excita- tion are of greater importance in maintaining the normal nutrition or at least the normal morphology of the cell than is the excitation by voluntary impulses. It is also possible to suppose that the continued excita- tion reaching the ganglionic cells through the peripheral roots is sufficient to maintain their nutrition even after section of their central roots, while, on the other hand, section of the peripheral roots leads to atrophy. A second question of importance is the pathology of the nerve cell here presents itself. Since characteristic changes in the ganglion cells consisting principally in central chromatolysis and eccentricity of nucleus have been found to follow the section of nerve trunks, and the loss 64 STUDIES ON GANGLION CELLS. of functional activity in the cell, is it safe to infer when these characteristic changes are found in ganglion cells that these cells are no longer functionally active ? That such an inference is justified appears very probable from the result of the experiments detailed above. As will be seen later, however, similar lesions of very irregular distribu- tion may be observed in many fatal general diseases, especially of the infectious type, and it is quite possible that other influences not interfering with the conductivity of peripheral nerve fibres may be capable of producing these lesions. A careful study of the conditions under which such typical lesions have been observed by the writer, has furnished no evidence against the view that cells in this condition are no longer functionally active. The further evidence on this point may be derived from the consideration of cellular changes in various other pathological conditions to be described later. A third important bearing of this series of experimental studies concerns the relation of cellular changes in the spinal ganglia and gray matter to peripheral neuritis, especially in alcoholic and diphtheritic cases. Before the publication of Nissl's method, many writers had described central cellular lesions in peripheral neu- ritis. (See Ballet92). One of the first observations on such lesions demonstrated by Nissl's method was reported by Ballet and Dutil93 in a case of fatal peripheral neu- ritis in which the usual appearances of " axonal degenera- tion " were found in the spinal stichochromes. Soon after, Marinesco94 reported a similar case which he had examined some time previously and found central chromatolysis in the spinal stichochromes. In a second case of polyneuritis with lesions in the cord, reported by Marinesco,9 6 central chromatolysis was found in the cells STUDIES ON GANGLION CELLS. 65 of the postero-external group of cells in the lumbar region, while the achromatic substance remained normal. The writer's series includes one case of fatal alcoholic neuritis in which advanced and very characteristic lesions were found in the central nervous system. The patient gave no previous history of disease. Had long been a hard drinker of beer and whiskey. Two months before admission to hospital, he began to have dull pains in both knees, calves, and ankles, followed in a few weeks by difficulty in walking, incapacitating him from work. The paralysis became complete and soon extended to both forearms. There were numbness and tenderness in the extremities but no pain. The knee-jerks were lost. The muscles of the arms reacted to faradism. The mus- cles of the right leg reacted slightly, those of the left, not at all to faradism. Three days after admission, there was paralysis of the diaphragm, double external strabismus, rigidity of neck and mild delirium. Without any rise in temperature the patient died. Autopsy by Dr. F. C. Wood, to whom the writer is indebted for the material from the case. There were no gross visceral lesions of importance. Microscopical examination. Alcohol, 95 per cent. Throughout the lumbar cord, the anterior horn cells showed in advanced degree all the changes described as following section of nerve trunks. Nearly every cell showed marked central or complete chromatolysis, with eccentricity of nucleus. Many of these cells had passed beyond this stage, and were entirely lacking in normal characters, containing no traces of chromatic substance and both cell body and nucleus appearing greatly shrunken. The earlier stages of the same lesions were found in the cervical cord. Throughout the cranial nerve nuclei the majority of the cells showed central or complete chromatolysis with eccen- tricity or protrusion of nuclei. Many of the cells in some nuclei however appeared quite normal. The nucleus X and nucleus ambiguus were extensively altered. The cells of the cortex and cerebellum showed only slight fading of chromatic bodies or appeared quite normal. The microscopical lesions in the central nervous system VOL. 1—no. 3—e 66 STUDIES ON GANGLION CELLS. in this case seem to accord in all essential particulars with the clinical history. The affection of the lower limbs was of long standing (2 mos.) and the shrinkage and loss of processes in the cells of the lumbar cord were the evidences of a rather old established lesion. The upper extremities were more recently affected and few of the shrunken cells were seen in the cervical enlargement, although many showed an advanced stage of the usual change. Respiration and the special senses were affected shortly "before death, and in the medulla only the earlier stages of cellular alteration were to be found. Opposed to these positive results, are the reports of some cases of neuritis in which the microscopical exami- nation failed to show cellular lesions to account for the clinical conditions. Not much significance can be attached to the report by Courmont, "of a case of probable neuritis in a rabbit in which no lesions were found in the cells of the spinal cord. The animal died with paraplegia four days after an intra- venous injection of a culture of the cholera bacillus. Dejerine and Thomas,9 7 report a case of alcoholic neu- ritis with paralysis in which the motor cells of the cord were found to be normal. Three years before death the patient suffered from complete paralysis of all extremities, but had gradually improved until motor power in the arms was normal, while the legs remained paralyzed. Nissl's stain showed no changes in the cells of the cord or medulla. This is an important case, but it appears to stand alone. Soukharoff98 also reports a case of undoubted toxic neuritis, in which he was unable to find any changes in the motor cells of the cord. STUDIES ON GANGLION CELLS. 67 Carriere,9 9 reports an absence of cellular lesions of the cord in two cases of peripheral neuritis, in tuberculous subjects, but the importance of his observations is lessened by the incomplete loss of function in the cases, and by the irregular distribution of the clinical lesions presented. The negative results reported in at least two of the above cases require that there should be further ob- servations in this department before it can be positively stated with what frequency and extent central cellular lesions may be expected in cases of peripheral neuritis. It seems reasonable to insist that no case should be accepted as showing no central lesions if only isolated groups of muscles are affected, or if every segment of the cord and medulla has not been submitted to the micro- scopical test. The weight of evidence seems to be strongly in favor of the belief that every case of established peripheral neu- ritis is associated with cellular changes in the spinal cord. Primary vs. Secondary Lesions of the Nerve Cell.—An interesting question developed by the study of central lesions in neuritis relates to the difference between primary and secondary lesions in the nerve cells. Marinesco1 ° ° was one of the first to note that the central cellular lesions in peripheral neuritis are similar to, though not quite identical with those following section of nerve roots. In one of his communications, he endeavors to distinguish between primary and secondary lesions of this type in the ganglion cell. When the cell is primarily affected, as after ligature of the aorta, or in Landry's paralysis, Marinesco finds that chromatolysis begins at the periphery of the cell, the nucleus remains central and the achromatic substance 68 STUDIES ON GANGLION CELLS. early shows changes such as vacuolation and rupture of processes. In secondary changes, as after section of nerve trunks, there follows partial or complete perinuclear chromatolysis, the nuclei migrate to the periphery, and the dendrites are not broken although their chromatic spindles are reduced in size and number. The writer cannot find that this plan of distinction between primary and secondary lesions of the nerve cell has been received with much favor. Ballet92 in discuss- ing Marinesco's and other views and reporting a case of central cellular lesions in beriberi, finds himself unable to state whether the cellular changes of peripheral neuritis are primary or secondary, since the lesions do not follow one type. Charcot, Marie, Raymond, and Babinski, (quoted by Marinesco) all believe that all polyneuritis depends on a primary lesion of the nerve cell. Colucci77 in an exhaustive discussion of pathological changes in ganglion cells demonstrated by various methods, is unable to distinguish between primary and secondary lesions. He finds great similarity between the primary lesions in Landry's paralysis, etc., and those in- duced by section of nerve trunks. Commenting on Mar- inesco's views, he concludes that the peculiarities of primary and secondary lesions as described by Marinesco indicate only variations in the resistance of the different elements of the cell, and depend upon the acuteness or chronicity of the morbid process, but do not show dis- tinctly any differences distinguishing a primary and a secondary origin. The writer's observations on a considerable variety of conditions, support the conclusion of Colucci. The changes described by Marinesco as secondary are certainly STUDIES ON GANGLION CELLS. 69 found in the great majority of altered cells in the general toxaemia of the infectious diseases. That a morphological distinction between primary and secondary lesions should exist seems to be a reasonable expectation, but further studies are needed before it can be demonstrated. II.—Myelitis.—Friedmann's101 well-known researches on the cellular lesions of acute exudative encephalitis and myelitis were among the first applications of Nissl's method to general pathology, and did much to bring the method into general prominence. After reviewing the scheme of degenerative changes in the ganglion cell, given by Mey- nert in 1868, Friedmann notes the distinct additions to the knowledge of the subject furnished by Nissl's method. On the second day of the myelitic process, Friedmann found some cells in an advanced stage of chromatolysis, which he calls "homogeneous swelling." This process, he concluded, begins at the centre of the cell and gradu- ally destroys all chromatic bodies. The dendrites and nuclei are often in good condition when the entire cell body is swollen and homogeneous, but later, the dendritic spindles fade, the nuclear outlines become irregular and indefinite and the nucleolus becomes divided. Another variety of lesion which he regarded as distinct from though often associated with simple chromatolysis, he denominates as "granular (molecular) or fatty degeneration." In this process the chromatic bodies first break up into fine, deeply staining granules, which later lose their affinity for methylene blue, undergo a fatty transformation, and the cell is reduced to a pale granular mass devoid of pro- cesses. This alteration is usually seen only in old inflam- matory foci, being rare in acute inflammation. Friedmann also noted in some cells a peripheral chromatolysis. 70 STUDIES ON GANGLION CELLS. As a result of these studies, and of other previous in- vestigations, Friedmann was convinced that the above forms of change, partially corresponding to Meynert's "simple atrophy" and "cloudy swelling," indicate a dis- tinct pathological condition in the ganglion cell. He was unable to find them in normal specimens or as the result of physiological involution processes (pigment degenera- tion). He concluded also that a partially degenerated cell may still functionate. III.—Landry's Paralysis.—In Landry's paralysis degen- erative changes in the ganglion cell have been described by Ottinger and Marinesco,102 Ballet,103 Remlinger,x °4 Bailey and Ewing,105 Marie and Marinesco,106 Picci- nino,107 and Mills and Spiller.108 These lesions con- sisted in all stages of chromatolysis, peripheral, peri- nuclear, and general; in the molecular disintegration of the achromatic substance, with the formation of vacuoles and clefts; irregularities in cell outline, and rupture of processes (Marinesco); and in a series of nuclear changes, terminating in the loss of this structure. These lesions have been found in cases showing distinct exudative in- flammatory changes, both in the vicinity of and at a distance from the inflammatory foci. In the case of Picci- nino, they were of general distribution, but distinct evidences of exudative inflammation were absent, although numerous cocci were found in the vessels and tissues. This case seems to furnish a much needed transition stage between fatal cases of Landry's paralysis, without lesions demon- strable by older methods, and the well marked forms with myelitis, and would apparently confirm the belief expressed by Bailey and the writer, that the employment of Nissl's stain would serve to explain this enigmatical group of cases, in which no lesions have hitherto been discovered. STUDIES ON GANGLION CELLS. 7 I IV.—Tabes.—It was anticipated that the employment of Nissl's stain in the study of tabes would greatly enlarge the knowledge of the early pathological changes in this disease, if not certainly determine the seat of the primary lesion. The researches of Wollenberg, Strobe (see Schaffer),109 and others, who by the application of Weigert's and Van Gieson's staining methods, had demonstrated a consider- able variety of lesions in the spinal ganglion cells in tabes, indicated that the primary lesion is located in these ganglia, and that more delicate technical methods might reveal some earlier lesions not previously demonstrated. Schaffer11 ° examined the cord of a fatal case of tabes, with Argyl-Robertson pupil, Westphal's symptom, and joint lesions. The cells of the cervical cord were nearly all normal. In the lumbar region there were some normal cells, but many showed a fine subdivision of chromatic bodies and diffuse .staining about the nucleus, while in others, this alteration had become general. Marinesco,111 in a case of general paresis and tabes, found marked central chromatolysis and eccentricity of nuclei in the cells of Clark's column. He endeavors to explain thereby the loss of reflexes in this disease, sug- gesting that the loss of centrifugal trophic influences which no longer reach these cells, on account of the im- pairment of the sensory root fibres, induces the cellular lesions described. Similar changes, which he states have been found in the anterior horn cells of tabes, may account for the relaxation of muscles and ligaments, characterizing tabes. On the other hand, Babes and Kremnitzer,112 as a result of their study of a case of tabes, conclude that the lesions in the spinal ganglia demonstrable by Pal's and a 72 STUDIES ON GANGLION CELLS. modified Nissl's method, are inadequate as a basis for the clinical symptoms found in tabes. Schaffer also found no pathological alterations demon- strable by Nissl's method in the cells of the spinal ganglia in three cases of fully established tabes. The cells show- ing advanced chromatolysis described by Marinesco in the spinal ganglia of tabes he identifies as the clear type of cells normally present, according to Lenhossek, et al., in these ganglia. Juliusberger and Meyer113 also report the entire absence of chromatolytic or other changes in the spinal ganglion cells in two cases of advanced tabes. While agreeing with Schaffer that these cells are usually of normal appearance in tabes, they fail to regard this fact as evidence against the belief that the spinal ganglia are the primary seat of the lesion in this disease. According to Juliusberger and Meyer the normal appearance of the spinal ganglia in tabes may indicate only that these cells have adjusted themselves gradually to their new and abnormal environment and still retaining their functions, at least in part, have preserved their chromatic structures. Finally, the writer found no marked or characteristic cellular lesions in the lumbar cord of a well advanced case of tabes, dying from intercurrent pneumonia, while the chromatic structures in the cells of the adjacent spinal ganglia were remarkably well preserved. In this case, however, the disease had long been stationary. The weight of evidence as gathered from the above observations, indicates very strongly that neither is the primary lesion in locomotor ataxia to be found in the cells of the spinal ganglia, notwithstanding the arguments of Juliusberger and Meyer, nor are these ganglia affected in STUDIES ON GANGLION CELLS. 73 any degree comparable to the changes found in the pos- terior tracts of the cord. V.—Descending Bulbar Paralysis.—Marinesco114 re- ports, in a case of this description, advanced chromatol- ysis in the cells of the XII, VII, VI, and III, cranial nuclei and in the anterior horn cells of the lower medulla. He hesitates, however, to claim that these changes are char- acteristic of the disease, as it is not yet known how often they occur in normal cases, nor what is their relation to the states of activity and repose, nor to what extent they may be produced by fever or artificial agencies. VI.—Diseases of the Cortex.—In dementia paralytica Nagy115 found various phases of chromatolysis and cellu- lar degeneration up to complete disintegration of the ganglion cell. These lesions were most general in the frontal lobes and most advanced in cases with epileptiform seizures. In cases of mania, he found the earlier stages of chromatolysis. Berger116 examined the anterior horn cells in twelve cases of dementia paralytica, and found lesions affecting principally the chromatic substance in 83 per cent of these cases. He failed to find a strict parallel between these cellular lesions and those of the fibres and cortex, or between them and the clinical symptoms of dementia and paralysis. Boedecker and Juliusberger117 found a marked reduc- tion in the number of cortical cells and various grades of chromatolysis and cellular atrophy in three cases of para- lytic dementia. In general paresis Belmondo118 has described advanced lesions in the cells of the zona Rolandica and in the frontal lobe, while in other parts of the cortex the cells were moderately chromatophilic. The type of lesion observed 74 STUDIES ON GANGLION CELLS. seems to be that of a molecular degeneration, in which chromatolysis is followed by changes in the achromatic substance, with partial atrophy and marked pigmentation. Crisafulli119 also notes in the same disease a great variety of cellular changes, most advanced in the frontal lobes, although the lesions were not limited to this region. He found pallor, granular disintegration and loss of chromatic substance. The cell bodies were often atrophic or contained an excess of yellowish pigment, and their numbers were reduced. The nuclei were often eccentric and all stages of the destruction of the nucleus were observed. While the alterations shown by Nissl's method were not less constant than those demonstrable by other methods, Crisafulli does not consider them characteristic of the disease, or in any way different from those seen in some other diseases. In epileptic insanity, Tirelli120 describes similar lesions in the cortical cells. He believes that the cellular lesions in the cases are not specific, but depend largely upon nutri- tive disturbances, probably of the nature of deficient oxy- genation. On the other hand, he believes that the lesions of Purkinje's cells are related to distinct cerebral processes, and are specially dependent upon convulsive seizures (Cf. the writer's observations on eclampsia). In general insanity, Christiani,121 also, describes very distinct cortical lesions. The cells in this case showed peripheral and perinuclear chromatolysis, their outlines were indistinct or irregular. The achromatic substance was chromatophilic and gave evidence of granular and pigment degeneration, and the formation of vacuoles. The processes were often pale, atrophic, and varicose. The nuclei were often granular, deformed, and eccentric. In a case of progressive paralysis, Heilbronner18 8 de- STUDIES ON GANGLION CELLS. 75 scribed the various milder grades of chromatolysis which he had noted in the cortical cells. The lesions resembled those seen in alcoholic neuritis, and after section of nerve trunks. In an acute case of paranoia, Cramer183 found the large pyramidal cells of the cortex to be homogeneous, and only in a few cells could he find any granular detritus of the chromatic structures. In acute delirium, Alsheimer124 describes three distinct conditions of the cortex. First.—All cortical regions are affected. The cortical cells are distinctly swollen, and there is general chromatol- ysis; the processes are visible for long distances (partial chromatophilia). The nuclei are little altered. Cases of cerebral neurasthenia (erschopfungspsychosen) showed changes of this character. Second.—All cortical regions are affected. The cells are swollen, their processes are traceable for long distances, the chromatic structures are fused together in a spongy or faintly reticulated mass. Nuclear changes are present, there being a distinct tendency toward cellular degenera- tion. The "intoxication psychoses" are associated with changes of this type. Third.—The deeper cortical layers are chiefly affected. The cells are in an advanced stage of degeneration and are often atrophic. The nuclei are swollen and irregular. Here belong the cases of acute delirium occurring in the course of chronic mental diseases. From his observations, Alsheimer concludes that the term "acute delirium" at present includes a variety of entirely different pathologi- cal processes. In a case of idiocy in a girl two and one-half years of age, Warda125 found that the cells were reduced in number, 76 STUDIES ON GANGLION CELLS. their protoplasm granular, their nuclei pale, and often lacking in nucleoli. The extensive monograph of Hammarberg126 trans- lated and published by Henschen, shows that the essential lesions of idiocy consist in congenital deficiency in number and development of the cortical cells. The more recent lesions in the chromatic substance of these cells are there- fore of secondary origin and importance. Juliusberger18 7 examined the anterior horn cells in two cases of epilepsy dying from convulsions, and found all stages of chromatolysis in many cells. He regards these lesions as identical with those seen after ligature of the aorta and in poisoning by arsenic. The review of the above cases indicates that in various mental diseases, the chromatic structures of the cortical cell are found after death to be considerably disturbed. With the possible exception of the studies of Alsheimer, it does not appear that any connection has been established between these cellular lesions and the mental disorder from which the patient suffered. In most of the reports the authors have failed to detail the immediate cause and manner of death, although, of course, such information is required before any conclusions may be drawn in regard to the significance of the cellular lesions found in these cases. B.—Acute Intoxications. Much of the experimental study of Nissl's method has referred to the pathological changes in ganglion cells, in- duced by the administration of various mineral or vege- table poisons. Arsenical Poisoning.—In 1891 Erlicki and Rybalkin,12 8 examining the spinal gray matter stained by carmine, from STUDIES ON GANGLION CELLS. 77 cases of chronic arsenical poisoning, noted a loss of stria- tion in the cell bodies which was probably referable to the destruction of chromatic masses. By the same method they observed that the number of cells in the anterior horns was reduced, that the borders of the remaining cells were rounded, that the dendrites were often lost, and that many cells were reduced to a mass of yellowish granules. Nissl129 first described the lesion of acute and chronic arsenical poisoning in rabbits. He found as the first effects an increase in size, rounding of contour of the chro- matic granules, and deeper staining of the achromatic sub- stance. Soon the enlarged bodies began to grow paler, to look "crumbly," and were at last subdivided into many fine granules, so that the entire cell body appeared "dusty." Finally even the fine granules disappeared, and the cell sometimes went on to disintegration. During the early stage of chromatolysis fine granules appear in the achro- matic substance indicating a simultaneous change in this element of the cell. These chr^is begin at one pole and gradually involve the entire cell. Schaffer130 in 1893 also employed Nissl's method in the examination of changes in ganglion cells from arsenical poisoning. He administered 149 cc. of yV per cent. sol. of potassium arsenite to a dog during 65 days, thereby pro- ducing paresis of the hind legs. He found that the first effects of the poison were the appearance of light points in the peripheral chromatic bodies, which gradually increase in size until the whole mass is bleached and pale. In a rabbit dying after six days from arsenical poisoning, the bleaching of the chromatic bodies appeared to affect the' entire chromatic mass from the first. Finally, the entire cell body showed a number of small, pale, bluish granules, the detritus of the chromatic bodies. 78 STUDIES ON GANGLION CELLS. According to Schaffer, the lesions produced by chronic antimonial poisoning are similar to those from arsenic The recent studies of Lugaro131 of the effects of arsen- ical and lead poisoning support the results of Nissl and Schaffer. Lugaro finds that the chromatic bodies are at first altered as these authors describe. Later the achro- matic substance is involved and when this point is reached the lesion is probably permanent. The character of the lesions produced by mineral and other poisons according to Lugaro, varies both with the nature of the poison and the type of cell. Dexler13 8 has recently reported a study of chronic arsen- ical poisoning and its effects, in the spinal cells of the horse. He discovered relatively few changes in the cord below the cervical region. In the cervical region many normal cells remained. Others showed a circumscribed area devoid of chromatic bodies, while some were entirely bereft of chromatic substance, or beset with fine granules. In a few cells the chromatic bodies had become homo- geneous and the achromatic substance was deeply stained. Lead Poisoning.—Schaffer's studies were extended also to the effects of chronic lead poisoning in rabbits and dogs. The first change noted was a subdivision of perinuclear chromatic bodies into fine granules, with the appearance of fine vacuoles in the peripheral bodies, and leading finally to the well known "dusty" appearance of the cell. In many cells he further describes the alterations now termed '' diffuse chromatophilia " and regarded as artifacts. Nissl133 reports that the changes due to lead poisoning in rabbits consist in granular disintegration of the chro- matophilic bodies of spinal ganglionic cells, while only the borders of the larger and more resistant masses are bleached. In the cortical cells, while the chromatic STUDIES ON GANGLION CELLS. 79 substance is lost, the achromatic portion stains deeply, and the outlines of the cells are intact. Sarbo134 and Nissl133 both find that in subacute phos- phorus poisoningthe anterior horn cells of the rabbit show chromatolysis, beginning irregularly at one or more poles of the cell, later affecting the entire cell. The nucleus becomes homogeneous and darkly stained. Somewhat indefinite changes are referred by Nissl to the effects of silver poisoning, from which the chromatic bodies of the spinal stichochromes gradually fade, while the achromatic subtance stains deeply and is transformed into a dark reticulated structure. This process leads to a characteristic striation by light and dark lines in the axis cylinder process. Later, the cells become atrophic, but chromatic bodies may persist. Strychnine Poiso?iing.—Somewhat peculiar changes have been described by Dehio135 and Nissl, after poisoning by strychnine. After fatal doses, followed by convulsions, Dehio found that the medial dorsal group of sp*in*al sticho- chromes was most affected, while the cells of the poste- rior horns and spinal ganglia remained normal. The chromatic bodies of the spinal stichochromes stained very deeply, and were in some instances reduced to a mass of fine granules. Nissl finds that in subacute strychnine poisoning, the changes are characteristic. The achromatic substance stains diffusely, while the chromatic bodies are thicker, more closely packed together, and appear coarsely gran- ular. Often these bodies are condensed about the nucleus leaving the periphery of the cell homogeneous, but deeply stained, while the dendrites are very distinct. Maneresi136 states that strychnine poisoning causes an 8o STUDIES ON GANGLION CELLS. increase in the size of the nucleus, while chloroform reduces the volume of the nucleus in the spinal stichochrome. Cellular lesions of a very similar character but usually less definite, have been described as resulting from the ad- ministration in poisonous doses of veratrine and trional by Nissl13 3; of nicotine by Vas13 7 and Pandi13 8; of cocaine, antipyrine, and the bromides by Pandi; of morphine by Sarbo and Saratschow13 9; of bichloride of mercury by Dotto140 and by Tirelli141, of carbonic oxide and sulphu- retted hydrogen by Borro142; and of phosphorus by Rossi143. Alcoholism.—The effects of alcoholic poisoning in the ganglionic cells have been investigated by several writers. Vas137 first described the alterations induced in the ganglion cells by chronic alcoholic poisoning. After the daily injection of moderate amounts of alcohol, during a a period of 6 to 12 weeks, a state of general malnutrition was produced in dogs and rabbits, and in this condition the spinal stichochromes and spinal and sympathetic ganglion cells, in areas of irregular distribution, showed central chromatolysis or the lesions described by Fried- mann as "homogeneous swelling." These changes he regarded as the result of the general malnutrition of the animal and not of a specific action of alcohol. Dehio144 described the changes in Purkinje's cells after acute fatal poisoning by alcohol, administered to rabbits through the stomach. In very acute cases no definite alterations were observed. When the animals lived 18 to 36 hours, characteristic changes were noted affecting the whole or a small portion of the body. The chromatic network of Purkinje's cells was replaced by many fine granules irregularly arranged, while the achromatic sub- stance stained diffusely light blue. The dendrites were STUDIES ON GANGLION CELLS. 8l usually unaffected and many normal cells were found. No definite lesions were found in other parts of the central nervous system. Andriezen,J 4 s investigating the lesions of alcoholic insanity by Golgi's and Nissl's methods combined, found by the latter, in the cortical cells, moderate chromatophilia of the cell body, swelling and indistinctness of the chro- matic masses, thickening of the intranuclear network, and increased pigmentation. Berkeley146 investigated the lesions of alcoholic poison- ing in the cortical nerve cells by Golgi's and Nissl's methods combined. Golgi's method revealed a distinct shrinkage of all cortical cells, varicose atrophy of the dendrites, disappearance of the gemmulae, and a roughen- ing of the cell body. After Nissl's method, the cell bodies stained more deeply than in normal specimens, the chro- matic bodies were indistinct, the achromatic substance was moderately chromatophilic, the nuclei contained numerous fine granules, and the nucleoli were much enlarged. Stewart147 verified the results of Dehio, injecting alco- hol into the peritoneal cavity of cats. Both in Purkinje's cells, and less evidently in the spinal stichochromes, chromatolysis, most marked peripherally, and diffuse staining of the achromatic portion of the cells, were observed. The writer is unable to contribute anything in the experimental study of alcoholism, but his series of cases furnish two examples of fatal alcoholism in which very striking cellular lesions were found throughout the central nervous system. These cases were males, aged 25 and 29 years. They vol. 1—no. 3—F. 82 STUDIES ON GANGLION CELLS. died after prolonged periods of intoxication lasting six and twelve weeks respectively, in the typical condition of delirium tremens. The temperature rose before death to 1040 and 1050. One case was complicated by acute de- generation of the kidneys, the other by terminal catarrhal pneumonia of slight extent. These cases represent the ordinary conditions found in fatal alcoholism in the human subject, and in spite of the complications, some of which are almost always present in such cases, are believed to represent in considerable purity, the lesions produced by prolonged alcoholic poisoning in the human subject. No such lesions have been found by the writer after fatal nephritis, pneumonia, or as the result of a temperature of 1060. The autopsies were made six and twelve hours after death, and the preservation of the tissues (Lang's fluid, twenty-four hours) was satisfactory. In both cases the lesions demonstrable by Nissl's method were nearly identical. In the spinal, medullary, and cortical stichochromes the usual type of lesion was that of extreme chromatolysis. No normal cells were seen anywhere, and in only a few were there any traces of the peripheral ring of chromatic bodies, often seen when the disintegrating process begins about the nucleus. In many cells, especially in the cranial nuclei, the lesions had advanced far beyond simple chromatolysis, and the cell outlines were irregular and ragged and considerable areas of the cells were almost transparent. The remains of the chromatic bodies appeared as a uniform deposit of fine granules or in the form of a network of fine granules, or no traces of them could be found. In badly altered cells, the nuclei were almost invariably markedly eccentric STUDIES ON GANGLION CELLS. 83 or projected beyond the cell border. They were not found to stain diffusely. Yellowish granular pigment was rarely seen in these cells. Many of the Purkinje cells contained a moderate num- ber of large distinct chromatic bodies, but usually these bodies were thin, ragged, granular, or absent, the deficiency being most marked at the poles and not about the nuclei. In the cortical archyochromes the chromatic network was markedly bleached, sometimes coarsely granular and indistinct. All through the central nervous system, the dilatation of capillaries was striking. In the first case (the patient was said not to have been sober for three months) the chro- matolysis was usually more complete than in the second. It appears, therefore, that acute alcoholism in the human subject is associated with lesions in the ganglion cells, comparable with, but much more marked than those found after experimental alcoholic poisoning in animals, nor can one hesitate to attribute in large measure the violent nervous symptoms observed in these cases, to the cellular lesions revealed by Nissl's stain and only faintly indicated by other technical methods. Carbolic Acid Poisoning.—Two cases of fatal poisoning by carbolic acid have come into the writer's hands for examination by Nissl's method. The ages of these sub- jects were twenty-two and forty years. Each had swallowed a large quantity of the acid with suicidal intent, and both died within two or three hours, with the usual well marked symptoms. At the autopsies made twelve and twenty-four hours after death, the gastric mucosa was found deeply necrotic. The brain and cord after removal exhaled a strong odor of carbolic acid, and it was evident that the poisonous agent had reached the 84 STUDIES ON GANGLION CELLS. central nervous system in considerable concentration. The cellular lesions found in these cases were indistinct, and unsatisfactory, a result for which the early deaths may be held responsible. In the cortical archyochromes the meshes of the chro- matic network were often much widened. The distinct- ness of the network was unchanged. In the spinal and cortical stichochromes, the only changes discovered was an irregularity and raggedness of the chromatic bodies. Many of the large stichochromes appeared normal in every respect. About some of these large cells there was a peculiar diffusion of homogeneous chromatic substance, outside the cell, which the writer is forced to regard as artificial, although it was not found in any other conditions. In both cases a few examples of partial perinuclear and peripheral chromatolysis were noted among Purkinje's cells and the cortical and spinal stichochromes. The examination of these cases failed to show any characteristic lesions as the result of fatal poisoning by an agent inducing pronounced nervous symptoms, such as coma, convulsions, and paralysis, and indicates that the functions of ganglionic cells may be very largely inhib- ited, perhaps completely, without leaving morphological changes demonstrable by Nissl's method. That cases of longer duration will furnish distinct general cellular lesions seems very probable. Hydrochloric Acid Poisoning.—A case of poisoning by hydrochloric acid came under observation during the course of this study. Male, 48 years. The patient was said by friends to have swallowed the contents of a bottle labeled '' muriatic acid." He was seized with violent pain in the epigastrium and brought in an incoherent mental condition to the hos- pital, dying twelve hours later with symptoms of shock. STUDIES ON GANGLION CELLS. 85 Autopsy three and one-half hours after death. There was superficial necrosis of the lips, mouth, oesophagus and stomach. The stomach and small intestine was filled with a bloody fluid of strongly acid reaction. The blood was everywhere fluid and of a brilliant red color. The lungs were very oedematous. The viscera, especially the liver and kidneys, were intensely congested. Fixation, 97 per cent alcohol. In the cord and medulla a great variety of the earlier stages of chromatolysis were observed. The main features of the lesion in these cells were the subdivision often minute, of the chromatic bodies, which gave the cells a rather diffusely stained appearance, and irregularity in the outlines of many cells. All cells appeared more or less affected. Central chro- matolysis was rare. In the cortex the changes were rather more distinct than elsewhere. The large ganglionic cells of the motor areas showed extreme subdivision and irregu- larity of chromatic bodies. The chromatic network of the archyochromes was granular and very irregular. No dis- tinct nuclear changes were observed. Purkirije^s cells showed an extreme reduction in the size and number of the chromatic bodies. There was distinct chromatophilia of the achromatic portion of the cell, not affecting the nuclei, which appeared very clear. With the exception of the tendency toward diffuse staining, none of these features can be regarded as specific, while the chro- matophilia, if not accidental, is probably to be referred to a slightly altered reaction of the nervous tissue and cannot be regarded as indicating a vital process. There was one small hemorrhage in the floor of the fourth ventricle at the level of the sixth nucleus. Morphine Poisoning.—The present series includes three cases of poisoning by morphine. Case I.—Male, 45 years. Had been addicted to the use of the drug for several years, finally using 16 grains of morphine hypodermically injected, each day, and had suffered in an extreme degree from the general symptoms referable to this habit. Was said to have eaten nothing for one week before death. After a very large injection, quantity unknown, was brought to hospital in coma, dying within a few hours with typical symptoms of morphine poisoning. Autopsy six hours after death. There was moderate fatty degeneration of heart-muscle, liver, and kidney. The lungs were very oedematous, and the viscera showed 86 STUDIES ON GANGLION CELLS. marked venous congestion. The pancreas was very atrophic, being largely replaced by fat. There was con- siderable oedema of the brain. Fixation, Lang's fluid, 24 hours. The chief feature of the changes revealed by Nissl's stain was a marked diminution in the quantity of chro- matic substance in nearly all cells of the central nervous system. The chromatic bodies in the cells of the cord, medulla, cerebrum, and cerebellum, were very deficient in size and number or often entirely absent. Purkinje's cells were very faint, showing a few small, narrow chromatic bodies, very regularly arranged in concentric rings. Nuclear changes, as a rule, were not noted. In the medullary nuclei, there were some cells still retaining chromatic bodies of considerable size but markedly subdivided. In some of these cells the nuclei were shrunken and often eccentric. The quantity of yellowish granular pigment was much more abundant than usual in most regions of the central nervous system. Case II.—Female, age 24 years. Had been addicted to the moderate use of the drug for a few months only, but was able to attend regularly to her work as dressmaker. In a fit of despondency she took a large quantity of mor- phine by mouth, and in spite of treatment, died twelve hours later, with typical symptoms of morphine poisoning. Autopsy six hours after death. There was extreme oedema of the lungs, and marked venous congestion of all viscera, but no other gross lesions of importance. Microscopical examination. Van Gehuchten's fluid. The stichochrome cells throughout the central nervous system showed changes which in many respects were peculiar. When examined with a low power these cells appeared to have lost their normal distinctly striated appearance, many appearing diffusely and unevenly stained, while their outlines were extremely irregular. When examined with a high power, the above peculiarities were found to consist in a marked subdivision of the chro- matic bodies, which were enlarged and very irregularly and minutely subdivided. In the medulla the large cells were extensively altered, further, by the appearance of clefts in the cell bodies, similar to those described in other conditions by Nageotti and Etlinger.14 8 In this region also the loss of chromatic substance was very uneven, some areas of the cells appear- STUDIES ON GANGLION CETLS. 87 ing completely bleached, others showing the minute sub- division, while in some spots the chromatic masses seemed fused together. The majority of the cell nuclei were shrunken and markedly eccentric, while the loss of chromatic substance was as a rule greatest about the nucleus. About many of the nuclei irregular masses and rods of chromatic sub- stance were heaped. See Plate VI, Fig. 5. Throughout the cortex changes of a similar character were noted. Purkinje^s cells of the cerebellum were less affected than the cells of most other regions. The irregularity in the effects of the chromatolytic process, the ragged appearance of the cell borders, the appearance of clefts, and the frequency of central chro- matolysis associated with eccentricity of nuclei, are the features peculiar to this case. The last mentioned abnor- mality is of special interest in connection with the well- known effect of morphine upon the peripheral nerve filaments. Case III was identical in all important respects with Case II. Miscellaneous Intoxications. Effects of Snake Poison—Phisalix, Charrin and Claude14 8 report the examination of the nervous system by Nissl's method in a rabbit dying some time after a series of in- jections with the poison of the viper. Five injections were given in a period of two weeks and the animal fell into a state of cachexia, marked by partial paralysis and anaesthesia of the limbs, and died at the end of three months. The nerve trunks showed advanced lesions of parenchymatous neuritis, while the cord presented the changes of myelitis. A great variety of changes were noted in the cells, including total loss of chromatic struc- ture, loss of processes and beginning atrophic lesions. Effects of Poisoning by Blood Serum.—Uhlenhuth and Moxter16 ° killed rabbits by two to ten daily injections of the serum of beef and human blood, and found uniformly 88 STUDIES ON GANGLION CELLS. in the spinal stichochromes the milder grades of peripheral chromatolysis, and swelling of the remaining chromatic bodies. Many of the animals died in convulsions. Effects of Toxines of Bacillus Botulinus.—In animals dying with characteristic symptoms of poisoning after the injection of the toxines of the bacillus botulinus (isolated from decaying meat by Van Ermengen) Marinesco161 found very extensive lesions of irregular distribution throughout the central nervous system, most marked in the medulla, basal ganglia, and cord. The earlier changes consisted in simple granular chromatolysis, peripheral or perinuclear, with swelling of the cell body and dendrites, and without alteration in the achromatic portion or nucleus. Later, lacunae formed in the cell body from destruction of the achromatic substance, and it appears from the report that certain nuclear changes were usually but not always associated with this affection of the achromatic structures. The lesions resembled those following experimental anaemia. Kempner and Pollak15 8 report some interesting observ- ations on the condition of the nerve cells in experimental poisoning by the toxins of bacillus botulinus. The changes described are very similar to those noted by Marinesco. In animals dying after a full dose of the toxine there was complete dissoluton of the chromatic structures of the anterior horn cells. The first distinct changes were noted only after the lapse of twenty hours. The injection of anti-toxic serum nine hours after the toxine prevented the cellular changes, and if withheld for twenty-four hours, sufficed to save the animal's life, but not to prevent marked cellular lesions. They failed to find a distinct parallel between the severity of the symptoms and the grade of cellular lesions. STUDIES ON GANGLION CELLS. 89 C.—A uto-Intoxications. Eclampsia.—The central nervous system was fully ex- amined in two cases of eclampsia, and the cord alone was secured for study in one other. Case I—Multipara, aged 38 years, was brought into the Sloane Maternity Hospital in convulsions, which had for fourteen hours been recurring in rapid succes- sion. The uterus was promptly emptied, and the patient kept under light anaesthesia by chloroform. She received also rectal enemata of chloral, an intravenous infusion of hot salt sol. and was placed in a hot pack. The urine boiled solid with albumen, and was finally sup- pressed. The temperature rose to 106.8°. She died about twenty-four hours after the first convulsion. The autopsy was held one and one-half hours after death, and revealed advanced chronic diffuse nephritis and hemorrhagic hepatitis, without other lesions of importance. Microscopical examination. Lang's fluid. The spinal and medullary stichochromes showed a great variety of appearances resulting from alteration of the chromatic bodies. A few cells appeared nearly intact. Most of them^showed a moderate grade of chromatolysis, usually peripheral. Some had lost nearly all trace of chromatic bodies, and were extremely pale. The nuclei were often eccentric In Purkinje's cells there was a peculiar type of advanced change, consisting in complete or nearly complete loss of chromatic bodies, with a fine granular network persisting. The nuclei were shrunken and moderately chromatophilic The nucleoli were enormously swollen, and many con- tained three to six small vacuoles. Plate VI, Fig. 6. In the cortex the small pyramidal cells were very pale, from deficiency of chromatic network, but without distinct nuclear changes. The large and giant pyramidal cells showed marked subdivision and loss of chromatic bodies. Case II—Multipara (8th child), 35 years; brought to hospital in semi-conscious condition. There was marked general oedema. The urine was scanty and highly albu- minous. There was one violent eclamptic seizure before delivery, which was promptly effected, and one after- wards. A hot pack caused slight diaphoresis, but the pulse failed rapidly, the temperature remaining low, and she died six hours after admission. 90 STUDIES ON GANGLION CELLS. The autopsy, twelve hours after death, showed slight chronic nephritis, hemorrhagic hepatitis, a deep cervical laceration, running above os internum. Hemorrhage was partially responsible for the death. Fixation, Lang's fluid. Microscopical examination. Lang's fluid. The spinal and medullary stichochromes, with few ex- ceptions, showed moderate or advanced chromatolysis, either diffuse, peripheral, or perinuclear. In the nuc. X most of the cells showed marked central chromatolysis with eccentricity of nuclei. In the Purkinje cells there was minute subdivision of the chromatic bodies, but no nuclear changes. The large and small pyramidal cells of the cortex showed moderate grades of chromatolysis of various types. In a third case of eclampsia, dying on the third day from pneumonia, very slight changes were found in the spinal stichochromes. The brain could not be secured. With the exception of the nuclear changes in the Pur- kinje cells of the first case, no peculiar cellular lesions were noted in these cases of eclampsia. The condition of Pur- kinje's cells being only an isolated observation, it will be sufficient to place it on record without drawing any con- clusions as to its probable significance. Urcemia.—The cellular changes in the central nervous system in experimental uraemia of dogs, have been studied by Acquisto and Pusateri.16 3 In the anterior horn cells of the cord they found loss of peripheral chromatic bodies, while the perinuclear bodies had undergone granular dis- integration. In the cerebral cortex different stages of chromatolysis were noted. In some cells the peripheral chromatic bodies and the dendritic spindles were normal, while in the perinuclear zones there was advanced chro- matolysis. Other cells were homogeneous, and their nuclei dark and indistinct. Sacerdotti and Ottolenghi184 also examined the central nervous system in dogs dying four to seven days after ligature of both ureters. By Golgi's method they demon- STUDIES ON GANGLION CELLS. 91 strated varicose atrophy of the dendrites while the axis cylinder process remained normal. The lesions were most marked in the cerebral cortex where all cells were affected, but were also abundant in the pes hippocampus. Nissl's stain failed to show the chromatolytic changes in the cortical cells described by Acquisto and Pusateri. They did not examine the medulla. Donetti15 5 examined by Golgi's and Nissl's methods the central nervous system of rabbits dying from uraemia after bilateral nephrectomy. By Golgi's method he found varicose atrophy of dendrites with other less definite changes in the cortical, cerebellar, and spinal cells. After Nissl's method there were no distinct alterations in the cortical cells. In the medulla and cord the nuclei of the large cells were very often eccentric, the chromatic sub- stance was reduced in amount, the bodies were finely frag- mented, and many cells contained vacuoles. He does not believe that these lesions are characteristic of uraemia. The writer's series includes six cases of uraemia in which marked cellular lesions were found, of irregular character and distribution. Case I.—Male, 19 years. Had suffered for one year from frequent headache and nausea. Nov. 9, he suddenly became unconscious, recovering shortly, with paralysis of right arm. Headache and nausea continuing, on Nov. 12, there was a general convulsion, followed by drowsiness. At this time the urine was scanty, s.g. 1010, and contained considerable albumen and a few casts. On Nov. 20 the drowsiness had deepened into coma. Temperature ioo°. Nov. 21, after a severe convulsion, he died. Temperature 1040. Autopsy four hours after death. The kidneys showed extreme changes of chronic diffuse nephritis and were very small. There were no other visceral lesions of im- portance. The brain and pia were oedematous. Microscopical examination. Sat. bichloride. In the medulla the cells of the nuc. XII were very 92 STUDIES ON GANGLION CELLS. slightly altered, the chromatic bodies in a few cells being moderately subdivided. Above the nuc. XII there were no perfectly normal cells. The perinuclear zones were usually lacking in chromatic bodies and either entirely homogeneous or presenting a few faint granules. Along the peripheries of the cells, or at the poles, a few bodies usually persisted, but were irregularly clumped or sub- divided. Some of the deeper cells were entirely bleached. Many Purkinje's cells appeared normal; in most of them the chromatic bodies were finely subdivided. In the frontal cortex the cells showed no distinct alter- ations, the chromatic network being distinct. In the motor areas the large cells exhibited changes similar to but less marked than those in the upper medulla. The capillaries were everywhere dilated. Case II.—Male, 60 years. Excessively alcoholic. Acute illness began April 3, when he was found dazed and help- less on the floor of his bedroom. April 4, he was feverish and complained of pain in the chest and cough. April 6, there were two general convulsions, and he was brought to hospital, comatose, pulse very weak, temperature 1040, urine suppressed. April 8, there were three severe con- vulsions. Stools involuntary. Urine suppressed. April 9, died; temperature 1040. Autopsy, five hours after death. The posterior two- thirds of right lower lobe were consolidated. Lying over the spinal column was a single, small, irregular shaped kidney, in a very advanced stage of chronic nephritis. The pia was very oedematous. The basal arteries were sclerosed. Microscopical examination. Sat. Bichloride. The lesions of the nerve cells were similar in nearly all respects to those described in Case I. The changes, how- ever, were more uniform and advanced, and pigmentation was everywhere extreme. Case III.—Female, 50 years. For three months had suffered continuously from headache, vertigo, oedema of legs, and dyspnoea. The urine contained a large amount of albumen and many granular casts. On her last admis- sion to the hospital vomiting and diarrhoea were added to above symptoms, the urine was often very scanty, and the dyspnoea was extreme. During the last weeks, the inter- mittent uraemic symptoms became pronounced, and there was continuous mild coma, scanty excretion of urine, and subnormal temperature. STUDIES ON GANGLION CELLS. 93 Autopsy one hour after death. The heart was much hypertrophied. The lungs moderately congested. The kidneys were enlarged; the capsules adherent, surface irregular, and presenting a few cysts; the markings greatly distorted. Microscopical examination. Alcohol 95 per cent. In the medulla, the cells of the nuc. XII were very slightly altered, most of them appearing quite normal. Above this nucleus there was uniform subdivision of chromatic bodies in nearly all cells. Central chromatolysis and eccentricity of nuclei were frequent. The superficial nuc. X, and nearly all the deeper cells at this level were extensively changed, many of them showing very few traces of chromatic bodies, while the cell bodies were often irregular and the nuclei eccentric. Purkinje's cells showed moderate general subdivision and fading of chromatic bodies. In the motor cortex the chromatic bodies were usually subdivided and often markedly deficient in number. The chromatic network in the cortical archyochromes was usually distinct. Case IV.—Male, 50 years. Moderately alcoholic. For one year had suffered from cough, spasmodic dyspnoea, anaemia, and dropsy. March 28, admitted to hospital in a state of mild chronic uraemia. On March 30, the delirium had passed into stupor, and urine and stools were voided involuntarily. On April 2, stupor deepened and the temperature, previously normal, rose to 1030. April 3d, with ante-mortem temperature of 1070, he died. Autopsy, 13 hours after death. Both kidneys were enlarged, and showed advanced changes of chronic nephritis. The pelvis of the right kidney and adjacent renal tissue was the seat of an abscess cavity filled with thick, somewhat dessicated pus. There were many foci of pus throughout the right kidney. The posterior por- tions of both lungs were partially consolidated. The arteries were moderately atheromatous. Microscopical examination. Sat. bichloride. In the cord the large cells were usually normal in appearance. In some there was commencing subivision of central chromatic bodies. The lower medullary nuclei were also but slightly altered, most of the cells appearing normal. In the cells of the X nuc. and above this point there was considerable subdivision and loss of chromatic bodies in most of the cells. A few cells appeared normal and some 94 STUDIES ON GANGLION CELLS. contained only a few fine granules limited to the periphery or poles. In the motor cortex, the large cells had lost most of their distinct chromatic bodies, but usually a few peripheral masses remained and the chromatic network was distinct. In Purkinje's cells there was considerable diminution in the size and number of chromatic bodies. Case V.—Female, 63 years. One year previously the right breast bad been removed for carcinoma. For four months she had suffered from cough and dyspnoea; for two weeks, from oedema of legs. The urine had been scanty. March 19, admitted to the hospital, with suppres- sion of urine and vomiting. March 20th, she became drowsy and there were marked muscular twitchings but no spasms. March 21st, deeply comatose. March 2 2d, died, temperature 990. Autopsy six hours after death. Body much emaciated and very anaemic. There was general carcinomatosis. Both ureters had been lightly compressed by the new growth, causing double hydro- nephrosis. Microscopical examination. Sat. bichloride. In the cord and medulla many cells appeared quite nor- mal. In the X cranial nucleus and above, most of the cells showed a moderate grade of central or diffuse chro- matolysis, and in some instances this change was advanced. In the Purkinje cells the chromatic bodies were small and slender, and often deficient in number, especially in the perinuclear zone. There was no distinct powdering of these bodies. In the motor cortex most of the large cells showed ad- vanced subdivision or absence of perinuclear chromatic bodies. In the archy-stichochromes the meshes of the network were widened and the chromatic bodies finely subdivided. In the frontal and occipital archyochromes the meshes of the chromatic network were widened and irregular. Case VI.—Male, 53 years. Brought to hospital Nov. 10, 1896, delirious, temperature 1040, urine scanty and highly albuminous. Th etemperature gradually fell to 1000, but the delirium, alternating with coma, continued. The urine was finally suppressed. Stools were passed involun- tarily. After two days of complete coma the patient died March 24th, temperature 101.0 STUDIES ON GANGLION CELLS. 95 Autopsy ten hours after death. The posterior portions of both lungs were irregularly and incompletely consoli- dated. Both kidneys were enlarged and showed the changes of advanced chronic nephritis. In the pelvis of one was a large calculus. The pia was very oedematous, and opaque. The vessels at the base were normal. Microscopical examination. Lang's fluid. In the cord and medulla a few of the large cells appeared normal. Most of them exhibited a moderately advanced stage of central or peripheral chromatolysis, but there were nearly always some remnants of the bodies in all parts of the cell, none being markedly bleached. In the motor cortex, the giant cells contained the normal number of chromatic bodies, usually much subdivided in the perinuclear regions. In the cortical archy-stichochromes the chromatic bodies were indistinct and limited to the poles of the cell, the perinuclear zones being partially bleached or occupied by pigment. In the Purkinje cells the changes were of the usual type in uraemia, the chromatic bodies being irregularly deficient in size, form, and number. General Observations on Cellular Lesions in Urcemia. The study of the above cases indicates that uraemia, as it occurs in the human subject, is associated with rather marked changes in the chromatic substance of the nerve cells, but these changes are very irregular in character and distribution. As a rule the spinal cells are but little changed in uncomplicated cases. The lesions are most marked in the medullary nuclei, especially in the nuc. X and above, as well as in the deeper cells throughout the medulla. Here, nearly every variety of chromatolysis may be observed, excepting very advanced or complete bleaching of the cells, which is rare. The cortical cells are usually better preserved than might be expected from the very marked cerebral symp- toms of fatal and prolonged uraemia. In the case dying with severe convulsions (Case II) the cortical as well as the medullary lesions were most marked. 96 STUDIES ON GANGLION CELLS. The condition of Purkinje's cells was very uniform in the cases examined, the chromatic bodies of these cells being very irregular in size and shape, and considerably deficient in number. The effects of pial oedema could not be distinctly traced in the cortical cells. No distinct or uniform nuclear changes were detected in these cases, although the nuclei were often abnormal in appearance. The achromatic substance of the cortical archyochromes frequently appeared greenish and opaque, suggesting an early stage of pigment degeneration. In two cases showing a terminal febrile movement reaching 1050 and 1080, the cellular lesions did not differ from those seen in cases with subnormal temperatures, and in these cases no changes were found resembling those seen in sunstroke. The most advanced cellular alterations of the series were seen in the nuc. X and deeper cells (nuc. ambiguus) in the case in which severe dyspnoea had been the chief complaint for five days before death. In general, it seems reasonable to conclude that the lesions of the nerve cells in uraemia are largely referable to local influences and partly also to general toxaemia. Among such local influences may be suggested (1) altered conditions in the peripheral fibres of the cells; (2) local circulatory disturbances; (3) overaction of particular groups of nerve cells; (4) and possibly also the effects of pyrexia. Finally, in the above cases, there was a fair parallelism between the grade of cellular change and the general severity of the symptoms. Sunstroke.—The first studies of nerve cell changes in sunstroke as seen by Nissl's method, were reported by Van Gieson (Lambert156). STUDIES ON GANGLION CELLS. 97 In three cases these authors found throughout the central nervous system, extensive changes in the chromatic struc- tures of the nerve cells. As described by Van Gieson, " The placques in some cells were changed in shape and fewer in number. In others they appeared to be broken into fine dust, and again in others have entirely disap- peared. The nucleus stained more deeply than normal, and within the nuclear membrane were some minute spherical granules." These changes Van Gieson regarded as evidences of an acute parenchymatous degeneration of the neuron, result- ing from the action of an autogenous poison which he regards as the basis of the symptoms in sunstroke. (See also Van Gieson15 7). The present series includes three cases of sunstroke in which the nervous system was examined by Nissl's method. Case I.—Male, 43 years. Excessively alcoholic, and drinking hard for the few days preceding his seizure. He fell in the street August 7th, 1896, and was brought to the hospital in an unconscious condition. Stools and urine' were passed involuntarily. The temperature registered 1090. Treatment by ice pack and stimulation. On the following day he was fairly rational, and highest tempera- ture was 1040. On August 9th he again became delirious and died with temperature of 1070. Autopsy, fifteen hours after death, showed congestion and oedema of lungs and fatty degeneration of the heart- muscle and liver. Microscopical examination. Lang's fluid. In the cervical and lumbar cord the large cells stained rather faintly, the chromatic bodies being present, of nearly normal size and shape, but staining faintly. In some cells there was moderate subdivision of chromatic bodies. The nucleoli were nearly all greatly swollen and vacuolated. In the medulla, the same appearances were noted in the larger stichochromes of the cranial nuclei, but in addition the majority of the cells, especially the smaller sticho- chromes and others, were entirely devoid of chromatic vol. 1—no. 3—G. 98 STUDIES ON GANGLION CELLS. bodies. The nuclei of these cells contained many chro- matic particles, but the nucleoli were not swollen. In Purkinje's cells, very faint outlines of the pale chro- matic bodies could with difficulty be distinguished, all of these cells appearing homogeneous by low magnification. The cortical cells were usually quite homogeneous, no traces of chromatic structure being discernible. In the posterior spinal ganglia, the cells were very pale, but here again, the faint outlines of chromatic bodies, often minutely subdivided, could usually be detected. The nucleoli appeared swollen. In the brain and medulla, less markedly in the cord, all other cells, as well as the ganglia cells, stained very faintly, suggesting that there had been some uniform alteration in the reaction of the tissue which reduced the affinity of all structural elements for methylene blue. No distinct traces of undoubted cadaveric alteration were noted. The condition of the nerve cells as well as the clinical record, suggest also that alcoholism was quite as impor- tant an element in this case as was the thermic fever. Case II.—Male, 45 years. Found unconscious in the street. Had an empty whiskey flask in his pocket. Brought to hospital comatose, cyanotic, pupils dilated, breathing stertorous, involuntary stools, pulse very feeble, temperature no°. Died in ice pack fifteen minutes after admission. Autopsy, eighteen hours after death, showed only fluidity of blood, and intense congestion of viscera. Signs of decomposition were marked in the viscera, but the brain and cord were quite firm. Microscopical examination. Sat. aq. bichloride. In the cord, the anterior horn cells presented character- istic changes. On low magnification, they failed to show the striated appearance, staining diffusely pale blue. The nucleoli were enormously swollen and pale, and were sur- rounded by six to ten large deeply staining granules. With high magnification, it could be seen that some cells still retained traces of chromatic bodies either of the original size and form, or swollen and fused together, or evenly and minutely subdivided, but invariably very pale. These differences may, perhaps, be referred to the varying thickness of the cell body found in the sections. Many cells appeared entirely devoid of chromatic structures. The nuclear membrane was often invisible. The changes STUDIES ON GANGLION CELLS. 99 in the majority of these cells were indistinguishable from those found by the writer in over-heated rabbits. In the medulla, nearly all cells showed the more advanced changes noted in the cord. Here many cells were entirely colorless. Some of the Purkinje cells were but slightly altered; many contained only a few slender and very pale chromatic masses; some appeared to be devoid of chromatic bodies. Most of the cortical cells failed to show distinct chromatic bodies or network, and the usual nuclear changes were very prominent. In the posterior spinal ganglia, most of the cells showed chromatic bodies very pale and minutely subdivided, while many were absolutely colorless. The nucleoli of these cells were much swollen. In most regions examined, cadaveric changes were noted in the presence of moderate vacuolation and nuclear chromatophilia. Case III.—Male, 38 years. Alcoholism not certainly known. Treated at another hospital one week before for sunstroke, where he was in a precarious condition, but recovered. On the day of admission fell off a wagon un- conscious, and was brought to hospital with usual symp- toms. Temperature 109.6°. With treatment in repeated ice packs, he continued twenty-four hours in a half con- scious condition, temperature ranging between 97.40 and 105°, but finally died. Autopsy, three hours after death, showed fluidity of blood, venous congestion of viscera, oedema of lungs, and moderate fatty degeneration of the liver. Microscopical examination. Sat. bichloride. In the cord the majority of the cells showed a very slight grade of subdivision of the chromatic bodies without any other abnormality. A few cells showed the more advanced changes, with uniform subdivision of chromato- philic bodies, but the loss of chromatic substance was not marked and no very pale cells were seen. In some of the medullary nuclei the pallor and subdi- vision of the chromatic bodies had reached a considerable degree, and many cells perfectly resembled those seen in Case II, but, on the other hand, the cells in some nuclei showed very little change. In this region, central chro- matolysis and eccentricity of nuclei was very frequent in some foci. In the cortical cells the changes in the chromatic struc- tures were not marked, nor in any degree characteristic. IOO STUDIES ON GANGLION CELLS. _ Purkinje's cells, on the other hand, were rather exten- sively altered, the chromatic bodies being usually finely subdivided, giving the cell a diffusely stained difference. This case is of special interest as showing that extreme and characteristic lesions in the nerve cells are not always present in sunstroke, and that high temperature alone is inadequate to cause the cellular lesions associated with thermic fever. The last case was the only one of the three which was comparatively free from the alcoholic element, and the suspicion may well be raised that the marked bleaching of the cells in thermic fever may be partly referable to the complicating alcoholism which is a nearly constant con- tributing cause in sunstroke. From extensive studies of the ganglion cells of rabbits, as affected by high temperature, the writer is convinced that the nerve cell changes in sunstroke are specific of this condition, and, in characteristic cases, are distinguishable from most other types of cellular lesions. Leukemia. Case I.—Male, colored, 50 years. For past three months had suffered from dyspnoea, general weakness, occasional epistaxis, and pains in the joints. On admission, Dec 17th, the above symptoms were present, the right knee was swollen and tender, the temperature was ioo.° Physical examination negative. Dec. 19th, temperature 103.8°; Jan. 4th there was a mild chill, followed by ab- dominal pain, tympanites, and temperature 1050. Jan. 8th the blood was examined and 55,000 leucocytes per cmm., mostly myelocytes, were found. Hemorrhages had oc- curred from mouth, nose, gums, and bowels. Jan. 9th another chill, temperature 105.40. Patient in stupor. Jan. 10th, coma, involuntary stools, temperature 1040, death. Autopsy eight hours after death. The viscera were markedly emphysematous and decomposed, from growth STUDIES ON GANGLION CELLS. IOI of bacillus arogenes capsulatus. The abdominal and tho- racic lymph nodes were moderately enlarged and very hyperaemic The spleen was very soft, moderately en- larged, pulp diffluent. The shafts of the long bones as well as all flat bones contained grayish cellular marrow. There were leukemic deposits in the liver, kidneys, and lungs. The brain and cord had escaped marked post- mortem changes and were firm and very anaemic. The pia was oedematous and contained a few small hemorrhages. Microscopical examination. Lang's fluid. There was a moderate grade of chromatolysis of very uniform degree throughout the central nervous system. Very few intact cells were found. In the cord, medulla, cerebellum and motor cortex, the chromatic bodies, especially those in the periphery of the cells, were moder- ately subdivided. The nuclei were usually central and showed no distinct alterations. A prominent feature was the extreme grade of pigment degeneration which affected the nerve cells throughout all parts of the central nervous system. Case II.—Female, eight years. Had been under ob- servation for four years, suffering from a mixed form of leukemia. During the last few months of the disease, there were extreme anaemia, frequent hemorrhages, ex- treme enlargement of the spleen. Before death the red cells numbered 880,000, the leucocytes 820,000, consisting of nearly equal numbers of lymphocytes, myelocytes, and polynuclear leucocytes. The patient was confined to bed and quite helpless for three months before death, and during this time there was a moderate febrile movement. Autopsy six hours after death. The brain could not be secured. The cells of the lumbar cord showed only a moderate grade of central chromatolysis, without special features. The small vessels of the cord were often choked with large mononuclear cells and there were a few larger collections of these cells in the pia. General Burns.—The present series includes one case of general burns, which proved rapidly fatal. Female, 40 years. Clothing caught fire from a stove and the skin over three-fourths of the body was severely burned. On admission there was vesication over most of the burned areas, and the patient, though conscious, was in extreme shock. Death ten hours after the accident. The temperature gradually rose, reaching 106.8°. 102 STUDIES ON GANGLION CELLS. Autopsy fourteen hours after death. The blood was everywhere fluid, and all the viscera were deeply con- gested. The brain and cord appeared normal. Microscopical examination. Ten per cent formalin. In the lumbar and dorsal cord the chromatic bodies were beginning to break up into fine granules and their outlines were very irregular and indistinct. The nuclei appeared normal. The change was most marked about the nucleus. Some cells were apparently unaltered. In the spinal ganglia (lumbar region) there were no cells which retained well-formed chromatic bodies in con- centric arrangement. The majority of cells showed only a few scattered chromatic granules and many were entirely bleached. Nuclear changes were absent. In the medulla, the cells were rich in chromatic sub- stance, but the chromatic bodies and network were usually indistinct in outline and partly subdivided. The larger cells of the nuc. ambiguus were similar in appearance to those of the cord. In the higher medullary nuclei, the changes were slightly more advanced, nearly all cells presenting a diminished number of chromatic bodies often partly subdivided. In the cortex, the cells were distinctly paler than normal, from uniform deficiency of chromatic substance. The giant motor stichochromes showed marked subdivision and loss of chromatic bodies. Many large pyramidal cells contained no chromatic bodies, but only a faint chro- matic network. In Purkinje's cells, the size, number, and distinctness of the chromatic bodies were uniformly diminished. Starvation.—Schaffer158 described minutely the stages of chromatolysis noted in the anterior horn cells in starv- ing rabbits. Vacuolation was a very marked lesion in these cases, and moderate or extreme nuclear chromato- philia was noted in many cells. Referring these changes directly to malnutrition of the cell, the author concludes that the chromatic substance of the nerve cell represents potential energy. Tauczek159 also killed rabbits by complete withdrawal of food and found lesions in the ganglion cells of the cord. After slow staivation he noted disintegration of the chro- matic bodies, especially in the spinal stichochromes of the STUDIES ON GANGLION CELLS. 103 cervical region. He doubts the propriety however, of referring all changes found under these circumstances to malnutrition of the cells or to any one pathological process. For the purpose of studying the condition of the nerve cells in states of hunger and complete muscular inactivity, Jacobsohn *• 6 ° selected eagles which had been confined in a cold compartment for six weeks, and rabbits killed after being starved for 7 to 10 days. The anterior horn cells of these animals differed in no respect from the normal. Lugaro and Chiozzi161 in a study of the cellular changes in the nervous system resulting from prolonged starvation, observed marked degenerative lesions in the cells of the cortex, medulla, cord, and spinal ganglia. These consisted principally in peripheral, central, or circumscribed chro- matolysis, vacuolation and disintegration of the achromatic portion of the cell body, and in occasional chromatophilia of nucleus. They used Delafield's hematoxylin to demon- strate the chromatic structures, and noted in the altered cells the distinct reticulated structure of the achromatic substance, where the chromatic .bodies had disappeared. The lesions were veiy irregular in distribution, and not always uniform in degree, while their similarity to the changes observed after poisoning by arsenic or lead was very striking. The authors conclude that the lesions observed must result from some form of auto-intoxication from intestinal absorption or internal metabolism, which they assume to exist in starving animals. Donetti162 has described the lesions in the central nerv- ous system after removal of the suprarenal glands. Guinea pigs survived the operation only 48 hours; rabbits, from 8 to 15 days. The cellular lesions were most marked in the 104 STUDIES ON GANGLION CELLS. medulla, but were very irregular in distribution, normal cells lying side by side with extensively altered ones. Some cells seem to be shrunken, others swollen. The nuclei were either central or eccentric. The chromatic masses in the medullary cells were usually reduced to granules and often limited to the poles of the cell. A few cells had lost their nuclei and were in the process of complete degeneration. Meningitis, Apoplexy and Disturbances of Cerebral Circulation. Excepting the reference of Marinesco163 to two cases of pneumonia complicated with meningitis, in which he found the spinal stichochromes but little affected, the writer has found in the literature no reports of studies of the ganglion cells in cases of meningitis. Dotto and Pusateri,18 5 alone, report studies on the cor- tical nerve cells in cases of intracerebral focal hemor- rhages. They found various grades of chromatolysis in the cortical areas whose function had been destroyed by basal hemorrhage. From lesions found in the Island of Reil they are led to conclude that this region is connected by fibres running through the external capsule. The present series includes the following cases of men- ingitis. Case I—Tuberculous Meningitis.—Male, 29 years of age; suffered from general pains and malaise for one month, headache, nausea, and vomiting, for two weeks, and had been delirious for two days before admission to hospital, Sept. 17, 1896, when he presented distinct symptoms of meningitis, the head being markedly retracted, the limbs rigid and twitching, and the temperature 1030. Delirium alternated with coma, and the temperature remained con- stant until Sept. 2 2d, when he died with a temperature of 1040. Autopsy 13 hours after death. STUDIES ON GANGLION CELLS. I°5 There was marked oedema of the pia, which was lightly coated with fibrin and pus at the base. The ventricles were considerably distended with turbid fluid. In all these regions and over the cervical cord there were many fine miliary tubercles in the pia. The brain was moderately soft. There was a small tuberculous focus at the apex of the left lung, and the liver and kidneys showed slight fatty changes. Microscopical examination. Lang's fluid. In the cord most of the large cells contained the usual number of chromatic bodies, but these were usually very ragged and often finely subdivided. In the medulla the lesions were very irregular in distribu- tion. Most of the superficial nuclei contained cells with many chromatic bodies either well formed or partly disin- tegrated. Similar cells were seen in the deeper zones, but here the majority of cells were markedly bleached, and presented only a few pale bodies along the periphery. A few of these deeper cells appeared entirely bleached. It was noted that the cells of one nucleus immediately adjacent to a miliary tubercle showed comparatively little change, while the deeper cells lying more remote from the tubercle were extensively altered. Moreover in some foci entirely bleached cells lay next to very slightly altered ones. Plate VI, Figs. 2 and 3. In the motor cortex the giant cells usually showed marked central chromatolysis, a few were entirely lacking in chro- matic bodies, while a few others appeared very little affected. In the arkyochromes the network was usually paler than normal. Purkinje's cells contained an abundance of chromatic bodies, which were usually reduced in size, irregular in shape and often partly subdivided. Case II.—Tuberculous Meningitis.—Male, 30 years of age. Formerly alcoholic. Illness began January 1, 1897, with symptoms of pulmonary tuberculosis of subacute charac- ter. Admitted February 2 2d, with signs of severe general bronchitis, without pneumonia or cavities, temperature 1040. Urine, 5 per cent of albumen. On February 23d, he was mildly delirious and passed considerable blood from rectum. Maximum tempera- ture, 1030. On the 27th there was vomiting, diarrhoea, great restlessness, mild delirium, temperature uniform. These symptoms continued until March 1st, when he be- came comatose, and on March 2d, died, temperature 1080. io6 STUDIES ON GANGLION CELLS. Autopsy eight hours after death. The pia over the convexity was dry and granular, at the base oedematous. The ventricles were slightly distended with turbid fluid. The brain was distinctly softened. There were every- where many fine miliary tubercles. The cervical cord was involved. The lungs showed the lesions of subacute miliary tuber- culosis of moderate extent. Microscopical examination. Sat. bichloride. The description of the previous case applies accurately to the present one, with some minor differences. In the second case the tuberculous process was much more active, following the vessels for some distance into the tissues. The marked bleaching of many large cortical and medullary cells described in the first case was seldom seen in the second. It may be noted that coma and rigidity were distinct and prolonged and the distension of the ventricles greater in the first case. In the second, the temperature was much higher and the general toxaemia more intense, but the cellular lesions were less advanced. Case III.—Sporadic Meningitis.—Female, 18 years. Illness began June 28th, 1896, with vomiting and convul- sions, passing into coma, which continued till death. On July 1st, the day of admission, there were several con- vulsions; maximum temperature, 104°. July 4th, several convulsions; temperature, 104.50. July 6th, the coma deepened; temperature, 1020. July 7th, the breathing became rapid and stertorous; temperature, 1050. July 8th, there was complete coma and the patient died with ante-mortem temperature 1050. Autopsy seven hours after death. The entire pia and brain were much congested. The pia was everywhere opaque and over the base and along the sulci moderately thickened. The ventricles were not distended nor markedly inflamed. There were no visceral lesions of importance. Microscopical examination. Lang's fluid. The pia over the base, convexity, and cervical cord, was much thickened and infiltrated with leucocytes and large mononuclear cells. There were numerous small extrava- sations of blood. Along the vessels of the brain and medulla there was moderate infiltration with round cells. The condition of the ganglion cells was similar in most details to that found in the first case of tuberculous meningitis. STUDIES ON GANGLION CELLS. I07 Case IV.—Chronic Hemorrhagic Pachymeningitis.— Female, 78 years. Had suffered for six months from headache, gradually increasing hemiparesis with muscular contractures, and from tremor resembling that of paral- ysis agitans. Two days before death she became uncon- scious, and died without marked rise of temperature. (The writer is indebted to Doctor Frederick Peterson for the reference to this case). Autopsy four hours after death. The dura all over the convexity was markedly thickened, lamellated, and infil- trated with blood. In the meshes of pia and arachnoid there was a little free blood widely distributed in a very thin layer over a large area of the convexity. The pia was considerably thickened. The arteries at the base were slightly atheromatous. The cord and viscera could not be secured. Microscopical examination. Ten per cent formalin. The preservation and staining were excellent, but thin sections were needed to avoid the appearance of chroma- tophilia. The superficial nuclei of the medulla were almost entirely normal in appearance, except for excessive pig- mentation of the cells. In the deeper lying cells there was usually an early stage of uniform chromatolysis, the perinuclear bodies being rather finely subdivided. In the cortex, there was also in many cells a slight grade of chromatolysis, but the majority of cells were practically normal. Beneath the thickest portion of the blood clot, the lesions were more general and advanced than else- where. In Purkinje's cells there was a moderate reduction in the size and number of the chromatic bodies. The absence of advanced lesions in this case may reasonably be referred to the lack of serious disturbances in the cerebral circulation. There was very little extra- vascular blood in the pia, and the resulting increase of intra-cranial pressure must have been comparatively slight. Case V.—Chronic Hemorrhagic Pachymeningitis.— Male, 37 years. Brought to hospital by ambulance, hav- ing had five convulsions. The convulsions continued and he died a few minutes after admission, temperature 101.80. Autopsy six hours after death. There was consider- able blood in the meshes of a thickened dura over both io8 STUDIES ON GANGLION CELLS. sides of the convexity. There was a flat blood clot iox 7 cm. and 1 cm. in thickness, lying in the meshes of arach- noid, compressing right parietal lobe. The pia was everywhere moderately thickened. The blood vessels at the base of the brain were normal. The left ventricle was moderately hypertrophied. The lungs showed evi- dences of chronic congestion. The kidneys were moder- ately enlarged, capsules not adherent, surface smooth, markings irregular. Microscopical examination. Lang's fluid. In the medulla the lesions were neither extreme in degree nor very uniform in distribution. Most of the large stichochromes in the lower medulla contained many pale but not disintegrated chromatic bodies. There were, however, isolated examples of advanced chromatolysis. Higher in the medulla and in the deeper lying groups, some moderately bleached cells were observed. In the cortex beneath the clot, the chromatic bodies were limited to the periphery and those present seemed reduced in size. The perinuclear zones were moderately bleached. Many of the large cells, however, showed only a beginning subdivision of perinuclear masses. Beyond the limits of the clot most of the cells appeared intact. In Purkinje's cells the chromatic bodies were pale, near the dendrites deficient, but elsewhere present in nearly normal number and appearance. The absence of advanced changes in this case may be referred to the rapidly fatal effects of the hemorrhage. Although no definite history of the beginning of the attack could be obtained, it seemed certain that death followed the initial seizure within two or three hours. Case VI. — Chro?iic Hemorrhagic Pachymeningitis. — Male, 50 years. For three months had suffered from severe headache and was unable to work. December 1, 1896, he was unable to walk, and was thereafter confined to bed. About January 1st, 1897, he became partially comatose, opening his eyes when roused, but soon relaps- ing into unconsciousness. January 2d, coma deepened and continued without other noteworthy symptoms, until death, January 12th. The temperature during this period was between 990 and 1010. Autopsy eight hours after death. The posterior por- tions of both lungs were partly consolidated from catarrhal pneumonia. The entire convexity of the STUDIES ON GANGLION CELLS. 109 brain was evenly compressed by a layer of clotted7* blood and fibrin derived from a thickened and lamellated dura- mater. This blood clot was 1 to 1.5 cm. in thickness and must have exerted considerable pressure upon the under- lying brain tissue. Microscopical examination. Lang's fluid. The cortical cells from various regions showed a marked deficiency in chromatic substance. In the motor regions beneath a thick mass of blood, very few cells showed any distinct traces of chromatic bodies, the majority of cells being extremely bleached, but still re- taining a distinct chromatic network. In some cells a few traces of the chromatic bodies persisted in the form of a peripheral ring of small granules. Beyond the limits of the blood clot, these changes were less marked. In the cerebellum, which was free from clot, Purkinje's cells contained a considerable number of chromatic bodies moderately reduced in size, and often limited to the peri- nuclear zone, or the base of the cell. Case VII.—Subacute Leptomeningitis.—Male, 7 years. Had tonsilitis in June, 1896. A few weeks later had a chill, followed by fever, lasting a few days, and had a mild general convulsion. Slight cough and irregular pains continued until September 16th, when he passed a restless night, waking with fever, repeated vomiting, great thirst, and within a few hours had five general con- vulsions. On admission, the patient was in stupor, tem- perature 104.8°. September 17th, stupor and delirium, temperature 1060. Urine and stools passed involuntarily. September 18th died, temperature 107.5°. Autopsy three hours after death. The lungs were congested. The consistence of the liver was reduced and outlines of lobules indistinct. The spleen was moderately enlarged. There was extreme engorgement of all cerebral sinuses and pial vessels. Over the frontal lobes there was a slight effusion of bloody serum along the course of the pial vessels. The ependyma was dry. The pia was con- gested and opaque, the cortical gray matter darker than normal. No tubercles nor foci of blood or pus were present. Microscopical examination. In the cord and medulla the large cells showed all stages of destruction of chromatic bodies, many cells in the medulla especially, being entirely bleached. In these bleached cells the underlying reticulum was sometimes no STUDIES ON GANGLION CELLS. visible, often indistinguishable. Irregularity in outline of cell body, and eccentricity of nucleus were frequently seen. No normal cells could be found. In the motor cortex, the large cells showed all stages of chromatolysis, and many were entirely bleached. The small cells exhibited a pale chromatic network with a few small chromatic granules at one or more poles. Purkinje's cells were usually extremely bleached, but many still showed faint remnants of chromophilic bodies. There was everywhere extreme congestion of the blood vessels and marked dilatation of pericellular lymph spaces. The pia was greatly thickened by a new growth of con- nective tissue, infiltrated with blood, round cells and leucocytes. A few cocci in short chains were seen in sections. Case VIII.—Subacute Traumatic Meningitis and En- cephalitis.—Male, 28 years. January 7th, 1898, was struck on right temporal region by a falling iron door. Was rendered temporarily unconscious, and afterward suffered severe and continuous headache, located in this region. He was often drowsy, but not delirious, and had no spasms or paresis. On admission, February 1st, temperature was 100.20; pulse, 90; right pupil slightly larger than left; internal strabismus of left eye; some stiffness of neck; spastic rigidity of legs and arms; increased reflexes; no anaesthesia or hyperaesthesia. February 2d, restless, mov- ing hands constantly in incoordinate manner. Tempera- ture 1030. February 3d, mildly delirious, involuntary urine, temperature, 1030. February 4th, stupor, tempera- ture 103.8°. February 5th, internal strabismus more marked. Legs rigid; delirious; temperature 1040. Feb- ruary 6th, temperature 105. February 7th, died, tem- perature 1050. Autopsy four hours after death. Over two-thirds of the left convexity, dura, pia, and brain are tightly adherent, and about this area the pia is granular, extremely con- gested, and ecchymotic. The underlying brain substance is much congested. In left superior occipital fossa, dura and pia are adherent to skull. Both ventricles are moder- ately dilated with turbid fluid. There are no fractures. Viscera congested. Miscroscopical examination. Alcohol 95 per cent. In the motor cortex beneath the adherent membranes the chromatic bodies of the giant cells are invariably very STUDIES ON GANGLION CELLS. Ill irregular in shape, often much faded and usually much subdivided. In some cells the entire perinuclear zone is replaced by fine granules, and in thick sections appears opaque. The nuclei stain diffusely. In the archysticho- chromes the chromatic bodies are usually limited to the poles and are subdivided. The chromatic network is everywhere retained. On the opposite side of the brain the meningitis is slight, and the same lesions rather less marked are to be observed. On the under surface of the cerebellum there is a layer of exudate of considerable thickness. Here the Purkinje cells are very deficient in chromatic bodies, which when present, are faint, irregular, and subdivided. Many cells show no bodies, but only a distinct but irregular chromatic network. On the floor of the fourth ventricle in the region of the locus ceruleus and III, IV nuc. there is a rupture of tissue, extending a few lines beneath the surface, and covered with fresh exudate. The cells of this region are similar to those of the motor cortex, showing marked subdivision of chromatic bodies, while the chromatic network and granular remains of the chromatic bodies are distinctly visible. In the lower medulla the changes are much less marked, many normal cells appearing. Case IX.—Intra-ventricular Hemorrhage.—Male, 30 years. Without previous illness was suddenly seized on March 28th with pain in the head, and was admitted to hospital with right hemiplegia. The paralysis was incom- plete and the muscles rigid. Temperature ioo°. Urine, passed involuntarily, was highly albuminous. There was deep coma. March 30th, coma persisted, temperature 1030. March 31st, coma and paralysis complete, temper- ature 1070. Died. Autopsy four hours after death. The pia was moderately oedematous, and, over posterior surface of cerebellum, infiltrated with bloody serum. The ventricles were considerably distended with clotted blood and serum. The left optic thalamus, Island of Reil, in- ternal capsule, and temporo-sphenoidal lobe were the seat of a large hemorrhage, 7 to 8 cm. in diameter. The arteries at the base were atheromatous, and there was advanced chronic nephritis. Microscopical examination. Sat. bichloride. In the medulla the cells of the superficial nuclei show 112 STUDIES ON GANGLION CELLS. general and, in the large cells, usually complete chro- matolysis. In the cells which are not bleached, there is usually a single mass of chromatic substance at one side or pole. In the frontal and motor cortex chromatolysis is extreme, most of the large cells presenting a wide homogeneous area about the nucleus, in which the cyto-reticulum is with difficulty distinguished. Some Purkinje cells contain the normal number of chro- matic bodies, but these are usually very small and slender. Many are entirely bleached. In some the bodies are limited to a narrow peripheral ring. Case X.—Extra-dural Hemorrhage.—Male, 24 years. Fell from a wagon on the evening of March 31st, was ren- dered unconscious, had one convulsion. Brought to hos- pital 2 a. m. April 1 st, in coma, pupils widely dilated, not reacting to light, breathing slow, stertorous, complete paralysis of limbs. Temperature 105.2°, pulse 64. Died at 4.50 p. m., temperature 1090. Autopsy ten hours after death. The entire coronal suture was separated % cm., the fissure crossing the groove of the left middle meningeal artery and passing into left medulla cerebral fossa. The left middle meningeal artery was ruptured. The dura was separated from the skull over an area 14 cm. in diameter by a large firm blood clot. The underlying con- volutions were flattened, but not lacerated. The under surface of the left temporo-sphenoidal lobe was extensively lacerated. Microscopical examination. Sat. bichloride. The viscera were uniformly congested. Throughout the medulla the deeper cells are extremely deficient in chromatic substance, many being entirely bleached, and the others retaining a very few small irregu- lar masses at one or more poles. The superficial nuclei are slightly less affected. Throughout the motor cortex, more marked on the side of the blood clot, all cells are extensively bleached, the remains of chromatic bodies being scanty, minute and usually limited to the periphery of the cell. In the arkyochromes the network stains faintly. In Purkinje^s cells the chromatic bodies are uniformly deficient in size, usually also in number, but the lesions are much less advanced than in the motor cortex. STUDIES ON GANGLION CELLS. H3 Case XI.—Thrombosis of Basilar Artery.—Male, 35 years. Admitted to hospital for operation on incarcerated inguinal hernia, but on day of admission became comatose and operation was postponed. The coma rapidly deepened and without convulsions or marked elevation of tempera- ture, he died, about 36 hours after the onset of cerebral symptoms. Autopsy twelve hours after death. There was an incar- cerated and partly strangulated right inguinal hernia. The lungs contained a few areas of catarrhal pneumonia. In the kidneys there were a few old infarcted areas. There was moderate general arterio-sclerosis. At the middle point of the basilar artery there was a firm thrombus entirely occluding the lumen. The brain was moderately oedematous, but there were no areas of softening. Microscopical examination. Lang's fluid. Throughout the medulla all the large cells are either completely or almost completely lacking in chromatic bodies. In some cells the remains of the chromatic bodies are visible as fine, pale granules scattered irregularly throughout the cell body. In most cells the cyto-reticulum is retained, and there are no evidences of nuclear changes. In the cortex nearly all the large pyramidal cells are very deficient in chromatic substance, but many of them show a few small masses at one or more poles. In the smaller cells the chromatic network is visible but faintly stained. In Purkinje's cells there is a striking diminution in the size and often in the number of chromatic bodies. Many of the cells contain a few pale and very slender rods. The chief features of this case are the extreme bleach- ing of the medullary cells and the uniformity in the cellu- lar lesions in this and other regions. The study of the foregoing cases indicates that purulent and tuberculous meningitis are usually associated with lesions in the chromatic structures of the ganglion cells often of extreme grade, but not of uniform distribution. Immediate proximity to a purulent or tuberculous menin- gitic process does not necessarily destroy the chromatic vol. 1—no. 3—H 114 STUDIES ON GANGLION CELLS. bodies in these cells. On comparison of these cases of meningitis with those of hemorrhagic pachymeningitis in which are added the elements of pressure from extrava- sated blood or anaemia from thrombosis of vessels, it will be seen that the character of the lesions changes and that the extreme grades of chromatolysis are, as a rule, uniformly present in the compressed or anaemic areas. Moreover, this fact is the more striking because the effects of bacterial toxine are absent in these latter cases. The lesions found in the cases of thrombosis of basilar artery and various forms of cerebral hemorrhage, were equalled in intensity only in cases of alcoholism, sunstroke, tetanus, etc., but not in cases of severe general bacterial toxcemia. The conclusion seems justified therefore that the chromatic substance of nerve cells is more susceptible to the effects of disordered circulation than to the action of most bacterial toxines. In many of the cases attended with high temperature the lesions were more advanced than in those in which the fever was moderate, but no uniform effect could be traced to this cause. The severity of the lesions seemed to depend almost entirely upon the extent and duration of the pressure or anaemia (Cf. Cases V and VI). The relation of cellular changes in the cranial nuclei to the neuritis of cranial nerves commonly present in menin- gitis, could not be thoroughly studied at this time, but is an interesting subject deserving investigation. " Axonal degeneration " was a common medullary lesion in the cases of meningitis. In connection with the cases of cerebral hemorrhage it is important to refer to Neumeyer's study186 of the effects of mechanical pressure upon the cortical cells. Neumeyer STUDIES ON GANGLION CELLS. 115 inserted lead plates beneath the skulls of rabbits, diminish- ing the intracranial capacity about -^. After a few hours of such pressure, the superficial cells showed a progressive loss of chromatic substance both in the nucleus and cyto- plasm, the chromatic bodies often being massed into clumps and appearing coarsely granular. After ten days, only a few granules of chromatic sub- stance remained in the cell body, usually in the perinuclear zone. Often the nuclear membrane seemed to have disap- peared. Many cells had lost all trace of cytoplasm, only the shrunken nuclei remaining. These lesions extended about 10 mm. beyond the limits of pressure, gradually fading into normal tissues. Of similar interest also are the experiments of Pellizzi18 7 which indicate that the simple loss of function of the cells in these cases is not sufficient to account for the destruc- tion of the chromatic bodies of the cells. Pellizzi separated the frontal lobe in dogs from most of its fibrillar connec- tions, while leaving the blood vessels partly intact, and found thereafter very minor changes in the chromatic structures of the nerve cells, which remained practically normal for many days. Some of the animals lived as long as two months. D.—Infectious Diseases. Typhoid Fever.—The writer has been unable to find any complete reports of the examination of the central nervous system by Nissl's method in cases of typhoid fever. Marinesco,163 however, states that in two cases of typhoid fever he found very slight cellular changes associ- ated with marked vascular disturbances, such as hyper- aemia and hemorrhage. In typhoid fever and diphtheria Babes72 refers to the n6 STUDIES ON GANGLION CELLS. cellular lesions in the cord as consisting in chromatolysis, vacuolation, and loss of nucleus and nucleolus, associated with vascular changes and increase of round cells. The present series includes two cases of typhoid fever. Case I.—Male, 36 years. Had been confined to bed with fever and diarrhoea, and had been delirious four days before coming under observation. On admission, Oct. 22, 1896, the patient was actively delirious, temperature 105, with distinct signs of severe typhoid infection. Oct. 23, maximum temperature 105.5°. Urine and stools passed involuntarily, pulse very rapid and feeble. Death Oct. 23; terminal temperature 1030. Autopsy three hours after death. Nearly all the Peyer's patches were the seat of deep necrosis. There were many small ulcers throughout the colon. The spleen was very large and soft. The mesenteric lymph nodes greatly swollen. No other visceral compli- cations. Microscopical examination. Lang's fluid, 24 hours. In the cord nearly all the stichochromes showed moderate subdivision of chromatic bodies, most marked about the nucleus. In the medulla, the ganglion cells showed all the less advanced types of chromatolysis. In some cells, especially of the nuc. X and deeper areas, only a few fine chromatic granules were left. The periphery of the cell was sometimes more affected than the perinuclear area, and in many instances there was a diffuse powdering of all bodies, most advanced near the nucleus. The cells of the nuc. XII were little changed, those of the nuc. X and nuc. VIII and deeper cells above, more markedly. In the olives, the cells showed only a narrow peripheral ring of subdivided bodies. In the locus ceruleus many cells looked normal, others were very deficient in chromatic bodies. The pigment was here of normal appearance. In the Purkinje cells there was uniform diminution in size and often also in numbers of the chromatic bodies, whose arrangement was still regularly concentric. Case II.—Male, 35 years. Said to be excessively alco- holic. Illness began Dec. 16, 1896, with fever, prostration and diarrhoea. On admission Dec 20, the patient was mildly delirious, temperature 104, abdomen moderately dis- tended, slight oedema of legs. The delirium and fever STUDIES ON GANGLION CELLS. 117 continued unchanged until the 26th, when he became partially comatose, with temperature 1050. On the 28th, the urine and stools were passed involuntarily. With persistent high temperatures, delirium and stupor, on January 2, he died, with slight indications of perforation, and with a terminal temperature of 1050. Autopsy five hours later. There was a localized puru- lent peritonitis in right iliac fossa about a perforated ulcer. The lungs contained numerous small areas of catarrhal pneumonia. There were many large and nearly healed ulcers in the location of Peyer's patches, and some more recent ones in the upper colon. Microscopical examination. Sat. aqueous bichloride. 12 hours; bichloride and formalin 5 per cent; and bichlo- ride and sat. aq. picric acid (aa). The cord was not examined. In the medulla there was a very marked loss of chromatic bodies, affecting the perinuclear zone or the entire cell body or leaving a few subdivided or irregularly fused chromatic masses at the poles of the cell. The lesion is distinct in the XII, X and VIII nuclei. The deeper cells, including the nuc. ambiguus and nuc. lateralis showed more pronounced changes, many cells being extremely bleached, often with eccentric nuclei, irregularity of out- line, and loss of cyto-reticulum. In the cortex the giant motor stichochromes showed changes similar to those of the medulla. The arkyo- chromes showed irregularities and partial bleaching of the chromatic network, retaining clumps of chromatic sub- stance at the poles only, and are often ragged in outline. There is distinct pulverization of chromatic bodies in the larger dendrites. Purkinje's cells were extensively altered, exhibiting many of the more advanced types of chromatolysis. Some of these cells were entirely bleached. The results of the examination of two cases indicate that in typhoid fever there are cellular lesions of consider- able intensity and of general distribution throughout the central nervous system. It would seem that these lesions increase with the duration and severity of the general toxaemia, and are partly influenced by a prolonged high temperature. They appear also to be essentially connected with the n8 STUDIES ON GANGLION CELLS. profound nervous disturbances which accompany fatal typhoid infection. In the above cases the lesions were much more pro- nounced than in cases of pneumonia of equal duration. Pneumonia.—Dejerine164 in 1897 reported a case of pneumonia, duration three days, with low delirium and a maximum temperature 43.30 C, in which he had examined the spinal stichochromes by Nissl's method. These cells were much altered throughout the cord, being swollen, homogeneous, and presenting only traces of chromatic bodies. The nucleoli stained poorly. Dejerine did not believe that this chromatolysis was accompanied by any marked symptoms, nor could it be considered as a lesion of importance. Marinesco163 reports similar results from the examina- tion of two cases of pneumonia complicated with menin- gitis, and also in broncho-pneumonia. In the cases complicated with meningitis the anterior horn cells were found unaltered. In cases of broncho- pneumonia, various grades of chromatolysis were noted in the spinal stichochromes. Marinesco seems to refer the result in the latter instance to '' the immediate action upon the cells of the more virulent toxine of broncho- pneumonia, while in the first cases the toxines appear to have exhausted themselves in producing the vascular lesions of meningitis." Marinesco goes on to infer, on grounds not stated, that the lesions of nerve cells in infectious diseases depend upon the age of the individual, being more marked in old persons, upon the intensity of the virus, on the duration of the disease, and as Goldscheider and Flatau165 have shown, upon the fever. The present series includes four cases of pneumonia in STUDIES ON GANGLION CELLS. II9 which the central nervous system was examined by Nissl's method. Case I.—Female, 48 years. Two weeks before ad- mission began to suffer from cough with mucoid and blood-stained sputum. Ten days later had a severe chill, complained of pain in the side and was prostrated. On admission was comatose, with paralysis of left limbs, dilated pupils, temperature 106.50. All symptoms per- sisted and she died on the 17th day. Temperature 105.50. Autopsy 24 hours after death. The upper two-thirds of right upper lobe were consolidated. The pia all over the base and convexity and for some distance down the cord was oedematous and lightly coated with pus, containing large numbers of capsulated diplococci. There was slight chronic nephritis. Microscopical examination. Lang's fluid, 24 hours. There was everywhere evidence of post-mortem change consisting in moderate nuclear chromatophilia and vacuo- lation of the bodies of the ganglion cells. In the cervical cord, which was lightly covered with pus, most of the chromatic bodies were moderately sub- divided and irregular, some were but little changed, and a few cells appeared normal. In the medullary nuclei the changes were of the same type but more distinct. The XII nucleus was but slightly affected. The X nucleus and deeper lying cells were extensively changed. In the cortex, there was a moderate subdivision of chromatic bodies in most of the larger pyramidal cells, but the chromatic network was usually well preserved. Many of the Purkinje's cells were extremely deficient in the size and numbers of the chromatic bodies, some appearing almost completely bleached but showing a distinct under- lying network. Others were but little changed. Pig- mentation was everywhere excessive. Case II.—Male, 28 years. Brought to hospital delir- ious, temperature 103°, with consolidation of both lower lobes. Alcoholism suspected. Alternating delirium and stupor continuing for three days, the temperature re- mained uniformly high, reaching 1090 before death, on the fourth day of observation. The urine was moderately reduced in quantity, slightly albuminous and contained coarsely granular casts. All lobes were partly and the posterior portions entirely consolidated. The liver was 120 STUDIES ON GANGLION CELLS. slightly fatty. There were signs of moderate chronic nephritis. The pia was very oedematous. The case was a typical example of acute lobar pneumonia in an alcoholic subject. Microscopical examination. Lang's fluid, 12 hours. No normal cells were anywhere seen. In the spinal, medullary and cortical stichochromes the usual type of lesion was that of extreme chromatolysis. In only a few cells was the peripheral ring of subdivided chromatic bodies still present. In the medulla many cells were en- tirely bleached, largely infiltrated with pigment and show- ing extreme eccentricity of nuclei. In many of these cells the underlying reticulum could not be distinguished. Purkinje's cells were much less affected than the medullary nuclei. Throughout the medulla there was well marked circumvascular infiltration with round cells of both the pial and deeper vessels. The lesions in this case are probably referable more to alcoholism or high temperature than to the pneumonia. Case III.—Male, 55 years. Moderately alcoholic Ill- ness began with severe chills, cough and rusty sputum, and continued for two weeks with the usual symptoms of pneumonia. On admission, at the end of the two weeks, there were signs of consolidation of right upper and lower lobes. The temperature ran between ioo° and 1020, till just before death when it rose to 1050 F. The patient was emaciated, vomited occasionally, and appeared stupid. The urine was slightly albuminous. Death on the eighteenth day. Autopsy twelve hours after death. There was con- solidation of most of right lung, but no signs of alcoholism or nephritis. The pia was very oedematous. Microscopical examination. Sat. bichloride, 24 hours. In the cord and medulla there was very marked subdi- vision and loss of chromatic bodies in all the larger cells. The nuclei were often eccentric. Some cells retained small but distinct chromatic bodies. Pigmentation was moderate. Some of the cells closely resembled those seen in the case of alcoholic pneumonia, but none were found entirely bleached. The cortical stichochromes and Purkinje's cells showed only moderate subdivision of chromatic bodies. Case IV.—Female, 40 years. Was seized on July 4th with chills, headache, vomiting and pain in chest, followed STUDIES ON GANGLION CELLS. 121 later by cough with bloody expectoration. On admission the temperature was 104° F.; there were signs of con- solidation of the right upper lobe and the patient was delirious. The delirium or coma continued, the tempera- ture rose to 1060 and remained at that point for five days when with marked abdominal distension and violent delirium the patient died. Autopsy two hours after death. There was consolida- tion, with the production of new intraalveolar connective tissue, of the right upper lobe. The pial and dural veins were gorged with blood. The pia was oedematous and, over the cerebellum, infiltrated with blood-stained fluid. The ventricles and brain substances appeared normal. Microscopical examination. Sat. bichloride, 8 hours. In the XII cranial nucleus there was very slight sub- division of chromatic bodies. In the X cranial nucleus, nucleus ambiguus, and all the deeper cells in this region of the medulla there was extreme chromatolysis, with irregularity of cell outlines and frequent eccentricity of nuclei. The same conditions, rather less marked, were noted in all the other cranial nuclei. The nuclei in the cells of the locus ceruleus were invariably eccentric, often bulging. In most of the Pur- kinje cells the chromatic bodies were moderately subdi- vided. In the motor cortex there were some typical examples of central chromatolysis, but many of the giant stichochromes were entirely intact. From the above cases it appears that uncomplicated acute lobar pneumonia may run a fatal course even with exaggerated nervous systems, without leaving uniform changes in the ganglion cells demonstrable by Nissl's method. In all the cases examined, the upper medullary nuclei were extensively altered, having lost most of their chromatic bodies, but the nuc. XII and the cells of the cord were not markedly changed or were practically normal, in uncomplicated cases. In one case there was prolonged violent delirium while the cortical cells showed very slight lesions, irregularly dis- tributed, and the majority of large cells appeared normal. 122 STUDIES ON GANGLION CELLS. The ordinary temperature of fatal pneumonia (1060) appears not necessarily to leave any changes in the gan- glion cells such as are seen in cases of sunstroke or in rabbits subjected to high temperature. In the case of alcoholic pneumonia with terminal tem- perature of 1090 the extreme bleaching of the cells recalls the very similar lesion in cases of sunstroke, but these changes are indistinguishable from those resulting from acute alcoholism and in this instance were possibly refer- able to the alcoholic element. There seems to be no good reason to deny that there is an essential connection between the failure of the heart and respiration in fatal pneumonia and the changes in the ganglion cells of the medullary nuclei, and it seems prob- able also that the exaggerated activity of the cells is the determining factor in the production of lesions. Diphtheria.—Pernici and Scagliosi l66 report the exam- ination of the central nervous system in cases of diphtheria. In the cortex they found many normal cells, but some were much faded, very pale, and a portion of their protoplasm was entirely uncolored, while the nuclei were small, and the dendrites appeared granular. By Golgi's method such cells showed varicose atrophy. The changes in the cord were indefinite. Many of the cells appeared smaller than normal and their protoplasm was granular. The nuclei were often shrunken. A few cells had lost their processes and were reduced to a mass of coarse granules. In guinea pigs killed or dying 5 to 22 days after subcu- taneous injections of diphtheria cultures, Murawjeff161 found in the anterior horn cells all grades of chromatolysis, reaching complete bleaching, and followed by degenera- tion, loss of nuclei, and vacuolation. The lesions were more marked in the lumbar than in the cervical cord. STUDIES ON GANGLION CELLS. 123 The spinal ganglia were unaffected in four or five days. Many fibres in peripheral nerve trunks were degenerated. In a later communication Murawjeff168 reports that diphtheria anti-toxine causes very similar lesions in the nerve cells as does the toxine. When, however, the toxine and anti-toxine in neutralizing doses are injected simul- taneously the nerve cells remain unaffected. Acute Bronchitis, Asphyxia.—Male, 45 years. Had suffered repeatedly from attacks of bronchitis with spas- modic asthma. Brought to hospital March 10, 1897, breathing rapidly, very cyanotic, temperature 102°, with signs of severe general bronchitis. March n, labored breathing and cyanosis continued without improvement, temperature 102.50. March 12, all symptoms aggravated. March 13, died with extreme cyanosis, temperature 103.50. Autopsy 11 hours after death. The blood was dark and fluid. The pleura and peri- cardium contained numerous ecchymoses. The lungs were intensely congested; the bronchi were thickly coated with muco-pus. The cerebral sinuses and pia were gorged with blood. Microscopical examination. In the medulla, the cells of the nuc. XII were usually normal in appearance. In the nucleus X and deeper lying cells the chromatic bodies were usually limited to a narrow peripheral ring, the remainder of the cell showing a more or less distinct chromatic network often infiltrated with yellowish pigment. The same changes were very marked in the cells of the corpora quadrigemina. In the cortex the large cells showed a loss of chromatic bodies in a perinuclear or peripheral zone of variable extent. The chromatic net- work of the arkyochromes was regular and distinct. In the Purkinje cells the chromatic bodies were usually of large size and regular contour, but deficient in number at the bases of the dendrites. Septicemia.—In this group are included five cases of general sepsis, including peritonitis, empyema, pyaemia, cellulitis. Case I.—Peritonitis.—Male, 49 years. Had been excess- ively alcoholic. For four months before admission had 124 STUDIES ON GANGLION CELLS. suffered from epigastric pain and marked tenderness, frequent vomiting of blood and occasional tarry stools, and had become excessively anaemic. Four days before death, he had sharp pain in the epigastrium, was prostrated, and died with symptoms of general peritonitis. The tempera- ture remained about ioi°. The last examination of the blood showed 10 per cent of haemoglobin. Autopsy 8 hours post-mortem. There was a circular ulcer of the duodenum which had perforated at one point directly into the peritoneal cavity. The peritoneum was everywhere the seat of a purulent inflammation and con- tained about one pint of free pus. There were evidences of chronic gastritis, fatty degeneration of the heart-mus- cle and liver, acute exudative nephritis, and extreme anaemia. Microscopical examination. Lang's fluid. In the cord many of the large stichochromes appeared normal or showed only a little raggedness of the chromatic bodies, probably of cadaveric origin. Others exhibited distinct signs of chromatolysis, either central or peripheral. In a few cells the chromatic bodies were all minutely subdivided. The above description applies also to the cells through- out the medulla, although here the changes were slightly more general and distinct. In the cortex most of the cells were very nearly normal, showing, with few exceptions, only slight subdivision of a few chromatic bodies, or slight irregularity of network. In the Purkinje cells the chromatic bodies were usually abundant, clear, and of normal size, but in a considerable number there was beginning subdivision of peripheral chromatic masses. In nearly all regions there were frequent evidences of post-mortem change consisting in nuclear chromatophilia, diffuse staining, and vacuolation. Case II.—Empyema.—Female, 22 years. Was delivered of m a dry air oven, in which the temperature ranged between 46° and 48° C. It began to breath rapidly at once. After STUDIES ON GANGLION CELLS. 153 one hour it lay panting on its side and seemed very weak, although kicking rather actively when prodded. Tem- perature 41.50. After one and one-half hours the animal seemed greatly exhausted, being hardly able to stand. The reflexes were markedly hyperaesthetic and breathing was very rapid. At the expiration of two hours the animal was found dead and rigid. Rectal temperature 44° C. The examination of the viscera revealed much venous congestion of cerebro-spinal meninges, and lungs. The other viscera were notably pale. The blood was very dark and entirely fluid, failing to clot also after shedding. The central nervous system was examined, after hard- ening 24 hours in Lang's fluid, by Nissl's method. In the medulla all the chromatic bodies of the nerve cells had disappeared, although some cells showed a faintly visible network or a few dark granules in the cytoplasm. Large, clear vacuoles were seen in some cells. The cell bodies looked waxy, staining light blue, their outlines were usually regular. The nuclei were, almost without excep- tion, diffusely stained dark blue. About the nucleoli were often two to five dark granules, while the nuclear mem- brane was irregularly invisible. In the cord, the chro- matic bodies of the stichochromes had almost entirely dis- appeared, the cell bodies looking waxy, swollen, and staining diffusely light blue, the periphery being very pale. In many cells traces of the chromatic bodies could be detected, (1) in the form of very pale ragged masses of the same general shape as in the normal condition. (2) In the form of fine granules scattered through the cytoplasm, sometimes in the form of a network; and (3) as a diffuse discolorization of the entire cell. The dendrites showed an irregular network composed of granules, or occasionally a ragged spindle. The nuclei were very darkly stained, their position was usually central, and they resembled the nuclei of the medullary cells. Experiment II. Similar in most respects to the first, except that after two and one-half hours, the animal, with *54 STUDIES ON GANGLION CELLS. a rectal temperature of 45° C, was removed from the oven and placed in a draught of fresh air, with the expectation that it would recover. Although the symptoms had been rather less marked than in the first case, one hour later the rabbit was found dead and rigid. Post-mortem appearances and condition of ganglion cells, the same as in former case. Experiment III. Was undertaken to ascertain more accurately the symptoms occurring before death. After one hour the rabbit's temperature registered 430. It lay on its side and was unable to stand for more than a few seconds, falling with very marked tremor. The respi- rations were 320 per minute and irregular. The reflexes were exaggerated. Placed in a draught for five minutes, it seemed greatly recovered, and sat in a normal position, the respiration falling to 200. After three and one-half hours, the temperature of the oven being 45°, the animal's temperature registered 44.6°, and it was again placed in a draught. At 3 hours, 45 minutes, temperature 43.6°; at 4 hours, 41.6°; at 4^ hours, 390. The fresh air very rapidly improved the animal's appearance, the respira- tion became nearly normal, and motor power seemed also normal. The reflexes were still exaggerated. It was again placed in the oven and its temperature raised in one hour to 45°. All the symptoms then returned, spasms of the limbs could readily be elicited, there was one short period of general clonic convulsions, later two general tonic spasms, ending in death, six hours from the begin- ning, with rectal temperature 45 °. The post-mortem appearances of the viscera and the condition of the ganglion cells throughout the central nervous system did not differ materially from those described in experiment No. 1. These experiments were repeated in a slightly altered form on four other rabbits, without eliciting any new facts in regard to the relation between the symptoms exhibited by the animals and the condition of the ganglion cells of the central nervous system. It may be noted in passing that the amphophilic STUDIES ON GANGLION CELLS. J55 network demonstrated in the cells of the liver and kidney of normal animals was partly or completely destroyed in a degree quite comparable to the changes observed in the nerve cells. The experiments, therefore, bear out completely the conclusions of Goldscheider and Flatau, that artificial ele- vation of temperature very rapidly distorts or destroys the chromatic structure of the ganglion cells of rabbits. A further set of experiments was conducted upon rabbits to determine how far the nervous function of these animals could be restored by prompt resuscitation after exposure to high temperatures, and in order to ascertain the condition of the ganglion cells in the resuscitated animals. The following report will serve to illustrate four very similar experiments of this order: A medium-sized black field rabbit, temperature 38.50 C, was placed in the oven, temperature 45.70C at 10 a.m. At 11 a.m. the temperature of the oven was 47° C, that of the rabbit 42° C. The usual symptoms were observed, the animal lay panting but kicked vigorously when prodded. At 12 m. the temperature of oven was 48° C, that of the rabbit 43° C. Dyspnoea was now very marked, and the animal was hardly able to sit up, and it was now placed in a draught for 15 minutes. At 12.45 p.m. the temperature of the oven being 52° C, and that of the rabbit 45° C, it was noted that the respirations had fallen to 134, and shortly thereafter to 100, when breathing became irregular. The circulation was now very feeble. The reflexes were not exaggerated. The animal lay on its side, and could not hold up its head. It was bathed in water for 10 minutes, as death appeared to be imminent, and improved consider- ably. At 1.15 p.m. its temperature was 44°C. At 2.15 it was running about the room and was difficult to catch. When carefully watched however, it appeared to be partly i56 STUDIES ON GANGLION CELLS. blind, as it repeatedly ran into the wall. The reflexes were now extremely exaggerated, the slightest touch start- ing a violent general tremor with occasional spasms. Cir- culation and respiration appeared normal. Temperature at 2.15 p.m. 4o°C. At 2.40 p.m., temperature 39°C, the animal was rendered unconscious by a light blow on the head and was then exsanguinated, two hours after the last exposure to heat. The examination of the central nervous system revealed the same changes as noted in the previous experiments. In three other experiments the animals were allowed to recover for three and four hours after the last exposure to heat, but no distinct improvement in the nervous condition of the animals and no restitution of the cellular lesions in the nervous system were noted. Having noted, as did Goldscheider and Flatau, a considerable re- storation of function in cells presenting extensive altera- tion or destruction of chromatic structures, it was thought unnecessary to continue these experiments further. The writer's observations accord with those of Gold- scheider and Flatau with the exception that in the above experiments the cellular lesions were accompanied by a per- sistent loss of functional capacity as indicated especially by the persistent hyperesthesia of the reflexes. It is, therefore, impossible to fully agree with the claim of the above investigators, that the functions of these ex- tensively altered cells are entirely normal. Moreover, it might well be urged that it is impossible to detect in rab- bits many finer disturbances of nervous function such as may be fully recognizable in man, and may, by analogy, be supposed to exist in animals thus treated. It is well known that patients recovering from sunstroke, a condition in which the writer finds cellular lesions very similar to those in heated rabbits, are very liable to suffer from a variety of functional nervous disorders, including tachycardia/paralysis, and sudden death, and this fact must STUDIES ON GANGLION CELLS. 157 stand as evidence that ganglion cells once affected in this way, are not immediately restored to full functional activity. It must be accepted, however, that a consider- able grade of functional capacity may remain in cells showing extensive lesions of the chromatic substance. Further than this the present state of our knowledge does not permit any deductions to be drawn concerning the relation between disordered function and altered structure of the nerve cell. It remains for future investi- gations to determine, either from peculiar characters of the chromatolysis, or, as seems more likely, from changes in the nucleus and achromatic portion of the cell what degree of functional capacity may remain in cells showing various grades of chromatolysis. Section VII. Effects of Hyperpyrexia in the Human Subject. The effects of artificial elevation of temperature upon the ganglion cells in rabbits naturally raises the suspicion that many of the cellular changes now attributed to various intoxications and infections are referable solely to the pyrexia attending these conditions and do not accu- rately measure the action of the circulating toxic agent. Moxter213 studied the effects of elevation of temperature in rabbits caused by puncture of the medulla after the method of Aronsohn and Sachs. (Ffluger's Archiv., 37, 1885). In one rabbit whose temperature rose to 41.50, 23 hours after a second operation, many of the cells of the anterior horn of the cervical cord showed advanced chromatolytic lesions. In four other rabbits killed after repeated opera- tions on successive days, and in which the temperature '58 STUDIES ON GANGLION CELLS. varied between 380 and 41 ° no changes were found in the cells of the cord. The author concludes from this rather meagre evidence that simple elevation of temperature is sufficient to induce chromatolytic lesions in the nerve cells. Goldscheider and Flatau214 reach the same conclusions from observing in cases of tetanus and scarlatina, cellular lesions similar to those seen in rabbits heated in the oven. Throughout the present series of cases the writer has observed a uniform fading of the chromatic substance in addition to other lesions in many cases attended with high fever. Among such cases may be mentioned—the case of tetanus; Case VII of subacute leptomeningits; Case II of pneumonia; the case of general burns; and the first two cases of sunstroke. The following case also is believed to be of special interest in this connection, (It will be fully reported later by Doctor Robert Abbe, to whom the writer is indebted for the reference to the nervous system). Sudden Death after Osteotomy. Female, five years old. Osteotomy of both tibiae was performed for bow legs at 3 p. m. July 8. The anaesthesia, by ether, and the operation, lasting thirty minutes, were uneventful and the child was put to bed in apparently good condition. At 6 p. m. the temperature was found to be 1030. At 7 p. m. 1050; at 12 p. m. 1060; at 3 a. m. 1090; at 5.30 a. m. the child died, antermortem temperature not taken. During the last nine hours the pulse became very rapid and the respiration rose to 40 per minute, but there was no cyanosis. There were no convulsions or paralysis, no subjective complaints, and no other noteworthy symp- toms. The temperature at death was probably no°. Autopsy ten hours after death. The thymus was considerably enlarged, measuring 4x5x1 cm. There were general evidences of old rachi- tis. The lymphatic system appeared normal. The lungs were intensely congested and slightly oedematous. The STUDIES ON GANGLION CELLS. 159 other viscera were moderately congested. No other lesions were discovered. Microscopical examination. Formalin 10 per cent. The question of embolic processes in the lungs and other viscera has not yet been determined, and in any case can prove only of secondary import in the purpose for which this report is now made. In the lumbar cord nearly all cells are extremely faint, the chromatic bodies having faded uniformly without ap- parent subdivision. They sometimes appear swollen. The nuclei are coarsely granular, and the nucleoli swollen and composed of coarse refractive granules. Some cells are composed exclusively of coarse, faintly bluish stained granules. In a few cells, the perinuclear chromatic bodies persist, but are swollen and considerably faded. The cyto-reticulum is invisible. In the cervical cord the changes are similar but slightly less marked. In the spinal ganglia extreme alterations of the same general type were noted, but the chromatolysis was more marked in the perinuclear areas of the cells; while along the peripheries there was a considerable remnant of chro- matic substance but no distinct bodies. Throughout the medulla nearly all the cells are exten- sively bleached. Many are entirely lacking in chromatic substance. In some the chromatic bodies are still pre- served but they are extremely pale, so that their outlines are barely distinguishable. The nucleoli are swollen and very pale. Purkinje's cells are least affected. Most of them show a few distinct chromatic bodies limited to the base or periphery of the cell. The other bodies are either invisible or extremely thin and pale. In the motor cortex there is uniform and extreme reduc- tion in chromatic substance in all the cells. The above case must be regarded as a specially favor- able opportunity of ascertaining in the human subject the effects of high temperature uncomplicated by other toxic influences. The extreme loss of chromatic substance in all regions of the central nervous system can be attributed, it would seem, solely to the pyrexia. Ether does not pro- duce such changes in animals, nor such symptoms in the human subject, and embolic processes could hardly have reached such general distribution as were shown by the lesions in the nerve cells. i6o STUDIES ON GANGLION CELLS. The chromatolytic process was here somewhat different from that observed in sunstroke, and in heated rabbits, for the chromatic bodies in both the latter conditions suffered much granular subdivision before disappearing, while in this instance, they appeared to fade usually without granular subdivision. It is important to note that the nuclei of all the cells in the tissues examined stained with diminished intensity by methylene blue. From the evidence thus reviewed it seems probable that in cases attended with extreme pyrexia, i. e., above 1070 F., extensive bleaching of the great majority of ganglion cells in the central nervous system may indicate only the effects of the febrile process and not those of an associated toxaemia. On the other hand, the present series offers several in- stances which prove beyond a doubt that extreme pyrexia lasting many hours may fail to induce such general chro- matolytic changes in the ganglion cells. Among these may be mentioned Case IV of pneumonia, and Case III of sunstroke, in which there was high and continuous pyrexia, but extreme examples of chromatolysis occurred in isolated foci only and many cells remained intact. On the other hand, also, the cases of the present series in which prolonged high temperature of 1050 to 1060, failed to induce extreme grades of chromatolysis of general distribution are rather numerous and one is forced to con- clude that the ordinary temperature of infectious diseases plays only a limited and secondary part in the chroma- tolytic changes observed in these conditions. It is hardly necessary to add that an observation, of ante-mortem temperature is an essential in the study of clinical material by Nissl's method. STUDIES ON GANGLION CELLS. l6l Section VIII. General Character of the Lesions in Nerve Cells. The confusion which has resulted from the use of a variety of terms to designate the same change in the chromatic bodies of the nerve cells, renders it very desirable that a uniform nomenclature should be em- ployed in the description of these lesions. Unfortunately for this end, the different stages of the process of chro- matolysis and the effects of different reagents give extremely varied pictures of these changes, although as the writer believes, the process is always essentially one and the same, consisting in a diminution of volume by one means or another of the mass of chromatic substance. The chromatolytic process is frequently, if not always, initiated by a preliminary swelling of the chromatic body. The exact nature of this change is not known, nor has its presence in suitable conditions invariably been noted. Examples of this stage are best demonstrated in the early periods of infection with tetanus, and in artificially heated animals. Either with or without the preliminary stage, the chro- matic substance begins to disappear from the mass. If the change proceeds slowly the chromatic body diminishes uniformly in size, and in the last stages appears as a slender and pale spindle or granule. Such appearances are com- mon in slowly fatal cases of obstruction to cerebral circu- lation, and the change may be designated as uniform diminution in size of the chromatic body. When the lesion advances more rapidly several points in the chromatic body may appear bleached, the mass may be partly sub- divided or reticulated, and the process may be designated as uniform subdivision of the chromatic body. Many such cells may be seen in the chronic toxaemias. 162 STUDIES ON GANGLION CELLS. In many severe and acute lesions the process seems to affect all portions of the chromatic body, reducing it to a series of granules, which at first indistinctly outline the original mass, later are found diffusely scattered through- out the cytoplasm and giving the cell a peculiar dusty aspect. This appearance may be designated as the granu- lar subdivision of the chromatic body. The distinctness of the granular appearance, at least in the early stages, will depend much upon the fixing agent employed. All stages of such alteration may be followed in most cases of acute poisoning. The final stage of the chromatolytic process may leave the cell entirely lacking in chromatic substance, and show- ing on close inspection only the original cyto-reticulum which is usually demonstrable by methylene blue. This stage is usually spoken of as complete simple chromatolysis. Whatever variation there may be in the intermediate stages, the end results of simple chromatolysis are usually identical. The writer has been unable to find upon close scrutiny any essential difference in the structure of the badly altered cells in sunstroke, alcoholism, thrombosis of the basilar artery, cerebral hemorrhage, the acute and chronic toxaemias, and most of the cells in tetanus. In most of these cases the complete bleaching of the cell has been reached without demonstrable changes in the cytoplasm or nucleus. It is usual for the chromatolytic process to affect exclu- sively the perinuclear zone {central chromatolysis), or the peripheral areas {peripheral chromatolysis), or, at times, one or more segments of the body {circumscribed chro- matolysis). Often all the chromatic bodies are uniformly subdivided, occasionally only the dendritic masses. The well known appearance of the cell affected by STUDIES ON GANGLION CELLS. 163 central chromatolysis and eccentricity of the nucleus has been aptly termed by Van Gieson the '' axonal degeneration." During the process of chromatolysis, however, other changes are often described, affecting the achromatic sub- stance and the nucleus. Thus a diffuse staming of the achromatic substance is often reported in the examination of the cells, pointing either to a diffusion of the chromatic substance into the achromatic, or to a chemical alteration of the cytoplasm. Nearly every pathological specimen contains cells of this appearance, yet it is far from certain that the achromatic substance ever really exhibits an in- creased affinity for methylene blue. Without insisting that such is invariably the case, the writer is convinced that the vast majority of these appearances are artificial, resulting from incomplete decolorization, an unusually thick section of cell body which may occupy the entire depth of the cut section, and from the diffused blue refrac- tion of finely subdivided chromatic bodies. See Plate IV, Fig. 2. Such cells are very striking in the cords of heated rabbits, but the diffuse bluish stain disappears in very thin sections. Likewise nuclear chromatophilia in thin sections dis- appears or resolves itself into the presence of numerous fine granules in the intranuclear network. The significance of vacuolation has already been discussed. It is very probable that vacuoles may form in moderate numbers and of small size from vital patholgical processes, in which case their presence indicates a true degenerative change in the cell body. Rupture of dendrites has often been referred to as a vital pathological process, but it is far from clear that the vol. 1—no. 3—L 164 STUDIES ON GANGLION CELLS. condition results from any other influence than trauma- tism, applied either in extracting the brain and cord from the body, or resulting from the shrinkage of tissues during the hardening process. The finer changes in the achromatic substance it is im- possible in the present state of our knowledge to describe accurately. In the majority of cells that have lost their chromatic bodies a delicate cyto-reticulum remains visible. In many of the severe toxaemias and especially in the acute infections of the nervous system, as tetanus, hydro- phobia, myelitis, etc., this cyto-reticulum may be found to be irregular, coarsely granular, distorted by vacuoles, or may become invisible. In some instances the coarse granules may show slightly altered staining reactions and refrangibility, and in some of the writer's cases, these granules seemed to approach the character of the ordinary yellowish pigment deposit. The formation of clefts and fissures is a distinct feature of the lesions of the achromatic substance as seen in various conditions. These changes, while of great interest, as bearing on the structure of the ganglion cell, have not yet received any explanation. The entire cell body may be found to be slightly swollen, especially in the early stages of chromatolysis. In simple chromatolysis no changes in the size or contour of the cell body is ordinarily found. In most human sub- jects dying from general diseases, some cells exhibit irregularity in outline which indicates a true degenerative process, affecting all elements. The possible effects of reagents must here, of course, be constantly recognized. In lesions of longer standing, the cell body may be markedly shrunken, its outlines rounded, the dendrites may disappear, the chromatic substance is entirely wanting, STUDIES ON GANGLION CELLS. 165 and the cytoplasm may appear uniformly and coarsely granular. A considerable variety of nuclear changes has been described. The nucleus is often shrunken, but it is difficult to see what vital process can induce such a change, and its sig- nificance is as yet uncertain. A peculiar appearance sometimes encountered, and de- picted in Plate VI, Fig. 5, is the gathering of granules and rods of chromatic substance about one side of a shrunken nucleus. This change also is without known significance. The nuclear membrane may be invisible in specimens stained by methylene blue. In some of these cells a counterstain by erythrosin may demonstrate a faint persisting membrane, or, in other instances, this structure seems to have entirely disappeared. The intra-nuclear network is often replaced by a series of pale granules, very irregular in size and position. The character and location of these granules is fully demon- strated by erythrosin. Nuclear chromatophilia the writer must refer to the presence of many of these fine granules or to an under- lying stratum of the cell body containing finely subdivided chromatic bodies, having rarely encountered a diffuse staining of this body apart from post-mortem processes. The nucleolus is sometimes distinctly swollen, and thin sections of such nucleoli, usually discloses a reticulated structure. Some of the meshes of this reticulum may project beyond the border of the nucleolus, giving the appearance of vacuolation. In such cases the changes in the central acidophile mass of the nucleolus may be fol- lowed in sections stained by Ehrlich's tricolor mixture. The nucleus may contain several large or small deeply i66 STUDIES ON GANGLION CELLS. staining masses grouped about the nucleolus, and suggest- ing a subdivision of this body. In these granules, often called secondary nucleoli, the writer has been unable to demonstrate any portion of the central acidophile mass of the nucleolus, and it appears that their origin is not cer- tainly understood. While the above changes in the ganglion cells as demon- strated by Nissl's method are those most frequently encountered, any attempt to exhaust all the possible peculiarities of the degenerating nerve cell must neces- sarily be fruitless. The minute lesions appear to differ in each case and the range of minor peculiarities is practi- cally limitless. Especially in the advanced stages of acute and chronic degeneration the aspect of the cells may be so heterogeneous that classification of lesions is impossible. Likewise the attempt to separate the lesions of simple chromatolysis from those of true degeneration, requires, in the present state of microscopical technics, too much conjec- ture for the conservative investigator, especially as the phy- siological and pathological processes are usually blended. The early stages of the true degenerative process have not yet been satisfactorily demonstrated, and it is only when we meet with vacuolation of the cell body, with clefts, raggedness of outline, destruction of cyto-reticulum, loss of dendrites, and distinct atrophy, and when marked nuclear changes are present, that it is safe to conclude that a generally destructive process has been at work. When acute degeneration, in a strict sense, affects the gan- glion cell, its changes are usually evidenced by various forms of chromatolysis, but the true degenerative process may not and, as the writer believes, frequently does not begin until after chromatolysis is complete. STUDIES ON GANGLION CELLS. 167 DESCRIPTION OF PLATES. Plate I. Figure 1.—" Polar dendrite " of lumbar stichochrome. Specimen teased in fresh condition, fixed by heat, stained by erythrosin and methylene blue. The chromatic bodies appear as integral parts of the reticulum, the blue fading insensibly into the red threads. The reticulated portion of the cell is sharply marked off from an envelop of granular acidophile substance which is continuous with the axis cylinder process. Figure 2.—Normal human Purkinje cell. Specimen teased in fresh condition, fixed by heat, stained by methylene blue. The chromatic bodies are continuous with a network staining distinctly with methylene blue. Figure 3.—Normal human archystichochrome, from motor cortex. Sat. aqueous bichloride. Methylene blue. Figure 4.—Normal human spinal ganglion cell. Van Gehuchten's fluid. Methylene blue. The large chromatic bodies are concentrically arranged. The achromatic substance at the pole is finely granular, and the granules are placed in indistinct radiating rows. These granules do not stain distinctly as does the reticulum of the cell body. Plate II.—Cadaveric Changes. Figure 1.—Medullary stichochrome of infant. Eight hours after death. Lang's fluid. Methylene blue. Very rapid and extreme vacuolation. Loss of cyto-reticulum. Coarsely granular appearance of chromatic bodies. Beginning nuclear chromatophilia. Figure 2.—Cortical arkyochrome of rabbit, after 36 hours ex- posure to air. Lang's fluid. Methylene blue. Vacuolation. Coarsely granular appearance of chromatic reticulum. Complete nuclear chromatophilia. Shrinkage of dendrites. Figure 3. —Purkinje cell of rabbit, after 48 hours exposure to air. Lang's fluid. Methylene blue. Extreme vacuolation. Growth of i68 STUDIES ON GANGLION CELLS. putrefactive bacteria. The chromatic reticulum and bodies are reduced to a series of coarse dark granules. Complete nuclear chromatophilia. Shrinkage and destruction of dendrites. Plate III.—Cadaveric Changes. Figure i.—Human Purkinje cell. Twenty-four hours after death. Lang's fluid. Methylene blue. Slight vacuolation. Coarsely granu- lar appearance of chromatic structures. Beginning nuclear chro- matophilia. Figure 2.—Human cortical arkyochrome. Twenty-four hours after death. Lang's fluid. Methylene blue. Slight vacuolation. Partial destruction of chromatic reticulum. Beginning nuclear chromato- philia. Figure 3.—Human cortical arkyochrome. Twelve hours after death from fracture of vertebra. Lang's fluid. Methylene blue. The chromatic reticulum is replaced by coarse granules. The nuclear membrane and network are markedly thickened. Figure 4.—Spinal stichochrome of asphyxiated infant. Ten hours after death. Lang's fluid. Methylene blue. Rapid destruction of chromatic structures, which are reduced to coarse granules, some of which are deposited in the pericellular lymph space. Plate IV. Figure 1.—Large archystichochrome of motor cortex in case of sunstroke. Sat. aqueous bichloride. Methylene blue. The chro- matic bodies have entirely disappeared, leaving a fine reticulum staining faintly with methylene blue. The nucleus contains several large granules, probably derived from the nucleolus. Figure 2.—Medullary stichochrome of rabbit, killed by heating. Sat. aqueous bichloride. Methylene blue. (Section 3 fi. Zeiss ^ apochromatic lens; artificial light; achromatic condenser; oil on condenser). By low magnification, this cell appears uniformly homogeneous and diffusely stained. On higher magnification and special illumi- nation, the cell is found to contain remnants of the chromatic bodies in the form of fine, pale granules. No cyto-reticulum could be discerned. STUDIES ON GANGLION CELLS. 169 Figure 3.—Human cortical archystichochrome, in case of tetanus. Alcohol, 97 per cent. Methylene blue. The chromatic masses are almost entirely wanting, the faint chromatic network persisting. The intra-nuclear network is thickened and coarsely granular and the nucleolus presents several small clear areas. Figure 4.—Human medullary stichochrome, in a case of sunstroke. Section 3 \i. Sat. aqueous bichloride. Methylene blue. The chro- matic bodies are destroyed. The cell is largely composed of coarse pale granules, which sometimes form an indefinite chromatic net- work. The cell borders are rounded and the processes missing. In sections 15 jit in thickness this cell appeared uniformly homo- geneous and chromatophilic, as in the small figure. Figure 5.—Purkinje cell in case of thrombosis of basilar artery. Lang's fluid. Methylene blue. There is uniform fading and marked diminution in size of the chromatic masses. The cyto-reticulum is very indistinct in the cell body, but a reticulum staining with methy- lene blue is visible in the dendrites. Plate V. Figure 1.—Cortical arkystichochromes compressed by distended capillary in case of acute uraemia (Case I). In both cells there is moderate perinuclear chromatolysis with preservation of reticulum. Figure 2.—Usual changes in cortical cells in uraemia. In the arkyochrome the network is distinct but its meshes are not always uniform in size. The nucleus contains many large pale granules replacing the intranuclear network. In the arkysticho- chrome there is moderate perinuclear chromatolysis and certain nuclear changes. Plate VI. Figure 1.—Human Purkinje cell in case of tetanus. Alcohol 97 per cent. Methylene blue. There is marked fading and partial sub- division of chromatic bodies. The reticulum of the cell body is indistinct and irregular but appears much sharper in the dendrites. The nuclear membrane is almost invisible and the intranuclear net- work is reduced to coarse pale granules. The nucleolus is distorted and presents the appearance of vacuoles. This cell must be regarded as showing true degenerative changes. 170 STUDIES ON GANGLION CELLS. Figure 2.—Medullary stichochrome adjacent to a miliary tubercle in Case I of tuberculous meningitis. Lang's fluid. Methylene blue. There is moderate subdivision of chromatic bodies especially about the nucleus. A chromatic network is visible between the bodies. The nucleus appears normal. Figure 3.—Deep medullary stichochrome in above case of tuber- culous meningitis. The chromatic bodies are entirely wanting. A faint reticulum persists, staining slightly with methylene blue. Some | processes appear to have been destroyed. The nucleus is shrunken and eccentric. Figure 4.—Axonal degeneration. Sunstroke, etc. Sat. aqueous bichloride. Methylene blue. The chromatic bodies have disap- peared from the centre of the cell, leaving a chromatic network and a few fine granules. The nucleus is eccentric, but is otherwise slightly altered. Figure j.—Medullary stichochrome in case of acute morphine poisoning. Van Gehuchten's fluid. Methylene blue. The chro- matic bodies in several parts of the cell are partly or completely destroyed leaving a faint chromatic reticulum. Some of the remain- ing bodies appear to have been fused together. The nucleus is shrunken and eccentric. The deeply staining rods heaped about the edge of the nucleus were abundantly present in this cell and are possibly referable to the shrinkage of the nucleus. Figure 6.—Purkinje cell in case of eclampsia. Lang's fluid. Methylene blue. The chromatic bodies are much faded and partly subdivided. A chromatic reticulum is visible. The nucleolus is enormously swollen, the nucleus is small and markedly chromato- philic. Ganglion Cells. PLATE f. ->" y "% .** j *>.. -» ? y * >'■ ■f f -fr -/.:""y ^ :'"'" f i - ^ ,- y t *(?* ^ Jlr' *-*N *g-3. ^- /■ jhT Fig. 2. * F/£.4. Archives of Neurology and Psycho-Pathology. HELIOTYFt PJU1TOU; C0.,B6ST0S Studies on Ganglion Cells. PLATE II. •v*- ■p ■;*V\. / $ >" i.v Fig. 2. v- fee.. -"' >7*"Nui.»*j' ""' ■"•"-■"•.*'" '-*»>•'■ j)' f«-a Archives of Neurology and Psycho-Pathology. HEUOTrTE PRIHTMi; CCSOSTOK Studies on Ganglion Cells. PLATE III. 7?/:-^>s^\^'. / % /. ■4T #/ \&vfr %V F/£.2. Fig. 3. F#* Archives of Neurology and Psycho-Pathology. Ewiurt, del. HELIOTTP; PSTNTms C Studies on Ganglion Cells. PLATE IV. Fig. I. 0 ' ' . ', . ' * .*.' % * «1 »" ' ' . ' s * ■ t ■ ■ * . ..-jr • • • • % . '•.\'V t7^\ -.U.;"; > 'i* • '«! «». > !' • . <9. .»- ♦ *'. ... # ..J O <" .. "» v<" \ :■' • '' .' * * .<■•'*'>' __JU**"J. „A ;-\ '" '■ ^i'.S* ' ■ .." . * : . ,j , Fig. 2. Fig. 3. m *• • • v \ \ \ N* \ Fig. 4. Archives of Neurology and Psycho-Pathology. F/£.5. Ewing, dRl. HELIOTYPE PRIKTWi CO,BOflT01t. Studies on Ganglion Cells. PLATE V. $•£:*''> J \ y s Fig. I. ■"»- >". ' ■"''■' •''"N"f••\^-i.■ w9. W^SR Yr:£v ,r.'.C ^ F/£.2. Archives of Neurology and Psycho-Pathology. Eu/lng, del, HO.I0TYTE PRJNTmi: CO.B0ST0K Studies on Ganglion Cells. w t\ * ,. **&■: w* lfe*V>^= <$•£ 5f 0 si >£#. ■•■7Tf-«. '%. -./ /^-. . :." ■ ;v^' •' 4fefc "^w F,g. /. F/£.£. •.-/:*., 5-:*'r**ri Wv Ik ,■ > © ** ■"*• \*> » IT' ' ..■' ';J.'VS,-'-r-5"*'** fi£.4. 19? ' / Fig. 5. Ewing, dH], Archives of Neurology and Psycho-Pathology. HELIOTYPr FRTNrTNi; C0.,B03TGH STUDIES ON GANGLION CELLS. 171 BIBLIOGRAPHY. On Technics : 1 Nissl: Ueber die Untersuchungsmethoden der Grosshirnrinde. Ref. Neur. Cent., 1885, p. 500. 2 Nissl: Allg. Zeit. f. Psych., 1890, 48 Bd., p. 197. 3 Nissl: Cent. f. Nervenheilk, 1894, p. 337. 4 Ehrlich: Deut. Med. Woch., 1886, p. 49. 5 Rehm: Munch. Medicin. Woch., 1892, p. 217. 6 Lenhossek: Feinere Bau d. Nervensyst., 2 Auf., p. 149. 7 Flemming: Anat. Hefte, 1896, XIX, XX, p. 561. 8 Colucci: Sulla morfologia e sulle valore delle parte constituenti la cellula nervosa. Annali di Neuroglia, 1896, p. 145 seq. 9 Held: Structur der Nervenzellen. Arch. f. Anat. u. Phys. Anat. Abt, 1895, p. 396; 1897, p. 204. 10 Savdovsky: Compt. Rend. d. Soc. Biol., 1896, p. 355. n Smirnoff: Rev. Neurologique, 1896, p. 61. 12 Marina: Eine Fixationsmethode, bei welcher sowohl die Nissl'sche Nervenzelle, als die Weigert'sche Markscheide farbung gelingt, Neur. Cent., 1896, p. 166. 13 Graf: N. Y. State Hosp. Bulletin, 1897. Vol. 2, p. 386. 14 Cox: Anat. Hefte, XXXI, 1898. 15 Gothard: Neur. Cent., 1898, p. 530. 16 Rossalimo and Murawjeff: Neur. Cent., 1897, p. 722. 17 Trezebinski: Einwink. d. Hartungsmethoden auf d. Beschaffen- heit d. Ganglienzellen: Virchow's Archiv., 107, p. 1. 18 Kronthal: Neur. Cent., 1890, p. 40; 1895, p. 797. 19 Fisher: Anat Anzeiger, Bd. IX and X. 20 Flesch and Koneff: Neur. Cent., 1886. 21 Nissl: Mittheil zur Anat. der Nervenzellen. Allg. Zeit. fur Psych., 1894, p. 370. 22 Eve: Sympathetic Ganglion Cells and their Basophile Con- stituent in Prolonged Activity and Repose. Jour, of Physi- ology, 1896, Nos. 4-5. 23 Turner: A Method of Examining Fresh Nerve Cells. Brain, 1897, p. 450. 24 Kreyssig: Virchow's Archiv., 102, p. 286. 25 Thanh offer: Cit. by Lenhossek (6), p. 149. 26 Arnold: Structur u. Architectur der Zellen. Arch. f. Micr. Anat, 1898, Vol. 52, p. 535. Histology : 27 Flemming: Henle's Festschrift p. 12, Bonn, 1882. 28 Benda: Verhand. d. Physiol. Gessell, Berlin, 1885, p. 12. 29 Nissl: Die Nomenclatur in d. Nervenzellen-Anatomie, Neur. Cent., 1895, p. 66. 30 Benda: Neur. Cent., 1895, pp. 117-759. 31 Van Gehuchten: Anat. d. System Nerv., 1897, pp. 240-1. 32 Colucci: Annali de Neur., 1896, p. 145. 33 Lenhossek: Feinere Bau. des Nerv., p. 316. VOL. I—NO. 3—M. 172 STUDIES ON GANGLION CELLS. 34 Nissl: Neur. Cent., 1896. p. 98. 35 Dogiel: Arch. f. Microscop. Anat., Vol. 46, p. 331. 36 Dogiel: Die Structur d. Nervenzellen d. Retina. Arch. f. Micr. Anat., Vol. 46, p. 394. 37 Nissl: Neur. Cent., 1896, p. 161. 38 Gescheidlen: Ueber die Chemische Reaction der Nervosen Centralorgane, Pfluger's Arch. Bd. VIII. Cit. from Held9. 39 Dogiel: Der Bau d. spinal Ganglien. Anat. Anzeiger, 1896, Bd. 12, p. 140. 40 Juliusberger: Neur. Cent. 1896, p. 386. 41 Van Gehuchten: Neur. Cent., 1897, p. 905. Heiman: Loc. cit. Virchow's Archiv., 1898, Bd. 152, p. 298. 42 Nissl: Zeit. f. Psychiatrie, 1896, Vol. 52, 43 Becker: Arch. f. Psych., Vol. 27, p. 953. 44 Benda: Neur. Cent., 1896, p. 161. 45 Flemming: Arch. f. Micr. Anat.., Vol. 46, p. 379. 46 Lugaro: Sul valore respetivo della parte cromatica della acro- matica .... delle cellula nervose. Riv. de Pat. nerv. e ment., 1896, Vol. 1, No. 1. 47 Dehler: Arch. f. Micr. Anat, Vol. 46, p. 724. 48 Lenhossek: Feinere Bau d. Nervensystem, 1895, p. 147. 49 Van Gehuchten: Anat. du systeme nerveux., 1897, p. 242. 50 Cajal: Riv. trimest, 1896, I, 1. 51 Simarro: Cit. from Van Gehuchten, p. 243, Anat. du system nerveux, 1897. 52 Schaffer: Neur. Cent., 1893, p. 844. 53 Levi: Riv. di Pat. nerv. e ment, 1896, I, H. 5. 54 Rosin: Deut Med. Woch., 1896, No. 31. 55 Pilcz: Pigmententwickelung in den Nervenzellen. Arbeit, aus Prof. Obersteiner's Lab. Wien., 1895. 56 Levi: Su alcune particolarita de struttura del nucleo delle cellule nervose. Riv. de Pat. nerv. e mentale, I, 1896, Fasc. IV. 56 Schiefferdecker: Gewebelehre, 1891, Bd. II, 1, p. 199. 58 Dogiel: Arch. f. Microp. Anat., XLVI, p. 305. Das leitende Elemente des Nervensystems und seine topographischen Beziehungen zu den Zellen. 59 Apathy: Mittheil aus d. Zool. Station Neapol,, 1897, p. 495. 60 Lenhossek: Untersuchungen iiber d. Spinalganglienzellen des Frosches, Archiv. f. Micr. Anat. Bd. 26, 1886, p. 370. Ueber den Bau der Spinalganglienzellen des Menschen. Arch. f. Psych. Bd. 29, p. 345. Bemerkungen u. d. Ban der Spinalganglienzellen, Neur. Cent, 1898, p. 577 61 Flemming: Vom Bau der Spinalganglienzellen. Festschrift fur Henle, Bonn, 1882, p. 12. 62 Nissl: Allg. Zeit. f. Psych., 1894, Bd. 50, p. 374. 63 Cox: Der Feinere Bau des Spinalganglienzellen des Kanin- chens. Anat. Hefte., 1898, Heft. XXXI, p. 75 64 Heimann: Beitrage zur Kenntniss der feineren Structur der Spinalganglien. Virchow's Archiv., 1898, 152, p. 298. STUDIES ON GANGLION CELLS. 173 65 Kolliker: Des fein. Bau und die Functionen des sympathet. Nervensystems. Wurzburg, 1894. Ueber die fein Anat. u. d. physiol. Bedeutung, etc. Wien. Klin., Woch. 1894, Nos. 40, 41. 66 Cajal: Neue Darstellungen vom Bau des Centralnervensystems. Arch. f. Anat. u. Phys. Anat. Abt, 1893. 67 Retzius: Ueber den Typus des symp. Ganglienzellen, etc. Biolog. Unters. Ill, Stockholm, 1892. 68 Sala: Sur la fine Anat. des Gang, du sympathet. Arch. Ital. de Biologie, Fasc. Ill, 1892. 69 Dogiel: Zur Frage, ub. d. fein Bau d. symp. Nervensystems. Arch. f. Micr. Anatomie, XLVI, p. 305. 70 Vas: Studien u. d. Bau d. Chromatins d. symp. Gang. Arch. f. Micr. Anat., Vol. 40, p. 375. 71 Dehler: Arch. f. Micr. Anat. Bd, 46, p. 724. 72 Babes: Ueber den Einfluss der verscheidenen Infectionen auf die Nervenzellen des Ruckenmarks. Berl. Klin. Woch., 1898, Nos. 1-3. 73 Eve: Journal of Physiol., 1896, Nos. 4-5. On Physiological Condition of Cells of Central Nervous System : 74 Parascandolo: Influence de la commotion sur les centres ner- veux. Arch. f. Physiol., 1898, p. 138. 75 Luzenburger: Su d'una speciale alterazione delle cellule gan- gliari prodotta da trauma. Ref. in Neur. Cent., 1898, p. 363. On Cadaveric Cellular Changes : 76 Schulz: Ueber artificelle, cadaverose, und path. Veranderungen des Ruckenmarks. Neur. Cent, 1883, p. 529. 77 Colucci: Contrib. alia istologia patologica d. eel. nerv. in alcune malattie men tale. Annali de Neuroglia, 1897, p. 12. 78 Neppi: Riv. di Pat. nerv. e mentale, 1897, p. 152. 79 Barbacci and Campacci: Sulle lesione cadaveriche delle cellule nervose. Riv. di. Pat. nerv. e ment, II 8, 1897. 80 Levi: Alterazione cadaverische della cellula nervosa, etc Riv. di. Pat. nerv. e ment, 1898, No. 1. On Neuritis, etc : 81 Onuf: The Constitution of Ganglion Cells as Influenced by Section of the Spinal Nerves. Jour, of Nerv. and Ment. Dis., 1895, p. 597- Ueber d. Veranderungen der Ganglienzellen . . . nach Ausreissung der Nerven. 82 Nissl: Allg. Zeit. f. Psych., 1892, p. 197. 83 Marinesco: Des lesions primitive et secondaires de la cellule nerv. Compt Rend. d. Soc. Biol., 1896, p. 106. 84 Lugaro: Riv. di. Pat. nerv. e ment., I, Fasc. 12. 85 Savdovsky: Compt. Rend. d. Soc. Biol., 1896, p. 355. 86 Flatau: Fort d. Med., 1896, p. 201. 87 Charrin and Thomas: Compt. Rendu, d. Soc. Biol., 1897, p. 37. 174 STUDIES ON GANGLION CELLS. 88 Colenbrander: Over de structur der gangliencel mit den voor- sten hoorn. Utrecht, 1896. Ref. in Neur. Cent, 1897, p. 787. 89 Marinesco: Presse Med., 1897, No. 8. 90 Flemming: Effects of Ascending Degeneration of Nerve Cells, etc. Edinburgh Med. Jour., T897, Vol. 1 (N. S.), p. 174, 91 Van Gehuchten: Neur. Cent, 1897, p. 908. 92 Ballet: Progres Med., 1896, p. 401. 93 Ballet et Dutil: Soc. Med. des Hopitaux, 1895, Dec. 13, p. 818. 94 Marinesco: Compt. Rend. d. Soc. Biol., 1895, p. 765. 95 Marinesco: Compt. Rend. d. Soc. Biol., 1896, p. 497. 96 Courmont: Rev. Neur., 1896, p. 497. 97 Dejerine and Thomas: Compt. Rendu, d. Soc. Biol., 1897, p. 399. 98 Soukarhoff: Arch. d. Neur., 1896, p. 177. 99 Carriere: Arch. clin. de Bordeaux, 1896, Sept. Ref. Neur. Cent, 1898, p. 856. 100 Marinesco: Rev. Neur., 1896, p, 129. 101 Friedmann: Ueber progress. Veranderungen der Ganglienzel- len. Arch. f. Psych., 1888, p. 244. Ueber acuten Encephalitis. Neur. Cent., 1890, p. 460; 1891, p. 1. Landry's Paralysis : 102 Ottinger and Marinesco: Semaine Medicale, 1895, p. 45. 103 Ballet: Soc. Med. des Hopitaux, 1895, p. 684. 104 Remlinger: Med. moderne, 1896, p. 213. 105 Bailey and Ewing: N. Y. Med. Journal, 1896, Vol. 2, No. 1. 106 Marie and Marinesco: Soc. d. H6pitaux de Paris, 1895, p. 659. 107 Piccinino: Annali di Neuroglia, 1897, p. 1. 108 Mills and Spiller: Jour, of Nerv. and Ment. Dis., 1898, June. Tabes : 109 Schaffer: Neur. Cent, 1898, p. 2. no Schaffer: Rev. Neur., 1896, p. 97. in Marinesco: Rev. Neur., 1896, p. 633. 112 Babes and Kremnitzer: L'anatomie microscopique des gan- glions spinaux et la pathogenie du tabes. Arch, des Sci- ences medicales, 1896, No. 2. 113 Juliusberger and Meyer: Neur. Cent, 1898, p. 151. Miscellaneous Nervous Diseases : 114 Marinesco: Presse Med., 1897, p. 167. 115 Nagy: Neur. Cent., 1894, p. 820. 116 Berger: Monatschrift f. Psych, u. Neur., 1898, H. 1. 117 Boedecker u. Juliusberger: Anatomische Befunde bei Demen- tio paralytica. Neur. Cent., 1897, p. 774. 118 Belmondo: Alterazioni dei centri nervosi nella paralisi progres- siva. Annali di Neuroglia, 1896, p. 475. 119 Crisafulli: Ulteriore contributo alia Istologia path, della paralisi gen. pro. Annali de Neur., 1897, p. 194. STUDIES ON GANGLION CELLS. 175 120 Tirelli: Sull anatomie pat. degli elementi nervosi e special- men te nella frenosi epilettica. La Ref. Med., 1895, 3, p. 246. 121 Christiani: Le fine alterazione .... negli alienati dimenti. Annali de Neur., 1897, p. 47. 122 Heilbronner: Allg. Zeit. fur Psychiatrie, 1896, Vol. 53, p, 172 123 Cramer: Path. Befund in einacuten. Falle der Paranoiagruppe. Arch. f. Psych., 1897, Bd. 29, p. 1. 124 Alsheimer: Das Delirium acutum. Neur. Cent., 1897, p. 617. 125 Warda: Beitrage zur Histopathologic der Grosshirnrinde. Deut. Zeit. fiir Nervenheilk, 1895, Bd. 7, p. 138. 126 Hammarberg: Studien uber Klinik u. Path. d. Idiotie, etc. (Translated by Henschen). Upsala, 1895. 127 Juliusberger: Neur. Cent., 1896, p. 386. Intoxications: 128 Erlicki and Rybalkin: Ueber Arseniklahmung. Arch. f. Psych., 1891, Bd. 23, p. 861. 129 Nissl: Allg. Zeit. fiir. Psych., 1892, Vol. 48. 130 Schaffer: Ueber Verand. der Nervenzellen by chron/ Blei-, Arsen-, und Antimonvergiftungen. Ung. Arch, fur Med., 1893, p. 43. 131 Lugaro: Riv. di Pat. Nerv. e ment, Bd. II, No. 2, 132 Dexler: Zur Histologic der Ganglienzellen des Pferdes .'"'. . . nach Arsenvergiftung. Arbeiten aus Prof. Obersteiner's Lab., 1897, Wien. 133 Nissl: Fortschritte der Medicin, 1896, p. 784. 134 Sarbo: Ungar, Arch. f. Med., 1893, p. 264. 135 Dehio: Verander. der Ganglienzellen bei Intoxicationen. Allg. Zeit. f. Psych., Vol. LI I, p. 689. 136 Maneresi: Cent. f. Allg. Path., 1897, p. 313. 137 Vas: Zur Kenntniss der chron. Nicotin u. Alcohol-Vergiftung Arch. f. exper. Path. u. Pharm., Bd. 33, p. 141. 138 Pandi: Ref. Neur. Cent, 1894, p. 900. 139 Saratschow: Neur. Cent., 1895, No. 8. 140 Dotto: La Riforma Med., 1896, p. 573. 141 Tirelli: Arch. Ital. de Biol., 1896, Vol. 26, p. 230. 142 Borro: Riv. de Med. legale, 1897, Fasc. 9. 143 Rossi: Riv. di Pat. nerv. ement, 1896. 144 Dehio: Unters. u. d. Veranderungen des Ganglienzellen bei'der acute Alcoholvergiftung. Cent. f. Nervenh. u. Psych., 1895, p. 113. 145 Andriesen: Newer Aspects of the Pathology of Insanity. Brain, 1894, pp. 548, 674. 146 Berkeley: Studies on the Lesions of Alcohol in the Cortical Nerve Cell. Brain, 1895, p. 473. 147 Stewart: Influence of Acute Alcohol Poisoning on'Nerve Cells. Jour, of Exper. Med., 1896, p. 623. 148 Nageotte and Etlinger: Compt. Rend. d. Soc. Biol., 1898, p. 101. 176 STUDIES ON GANGLION CELLS. Miscellaneous : 149 Phisalix, Charrin, et Claude: Lesions du systeme nerveux dans un cas d'intoxication experimentale par le venin de vipere. Compt. Rend. d. Soc. Biol., 1898, p. 317. 150 Uhlenhuth u. Moxter: Ueber Veranderungen der Ganglien- zellen bei experimenteller Vergiftung mit Rinder- und Menschenblut-serum. Fort, der Med., 1898, p. 361. 151 Marinesco: Lesions produite par le toxine du Bacillus botu- linus. Compt. Rend. d. Soc. Biol., 1896, p. 989. 152 Kempner u. Pollak: Die Wirkung des Botulismustoxins (Fleischgiftes) und sein. specif. Antitoxins auf die Nerven- zellen. Deut Med. Woch., 1897, p. 505. Auto-Intoxications. Uraemia : 153 Acquisto e Pusateri: Sull anatomia nervosa . . . nell'uraemia sperimentale. Riv. di Pat. nerv. e ment., 1896, No. 10. 154 Sacerdotti e Ottolenghi: Sulle alterazione degli elementi nerv- osi nella discrasia uremica sperimentali. Riv. di Pat. nerv. e ment, 1897, No. 1. 155 Donetti: Comp. Rend. d. Soc. Biol., 1897, p. 502. Sunstroke : 156 Lambert, A.: Med. News, July 24, 1897. 157 Van Gieson: Toxic Basis of Neural Diseases. N. Y. State Hospitals Bulletin, 1896, Vol. 1, No. 4. Starvation : 158 Schaffer; Ueber Nervenzellenveranderungen wahrend der In- anition. Neur. Cent., 1897, p. 832. 159 Tauczek: Neur. Cent., 1896. 160 Jacobsohn: Ueber das Aussehen der motorischen Zellen .... des Ruckenmarks nach Ruhe und Hunger. Neur. Cent., 1897, p. 946. 161 Lugaro e Chiozzi: Sulle alterazione degli elementi nervosi nell' inanizone. Riv. di Pat. nerv. e ment., 1897, p. 394. 162 Donetti: Les lesions des cellules du systems nerveux central apres l'ablation des capules surrenales. Compt Rend. Soc. Biol., 1897, p.'535. Infectious Diseases. Typhoid Fever : 163 Marinesco: Compt. Rend. d. Soc. Biol., 1897, p. 796. Pneumonia : 164 Dejerine: Compt. Rend., 1897, p. 728. 165 Goldscheider und Flatau. Beitrage zur Path, der Nervenzellen. Fort, der Med., 1897, p. 241, 609. Diphtheria : 166 Pernici e Scagliose: II Pisani, 1895, 2. Ref. Riv. di Pat. nerv. e ment, 1896, p. 69. STUDIES ON GANGLION CELLS. 177 167 Murawjeff: Arch. f. Med. exper., etc., 1897, p. 1165. 168 Murawjeff: Die diphtherischen Toxine und Antitoxine in ihrer Wechselwirkung auf das Nervensystem der Meerschwein- chen, Fort der Med., 1897, p. 93. Tetanus: 169 Beck: Veranderungen der Nervenzellen bei experiment Te- tanus. Ung. Arch. f. Med., 1894, p. 345. 170 Marinesco: Compt. Rend, de Soc. Biol., 1896, p. 726. 171 Claude: Presse Med., June 30, 1897. 172 Courmont, Doyon, et Paviot: Des pretendues lesions cell___ dans le tetanus. Compt. Rend, de Soc. Biol., 1897, p. 819; 1898, p. 604. 173 Goldscheider u. Flatau: Fort, der Med., 1897, p. 609. 174 Pechoutre: Compt. Rend, de Soc. Biol., 1898, p. 674. 175 Hunter: The Spinal Cord in Tetanus. Brit. Med. Jour., 1897, II, p. 333- 176 Goldscheider u. Flatau: Fort, der Med., 1898, p. 124, 212. 177 Goebel: Monatschr. f. Psych, u. Neurol., 1898, p. 1. Westphal, Fort, der Med., 1898, p. 483. Hydrophobia : 178 Schaffer: Annal. de l'lnstitut Pasteur, 1889. 179 Hogyes: Lyssa, Bd. V. Abt. II, Nothnagel's Spec. Path. 180 Nagy: Ref. in Hogyes' article, p. 52. 181 Nagy: Neur. Cent, 1896, p. 68. 182 Sabrazes et Cabannes: Nouvelle Iconographie de la Salpetriere, 1897, No. 3. Miscellaneous Infectious Diseases : 183 Lugaro: Alterazione d. cell. nerv. nella peste bubbonica speri- mentale. Riv. di Pat. nerv. ement, 1897, p. 241. 184 Muller u. Manicatide: Ueber die fein. Nervenzellenverander- ungen bei magendarmkranken Sauglingen. Deut Med. Woch., 1898, p. 139. Meningitis, Apoplexy, etc.: 185 Dotto e Pusateri: Riv. di Pat. nerv. ement, 1897, p. 8. Effects of Pressure : 186 Neumeyer: Veranderungen der Grosshirnrinde bei localem Druck. Deut Zeit. f. Nervenheilk, 1896, p. 167. 187 Pellizi: Sulle alterazione delle cellule nervose neli'atrofia da mancate funzione. Annali di Freniatria, 1897. Significance of Chromatic Bodies : 188 Lenhossek: Arch. f. Psych., Bd. 29, p. 345. 189 Levi: Richerche citologiche comparate suUa cell. nerv. dei vertebrati. Riv. di. Pat. nerv. e ment, 1897, p. 193. 190 Hodge: Study of Changes Due to Functional Activity in Nerve Cells. Journal of Morphology, 1892, Vol. 7, p. 95. r78 STUDIES ON GANGLION CELLS. 191 Mann: Changes Induced in Nerve Cells by Functional Activity. Jour, of Anat. and Physiol., 1894. Vol. 29, p. 100. 192 Nissl: Die Bezuhungen der Nervenzellensubstanzen zu den thatigen, ruhenden, und ermudeten Zellzustanden. Allg. Zeit. f. Psych., Vol. 52, p. 1147. 193 Korybutt and Daskiewicz: Arch. f. Micr. Anat, 1889, Bd. 32, P- 5- 194 Lambert: Compt. Rend. Soc. Biol., 1893, p. 879. 195 Levi: Contributo alia fisologia della cellula nervosa. Riv. di Pat. nerv. e ment, I, fasc, V. 196 Magini: L'orientation des nucleolus des cellules nerv. motrices dans le lobe electrique de la torpille. Arch. Ital. de Biol. 1, 22, p. 212. 197 Coggi: Quoted by Lambert, loc. cit, 1893. 198 Valenza: I cambiamenti microscopici nelle cell. nerv. nella loro attivita funzionale e sotto l'azione di agenti stimolanti e distruttori. Atti della R. Ac. della scienze fisiche e naturali di Napoli. Vol. 8, S. 2, No. 3. 199 Nissl: Ref. Neur. Cent, 1896, p. 39. 200 Lugaro: Sur les modifications des cellules nerv. dans les divers etats fonctionels. Arch. Ital. di Biol., Vol. 24, p. 258. 201 Pergens: Action de la lumiere coloree sur la retina. Annal. d Soc. Roy. d. Sciences Med. de Bruxelles, 1897, p. 1. 202 Pick: Ueber morphologische Differenzen zwischen ruhenden und erregeten Ganglienzellen. Vorl. Mittheil. Deut. Med. Woch., 1898, p. 341. 203 Luxenburg: Morph. Veranderungen der Vordenhornzellen des Ruckenmarks warend Thatigkeit Deut. Med. Woch., 1898, p. 4i5- 204 Levi: Annali di Neuroglia, 1896, p. 468. 205 Marinesco: Revue Neurologique, 1896, p. 633. 206 Monti: Sur l'anat. path, des elements nerveux... .del'embolism cerebrale. Arch. Ital. de Biol., 1895, p. 20. 207 Lamy: Sur les lesions medullaires d'origine vasculaire. Arch. de Physiol., r8g5, 1897. 208 Sarbo: Ueber Ruckenmarksveranderungen nach zeitweiliger. Veschliessung der Bauchaorta. Neur. Cent., 1895, p. 664. 209 Marinesco: Pathologie generate de la cellule nerveuse. La Presse Medicale, 1897, II, p. 246. 210 Colucci: Sulla morfologia e sul valore delle parti constituenti la cellula nervosa. Annali di Neuroglia, 1896, p. 145. 211 Goldscheider and Flatau: Beitrage zur pathologie der nerven- zellen. Fort. de. Med., 1897, p. 241, 609. 212 Heymans and Masuin: Fort, der Med., 1897, p. 215. 213 Moxter: Ueber Ganglienzellenveranderungen bei kunstlicher Steigerung den Eigenwarme. Fort, der Med., 1898, p. 121. 214 Goldscheider u. Flatau: Normale und path. Anat. der Nerven- zellen. Berlin, 1898, p. 114. Laboratory of the College of Physicians and Surgeons, Columbia University, New York. July 26, 1898. INDEX BY SUBJECTS. PAGE. Achromatic substance, Structure of........................... 27 Acute delirium............................................. 75 Acute intoxications........................................ 76 Apoplexy............................................ 104. 11 r, 113 Artificial changes in ganglion cells............................ 55 Asphyxia.................................................... 123 Auto-intoxications........................................... 89 Axonal degeneration........................................ 163 Bacillus botulinus, Effects of toxines of...................... 88 Bibliography............................................. 171-178 Blood serum, Effects of...................................... 87 Bronchitis................................................... 123 Bubonic plague............................................. 136 Burns, general............................................... 101 Cadaveric changes........................................... 45 Cerebral cortical cells, Structure of............................ 37 Chromatic substance, Structure of............................ 18 Chromatophilic condition..................................... 11 Classification of nerve cells................................... 18 Dementia paralitica........................................... 73 Descending bulbar paralysis.................................. 73 Description of plates..................................... 167-170 Diseases of central nervous system............................ 57 Eclampsia ................................................. 89 Empyema, Effects of......................................... 124 Epilepsy................................................... 76 Fatigue on nerve cells, Effects of............................. 140 Functional capacity of cells deficient in chromatic substance___ 150 General paresis.............................................. 73 l8o INDEX. General characters of lesions in nerve cells.................... 161 General sepsis, Summary of observations on.................. 128 Heat, Experimental effects of................................ 152 Histology.................................................... 18 Hydrophobia................................................. 134 Hyperpyrexia............................................... 157 Idiocy....................................................... 75 Infectious diseases........................................... 115 Intestinal lesions. Toxaemia of acute......................... 137 Introduction................................................. 1 Landry's Paralysis........................................... 70 Leprosy..................................................... 137 Leukemia................................................... 100 Medullary nuclei, Structure of cells of......................... 38 Meningitis................................................... 104 Myelitis..................................................... 69 Nucleus, Structure of......................................... 29 Neuritis..................................................... 57 Pathological changes in chromatic structures.................. 56 Peritonitis................................................... 123 Pernicious malaria........................................... 137 Phlegmonous inflammation, Diffuse........................... 126 Physiological condition of ganglion cells...................... 41 Pneumonia.................................................. 118 Poisons, Effects of........................................... 76 Antipyrine......................................... 80 Alcohol............................................. 80 Arsenic............................................. 76 Blood serum........................................ 87 Bromides........................................... 80 Carbolic acid...................................... 83 Carbonic oxide..................................... 80 Cocaine............................................ 80 INDEX. l8l Poisons, Hydrochloric acid........................... 84 Lead........................... -g Mercury, bichloride of............................... 80 Morphine........................................ 8o> 8s Nicotine................................. 80 Phosphorus................................ 7q Silver.......................................... -„ Snake poison........................................ 87 Strychnine......................................... «o Sulphuretted hydrogen.............................. 80 Toxins of Bacillus botulinus........................ 88 Primary vs. secondary lesions of ganglion cells................. 67 Purkinje's cells, Structure of................................. 36 Pyaemia..................................................... I25 Relation of chromatic bodies and state of nutrition of ganglion cells.................................................. I46 Septicaemia.................................................. I2a Significance of chromatic bodies.............................. 138 Spinal ganlion cells, Structure of............................. 33 Starvation........................................ io2 Sunstroke......'............................................. 06 Supra-renal cachexia........................................ I00 Spinal ganglion cells, Structure of............................ 33 Sympathetic ganglion cells, Structure of...................... 35 Tabes....................................................... 7I Technics.................................................... 3 Tetanus.............................................. I28 Thrombosis of basilar artery.................................. l rg Typhoid fever.............................................. n j Uraemia...................................;................ q0 Vacuolation.............................................. I3> ^3 I J 3 ;:-r-.c .: "«.**■■ v- .V.V'< '■*■ / ?T STATE HOSPITALS PRESS. UTICA NEW YORK, 1899 :'c-4h < •■;•