COLUMBIA LIBRARIES OFFSITE HEALTH SCIENCES STANDARD HX64051390 RC1 41 .E6 As7 1 921 Acute epidemic encep An Inv^t^^^i^i ^^r'^$$ocutimt for Research in Tfyrvous and Mental Diseases ^Jff? - v ■-<■'- v:X V< •.. ; ^-*4.^"' ; J : ^'.V' I 't--^% Frontispiece Human brain. Mononuclear cell infiltration and congestion of vessels in meninges of cerebrum in acute epidemic encephalitis. ACUTE EPIDEMIC ENCEPHALITIS [LETHARGIC ENCEPHALITIS] An Investigation by The Association for Research in J\[ervous and TsAental Diseases Report of the Papers and Discussions at the Meeting of The Association; New York City, December 28th and 29TH, 1920 PREPARED UNDER THE DIRECTION OF WALTER TIMME, M.D. GEORGE H. KIRBY, M. D. PEARCE BAILEY, M.D. HUGH T. PATRICK, M.D. LEWELLYS F. BARKER, M.D. BERNARD SACHS, M.D. SANGER BROWN, 2D, M.D. WILLIAM G. SPILLER, M.D. CHARLES L. DANA, M.D. ISRAEL STRAUSS, M.D. J. RAMSEY HUNT, M.D. E. W. TAYLOR, M.D. FOSTER KENNEDY, M.D. FREDERICK TILNEY, M.D. T. H. WEISENBURG, M.D. 4fr NEW YORK PAUL B. HOEBER MCMXXI //*:<*- Copyright, 1921 By Paul B. Hoeber Published, December, 192 1 K ■ t ? Printed in the United States of America OFFICERS OF THE ASSOCIATION FOR RE- SEARCH IN NERVOUS AND MENTAL DISEASES 192 1 Walter Timme, M.D., New York President E. W. Taylor, M.D., Boston Vice-President Sanger Brown, 2d, M.D., New York. . . . Secretary-Treasurer COMMISSION Walter Timme, M.D., New York Pearce Bailey, M.D., New York Lewellys F. Barker, M.D., Baltimore Charles L. Dana, M.D., New York J. Ramsay Hunt, M.D., New York Foster Kennedy, M.D., New York George H. Kirby, M.D., New York Hugh T. Patrick, M.D., Chicago Bernard Sachs, M.D., New York William G. Spiller, M.D., Philadelphia Israel Strauss, M.D., New York E. W. Taylor, M.D., Boston Frederick Tilney, M.D., New York T. H. Weisenburg, M.D., Philadelphia VII ASSOCIATION FOR RESEARCH IN NERVOUS AND MENTAL DISEASES LIST OF CONTRIBUTORS Abrahamson, Isador, M.D. Clinical Professor of Neurology, New York University and Bellevue Medical School; Associate Neurologist, Mt. Sinai Hospital, New York. Ayer, James B., M.D. Instructor in Neurology and Assistant in Neuropathology, Harvard Medical School, Boston. Amoss, Harold L., M.D., P.H. Associate Member, The Rockefeller Institute, New York. Banzhaf, E. J., Ph.D. Director Antitoxin Laboratories, Department of Health, New York. Barker, Lewellys F., M.D. Professor of Clinical Medicine, Johns Hopkins University, Baltimore. Boyd, William, M.D. Professor of Pathology and Histology, University of Manitoba, Winnipeg. Cadwalader, William B., M.D. Associate in Neurology and Neuropathology, School of Medicine, University of Pennsylvania, Philadelphia. Davis, Thomas K., M.D. Clinical Instructor in Medicine, Department of Neurology, Cornell University Medical College, New York. Friesner, Isidore, M.D. Otologist, Mt. Sinai Hospital, New York; Assistant Aural Surgeon, Manhattan Eye and Ear Hospital, New York. Griffith, J. P. Crozer, M.D. Professor of Pediatrics, University of Pennsylvania, Phila- delphia. ix x ACUTE EPIDEMIC ENCEPHALITIS Grossman, Morris, M.D. Adjunct Attending Neurologist, Mt. Sinai Hospital, New York. Hassin, George B., M.D. Associate Professor of Neurology, University of Illinois College of Medicine, Chicago. Hohman, Leslie B., M.D. Assistant Physician, Phipps Psychiatric Clinic, Baltimore. Holden, Ward A., M.D. Professor of Clinical Ophthalmology, Columbia University, New York. Howe, Hubert S., M.D. Associate in Neurology, Columbia University, New York; Assistant Professor, Department of Neurology, New York Post-Graduate School and Hospital. Hunt, J. Ramsay, M.D. Consulting Neurologist, Neurological Institute, New York. Kennedy, Foster, M.D. Associate Professor of Neurology, Cornell University Medical College, New York; Visiting Physician in Charge of the Neurological Department, Bellevue Hospital, New York. Kirby, George H. ; M.D. Director, New York State Psychiatric Institute; Professor of Psychiatry, Cornell University Medical College, New York. Kraus, Walter M., M.D. Clinical Instructor, Department of Neurology, Cornell Uni- versity Medical School, New York. Larkin, John H., M.D. Professor of Pathology, Columbia University, New York. Loewe, Leo, M.D. Research Fellow, Mt. Sinai Hospital, New York; Adjunct Attending Physician in Medicine, Beth Moses Hospital, Brooklyn, N. Y. McConnell, John W., M.D. Associate Professor of Neurology in the Graduate School of Medicine, University of Pennsylvania, Philadelphia. Neustaedter, Marcus, M.D. Assistant Attending Neurologist, City Hospital, New York; Chief, Neurological Division, Stuy vesant Polyclinic, New York. LIST OF CONTRIBUTORS xi Pardee, Irving H., M.D. Instructor in Neurology, Columbia University, New York; Associate Physician, Neurological Institute, New York. Pike, Frank H., Ph.D. Associate Professor of Physiology, Columbia University, New York. Riley, Henry A., M.D. Associate in Neurology, Columbia University, New York; Assistant Professor of Neurology, New York Post-Graduate Medical School and Hospital. Spiller, William G., M.D. Professor of Neurology, University of Pennsylvania, Philadelphia. Stephenson, Junius W., M.D. Clinical Instructor in Neurology, Cornell University Medical School, New York. Strauss, Israel, M.D. Associate Neurologist and Associate in Neuropathology, Mt. Sinai Hospital, New York. Thalhimer, William M., M.D. Director of Laboratories, Columbia Hospital, Milwaukee. Tilney, Frederick, M.D. Professor of Neurology, Columbia University, New York. Timme, Walter, M.D. Attending Neurologist, Neurological Institute, New York. Wechsler, Israel S., M.D. Associate in Neurology, Columbia University, New York. Wynne, Shirley W., M.D. Chief, Division of Statistical Research, Department of Health, New York. Zabriskie, Edwin Garvin, M.D. Attending Neurologist, Neurological Institute, New York. CONTENTS Chapter Page Preface xv Introduction xvn I. General and Historical Considerations, Incidence, Etiology and Pathogenesis • • • l 1 1 . Symptomatology : Symptoms Referable to the Brain. 2 1 III. Symptomatology : Symptoms Referable to the Spinal Cord and Peripheral Nerves 7 1 IV. Symptomatology: Psychotic Manifestations of Epidemic Encephalitis 103 V. Diagnosis, Course and Prognosis; Late Results. . 123 VI. Morbid Anatomy: Pathology of the Brain and Spinal Cord; Lesions Outside the Nervous System 158 VII. Bacteriology and Animal Experimentation; Further Studies in Pathogenesis, Immunology and Physiological Functioning 197 xiu PREFACE During the preparation of this volume for publication there was considerable discussion by members of the Publica- tion Committee as to the best way of presenting the material which it contains. It was felt that a formal report of papers and transactions of the society would be less readable than the present form of presentation. In preparing the material the endeavor was made to harmonize two conflicting aims. It was felt that each contributor should be credited with all the facts which he had established, and at the same time it was thought unwise to include duplicate reports of work by different investigators. As a result, the Com- mittee found it necessary to publish only such material submitted by a given contributor as had not already been submitted by another. This naturally led to the deletion of parts of contributions. It should be appreciated by both contributors and readers that this was done solely in order to avoid duplication of material, and not because of lack of excellence of any parts of the contributions received. A further object of the Publication Committee has been to allow no contribution, either in the written report of inves- tigators or brought out in discussion, to go unrecorded. For this reason all questions of clinical bearing submitted by the Committee and answered by contributors, are in- cluded in the text. The Committee wishes to take this occasion to express its thanks to contributors to the volume for the detailed and painstaking studies which they have made and reported in their abstracts. In preparing the material for publica- tion the members of the Organization and Programme Committees of the Association, after going over the various articles, recommended the above outline of publication to the xv XVI PREFACE President. This outline the President approved, and there- upon assigned the various sections to different members of these Committees for editing. In succeeding volumes it may be found desirable to alter or modify this mode of presenta- tion. In the case of this volume, blame for certain of its fail- ures or praise for what excellence it may possess in the way of presentation should be distributed among the various members of these Committees of the Association. P. B. New York, September, 192 1. INTRODUCTION i A new organized effort, a new association, operating along untried lines, has been suggested to you in the belief that it might have as a result the scientific advance of neurology and psychiatry. From the outset the proposal met with your hearty endorsement; you have brushed aside the misgivings which, nowadays, assail all of us when anything to add to our labors is proposed; you have done this in the belief that what we are going to do now will bring substantial return to our science. Those of us who conceived and nurtured the idea wish, first of all, to express gratitude for your immediate and hearty support. Time will show, we believe, that your faith has not been misplaced, and that the new association will bring us into closer relationship, always in the interest of our life's work. The present era of turmoil exerts its baneful disintegrative influence upon all educational and scientific advance. If in medical research this debasement were limited to a diminu- tion of output, the matter would be of no special concern, for it would allow time for a criticism and assimilation of much that had been presented heretofore. But unfortunately, the deficiency does not show itself in lack of production; for never before were there as many medical journals as at the present time; never before were the mail boxes of medical editors more crowded; and it must be added, the scientific value of the articles offered seems to be in inverse ratio to their number. The amount of necessary reading entailed 1 Presidential address by Dr. Walter Timme delivered at the opening of the first meeting of the Association for Research in Nervous and Mental Diseases, New York, December 28, 1920. xvii xviii INTRODUCTION by this enormous output in a vast number of scattered publications becomes a serious matter, even if only as con- cerns time. Time expenditures can be made only out of a limited capital, of which inevitable subtractions make a rapidly diminishing fund. The burning question of the times is the intensive use of the minute. How shall we econo- mize our time-energy unit? And then, how shall we best use it? Specialization has seemed to solve partially our problem. But more and more is the realization driven home that specialization, far from becoming narrower must be planned in accordance with its obligations to medical science as a whole, and not exclusively to the clinic and laboratory. It must consider not only itself but also the sociological and industrial conditions of our environment. Thus viewed, specialization becomes universalization. In no field is this more in evidence than in neurology and psychiatry. The neurology of a few years ago was content and com- placent with a bald diagnosis of some disease, — let us say, for example, lead polyneuritis. The diagnosis with its prescribed treatment was all there was to it. But it is now glaringly evident that we owe a duty to the community, commensurate with that which has brought about compul- sory vaccination. This duty requires us to define, in the first place, the safeguards to be erected for the protection of our fellows; we must interest ourselves further and inquire, Why should lead have singled out this particular individual? Is it a matter with him of less resistance to that particular poison, carelessness in its use, or both. Are other co-workers similarly affected or likely to be? What methods are pro- vided by the plant to protect the workers? Are they ade- quate? Is there supervision? Does the state take cognizance of laxity in the enforcement of proper laws for the safety of lead workers in all plants, and are there proper state laws to insure safety to lead workers? What is the loss to the com- munity of an improperly regulated industry? The answer to these questions implies an active and widespread investiga- INTRODUCTION xix tion undertaken to improve medico-sociological conditions. In England, for instance, Sir Thomas Oliver has accom- plished results in this particular field that make him a public benefactor. We cannot escape our responsibility here. Our psychiatry would be poor indeed if, for example, it stopped with the discovery that the cause of paresis is syphilis. It is its duty to go into the sociological problems involved in the dissemination of syphilis and attempt to solve them. These problems are apparent and need not particularly be detailed now. The point I desire to make is that our specialization must be of universal application. In practically all our work a similar situation exists. Multitudinous problems confront us. The time element, the energy factor, the bread and butter necessity- — to say nothing of the opposition that is always encountered — are almost beyond encompassment. Shall we deny the responsibility? We cannot. Ours is the problem; ours as well must be the quest for the solution. The largest factors in the solution are the energy and time elements. I think you will agree with me that much that we do as individuals in our chosen field is opportunistic. By this I mean that if in the course of our work an interesting case, or a series of such, arises or an apparently new symptom is discovered, or a new method of enquiry suggests itself, we make a memorandum, and, when time allows, we expand upon it and publish a paper. Such publications fill the medi- cal journals. They are discrete, non-related, not properly balanced, all too often redundant and verbose; many are mere duplications and some few are reliable. There is a multiplicity of single, uncritical clinical observations to one of well-founded merit. And the number of theories of disease advanced on the flimsiest of groundwork makes the reading of medical journals much like attendance upon the moving picture: logical sequence is thrown to the winds so long as weird contrasts and rapidity of change dominate the story. But we have a ready excuse. When our work shows incoordi- nation of thought and plan, limitation of scope, slight and xx INTRODUCTION uncertain conclusions, and, as a result we are accused of superficiality, we usually fall back upon the statement that medicine in America cannot properly advance until our clinical observations and deductions are checked up, and more post-mortem material is made available. In spite of the truth which such an apology holds, I believe our position would be better if we decried less our lack of such oppor- tunity, and bent our energy more to intensive ante-mortem study. One thing we Americans possess, and that is a vigorous initiative for combined effort. Let us make applica- tion of this quality to our present problems. Such combina- tion of effort, to be successful, requires several conditions: First, a goal to be attained; second, a coordination of the forces available; third, a proper supervision and control to prevent overlapping or undermanning. If these factors can be furnished, results will follow; there will be concerted, coordinate action by a group of men on a definite problem without loss of time or duplication of work. It will reduce the amount of reading necessary while enhancing the interest; there will be one story in several chapters, with a conclusion. It is in accordance with these principles that our present Association for Research in Nervous and Mental Diseases was founded. Let us understand at the outset that this Association is not merely one more society added to innumerable others for the bedevilment of the medical fraternity. It is congenitally different and will functionate in a manner quite its own. The discussions with their tergiversations incidental to large meetings will retire before sounder methods of getting at truth. To outline briefly the functions of the organization which we have brought into being, to declare its aims and purposes, and to show that by its existence many of the evils before enumerated and which automatically are increasing, will be lessened or eradicated, is my chief function today. Foremost of all, the coordination of efforts in one direc- tion, following a' plan outlined in advance with a definite INTRODUCTION xxi object in view is the main principle underlying our proposed activities. A group of men of experience in neurology and psychiatry elected by the members of the Association, after due and mature deliberation, decide upon an object of research — some disease entity — which has ever balked and baffled us. The choice of the subject is made one or possibly two years in advance of the date set for its intensive dis- cussion and workers in all fields of medicine are urged to engage in the investigation in their own special lines. Lab- oratory workers, pathologists, physiologists and clinicians set to work along definite paths, each group in its own way attacking the problem. The material for them to study is furnished by all physicians of the Association and by others interested, and due credit is given for such assistance. In this way, practically all cases of the disease in the territory covered by the Association will come under the observation of those studying the problem. At once the multitudinous, incoordinated, single observations which fill our medical journals become superfluous; redundancy and reduplication fade away. What otherwise would have taken years to accomplish by the most painstaking efforts and collaboration becomes a matter of a few months. When, finally, the day for a casting up of results of this coordinated and intensive study arrives, the papers embodying the results of the individual researches are carefully studied by the members of the Com- mission; and when presented to the Association by them, the proponents of the various theses are interrogated as to their work, their conclusions, and on any details that may still need elucidation. At the conclusion of the meeting, the Commission will prepare for publication all the matter presented to it in coordinated, sequential form, together with its own comments as a commission, and issue a volume to be distributed to the members of the Association. Each of us will then be in possession of all that is known about the disease in question to the last minute, almost up to the "time of going to press." In a comparatively short period of time, a series of such volumes will constitute American xxii INTRODUCTION archives of our specialty of surpassing completeness. Re- search thereafter will need to begin only with the latest American archives on the subject, and the weary task of looking up the literature, which is as far as many intrepid but time-limited souls get, will be a thing of a revered past. You should know that the plan of the organization was evolved only by the very assiduous constructive work of the members of the various organization committees, who gave generously of their time and advice during the past year and without whose initiative and support there could have arisen no such association as ours. I violate no confidence in stating that the brunt of the work and responsibility fell upon our devoted friends, Drs. Charles L. Dana, Frederick Tilney and Foster Kennedy, and that whatever merit there may be found is due in the largest part to them. I believe that little analysis will be necessary to demon- strate the enormous advantage accruing to all of us, and to neuropsychiatric science in particular, by the applica- tion of the methods, the trial of which begins today. There will, doubtless, be many faults uncovered; many changes in procedure will become necessary before a fairly perfected plan will come out of it all; but with your kindly cooperation and constructive criticism, I see arising out of this modest beginning a powerful force for good, a unified and inspired ail-American group of neurologists and psychiatrists, whose basic aim is the advance of American Medicine. Chapter I GENERAL AND HISTORICAL CONSIDERATIONS, INCIDENCE, ETIOLOGY AND PATHOGENESIS THIS first chapter deals with certain general considera- tions of epidemic encephalitis. The general character- istics of the lesions and the extent of our most recent knowledge of the disease are discussed by Dr. Lewellys F. Barker of Baltimore. Dr. Shirley W. Wynne, of the Health Department of New York City, has made a contribution to its epidemiology, making use of the data available to the Health Department. Dr. Israel S. Wechsler has collected statistical data from hospital reports, reports of physicians and other sources, covering both this country and Canada. A summary of the observations of Dr. William M. Thal- himer of Milwaukee, Dr. Leo Loewe and Dr. Israel Strauss of New York City on pathogenesis concludes the reports of this chapter. A more detailed report in reference to pathogenesis, including animal experimentation, is presented by these writers, as well as by several others, in Chapter VII of this volume. General Considerations (Lewellys F. Barker). Since von Economo in 191 7 described as "lethargic encepha- litis" an epidemic disease in which the diagnostic criteria consisted of the triad — somnolence, ophthalmoplegia, and profound asthenia, our knowledge of the symptomatology and pathology of acute, subacute and chronic nonsuppura- tive inflammations of the nervous system has undergone rapid and prodigious augmentation. The spread of the disease in epidemic form over the whole civilized world and the occurrence of successive outbreaks in modified 2 ACUTE EPIDEMIC ENCEPHALITIS form in each of several countries have given an unusual opportunity to clinical and pathological investigators for the exact study of this remarkable malady under the most different conditions. It is but little wonder that progress has been made by leaps and by bounds; and though we are still ignorant of a vast deal that we should like to know, the conceptions of the disease held today are very far removed from those of 19 17. A great variety of states, which at that time would not have been classified under the rubric of this disease, are now immediately recognized as belonging there by all familiar with the malady and the bibliography. The number and the variety of symptoms which may be presented by patients suffering from this infection, and the diverse combinations and sequences of the symptoms in single cases, are striking features of the disease. A French writer, C. Achard, has well expressed it, "the disease is polymorphous and acyclic." It occurs in an endless number of clinical forms, and though in most cases the course of the malady is divisible into several stages, the serial sequence of these stages may be very different in different epidemics and even in single cases in the same epidemic. The variegated symptomatology, the great diversity of syndromes met with, the apparent absence of any constant chronology in the development of the syndromes, and the aping by this malady of almost every well-known and well-defined neurological symptom-complex, have been responsible for many mistakes in diagnosis and have caused even some of the best-informed students of the disease almost to despair of creating any sort of order out of the clinical chaos presented. That there is, however, a fundamental unity in this per- plexing diversity, we are now fairly certain. We have to deal with a single disease, due doubtless to a specific virus, in which the clinical manifestations are very diverse, owing to differences in intensity of the virus and its toxins and to variations in the localization of the multiple lesions pro- duced. The epidemic character of the malady, a prevalence so wide that an acquaintance with it has become possible to GENERAL AND HISTORICAL CONSIDERATIONS 3 all consulting internists, neurologists and ophthalmologists, as well as to large numbers of other general and special practitioners, the characteristic pathological histology of the widely disseminated lesions in the nervous system, the combinations and overlappings in certain cases of two or more syndromes that are often met with singly in others, have placed beyond doubt the fact that we, despite the mul- tiplicity of symptoms, are dealing with a unitary disease de- pendent for its causation upon some specific infectious agent. Epidemiology (Shirley W. Wynne). Our knowledge of the epidemiology of encephalitis is very meager, but it may serve a useful purpose if we briefly set forth those facts which we possess. It is agreed that it is an acute disease; that it affects the nervous system, and that its outstanding symptom is lethargy. It occurs in epidemic form, and most observers are agreed that during the last two hundred years we have had several epidemics of this disease. Crookshank, in a very interesting article in the Boston Medical and Surgical Journal, 1 attempts to trace the disease back to the time of Hippocrates. He calls attention to the fact that during the last four hundred and fifty years there have been a number of epidemics of the disease in many countries of Europe, but that in these epidemics there is apparently a confusion of encephalitis, poliomyelitis and influenza. The one out- standing fact in Crookshank's history of this disease which, as he tells us, was described under different names and attributed to different causes, in the different countries in which it occurred, is that the diseases which he thinks were enceph- alitis, poliomyelitis and influenza bore a resemblance in their symptomatology and occurred more or less simultaneously. There was in 1712 a well-defined outbreak of sleeping sickness in Germany, which was attributed to the eating of poisonous food, and it is interesting to note that food poison- ing was again advanced as the cause of this disease in the last epidemic. The present epidemic started in Vienna in the 1 Crookshank, F. G. A note on the history of epidemic encephalomyelitis. Boston M. & S. J., January 8, 1920, clxxxii, 34. 4 ACUTE EPIDEMIC ENCEPHALITIS winter of 191 6 and 191 7. In 19 18 it appeared in England and its greatest incidence was in the spring of that year. In March, 1919, the first cases appeared in New York, at least these were the first to be officially reported to the Health Department. From that time until the present, cases have occurred from day to day. During 1919 there were 46 deaths reported from this disease in New York City. During the first eleven months of 1920 there have been 228 60 50 40 3U 20 10 hrr-rrl -I~|-?T j-rt^"1t H 1- 1 h j j | 1 ! 'Ml -f-f-H- 60 i 1 50 40 30 20 : 10 M- i | ■ 1 ' U- f [ i j 1 ! 1 ^fi^ 1 -cn^r , 1 V -IX' L;_L 1 Mi ^ ' 1 ] ( # ] *^i MM 1 1 1 ~T 1 ! 1 1 1 | ' i ! . M i . -j-4 r-j- ifo: h \ Mil 1 ' ; ; 1 ! : •1 i \ 1 i 1 1 r^r ! j _i_ ' XX- it 1 ' ' 1 1 ! 1 1 ■\- hh V' 1 ' 1 ! 1 1 ! | | ! # ; i 1 1 . : Ml-X i~rn/ A : : 0. __L i ' ! J -H-h 1 \flT V , i : 1 V I 1 : 1 1 J'l'l 1 iVTT'T | Mm 1 1 -f~r Hh- J_\i ! 1 ; i ; 1 1 > » T M 1 1 ' 1 \ in 1 ■ \T \ 1 i _i i 1 1 j i i 1 , \ 1 1 / i\ i 37E . — _L___ j 1 j : ' I V ! 1 i 1 1 -j- - u \ : i 1 ! \ 1 j ± 1 1 XXIX" ~ \ 1 — - #- 4--|j- i > ■ u, ; 1 ' Tl M ! "t~[" Ml 1 ! 1 J_ ! ~i" + Ti 1 IN " ^ ^XMXXI 1 i 1 1 i 1 1 _x__. - Mli .:. :..!. Mii-T— 4 M MM \ 1 ' < I 1 - 4-1- 4 4-1- n n + ^ i ... i . : i JAE. FEB. MAR. APR. MAY JUMJS JULY AUG. SP^T. OCT. H07i DBC . , Fig. 1. Monthly mortality, 1920, in City of New York. deaths reported. In January, 1920, there were 12 deaths; in February, 53; in March, 57; in April, 29; May, 30; June, 1 3 ; July, 1 1 ; and after that the rate fell to 6 deaths a month during the remaining months until the first of December. The deaths were distributed throughout all the boroughs of the city, the largest number of cases being reported, of course, from the most populous boroughs. The Public Health Reports show cases reported from California, from Florida and from Maine, during the same week, denoting a widespread distribution. But we have been unable to trace any definite path that the epidemic followed, as we did in the epidemic of influenza. Three theories have been advanced as to the cause of the GENERAL AND HISTORICAL CONSIDERATIONS 5 disease during the last year and a half: (1) That it was due to food poisoning, a theory quickly disproved. (2) That it is a mutated form of influenza. Some still cling to this idea and advance as the reason for this theory the fact that both diseases occurred about the same time. (3) That encephalitis and influenza were very widespread, and roughly followed the same course in traveling from one country to another, the proponents of this theory also stating that influenza has in different phases of the same epidemic affected different tissues of the body: thus at one time the respiratory tract, at another the gastro-intestinal tract, and at still another the nervous system. There has also been a striking similarity in the age distribution of encephalitis and influenza. On the other hand, the epidemic of encephalitis started in Vienna in the winter of 19 16 and 191 7, before the outbreak of influenza had made its appearance. In England the time of the epidemics of encephalitis and of influenza more nearly coincide. In the United States the epidemic of encephalitis has followed more closely the epidemic of influenza. Further- more, in none of the series of cases that has been studied have we been able to secure a sufficiently large number of histories of previous attacks of influenza or of exposure to influenza to justify the belief that there was any connection between the two diseases. Dr. Louis I. Harris, of the New York Health Department, studied 63 cases, and of these 16 gave a history of a previous attack of influenza, 14 gave a definite history of exposure to influenza, and 40 gave no history of a previous attack or of exposure to influenza. In the 3 remaining cases the histories were unsatisfactory and were disregarded. Similarly, in 117 cases of encephalitis there were but 17 cases which gave a history of influenza. Our experience during the last epidemic was that there were multiple or secondary cases of influenza in almost every family where encephalitis occurred. So far reported, there has been only one instance where there has been a secondary case of encephalitis lethargica. Indeed, in going over the report of the Committee that studied the epidemic in Eng- 6 ACUTE EPIDEMIC ENCEPHALITIS land, there is related the case of a boy whom they observed sleeping in the same bed with four other children of the family. The boy died, but none of the other children had the disease or showed any symptoms of it. This would seem to indicate that there was no relation — no direct relation — between encephalitis and influenza. The influenza epidemic or pandemic, as Flexner states, perhaps served only to prepare the soil for the epidemic of encephalitis by lowering the resistance of the communities invaded. As to poliomyelitis, it has been said that this disease was similar to encephalitis and was caused by the same agent, because both diseases attack the central nervous system, both occur in epidemic form, and because, as some authors have attempted to point out — Crookshank notably — there was a chronological relation between the epidemics of poliomyelitis and encephalitis. On the other hand, there are many differences in the epidemiology of the two diseases. Encephalitis is distributed throughout all age groups. Cases have been found in children under one year of age and in persons over seventy-five years of age. The greatest inci- dence, however, is during adult life, particularly between the ages of twenty-five and forty-five. Poliomyelitis, on the other hand, is found for the most part among children, and during the epidemic of 191 6 in New York City over 90 per cent of the cases of poliomyelitis occurred among children under ten years of age. The seasonal occurrence of the two diseases also differs. Encephalitis occurs in all seasons of the year. Deaths were reported during every month of 1920 up to December 1st, but the greatest incidence was in February and March. Poliomyelitis, on the other hand, occurs most frequently in warm weather. Another point is that if both diseases were due to the same organism, we should expect to find frank cases of poliomyelitis during epidemics ' of encephalitis and vice versa. This has not been the case/[The Committee appointed to study the disease in England observed in certain communities the occurrence of encephalitis where no GENERAL AND HISTORICAL CONSIDERATIONS 7 cases of poliomyelitis were reported, and the occurrence of poliomyelitis where no cases of encephalitis were reported. In the largest centers of population, cases of both diseases were found simultaneously, but that is true of almost all the acute contagious diseases. In New York City we have cases of diphtheria, scarlet fever, and measles occurring at the same time. The following questions submitted to Dr. Wynne before the Commission, together with the answers to them, are here reported verbatim. Dr. Williams: Have you studied the bacteriology of alleged cases of influenza preceding or in contact with cases subsequently shown to be encephalitis of specific etiology? Dr. Wynne: No sir. Dr. Williams: Are you satisfied that many alleged influenza cases are not abortive encephalitis forms first? Dr. Wynne: I think they are not. I don't think it is within the province of our office to pass on that; it is a question of diagnosis. Dr. Dana: How correct do you suppose is the diagnosis of deaths from encephalitis? You say you had 200 odd cases in 1920. Do you suppose most of the diagnoses are correct? Dr. Wynne: That is a rather difficult question to answer. You realize what difficulty the statistical office has in determining whether the causes of death reported are reliable. In this instance we have checked up a number of diagnoses by sending out our diagnostician, and I think that the large proportion of these deaths have been true cases of encephalitis. Furthermore, the majority of these deaths have been reported from hospitals where the opportunities for diagnosing them correctly have been greatest. We have not had many cases reported in general practice from private homes. Dr. Dana: How does the mortality rate compare with that in other cities in this country? Chicago and Philadelphia? Dr. Wynne: I have been unable to get any information along that line. I referred to the Public Health Service as the quickest means, and they informed me that the records are far from com- plete. The cases have not been reported promptly but have been 8 ACUTE EPIDEMIC ENCEPHALITIS scattered throughout the year, so that I am unable to answer that question at this time. Dr. Skoog: Have you a record of verification by autopsy of the fatal cases? Dr. Wynne: There was no way of getting that on the short time I was given to prepare this little paper, because the method of tabulating in statistical offices does not show on the tabulating card the fact that the diagnosis has been verified by autopsy or other methods. It would require a return to the original method and taking the matter up with the physician who reported the case. Dr. Patrick: May I ask Dr. Wynne how, as he expresses it, the influenza prepares the soil for encephalitis if there is no direct relation? Dr. Wynne: Rather by weakening the resistance of the persons in the community which has been invaded by an epidemic. Dr. Patrick: That would be assuming that their resistance has been diminished although they have not had influenza. Dr. Wynne: I realize there is a school that adheres to the belief that the susceptibility of the individual has nothing to do with the infection; that it is due entirely to the virulence of the infecting organism. On the other hand, while we are awaiting positive proof of such a theory, I think most epidemiologists are agreed that other diseases, especially epidemic diseases, will lower the resistance of the persons in the community to another epidemic disease, and it was on that ground that I made that remark. I find in going over the literature that Flexner felt the same way about it. Dr. Patrick : I don't know if I get the point of your reply or if you get the point of my question, but I gather from your state- ments that in cases of encephalitis, influenza has not preceded it in the individual. How then does it follow that influenza prepares the soil if the individuals who acquire epidemic encephalitis have not had influenza? Dr. Wynne: Simply by lowering the resistance of all the people in the community. Where there may have been some cases not reported, they simply served as a means of passing it along to the others who came down with the disease. Dr. Patrick: Do you think that these encephalitis cases should be reportable as a disease? GENERAL AND HISTORICAL CONSIDERATIONS 9 Dr. Wynne: That is a question which it is not fair to ask me to answer. A Member: What is your total percentage of mortality? Dr. Wynne: Among the cases studied the mortality was 40 per cent. We have no way of knowing the mortality rate for the entire city. Dr. Sachs: Isn't it true, Dr. Wynne, that at the time of an epidemic the diagnosis of the disease is apt to be made just as often in cases not really definitely established? Dr. Wynne: I think that is true of such widespread conditions as influenza, and undoubtedly during the influenza epidemic we had deaths reported that were probably not from influenza; but in a disease where we have only 228 deaths in an entire year out of a population of six millions, and where most of the deaths have occurred in institutions, I think it is safe to say that the percentage of error in those 228 deaths is small. Dr. Strauss: Have you not noticed that both in the epidemics of 19 1 8-19 19 and 19 19-1920 as the epidemic of influenza waned the epidemic of encephalitis began to reach its height? Dr. Wynne: The first phase of the influenza epidemic was in the spring of 1918; the second heavy phase was in the fall of 1918. In the spring of 19 19 our first cases of deaths from encephalitis were reported. During that year, however, there were only 46 deaths from encephalitis reported in the city. During January, 1920, there were less than 20, in February there were 54, and in March there were over 50 deaths reported from this disease, and then it began to wane after that until the last month when there were but 6 deaths reported. Hence, it is true that the influenza epidemic waned before the cases of encephalitis appeared in this country, or in this city at any rate. Abroad, I believe, the cases of encephalitis antedated those of influenza. In France and England the period more nearly coincided. Dr. Taylor: Are there any statistics available regarding dis- tribution as to social position, — that people living in salubrious surroundings are less liable? Dr. Wynne: Apparently not. There are no definite statistics along those lines, but judging from distribution by nationalities and occupations in the city, there seems to be little difference. Dr. Kennedy: Dr. Wynne, your death-rate seemed very high. Is it not possible that the death-rate seems higher to a public 10 ACUTE EPIDEMIC ENCEPHALITIS board of health who are looking at marked cases, cases which are very severe, in which the death incidence would be higher? Dr. Wynne: Those cases in that group were of the severe type. The milder cases had not been reported, and therefore were not investigated. Dr. Kennedy: It is our belief that jx)_per cent is rather high; I think there were a good many minor cases~ which were not reported and which didn't come under your view. Dr. Wynne: Yes, we had to depend upon the voluntary reports of physicians to send us in the questionnaire. Incidence (Israel S. Wechsler). The statistical data of 864 case reports were studied. Practically every part of the United States, as well as Montreal, Canada, is represented, although more than half of the records came from New York City. Cases from clinics and dispensaries were purposely omitted, since many of them had previously been seen in hospitals. The discrepancy in the various totals is due to the fact that in a few instances the necessary data were left out in the records submitted. Age. The youngest cases on record are in infants of four weeks. There were 3 such cases. One occurred in an infant of six weeks and 1 in one of seven weeks. The oldest case re- corded is that of a man of eighty-four. Evidently no age was spared, although the greatest number occurred between twenty and fifty. To those who have sought to correlate epi- demic encephalitis with poliomyelitis this fact is of some importance. If the percentages in the various decades were compared with the percentages of the population of the various decades it will be seen that childhood was practically spared and even adolescence was not much affected. Table I age incidence | Below II 5 6-io| 11-20 21-30I31-40 41-50 51-60 61-70 Over 70 [ Total No. 13 37 136 222 215 140 72 23 6 864 Per Cent. ..5 1 4 1 15-7 25. 7j 25 16.2 8.3 2.8 •7 | 100 GENERAL AND HISTORICAL CONSIDERATIONS n Sex. The male sex was affected much more severely than the female. There were 522 males and 342 females — a per- centage of 60.5 to 39.5 or a ratio of almost exactly 3 to 2. This is difficult to explain. Greater exposure of the male sex or occupational strain may possibly be held to account, but the suggestion is merely speculative. The fact itself, however, is sufficiently interesting and worthy of note. Occupation. Every conceivable occupation was repre- sented among the cases. There are seventeen physicians in the group, almost 2 per cent of the total number of cases. When one considers that the total number of physicians of the country is slightly over 1/8 of 1 per cent of the whole population, the incidence among doctors was exceptionally high, or almost 16 times as frequent as among the average population. Whether this fact has any bearing on exposure or infectivity can merely be conjectured. Among the physi- cians were two hospital interns. Nativity. Of 860 cases reported upon there were 387 natives and 473 foreign born, that is 45 per cent of the former and 55 per cent of the latter. The native population of the country in general and even that of New York City exceeds greatly the foreign population and yet the disease incidence was greater in the latter. This fact is difficult to explain even when one takes into consideration the high incidence of disease among adults who furnish the bulk of the foreign population, and the fact that most of the cases here recorded came from New York City. Civil Status. There were 300, or 34.7 per cent, single patients, 491, or 56.9 per cent, married and 73, or 8.4 per cent, not stated. This preponderance of the married over the single may perhaps be explained by the fact that most of the cases (about 65 per cent) occurred in persons over twenty- five years of age. Pregnancy. There are records of twenty-two pregnant women who had encephalitis. Two of these aborted and one had a caesarian section done. One woman was delivered in the eighth month of pregnancy, both mother and child 12 ACUTE EPIDEMIC ENCEPHALITIS +3 bC i-h aj . ^ >-rt ffl O "'" ^ 5 g 5 S 5 g 2 £ 2 ^ c ) r n •) oc ) r o o ^ f O h r oc o so O IN o c IN U > o o 2~ o H •\ c - 1 r- (V 5 *«c 00 GENERAL AND HISTORICAL CONSIDERATIONS 13 surviving, but no mention is made whether the child showed any lethargic symptoms. Four deaths are recorded. It is interesting to compare the low mortality in these patients with the extremely high mortality of influenza in pregnancy. The question of the influence of encephalitis on the offspring is of even greater interest, but is rather difficult to answer at present. Familial Incidence. In^only five instances, a little over one-half of 1 per cent, did the disease occur in two members of one family. There were two other instances, but both are doubtful and one of them occurred in a servant of the house. Considering the rarity of the instances one may well look upon them as accidental; and in view of the practical absence of contagion in hospital cases (two interns did contract the disease), one may consider the fact of direct transmission as almost negligible. Clinical Forms and Anatomical Localizations. The great variety of clinical forms or types which were encountered, make a uniform classification very difficult, if not impossible. The nomenclature varied with many observers, which added to the difficulty. Some divided, subdivided and classified their cases by creating types for every noticeable departure from the general picture, while others grouped them all under one or two heads. The anatomical substratum fur- nished justification for the former, whereas clinical and etiological considerations guided the latter. The following questions submitted to Dr. Wechsler before the Commission, together with the answers to them, are here reported verbatim. Dr. Barker: I would like to ask if the incidence among physi- cians could be due to the fact that all of the cases were recognized by most of them. They would know where to go to get a diagnosis in the first place, whereas large numbers of the general population perhaps don't recognize it. Would that be a possible explanation? Dr. Wechsler: I do not know if that would be a warranted assumption. Most of the men reported on all the cases. It is a fact that struck me as exceptional. i 4 ACUTE EPIDEMIC ENCEPHALITIS Pathogenesis (Leo Loewe and Israel Strauss). Ber- kefeld filtrates of brain material, nasopharyngeal mucous membrane and nasal washings from cases of epidemic encephalitis have produced in rabbits and monkeys lesions typical of this disease. Spinal fluid and blood of cases have also produced the disease experimentally in these animals. Many of these animals have succumbed with the typical picture of epidemic encephalitis. The virus has been passed through many series of animals. It can be preserved for many months in 50 per cent glycerol. Cultures made on ordinary mediums and by Rosenow's technique have proved negative. By means of the ascitic-tissue culture methods perfected by Noguchi a minute, filtrable or ganism fr om cases of epidemic encephalitis has been cultivated, using brain, nasopharyngeal mucous membrane, nasopharyngeal wash- ings, spinal fluid and blood. This same organism has been recovered from the brain and nasopharyngeal mucous membrane of animals that have been inoculated with virus, and with cultures which have suc- cumbed to the experimental disease. The cultures recovered from these animals have produced the disease when injected into other animals and the organism has again been isolated. Positive animal inoculations have been obtained with the 15th generation of this organism. It has been established that the organism survives contact with 50 per cent glycerol for several days, and, providing strict anaerobic conditions are maintained, remains viable in individual cultures as long as twelve months. Isolated colonies of the organism in the solid Noguchi medium have been picked and successful subinoculations secured in fluid medium. These fluid cultures have also produced encephalitis in animals. Results indicate that epidemic encephalitis can be dif- ferentiated from epidemic poliomyelitis for the following reasons: Rabbits are susceptible to infectious material from epidemic encephalitis and not from poliomyelitis. Monkeys GENERAL AND HISTORICAL CONSIDERATIONS 15 are very susceptible to poliomyelitis and relatively refractory to material from epidemic encephalitis. Spinal fluid from poliomyelitis cases is innocuous when injected into rabbits and monkeys, whereas spinal fluid from cases of epidemic encephalitis produces typical lesions of the disease in both of these animals. Control studies have been uniformly negative with material obtained from patients suffering from or dead of conditions other than epidemic encephalitis. Further work done by Loewe and Strauss since their last publication in the Journal of Infectious Diseases (1920, xxvii, 250), affords them additional data for affirming the conclu- sions just cited. They have had occasion to subject to animal inoculation and culture additional infectious material, such as brain, nasal washings and cerebrospinal fluid from en- cephalitis cases. A tabulation reveals that their experimental evidence has been adduced from a study of the following human material: 26 brains, 18 nasopharyngeal mucous membranes, 29 nasopharyngeal washings, 40 spinal punc- tures, and blood from 4 cases. In the course of their experi- ments to date they have utilized some 640 monkeys and more than 600 rabbits. Human brain from cases of epidemic encephalitis is infectious for both rabbits and monkeys, decidedly more so for rabbits. Only 20 per cent of monkeys are susceptible; on the other hand, at most, go per re nt of rabbits have a natural immunity. It has been possible, by repeated trans- missions Tnrough rabbits, to obtain a fixed virus which is more potent for monkeys. It has been found likewise that with "fixing" of the virus a definite incubation period is established. Filtration, refiltration and glycerolation all tend to increase the incubation period. Material for inoculation was taken usually from the midbrain where the most pro- nounced lesions of this disease are found. Berkefeld filtrates of brain from 9 cases of epidemic encephalitis were injected intracranially with a total of forty-seven rabbits. Of these, twenty-four succumbed to the disease, the average incuba- i6 ACUTE EPIDEMIC ENCEPHALITIS tion period being ten days. The virus was carried in series through as many as five generations. Encephalitis was produced in nine out of seventeen rabbits by means of emulsions of human brain from 3 cases, the average incubation period being five days. Here again the virus remained virulent through as many as five animal transmis- sions. Monkeys succumbed to inoculation of infected central nervous tissue in six instances. The clinical manifestations in many instances were remarkably like those found in the human. (See lethargic states, paralysis, convulsions and myoclonus.) Dr. Harold T. Amoss and his confreres at the Rocke- feller Institute, using similar material to that used by Loewe and Strauss, described above, have been unable up to the present time when the meeting was held (December, 1920) to verify the findings of the latter. For a description of their work the reader is referred to the chapter on laboratory experimentation. Confirmation of Findings of Loewe and Strauss (William M. Thalhimer). The epidemic encephalitis material on which my investigation and report are based consist of two spinal fluids and four autopsies. Mandler filters, tested to hold back bacillus prodigiosus, were used in preparing filtrates from the central nervous system. Rabbits were injected intracranially by the method of Loewe. Guinea-pigs were also injected by a similar method. Cultures were made on ascitic fluid tissue medium, as per- fected by Noguchi. The brains of the rabbits and guinea-pigs which succumbed to the infection were removed with aseptic precautions. About 50 per cent of the rabbits succumbed after inoculation. They died on the average of from ten days to three or four weeks. Some of them apparently died rather suddenly and were found dead in their cages, after having been apparently well the day before. Various types of palsy appeared in some of the rabbits, corresponding to different types in human cases, such as peripheral palsy, GENERAL AND HISTORICAL CONSIDERATIONS 17 difficulty in swallowing, inability to swallow, typical myoc- lonus, etc. Palsy and apparent illness did not appear in guinea-pigs, the animals being found dead in their cages after having been apparently well. The central nervous system of the rabbits and guinea-pigs showed typical lesions of epidemic (lethargic) encephalitis. These were not always the same and there was not always present the well-marked perivascular round cell infiltration. In some animals only minute hemorrhages were present. In the cultures of ascitic fluid tissue media a minute, filtrable organism, identical in all respects with that described by Loewe and Strauss, was cultivated from the original material and from material secured from the animals. Cultures of this organism were injected into rabbits and also into guinea-pigs and produced the disease with typical lesions. These animals did not die as quickly as those inocu- lated with the virus, as they usually lived from eight to twelve weeks after inoculation. The organism was again recovered from these animals. This organism has been carried through many generations. Some of the strains are at present in the 12th generation. Control cultural studies were made of the medium used and of all the types of the material cultured, with negative results. Control animals were inoculated with materials similar to the various types used in the experiments. These animals continued well. Some of them were sacrificed and showed no lesions in their central nervous system. The results of this investigation are confirmation of both the experimental and the cultural studies of Loewe and Strauss. The following questions submitted to Dr. Thalhimer before the Commission, together with the answers to them, are here reported verbatim. Dr. Sachs: I would like to ask Dr. Thalhimer if his methods were essentially the same as were pursued at the Mt. Sinai Laboratory? 18 ACUTE EPIDEMIC ENCEPHALITIS Dr. Thalhimer: They were essentially the same. I think they were quite identical. Dr. Skoog: Has Dr. Thalhimer had any training with Noguchi in the Rockefeller Institute prior to his work in this subject? Dr. Thalhimer: No. I had no training with Dr. Noguchi whatsoever. On several visits, however, to New York, I was with Dr. Loewe and Dr. Strauss at their laboratory, and they were kind enough to show me their work and their methods very thoroughly, and I was in communication with them quite con- stantly during the work, and can say that I learned a great deal from them as to how to conduct this work culturally and experimentally in animals, etc., and I also had the privilege and pleasure of having Dr. Loewe out in my laboratory for almost two weeks last summer, where I was able to show him my work and able also to give him some of my material which he brought back with him and I think also worked with. Dr. Sachs: May I ask whether the methods of the French authors, of Levaditi, etc., are identical with the methods that have been employed by these three gentlemen in this group? Dr. Thalhimer: There has been no publication by any of these other investigators as to the successful cultivation of a filtrable organism, and there has been no mention in the literature that I have seen that they have been using the tissue ascitic fluid culture method perfected by Noguchi. Whether that work is under way there or not one cannot judge from literature. So far as one can make out the nature of the filtrates which they have prepared, — and if I am wrong I hope you will correct me, — the nature of the filtrates that have been used, is very similar, and the injection of emulsions and things of that sort are of course simple methods and are necessarily identical. An important phase of the work is whether this is a filtrable virus and a filtrable organism; and there not having been published any work whatsoever on an organism it would leave that question unsolved. But the filtrates which they have used would confirm the work that has been done by Loewe and Strauss as far as the disease being caused by virus which will pass through a clay filter that will hold back ordinary organisms. Dr. Loewe: They state definitely that virus experiments have been formed with definite filtrates, and in this case they use both Berkefeld's and Chamberland's filters. They make no mention at all of employing the Noguchi medium. GENERAL AND HISTORICAL CONSIDERATIONS 19 Dr. Skoog: Is every filtrable virus anaerobic? Dr. Thalhimer: I don't think that I can answer that. That would mean — Can one cultivate from a filtrable virus an organism only by anaerobic methods? Dr. Loewe seems to think he can answer that question. Dr. Loewe: The cultural work done by Noguchi on his organism reveals the fact that after the organism has become saprophytized it is possible to grow the organism in the presence of oxygen, and Noguchi in his yellow fever work which also described the filtrable virus, filtrable organism, grows it in a medium and shows that certain strains will grow nearer the surface of the medium, indi- cating a necessity for a certain amount of oxygen being present. Dr. Strauss: Dr. Loewe has forgotten to state that we have attempted to grow this organism aerobically and we have failed. The question was: Is the virus necessarily anaerobic? A virus isn't anaerobic. A virus lives in any atmosphere. That is the answer. The organism that we have obtained from the virus is anaerobic, and until now we have not succeeded in growing it aerobically. CONCLUSIONS OF THE COMMISSION The Commission is of the opinion that final conclusions as to etiology, pathogenesis and incidence are not warranted at this stage of our knowledge of lethargic encepKalitis. The general historical consideration of the disease, as discussed by Dr. Lewellys F. Barker, indicates the extent and the limits of our knowledge of lethargic encephalitis. The data furnished by Dr. Shirley W. Wynne indicate the extent, characteristics and mortality of the disease, not only in the neighborhood of New York, but in other localities; and the statistical material collected by Dr. Wechsler forms a particularly valuable contribution to the history of the disease in this country up to the time of his report. Comment is reserved on the observations of Drs. Leo Loewe and Israel Strauss and likewise upon Dr. William M. Thal- himer's report in Chapter VII. It is well understood that at this stage of our knowledge the life history of the disease is not fully known. We know it 20 ACUTE EPIDEMIC ENCEPHALITIS as yet chiefly in cross section. The characteristics of the causative organism are not fully established; the mode of conveyance cannot, therefore, be determined. Neither is the clinical course entirely appreciated in all respects. Further knowledge of the disease from all these standpoints is neces- sary before a final description and definition of it is war- ranted. It is one of those conditions, like syphilis, of which a life history is necessary before it is fully understood. Chapter II SYMPTOMATOLOGY: SYMPTOMS REFERABLE TO THE BRAIN THIS chapter deals with the symptomatology of epidemic encephalitis referable to the brain. The general features of symptomatology are discussed by Dr. Lewellys F. Barker of Baltimore; the modes of invasion of the disease are dis- cussed by Dr. Isador Abrahamson of New York City; the cerebral types by Dr. John W. McConnell of Philadelphia; the striatal of thalamic symptoms by Dr. J. Ramsay Hunt of New York; the auditory and vestibular disorders by Dr. Isidore Friesner of New York; symptoms referable to the eye by Dr. Ward A. Holden of New York; and cerebellar symptoms by Dr. J. P. Crozer Griffith of Philadelphia. Modes of Onset (Lewellys F. Barker). The initial symptoms of epidemic encephalitis have varied much in different epidemics. Thus, in the first Vienna epidemic, there was usually a fore-stage with symptoms of slight meningeal irritation, which was soon followed by somnolence and by ophthalmoplegia. In the 191 8 epidemic in Australia, there was an initial stage of excitation (with headache and, some- times, convulsions), and only several days later did the somnolence, the fever and the signs of paralysis appear. In the cases first observed by Netter in France (19 18) symp- toms of meningeal irritation were absent, but fever was more common than in the Viennese experience; the symptomatic triad described by Netter consisted of fever, somnolence and ophthalmoplegia externa. English observers (19 18) recorded asthenia, malaise, headache, general pains, chills, nausea, anorexia and catarrhal inflammations of the respiratory tract as symptoms of the initial stage, to be followed in a 21 22 ACUTE EPIDEMIC ENCEPHALITIS few days, or sometimes almost at once, with any one of several clinical pictures (somnolence with ophthalmoplegia; bulbar paralysis; catatonic stupor; or, comparatively fre- quently, a Parkinson-like syndrome). In the United States, initial stages of various sorts have been described. When the onset was sudden, there was often severe pain in the head, fever, and delirium, followed by a period of improvement for a few days, after which apathy, somnolence and cerebral nerve paralyses of different sorts or Parkinson-like syn- dromes developed. When the onset was more insidious, the initial symptoms often consisted of diplopia and slight mental confusion, or, in some cases, of neuralgias or of pareses in the domain of one or more of the cerebral nerves; and these patients, too, often showed improvement for a few days only to become somnolent later. Not infre- quently there was marked restlessness at night with insomnia before a stage of somnolence was reached. In the Hamburg epidemic of 19 18-19 described by Nonne, such an initial stage as above described does not seem to have been marked, the disease frequently having been ushered in by paralyses in the domain of the cerebral nerves or by a Parkinson-like syn- drome. In the recent epidemic in Italy, Switzerland, Austria and parts of Bohemia (19 19-1920) the prodromal phenomena have consisted of anorexia, headache, vague rheumatic pains, sometimes diplopia, and slight fever lasting for three or four days. Then somnolence and external ophthalmoplegia followed as in other epidemics, but in addition, certain hyperkinetic phenomena (myoclonia, choreatic disturbances of motility, etc.) have been very common. During 1920, hyperkinetic cases have been occurring also in America. It would seem probable, now, that some of the cases de- scribed in France as early as 191 7 as "Cruchet's disease" were instances of the hyperkinetic form of epidemic enceph- alitis. Prodromata and Invasion (Isador Abrahamson). Le- thargic encephalitis has the prodromata common to all SYMPTOMATOLOGY 23 general infections. There are in addition certain special characteristics. Thus a catarrhal inflammation accompanied by fever of a certain degree and course, and by certain changes in the contents of the blood and cerebrospinal fluid, may raise the possibility of lethargic encephalitis; con- comitant eye symptoms may increase that possibility to a probability; and the mental picture may make that prob- ability a certainty. The nasopharyngeal area of the res- piratory tract is the mucous membrane usually infected, but in one case or another, almost every mucous membrane in the body may be affected. The lining of the auditory passages seldom escapes; and the nasal and accessory sinuses are very often attacked too. Sometimes the bronchial mucosa, some- times the intestinal is the main seat of invasion. And the localization or spread of the catarrhal inflammation may further serve to multiply differences between individual cases. But whether a rhinitis, or a sinusitis, or otitis, or an enteritis, or a pneumonia dominantly confronts us, the morbid process is fundamentally the same. From the initial site of attack the toxin is diffused through- out the body, but the organisms tend to spread chiefly along the lymphatics of the nerve trunks. Hence, to local catarrhal inflammation and general toxemia, are added signs of implication of the nerve structures in anatomical connec- tion with the first infected mucous sites. In the middle ear involvements, otic ganglion pain and seventh nerve weak- ness appear; in sinus involvement, the fifth nerve; in naso- pharyngeal involvement, the medullary and upper spinal nuclei; in gastro-intestinal involvement the dorsolumbar cord. While, as a rule, the attack, having become evident, reaches its height and then progressively declines within a period of ten to twenty days, sometimes it lasts longer, and sometimes it is intermittent and sometimes it recurs. In such cases, we are dealing either with reinfections or with multiple infections or with a wavering resistance. It is noteworthy that the main stress of this infection falls upon the most highly organized cells, the nerve cells. 24 ACUTE EPIDEMIC ENCEPHALITIS The more highly organized a cell is, the more vulnerable it is. When all cells are exposed to the same toxic agent, the more vulnerable suffer most; and the rest suffer in the order of their vulnerability. And among the nerve cells certain cells are more delicate than others. Hence, the function of thought almost invariably is deranged in lethargic encephalitis. We see somnolent, maniacal, depressive and other psychotic cases. Again, we should emphasize the necessity of consider- ing such cases not as types of disease but as types of reaction; not so much from the point of view of the organism as from the point of view of the individual. The functional derange- ment is excited by the infection, but the form and the degree of the derangement are determined, at least in part, by the circumstances which determined the mental constitution of the case. The infection evokes not a special type of the disease but makes manifest a latent weakness in the mental make-up, and this weakness may persist after all other evidence of the infection has passed away. The following questions submitted to Dr. Abrahamson before the Commission, together with the answers to them, are here reported verbatim: Dr. Dana : Do you think it is well established and agreed upon by all observers that the disease always begins by attacking certain mucous membranes, so that these can be observed to be attacked and to be diseased? Dr. Abrahamson: A careful study of the histories which has been neglected by the other observers — they have gone right to the lethargic encephalitis and neglected the original point — will elicit that practically every on& has started with some catarrh of one of the mucous membranes/If you read the histories in litera- ture, they mention this, but pass it by and regard it as a symptom of fever. I have seen it begin originally with conjunctivitis of one eye, followed by a fearful pain in the face, and then a neuropara- lytic ophthalmia of that one eye. Dr. Dana: You have stated that the more highly organized the nerve cell the more vulnerable it is to attack. Do you not con- SYMPTOMATOLOGY 2 $ sider the motor nuclei of the third nerve as more highly organized than those of the rolandic area? Dr. Abrahamson: There are certain accidental conditions in the disease. In the first place, I am speaking of the general effects of the toxemia of lethargic encephalitis, causing the general symp- toms, such as lethargy and changes in the mental states which occur at the same time. It is an accident, owing to the nasal locali- zation, that the oculomotor nuclei are involved. That is an accident of the spread of the infection from the nose and throat to the pons, which I thought I brought out in the paper, but the general effect of the toxemia of the disease causes the nuclei to be lethargic, and causes typical mental symptoms which I believe are characteristic and present in every case. Dr. Dana: In other words, if you had the poison or toxemia of this disease and could inject it into a man or an animal, do you think it would affect his physical functions first and the more highly organized cells of the cortex, and would not affect the midbrain? Dr. Abrahamson: I believe that if you inject the toxin intra- peritoneally, the oculomotor nuclei would not be especially involved. This is not established; it is my opinion only. Dr. Dana: In the experiment on animals, does it work that way? Dr. Abrahamson: The toxin has been injected intraperitoneally and the spinal cord has been involved along with a more general involvement, but it is difficult in animals to differentiate as to mental changes. All humans show mental changes. Dr. Dana: In describing or classifying this disease, would you not, after all — apart from any question of accident on account of the nasopharynx being near the midbrain — say that practically all of the disease groups itself around the midbrain syndrome? After all, you look for symptoms due to some trouble with the midbrain and motor nerves of the eye, and particularly the motor functions, as being the dominant thing right through. Dr. Abrahamson: The dominant point of entrance after all happens to be the nasal pharynx. You have to postulate away the point of entrance, and I think it is definitely proven that the infection passes through the nerve sheaths. Those of you who are familiar with the work of Orr and Rows may remember that by 26 ACUTE EPIDEMIC ENCEPHALITIS placing capsules of bacteria at various levels they got infections corresponding to the level at which they placed the capsule, and the nearer the point was to the capsule the more diseased it was, and the further away it spread from the capsule of germs the less the disease was. It is a fact that the majority of cases begin in the nasopharynx. There are spinal types, too. I have seen three definite spinal types. Dr. Dana : I would like to ask you if you get many symptoms involving the functions of the olfactory nerve? Dr. Abrahamson : That is a very difficult thing to test in these individuals. In the first place, we have not laid much stress on it because so many have rhinitis and pharyngitis that it is very difficult to test the olfactory function. Again, during the lethargic stage, it is very difficult to test these individuals so far as the olfactory function is concerned. The olfactory function varies so much that one can hardly lay much stress on it. Dr. Taylor: From a practical standpoint would you overthrow all the classifications which you allude to in the beginning, — all the types? I am speaking purely from a practical standpoint. Dr. Abrahamson: Dr. Wechsler who will speak upon types, has collected about 38 types, I believe. I think they create con- fusion, and especially when we regard the chronic cases. When you see the chronic cases and you see the mental cases and find that the make-up of the individual is responsible for most of the mental reactions in the mental cases, just as is the case in influenza, — that is the reason I accentuate the make-up of the individual and the type of resistance rather than the localization. Dr. Taylor: That is the theoretical. What I asked was whether we should stop at theorizations and not carry them out to the practical. Dr. Abrahamson : No, I would not absolutely throw them over, but I think, rather than anatomically, I would go according to the severity of the disease in the way one does ordinarily in infectious diseases. Dr. Taylor: You say "the severity of the disease." Would you call the paralysis agitans, type A, more severe than the psychotic type? Dr. Abrahamson: No. Dr. Taylor: That is a vague idea, it seems to me. SYMPTOMATOLOGY 27 Dr. Patrick: I would like to inquire whether you have any definite evidence that in this disease the virus travels from the nasopharynx along the nerve trunks to the midbrain? Dr. Abrahamson: There is nothing definite. I am giving you a clinical view, not a pathological view. Cerebral Types (John W. McConnell). This term should be applied only to those cases that exhibit a sympto- matology in consonance with the known anatomy and physiology of the cerebrum. This would include such symp- toms as headache, vertigo, delirium; hebetude; euphoria; an unusual tendency to facetiousness; liability to automatism and to the automatic reproduction of familiar movements in purposeless fashion; speech disturbances and amnesias, the latter however most commonly seen in cases presenting marked hebetude; convulsions , both general and Jacksonian; monoplegias; hemiplegias with increased deep reflexes, Bab- mski's sign and persistent ankle clonus. Lethargy, somnolence and insomnia are symptoms mentioned in order of the frequency of their occurrence, the lethargy being less marked than the clinical signs pertaining to the motor system. Occasionally, the fulminating character of the symptoms suggested a cerebral apoplectic f orm of epidemic encephalitis. In the cases observed there was little deviation from the symptomatology of recorded cases. The aphasia was of the so-called motor type. Perception was intact, but the ability to use articulate language was gone. The paralytic phenomena were associated with increased reflexes, Babinski's sign and persistent ankle clonus. Lethargy was noticeable and could probably be better termed apathy. Insomnia was found in one case in the height of the disease; in one or two others in the convalescent stage. The absence of sensory features, or rather f ne em phasis of motor featu res was a striking observation in all cases. The accompanying clinical histories give a picture of the so-called cerebral type. 7U OJUA 28 ACUTE EPIDEMIC ENCEPHALITIS Case I. A man, aged sixty-two, clerk by occupation, was admit- ted to the University Hospital early in 1920, having been ill for about two weeks with headache, vomiting, fever, and general prostration associated with double vision. On admission he was somnolent, confused, disoriented, and showed some weakness of ocular muscles, together with slight weakness ot the right face. There was no weakness of the extremities. The tendon reflexes were normal. During his stay in the hospital he gradually developed a right hemiplegia, with inability to speak distinctly.The tendon reflexes were increased on the right side; ankle clonus was obtained as well as the Babinski sign. He became addicted to facetious remarks, most of which were without foundation or relation to conversation. He was delusional, and expressed ideas of great wealth. The hemiplegic state lasted about one week and cleared up without any vestige remaining. His improvement was gradual but steady. During convalescence there was insomnia, headache, inability to concentrate, and weakness of the lower extremities At the present time he is apparently well, all of his major and minor symptoms having disappeared. Case II. A woman, aged seventy-one, suffered a mild attack of influenza in 19 18, from which she wholly recovered. For four weeks previous to my seeing her she complained of general head- ache, feverishness, physical weakness and verbal amnesia. She was more somnolent than usual. In this lethargic state she presented the appearance of bilateral ptosis, but could elevate the upper lids by putting all her energy into the act. Gradually she lost strength and was forced to go to bed, having developed a complete inability to speak and a weakness of the right face, right arm and right leg. At this time she was apathetic, somnolent and was aroused with difficulty. Efforts to get answers to questions were fruitless because of her aphasia. She seemed unable to cerebrate sufficiently to pantomine. She had no demonstrable disturbance of the cranial nerves. The eyegrounds were not pathological. She was not deaf and she could see. No disturbances in the fields of vision were demonstrable. She had a right-sided hemiparesis with increased reflexes, Babinski's sign and ankle clonus. The left side was not involved. She had no incontinence of urine or feces. There was no demonstrable sensory defect. There was no stiffness of the neck or of the spine, and Kernig's sign was absent, no tache cerebrale. The diagnosis of epidemic encephalitis was made. She became SYMPTOMATOLOGY 29 more stuporous, less responsive to external stimuli, and without any change in her motor condition died from exhaustion two weeks later. Necropsy was not allowed. The following questions submitted to Dr. McConnell before the commission, together with the answers to them, are here reported verbatim. Dr. Dana: Is there not a better word than "cerebral" type to indicate the group of cases that you are referring to? What is a cerebral type from your point of view? Dr. McConnell: My point of view of the "cerebral" type is the same as yours; but I took it, the way the title was given to me, that I was to devote my attention to the portion of the brain exclusive of the basal ganglia and medulla oblongata, etc. Dr. Dana: I was wondering whether the term "pallidal" type would not be better than "cerebral." Dr. McConnell: I should think so. Dr. Taylor: The adjective "cerebral" belongs to the forebrain and the midbrain. Basal Ganglia Group: Striatal and Thalamic Types (J. Ramsay Hunt). Of clinical manifestations, those related to the corpora striata have aroused, perhaps, the greatest interest. This is partly due to the recent advances in our knowledge of the function of these structures, but also to the extreme rarity of this localization in other types of inflammatory disease. No other acut e affection of the central nervous system has yielded so many, and such striking evidences of involvement of the great basal gangl ia as encephalitis Iethargica. While the optic thalamus is frequently involved in encepha- litis, the thalamic symptoms are milder and less serious than are those of the striatum, and the chief emphasis of this study will be placed upon the latter. Anatomical Considerations. The corpus striatum is a large ganglionic structure which is divided by the anterior 3 o ACUTE EPIDEMIC ENCEPHALITIS limb of the internal capsule into two parts, the nucleus Ienticularis and the nucleus caudatus. The nucleus Ienticu- Iaris is still further subdivided into an external segment, the putamen, and an internal, which is termed the globus »• * . . it- J J <■*>% ■ Fig. 2. Juvenile paralysis agitans of twenty-five years duration. Section through the putamen. Note the increase of the glia nuclei and almost com- plete absence of the large pallidal cells. The small ganglion cells are not reduced in number. pallidus. These anatomical divisions are based upon the gross appearance of the ganglion and are purely topographical. The putamen and caudate nucleus are identical in histo- logical structure and constitute the neostriatum. The globus pallidus is composed of two segments, an inner and an outer. This portion of the striatum is older phylogenetically and is termed the paleostriatum. SYMPTOMATOLOGY 31 A much greater importance is to be attached to the cellu- lar types of this region than to the gross anatomical appear- ance and subdivisions. The paleostriatum (pallidum) contains aggregations of ..jk'-X.'.s-'j*. Fig. 3. Juvenile paralysis agitans. Section through the globus pallidus, showing atrophy and diminution in the number of the motor cells. Note the increase of glia nuclei and irregularly formed concrements. large multipolar cells, which are histologically of the motor type (paleostriatal or pallidal cells). The neostriatum (caudate and putamen) is composed of two cell types. Of these, the more numerous are small, polygonal cells which give the characteristic histological picture of this region (neostriatal cells). Scattered among these cells, are cells of much larger size. These are giant 32 ACUTE EPIDEMIC ENCEPHALITIS multipolar cells, containing NissI granules and deposits of yellow pigment, and are of the same type as the motor cells of the pallidum (giant pallidal cells of the neostriatum). The motor or pallidal type of cells is present, therefore, in both paleostriatum and neostriatum; while the small neostriatal cells are peculiar to the neostriatum. In 19 1 7 I was able to demonstrate in juvenile paralysis agitans, widespread atrophy and loss of the large pallidal cells of the corpus striatum, and referred this disorder to a primary atrophy of this motor projection system of the corpus striatum (primary atrophy of the pallidal system). The peculiar and characteristic feature of this lesion was its limitation to a special system of motor neurons. When the pallidal system is diseased there is produced the motor syndrome which we associate with paralysis agitans. This is characterized by paralysis of automatic associated movements, muscular rigidity and rhythmical tremor. The writer also pointed out that the small ganglion cells of the neostriatum which were well preserved in juvenile paralysis agitans, showed extensive degeneration and atrophy in Huntington's chorea. The small neostriatal cells were, therefore, regarded as coordinating and inhibitory in func- tion. Because of this elective atrophy of special systems of cells the syndrome chorea was referred to a loss of the strio- pallidal or neostriatal system, and the syndrome paralysis agitans was referred to a loss of the pallidal or paleostriatal system. Two fundamental syndromes of the corpus striatum were therefore recognized, based upon the differences of function of these two cellular systems. This conception of the function of the corpus striatum which the writer formulated in 19 17, is not at variance with the other syndromes which have been ascribed to this region, but rather tends to reconcile and explain certain contradic- tory features. SYMPTOMATOLOGY 33 The Vogt syndrome based upon a destructive lesion of the neostriatum, is characterized by choreic and athetoid move- ments, spastic diplegia (without pyramidal involvement) and dysarthria. In this syndrome both cell types of the neostriatum, the small neostriatal cells and giant pallidal cells, are the seat of a destructive lesion, the clinical result of which is an admixture of the symptomatology referable to both sys- tems. There is muscular weakness and rigidity associated with choreiform and athetoid movements. The choreo- athetosis is regarded as a choreiform manifestation to which has been added a certain degree of muscular rigidity, which would ensue from involvement of the motor cells of the neostriatum. The Wilson syndrome, on the other hand, based on the progressive lenticular degeneration produces a more exten- sive lesion of the corpus striatum. Here the paleostriatum and the neostriatum are both involved, the symptoms of which are paralysis, muscular rigidity, and tremor of the paralysis agitans type associated with clonic and tonic spasms, and in some cases involuntary movements of a choreiform and athetoid nature. Here again there are evidences of involvement of the two essential neuronal systems of the striatum. The paralysis, rigidity and tremor are dependent upon involvement of the pallidal system, while involuntary motor disturbances, namely, the clonic and tonic spasms, and choreo-athetoid movements would be occasioned by a destruction of the striopallidal system. The great variation in the symptomatology of the corpus striatum is therefore dependent upon the relative degree of involvement of these two systems. When the neostriatum is chiefly affected, the choreo-athetoid element of the symp- tomatology is more in evidence; when the pallidal mechanism is chiefly involved the dominant symptoms are those of paralysis agitans. Symptomatology. Encephalitis Iethargica has given rise 34 ACUTE EPIDEMIC ENCEPHALITIS to almost every possible variety and degree of involvement of these two fundamental systems of the striatum. These manifestations have been slight or severe, tranistory or progressive, general or local. In addition many bizarre and fragmentary motor manifestations have been observed which were probably also of striatal origin. This study is based on the analysis of 25 cases in which evidences of striatal involvement were present at some period of the disease. Symptoms referable to the corpus striatum occur very frequently in the acute stage of the disease, and are evidently associated with an early localization of the inflammatory process in this region. They may also appear at a later period, after all acute symptoms of the disease have subsided. Very remarkable is the appearance of striatal symptoms as late sequelae, weeks or even months after apparent recovery, suggesting a recrudescence of the infectious process. Striatal symptoms are of two types corresponding to the two chief syndromes of the corpus striatum, as already defined. There is a pallidal type, characterized by paralysis agitans; and there is a neostriatal type, characterized by choreiform movements. While these two clinical syndromes may appear in pure form there is often an admixture of the two, as a result of which many curious clinical pictures are produced. Mixed striatal types are characterized by a combination of the symptomatology of both paralysis agitans and chorea, a mixed paralysis agitans-choreiform type. Of the two, the paralysis agitans type is the more frequent and usually the more severe in its manifestations. This is probably due to the course and relations of the pallidal sys- tem and the closer proximity of the paleostriatum to the midbrain which is the chief center of the inflammatory area. Of the 25 observations, 18 were of the paralysis agitans type, 4 of the choreiform type, and 3 were mixed striatal types. SYMPTOMATOLOGY 35 Pallidal Type (Paralysis Agitans Type). The paralysis agitans type is characterized by fairly acute involvement of the voluntary musculature. Within a brief period of two or three days, there develops the typical muscular rigidity, postural deformities, mask-like expression of the face and the paralytic disturbances of motility characteristic of paralysis agitans. Fig. 4. Corpus striatum; presenile paralysis agitans. Note diminution of the fiber network of the globus pallidus. The internal capsule is well preserved. Generally speaking the tremor is much less constant and when present less conspicuous than in true paralysis agitans. This is probably caused by the sudden development of mas- sive rigidity which masks the tremor, producing the clinical type known as paralysis agitans, sine tremore. When tremor is demonstrable at this stage it is usually slight and localized in the tongue, face or hands. The char- acteristic pill rolling movement which we associate with paralysis agitans is quite rare and I have only observed it as a 36 ACUTE EPIDEMIC ENCEPHALITIS late residual symptom in 2 cases, and never in the acute stage. One side is frequently more affected than the other, and hemilateral types are encountered in a late stage of the disease. Even more limited forms occur (segmental types), as, for example, isolated involvement of the face (the Parkinsonian mask). Involvement may also be limited to the upper or lower extremities. Segmental types I have only observed after the subsidence of the acute stage, as a late residual manifestation. The tremor may show a similar limitation and typical rhythmical tremor may be hemilateral or sometimes seg- mental, i. e., confined to the head, an arm or a leg. These fragmentary clinical types are usually encountered only as late or residual symptoms. The rhythmical tremor when present is often coarse and increased by movement. It is then an action tremor, and is increased, not diminished, during the passage of a move- ment. In this respect it differs from the classical tremor of paralysis agitans, but is very similar to what has been ob- served in the earlier stages of the juvenile paralysis agitans (primary atrophy of the pallidal system). True paralysis agitans is produced by a progressive lesion of the pallidal system, which is atrophic or degenerative in nature, while the paralysis agitans of encephalitic origin is merely a symptomatic manifestation due to injury of the pallidal system by inflammatory lesions or toxins. As the acute lesions subside, the clinical symptoms disappear, which explains the often rapid improvement in this group of cases. We are not accustomed to this favorable outcome in true paralysis agitans, which is a progressive disorder. Recoveries are, however, noted after inflammatory lesions affecting other motor systems, and it is only interesting to note that the pallidal system is no exception in this respect. A cataleptic type of encephalitis has also been described. The association of general muscular rigidity of the paralysis SYMPTOMATOLOGY 37 agitans type with the peculiar lethargy characteristic of epidemic encephalitis produces a clinical picture closely resembling catalepsy f flexibilitas cerea ). Abortive Type. It is also interesting to note that in the acute stage of the disease mild transitory striatal symptoms are sometimes present. These consist of a certain tightness or tenseness of the musculature, a certain monotony and mild %v, V. Fig. 5. Presenile paralysis agitans. Vertical section through middle of corpus striatum, showing thinning of the ansa Ienticularis. fixity of expression, with slight tremors of the tongue, face or extremities which disappear as the acute symptoms subside. Progressive Type. A tendency to progression in the paralysis agitans group is not uncommon. In my experience this tendency has been greater in those cases in which the symptoms make their appearance late in the disease, or as relapses after improvement or apparent recovery. It would appear to depend upon a renewal of the inflammatory process, or an actual lighting up of old lesions. A relapsing form, unfortunately not uncommon, is a well- 38 ACUTE EPIDEMIC ENCEPHALITIS recognized type of the disease. Its existence has been em- phasized by von Economo, Buzzard and Greenfield. Pallido-Pyramidal Types of Encephalitis. In previous studies of the symptomatology of the efferent pallidal system of the corpus striatum by Ramsay Hunt, attention was directed to the existence of pallido-pyramidal types of palsy. This form is characterized by a combination of the symptoms of both spastic paralysis (pyramidal tract system) and paralysis agitans (pallidal system), and is by no means uncommon because of the close anatomical relationship of the internal capsule and the corpus striatum. In pallido-pyramidal types, the paralysis is more complete because both the pyramidal and extrapyramidal systems are involved; the one controlling isolated synergic movements of cortical origin, and the other striatal movements of the automatic associated type. The muscular hypertonicity is also greater and combines the peculiar features of spasticity and paralysis agitans rigidity. Especially characteristic of the pallido-pyramidal type are exaggerated tendon reflexes, clonus and the Babinski phenomena of the spastic type in conjunction with a loss of automatic associated movements of the striatal type. It is rather remarkable that, in this series of 25 cases of striatal encephalitis, definite involvement of the pyramidal tracts was noted in only 3 cases. This is all the more peculiar as we are dealing with a rather diffuse disseminated inflammatory reaction, a type of lesion which one would naturally expect to involve the adjacent pyramidal system of the internal capsule and pes pedunculi. It is possible that certain toxins of encephalitis may possess a special affinity for the cellular systems of the striatum, which render it particularly susceptible to the infection. The Neostriatal Type (Choreiform Type). The other essential syndrome of the corpus striatum which may develop as a result of epidemic encephalitis is chorea. The choreiform movements of striatal origin are involuntary and irregular in character and are of the automatic associated type. Ac- cording to the view which has already been expressed, they SYMPTOMATOLOGY 39 represent a motor discharge of the striatal mechanism in contrast to paralysis agitans, which is a paralytic mani- festation. The choreic movements may be general, hemilateral or segmental (local) in their distribution. They may vary somewhat in character, e. g., mild and severe, large and small amplitude, and occasionally rhythmical. A certain degree of hypertonicity is sometimes present, giving an athetoid character to the movement. Athetosis, or choreo-athetosis, I would regard as an admixture of chorea and muscular rigidity due to involvement of both the neostriatal and pallidal systems. Acute Choreiform Type. Some writers on the subject of encephalitis have described cases characterized by gen- eralized choreiform movements appearing in the acute stage of the disease, associated with delirium and other severe psychotic symptoms. A clinical picture very similar to the chorea insaniens of systematic writers. Archambault has reported cases of this type, as have also Oehmig in Munich and Dimitz in Vienna. Choreo-Athetoid Types of Movements. In addition to chorea, movements of an athetoid and choreo-athetoid type may also occur, both in the early and late stages of the disease; of special interest is their appearance as late sequelae, months after apparent recovery. The movements of this type, like those of chorea, may be general, unilateral or segmental (local) in distribution. They differ from chorea in being slower, more stereotyped, and associated with hyper- tonicity of the affected muscles. In the more localized forms there is a peculiar repetition of slow stereotyped movements occurring at regular inter- vals. These, except for the limited and rather fragmentary character of the movement, are very similar in their character to other well-known forms of choreo-athetoid movements of striatal origin. Belonging to this group are other types of movement of somewhat larger amplitude which affect more particularly 4 o ACUTE EPIDEMIC ENCEPHALITIS the trunk and root portions of the extremities, causing curious contortions of attitude and gait. Some of these movements bear a striking resemblance to those observed in the dystonia group of motor disorders, which, since the autopsy report of Thomalla (dystonia Ienticularis) must now be definitely allied with the symptomatology of the striatal body. Rhythmical Chorea (Bradykinetic Oscillation). This dis- order of motility varies somewhat from the recognized lenticular types. It is characterized by slow rhythmical movements of an extremity, sometimes involving both the arm and leg on the same side, and occurring with great regularity, 18 to 20 movements to the minute. With the slow rhythmical oscillation of the extremity there is a simultaneous hardening of many of the muscles of the arm or leg, showing the diffuse nature and wide distribution of the muscular contractions. This form of spontaneous move- ment, in my opinion, is referable to the extrapyramidal system and in all likelihood to the striatal mechanism. It differs however in the monotonous regularity of its syn- chronous rhythm and stereotyped repetition from other forms of striatal movement. Marie and Levy have described cases of this character as bradykinetic oscillation, and emphasize the peculiar nature of this type of movement and its lack of correspondence with any recognized clinical type. While agreeing with these writers as to the unique character of this curious spasmodic type, of which 4 cases occurred in my series, there is a strong resemblance to certain types of movement which I have occa- sionally observed in the dystonia musculorum deformans. I would, therefore, regard it as related to the neostriatum. Acute Chorea of Childhood (Chorea of Sydenham). Before leaving the neostriatal type, it will be interesting to mention some recent work on the chorea of Sydenham. Attention has already been directed to the fact that certain well-recognized types of epidemic encephalitis were observed in sporadic form, long before the existence of the present SYMPTOMATOLOGY 41 epidemic. The question naturally arises, Have other clinical types of infection of the central nervous system a similar origin and relationship? A recent pathological study by Marie and Tretiakoff of the nervous system from a case of chorea is very suggestive from this point of view. The case was a typical one of Syden- hjW^__chorea, occurring in a child, aged ten, and which terminated fatally ten days after the onset of the disease. Evidences of inflammatory reaction were found throughout the brain and spinal cord, with the exception of the bulb and cerebellum. The_ neostriatum and central cortex were partioilarly^ affected. These investigators, having also studied the "lesions of epidemic encephalitis, emphasize their great resemblance to those found in the central nervous system of Sydenham's choreas. Their observations would suggest a possible relationship between the acute infectious chorea of childhood and the choreic type of encephalitis Iethargica. The occurrence of neostriatal symptoms in such a case, with evidences of diffuse involvement of the nervous system, I would explain by a special affinity of the toxin for the neostriatal system of neurons (striopallidal system). Mixed Striatal Type (Mixed Choreiform and Paralysis Agitans Types). While the paralysis agitans and chorei- form types may occur in pure form, it is well to emphasize the fact that these two clinical pictures are not infrequently combined in greater or lesser degree. Indeed, among the most striking features of involvement are the many bizarre combinations which combine both the elements of chorea and paralysis agitans. Rare Myoclonic Types. Occasionally one observes, after an attack of encephalitis, rhythmical movements of the distal portion of the extremities. In one of these cases which presented typical symptoms of paralysis agitans, there was rhythmical flexion of all the fingers, occurring about 20 times a minute. Movements of this type are so fragmentary that it is rather difficult to localize them with certainty. 42 ACUTE EPIDEMIC ENCEPHALITIS The association with paralysis agitans and the stereo- typed regularity of the movement are in favor of a striatal origin. Rhythmic twitchings oj the Jace and jaw, either alone or in combination, have also been observed. When combined, the movements of the jaw and face may be synchronous. Such manifestations may represent disjointed fragments of stria- tal motility or may indicate a release of kinetic impulses in subsidiary centers of the pons varolii which contain the motor nuclei governing the facial muscles and mastication. Bilateral Synchronous Myoclonia. There is still another type of movement which has been encountered in this dis- order, the classification of which is somewhat difficult in the present state of our knowledge. This is a movement of the myoclonic type, involving a large number of muscles and causing bilateral synchronous movements of the trunk and root segments of the extremities occurring in very rapid tempo — 50 to 60 to the minute. These movements differ from those of the "myoclonus multiplex type of spinal origin" in the large number of muscles which are simultaneously involved, and the extent of the locomotor effect. They are also unlike those types of movements which we associate with the striatum. Hamill has described a group of cases representative of this type, in all of which the movements were increased during sleep in contrast to the ameliorating effects of sleep on the pure striatal types. He suggests their relationship to certain subordinate motor centers in the pons or medulla, which in conjunction with there spiratory center act as auxi- liary centers of breathing. I have also observed movements of this type. In my opinion they are neither cortical nor spinal, and if they do not represent lower forms of movement under striatal control they are probably referable to some infrastriatal mechanism of the paleokinetic system of motility. Thalamic Types. The optic thalamus is the sensory counter- part of the corpus striatum. It is the great ganglion station SYMPTOMATOLOGY 43 where the neurons of the sensory paths terminate for their final grouping and distribution. Some of these neurons terminate in the optic thalamus itself, subserving the affective sensibility; the great number pass to the sensory area of the cerebral cortex to subserve the higher form of discriminative sensibility. Lesions in this region may produce sensory symptoms of the following character: Spontaneous pain of intolerable intensity and of persistent character; loss of superficial and deep sensibility with anesthesia; ataxia and astereognosis. There may also be present slight hemiplegia, as well as choreic and athetoid movements. The sensory loss and pain are alone of thalamic origin, the other symptoms are refer- able to surrounding parts. Symptoms of thalamic origin are not infrequent in cases of epidemic encephalitis. They are often associated with evi- dences of striatal involvement, but in my experience are neither so severe nor well defined. I have observed no case presenting the complete thalamic syndrome as outlined by Dejerine and Roussy. My experience has been limited to sensory symptoms which it seemed reasonable to assume were of thalamic origin, although one could not deny their possible relationship to the central sensory mechanism of the spinal cord and brain stem. The most frequent symptom of thalamic involvement in encephalitis, in my experience, has been pain. This may be of agonizing intensity and is very resistant to all analgesic remedies. It may be generalized or localized and may persist for weeks or months. It is difficult to differentiate localized thalamic pains from those referable to the posterior gray matter and posterior root system of the spinal cord. In differentiation, I would lay some stress on the coexistence of striatal symptoms which would appear to show inflamma- tory involvement of both structures at the same level. In no case have I encountered any extensive anesthesia, either superficial or deep. Tactile sensation has shown little or no involvement, and the chief sensory disturbances when 44 ACUTE EPIDEMIC ENCEPHALITIS present have been of pain and temperature sensibility. In no case was the deep sensibility affected. From my personal experience, and that of others, I am inclined to believe that the thalamic symptomatology is largely limited to intractable and persistent pain associated with mild evidences of sensory loss, especially of pain and temperature sensibility. As the optic thalamus is the sensory counterpart of the corpus striatum and as both ganglia are closely connected by short commissural systems, it is interesting to speculate on the possible role which irritative lesions of the thalamus may play in the production of striatal types of movements, such as chorea and athetosis. While the facts of pathological anatomy point to the neostriatum, and especially the neo- striatal system as the seat of the essential lesion of chorea, it cannot be denied that an irritative focus in the pallidum or the thalamus might give rise to spontaneous striatal motor manifestations of the same character as those result- ing from loss of its inhibitory mechanism. The following questions submitted to Dr. Hunt before the Commission, together with the answers to them, are here reported verbatim. Dr. Taylor: Do you make any distinction between the two parts of the corpus striatum in your localization of these or other lesions? Dr. Hunt: I do. The globus pallidus is the paleostriatum, and the caudate nucleus and the putamen represent the neostriatum of comparative morphologists. The small cell, neostriatal system, is related to chorea; the large motor cells, pallidal system, which I associate with paralysis agitans are found in the paleostriatum, but they are also present in giant cell form in the neostriatum. Hence I conceive the corpus striatum in terms of cellular systems rather than in terms of its larger anatomical constituents. This explains many of the curious phenomena in the symptomatology of this epidemic and of other striatal syndromes with which we are familiar. SYMPTOMATOLOGY 45 Dr. Taylor: Would you regard a late paralysis agitans type as a degeneration of the striata? Dr. Hunt: No; I would regard it as related to a recrudescence of the inflammatory process rather than to a slow degeneration. When paralysis agitans develops after all acute symptoms have subsided, or after an interval or period of apparent temporary recovery, I would associate this with an inflammatory process — a recrudescence, a lighting up rather than a slow degeneration, for the reason that if it were a degenerative process evidences of paralysis agitans would have been present at once in the acute stage. Dr. Taylor: Is there any evidence yet as to what becomes of the paralysis agitans types? So far as I have seen them they have steadily improved, but I have seen one case which after a year seems to me definitely fixed in a sort of paralysis agitans condition in part only. He has the mask-like face of paralysis agitans, but he has not got any of the tremors or rigidities. It looks like a case of paralysis agitans. Dr. Hunt: I think the consensus of opinion is that this group of cases tends to improve, tends even to get well. I have had 2 cases in which after a year there has been rather a tendency to progres- sion and to relapses. Von Economo has reported the pathological histology of such a case in which there was this progression, with intervals of improvement and intermissions of both paralysis agitans and choreo-athetoid symptoms. He found post mortem both old and recent lesions, which I think proves beyond any doubt that in some iorms of the infection the old lesions may come to a standstill while the infective agent is still active in the production of newer inflammatory lesions. Dr. Taylor: There are some cases that suggest the segmental arrangement of the automatic mechanism of the brain, but there are not any cases of the paralysis agitans type that show any- thing like a segmentation, I mean paralysis agitans showing only in the head or arms or in the legs. Have you seen anything that suggests a segmental arrangement? Dr. Hunt: Yes, I have referred to this in my paper as local or fragmentary types. I have seen cases in which the only symptom of paralysis agitans that I could detect was a very definite mask; another case in which there was a paralysis of the "paralysis agitans" or pallidal type of the lower extremities, not affecting 46 ACUTE EPIDEMIC ENCEPHALITIS the arms, and I have also seen "paralysis agitans tremor" of the head with the mask, but with no other symptoms of the disease that I could detect. . Dr. Tilney: Does the age of the patient have any relation to' the Parkinsonian type or choreic type? Dr. Hunt: I couldn't answer that very definitely except to say that I have seen the paralysis agitans type, or what I thought was the paralysis agitans type, at the age of two ; and of course in the present epidemic it has not been uncommon in young people from eleven to fifteen. In this respect it is interesting to mention that ten years ago there was described a case of paralysis agitans resulting from encephalitis in the Bristol Infirmary. Frequent mention has been made in this meeting of the sporadic occurrence of various clinical types in previous years. It is interesting to know that this is true of the paralysis agitans type. Dr. Abrahamson: Why use the term "paralysis agitans" to cover all the movements not choreiform? Dr. Hunt: I use the terms "Parkinsonian" or "paralysis agi- tans" because they are so fixed in the description of this particular group of symptoms. I have suggested and prefer the term pallidal to denote this fundamental type of striatal palsy. This term denotes the relation of the palsy to the pallidal system of the corpus striatum and is analogous to the use of the term pyramidal type of palsy, when the pyramidal tract or system is involved. When both motor systems, namely, that of the corpus striatum and internal capsule are simultaneously involved, as so frequently occurs in vascular lesions in this region, this I would term a pallido-pyramidal type of palsy. Dr. Patrick: Do you think that all the abnormal movements arising from lesions of the striatal region can be classified either under the paralysis agitans or the choreiform types? Dr. Hunt: I do. The existence of an admixture of these two types or syndromes must however be recognized, namely, symp- toms of paralysis agitans associated with those of chorea in various combinations and degree. A Member: I want to bring out whether in the various autopsies made in this particular encephalitis, anyone has investigated them to see whether the small cells are affected in the choreiform type and the other cells in the Parkinsonian type of disease — whether it is actually demonstrated or by analogy with what we already know. SYMPTOMATOLOGY 47 Dr. Hunt: No; this selective involvement has not been demon- strated in encephalitis, but only in certain types of paralysis agitans and in Huntington's chorea. For example, in a case of acute chorea of childhood (Sydenham's chorea) reported by Marie, he finds lesions in their essential character similar to those of epidemic encephalitis. Those lesions were not limited by any means to the corpus striatum. They were present in but not confined to the neostriatum, and yet the essential symptom is chorea. This would suggest that the particular form of infection which produces the acute chorea of childhood has a selective action on the small inhibitory cells of the neostriatum and that this action is toxic in its nature; and while there are small scattered foci of inflamma- tory reaction throughout the central nervous system the chief effect of the toxin by virtue of this selectivity is concentrated on the neostriatum. This special selective action of the toxin on certain limited groups of cells or neurons is manifested in other clinical types of epidemic encephalitis, e. g., the myoclonic type. Clinical Aspects of Non-Purulent Infections of the Cerebellum (J. P. Crozer Griffith). Undoubtedly the epidemic of lethargic encephalitis has exhibited cases in which the process had affected especially the cerebellum and adjacent parts of the brain more than the cerebrum; but the vastness of the literature on the subject of this disease prevented any collection of cases of this sort. The author had had under his care 4 cases of encephalitis in which the cerebellum had suffered very decidedly from the attack; indeed, in most of them bearing the brunt of it. There was great variety in the symptoms; but, basing the description of what might be called a typical case upon those observed by him, and upon the reports obtained from medical literature, it might be said that the principal acute symptoms consisted of unconsciousness and absence of speech, with later a very decided ataxia of the limbs, and often of the head and trunk, at first usually interfering entirely with walking or even with standing. Unconsciousness was re- ported in more than half of the cases. Although this was usually of brief duration, it sometimes lasted for weeks, and at times a soporose condition without entire unconsciousness 48 ACUTE EPIDEMIC ENCEPHALITIS persisted for a much longer time. In some instances, instead of the soporose state, there was violent screaming, a state of fear, a maniacal condition, and a diminution of intelligence. Even apart from unconsciousness the mentality was affected in about two-thirds of the reported instances. In the cases improving most rapidly this disturbance of mentality might last but little more than a week. In others it sometimes con- tinued for months, or even to some degree for years. Dis- turbance of speech was nearly always present; and by this was meant a disturbance apart from the loss of speech due to unconsciousness. With improvement of the general condition the speech returned, but was often drawling, slow, jerky, or affected in some other way. In a few instances, speech was entirely absent for months. Even in the milder cases the return of perfect control of speech was sometimes quite slow, the disturbance still being present in some instances over three years after the attack. Ataxia was observed in all the cases, and was usually an early and promi- nent manifestation. Sometimes the gait was typically drunken. The arms were involved also in most instances. Generally, the power to walk was regained in a few weeks, although the gait was far from perfect. The other symptoms which have been reported are oftener absent than present, and cannot be called entirely characteristic, although sug- gestive. Among them may be mentioned nystagmus and vertigo. The former is sometimes very marked. The immediate causes of the disease have been varied. Some infectious disorder directly preceded the attack in about two-thirds of the cases. In one instance, trauma was reported as an immediate precursor; in another, dysentery. The nature of the disease is of great interest. It is appar- ently without doubt an encephalitis, and also one which is not limited to any one portion of the brain. Symptoms other than those supposedly cerebellar have been seen in prac- tically every case. Fever, unconsciousness, delirium, con- vulsions, and the like, indicate the involvement of some portion of the brain other than the cerebellum. The absence SYMPTOMATOLOGY 49 of speech as the case progresses is due, apparently, to a lack of control, but early in the attack it probably depends upon unconsciousness or some other disordered mental state. It would appear to be clear that the cases upon which this report is based cannot be said to have been due to any specific micro-organism. The fact that but one case came to autopsy, and this many years after the attack, prevented any actual determination of the lesions which were present during the acute condition. The prognosis in general is good, at least so far as life is concerned; but the ultimate condition of the patient is uncertain. Some cases are on record which show that final complete recovery may take place, even though the symptoms have lasted for several years. A total duration of three or four months may be taken as an average for the more acute symptoms. Although it is probable that from one-third to one-half of the cases may be said to have recovered completely, a number of instances in the list indicated that there is decided danger of some symptoms remaining permanently, and among these is especially to be noted a persistence of some degree of mental defect. The following questions submitted to Dr. Griffith before the Commission, together with the answers to them, are here reported verbatim. Dr. Taylor: Would you regard the symptoms in these cases as predominantly cerebellar? Dr. Griffith: I would, decidedly. Dr. Taylor: So that you may in justice assume that there were actual lesions of the cerebellum in these cases? Dr. Griffith: I think so. Dr. Weisenburg: What is the nature of the speech disturbances? Dr. Griffith: It was irregular or jerky or slow, sometimes just an irregular speech. As it improved it became more regular but still slow; the child had to wait a bit before it could enunciate. Dr. Weisenburg: In what way would the cases differ from the other types of encephalitis with which you have come in contact? Dr. Griffith: You mean not cerebellar? They differed in their 4 5 o ACUTE EPIDEMIC ENCEPHALITIS irregular speech and particularly in the ataxia. There were no other positive symptoms; there were suggestive symptoms. Dr. Weisenburg: In other words, you made the diagnosis on the obstructed speech and the ataxic movements of the arms and legs in the case? Dr. Griffith: Yes. Dr. Sachs: May I ask Dr. Griffith whether he has seen in children distinct cerebellar cases beginning in very acute fashion and during the time of the epidemic, or whether he knows about such cases in which the cerebellar symptoms have been as definite as they could possibly be? I am referring especially to such cases in which the child in a very acute fashion shows no other symptom except an absolute inability to stand or walk. I remember one case, for instance, where the child had to walk around by the wall instead of crossing the room. I want to know whether any such cases have come to your attention without any cerebral symptoms? Dr. Griffith: One of my cases began with ataxia — tumbled down the stairs — came on all of a sudden, and according to the parents' report there was no history whatever of any cerebral involvement of any kind that we could find with the exception of her ataxia, and that disappeared completely. She came to my office at my request a year or two later and everything seemed to be gone. That was, however, not the epidemic type. The only one I have seen in connection with the epidemic had distinctly cerebral symptoms as well, more marked than the cerebellar. Dr. Barker: Were Dr. Griffith's cases coincident with influenza outbreaks or poliomyelitis outbreaks? And if he saw one of those cases today, could he differentiate it from epidemic encephalitis or would he take it to be encephalitis? Dr. Griffith: I could not differentiate it because I think it is only a matter of position. I think the lesion would produce much the same symptoms. Auditory and Vestibular Lesions (Isidore Friesner). The following clinical studies are based upon 6 cases of epidemic encephalitis in which the manifestations were wholly, or in large part, due to disturbances of the auditory or vestibular apparatus. Four of these cases were observed by me in the past two and a half years. For the histories of the 2 remaining cases I am indebted to my colleagues. It SYMPTOMATOLOGY 51 must be apparent, at a glance, that general conclusions regarding this phase of the disease cannot be well drawn from so meager clinical material, and yet the almost total absence of similar studies in the literature is, in itself, suffi- cient justification for this survey. After a fairly thorough search of the literature regarding this disease I have been impressed with the comparative rarity of involvement of the eighth nerve. I have been able to examine the records of 145 cases of epidemic en- cephalitis treated at Mt. Sinai Hospital during the last two years. Among these there was one instance of bilateral total deafness. In many the stupor and the consequent lack of cooperation made complete functional ear tests impossible. However, with the exception cited above, there was no other evidence of eighth nerve involvement. Barker, in his report of 8 cases, mentioned tinnitus as a symptom but once. Here the ears and presumably both the auditory and vestibular apparatus were normal. Eagleton reports a similar case with tinnitus and normal hearing. In Tilney's 20 cases there is no mention of auditory or vestibular manifestations. In Skversky's 10 cases the ears were normal. In Hall's analysis of 16 cases there is one with vertigo and tinnitus. Functional tests are not recorded, but the general manifestations of the disease were far more severe than those of any of the cases observed by me. Occa- sionally, one meets with recorded evidences of a disturbance in the vestibular apparatus, as in Alexander's Case II, where a vertical nystagmus upwards was present. Case IV of the series here reported showed a similar phenomenon due undoubtedly to a lesion in the pons. Mills and Wilson also report a case with vertical nystagmus upwards. Alexander and Allen reviewed 182 cases in the literature, and selected 100 from that number as being typical. In their analysis of the symptomatology of these cases there is no mention made of eighth nerve involvement. Most of the cases in this series lacked some of the cardinal symptoms of epidemic encephalitis. Thus, in only one 52 ACUTE EPIDEMIC ENCEPHALITIS instance was there either lethargy or asthenia. Cases of the type reported here, several of them with exceedingly cir- cumscribed lesions, probably represent a very mild, or even an abortive form of the disease. Yet it has seemed that in all the cases the diagnosis was well established. An explanation of some of the cases on a basis of toxicity has been offered. One case was originally reported as an instance of botulism. Hall, however, has pointed out that the Cinderella foot of botulism will not fit into the glass slipper of this syndrome, and in the light of our later knowledge it must be considered a case of epidemic encephalitis with typical multiple lesions. Toxic agents may cause an endemic, rarely an epidemic; never a pandemic. Case I. School-boy, aged nine. On April 30, 1920, he complained of tinnitus in the left ear, followed by vertigo, vomiting, and diffi- culty in walking. His temperature was never over ioo°F. On May 3rd, examination showed no tympanic disease on either side. Normal hearing right; total deafness left. There was slight sponta- neous nystagmus to the right and a positive Romberg. The direction of the falling was toward the left, but could be influenced by changing the position of the head. In the interval between May 3rd and May 10th, the date of the second examination, a lumbar puncture was done. The fluid was clear, containing no cells, and no excess globulin. On May 10th, falling was no longer regularly toward the left and could not be influenced by changing the position of the head. The total deafness persisted. The left static labyrinth, however, was normally irritable calorically, and there was normal vertigo and normal past pointing following stimulation. On May 19th, with a noise apparatus in the right ear, patient heard 26 double vibrations but not 2048 (C d ). On June 5th, with a noise apparatus, he heard a forced whisper: heard 26, and June 26th he heard ordinary conversation. The upper and lower tone limits are normal. The Weber is referred to the head. At this time he showed a peculiarity which has persisted to date, i. e., with a noise apparatus in his right ear, when one whistles with the lips, he interprets the sound as a grunt. Asked to imitate the sound, he reproduces the pitch of the tone accurately, but has no idea of its quality. SYMPTOMATOLOGY 53 Remarks. This is an instance of total loss of function of the auditory branch of the eighth nerve with what was perhaps, in the beginning, a collateral edema of the vestibular branch. The slight, if any, loss of function in the vestibular branch disappeared rapidly. Some hearing returned in about three weeks from the onset of the disturbance. It is now, however, about seven months since the beginning of the attack, and it appears that we are justified in concluding that a total restitution of hearing in the left ear will not occur. Case II. A jeweler, aged^ forty- two;" never^ had any previous ear trouble. Was seized suddenly four days ago with tinnitus and deafness in the right ear. Slight pain, no vertigo. There was no tympanic disease. Weber was referred to the left. Rinne, left side plus, right side minus ad infinitum. The hearing in the left ear for voice, whisper, watch, etc. was normal. The tone limits were normal. The right ear was totally deaf. There was no spon- taneous nystagmus, no falling, no past pointing. Rotation to the right and to the left was followed by a nystagmus of good ampli- tude lasting twenty-five seconds. Vertigo and past pointing were normal. Caloric of both right and left labyrinth positive in forty- five seconds. Both the vertical and horizontal canals were active on both sides. Blood and spinal fluid Wassermann, negative. Spinal fluid was under moderate pressure, clear, no cells, plus 1 globulin. After the lumbar puncture there appeared a weakness of the right facial of the central type, and right Babinski and Oppenheim. All these symptoms disappeared rapidly, and in July it was reported that the man had normal hearing. Case III. That there are degrees of disturbances without total loss of function is illustrated by Case III. S. G., married; family and personal history have no bearing on present illness. Patient was in good health up to four days ago. At that time he had an attack of diplopia. A few days later there was some paresis of the facial muscles on the left side. He was tired and drowsy. Spinal fluid was obtained under normal pressure. Cell count was normal, and no excess of globulin was detected. Hearing on the right side was diminished to about one-half of what was present on the left side. The Rinne was positive, and he localized the Weber to the left ear. 54 ACUTE EPIDEMIC ENCEPHALITIS Remarks. Taylor also reports a case with a bilateral disturbance of hearing of the nerve type. Tinnitus is a symptom occasionally met with in lethargic encephalitis. Eagleton, however, has shown that tinnitus may occur in such a case with no demonstrable disturbance in hearing. Grahe, in his studies of the internal ear in lethar- gic encephalitis, states that in 6 of the 13 cases examined, the bone conduction was shortened. It is especially noteworthy that a case with shortening of bone conduction, but other- wise with normal findings, presented a perfectly normal duration of hearing by air conduction. Grahe is under the impression that there is no relationship between this condi- tion and meningeal changes, since shortened bone conduction occurred both in cases with normal cerebrospinal fluid, and in others with pathological changes in the spinal fluid. Case IV. A dentist, aged thirty-six, was seized with vertigo, nausea, vomiting, deafness in left ear, diplopia and ataxia which confined him to his bed for one week. He had no fever. He was unable to leave his home or to attend to his professional duties for several weeks, so that by the time he was seen during the fourth week of his illness, many of his earlier symptoms had disappeared. The history, in addition to the above, was that his blood Wasser- mann was negative. His cerebrospinal fluid showed no cells, globulin content normal, Wassermann negative. The otological tests were as follows. Weber is referred to the head. Rinne, both sides positive. Schwabach, slightly shortened both sides. The upper and lower tone limits are normal for both ears. Tested with a noise apparatus, both ears hear low conversation readily. With the exception of the slightly shortened Schwabach, the hearing of both ears is normal. Static Labyrinth. Station is good, very little swaying. There is no spontaneous past pointing in the right arm; the left arm past points 2 inches to the left. This persists on repeated tests. There is a spontaneous nystagmus of the rotary type directed to both sides, slightly more marked to the right. There is also a vertical nystagmus upw T ard. Rotation to the right is followed by a horizontal nystagmus of fair amplitude, lasting twelve seconds. Rotation to the left is followed by a nystagmus of very good amplitude, lasting twenty-five seconds. Tests for Vertigo. SYMPTOMATOLOGY 55 Rotation to the right; the right arm touches, the left arm past points 1 inch to the left (spontaneous past pointing). Rotation to the left; both arms past point 2 inches to the left. Caloric reaction of right vertical canals positive but faint, one minute and fifteen seconds. No past pointing in either arm. Stimulation causes diplopia. Caloric reaction of the right external (horizontal) slightly more marked than that of the vertical canals. No past pointing in either arm. Caloric stimulation of the right external canal arouses an oblique nystagmus upwards. Caloric reaction of left vertical canals positive faint, fifty-seven seconds, reaction of external canal more marked. No past pointing in either arm. Remarks. The hearing is normal. There is a spontaneous nystagmus to both sides and also upward. Functional tests show an interference with all reactions following stimula- tion of the left labyrinth. Caloric stimulation of the right vertical canals causes diplopia, of the right external canal an oblique nystagmus upwards. The nystagmus following stimulation of the right labyrinth is nearly normal while the vertigo is markedly suppressed. These facts indicate that the lesions are not peripheral, but are situated in the brain stem and probably in the cerebellum as well. Case V. F. W., physician. Was seized about March 4, 1920, with an attack of vertigo, nausea and vomiting. On March 5th and 6th there was diplopia. The vertigo continued for three days and gradually subsided within a week. Never any fever or headache. At the end of the week he was examined. There was no tympanic disease. The hearing of both ears was normal. There was a coarse rotary nystagmus to the left. In walking he swayed to the right, and supported himself in his right side. Unfortunately no other stimulation was applied to the static labyrinth, except rotation. This was repeated several times, and showed definitely a total loss of reaction, i. e., of both nystagmus and vertigo on rotating to the left, whereas on rotating to the right there was a normal nystagmus lasting twenty-two seconds, with normal vertigo. Remarks. There may be some question as to the validity of the conclusion that we are dealing here, so far as the ears are concerned, with an isolated lesion of one vestibular $6 ACUTE EPIDEMIC ENCEPHALITIS nerve. It may be remembered, however, that this patient fell to the right, that he supported himself on his right side, that he had a typical rotary vertigo, with objects moving about to his left and that he had a spontaneous rotatory nystagmus to the left. These facts, with the results of the rotation tests, seem sufficient to warrant our conclusion. In conclusion, it may be stated that lesions of the eighth nerve in epidemic encephalitis are rare. This rarity may be more apparent than real, for Eagleton, in his examination of 4 cases, states that he was able to demonstrate disturbances in the vestibular apparatus in every one of the four. The involvement may result in a diminution of, or a total ablation of function. I have had no personal experience with lesions affecting both branches of the eighth nerve followed by total ablation of function, but Mills and Wilson report 2 such cases. Either the auditory or vestibular branch may be involved. Judging from the number of cases examined and reported, there is an unusual proportion of vestibular lesions. The virus appears to exercise an exceedingly fine selective action. Restitutio ad integrum occurs perhaps more frequently in the vestibularis than it does in the cochlearis. The polioencephalitic cases, with exceedingly limited le- sions, undoubtedly represent an abortive type of the disease in which many of the cardinal symptoms of epidemic en- cephalitis are lacking. The diagnosis in the absence of other confirmatory findings is based upon the exclusion of middle ear disease, of tumor, the absence of the usual serological findings, and other evidences of syphilis, and finally upon the occurrence of these cases during an epidemic of encephalitis followed by fairly rapid recovery. The following questions submitted to Dr. Friesner before the Commission, together with the answers to them, are here reported verbatim. SYMPTOMATOLOGY 57 Dr. Sachs: Evidently Dr. Friesner himself has found some things entirely peculiar to this disease? Dr. Friesner: Yes; this one instance, which I studied in connection with Dr. Strauss, I have been unable to explain satisfactorily to myself. It is an exceedingly curious phenomenon; I do not know what it means. This child is able to reproduce accurately the tone of my whistle, but is unable to grasp the quality of the tone. In other words, asked to reproduce the pitch he sings the note accurately, but when I ask him, "What noise did I make?" he says: "You grunted." I do not think my whistle is anything like a grunt. He reproduces the pitch but not the quality. He is an exceedingly intelligent chap, about ten years old. Dr. Dana: When he reproduced your whistle did he whistle or grunt ? Dr. Friesner: He grunts. I have him close his eyes, and I put the noise apparatus in the ear with which he hears normally, and I whistle. Then I ask him what sound he heard and he grunts. I ask him to sing the note and he produces the pitch accurately, and he does that whether my whistle is high-pitched or low- pitched. I never have seen that before nor has any other otologist with whom I have spoken, but it is really present and there cannot be any question about it, because I have tested him at least four or five times since he first showed this curious thing. Dr. Dana : You make a diagnosis of encephalitis in these cases largely by exclusion, do you not? Dr. Friesner: Frankly, most oi the diagnoses are made by the attending neurologist or physician; it is only because of the ear symptoms that I have been asked to examine cases. Dr. Dana: Nevertheless, you concluded by giving the data for making a diagnosis practically by exclusion. Dr. Friesner: I did that. Of course, as I have said, these data are so meager that it is almost impossible to draw any conclusions. With regard to the diagnosis, that statement was passed upon one case; this case was referred to me because he had tinnitus and deafness. When I examined him I noted that he had none of the usual phenomena which occur with specific disease, and at once it occurred to me that it might be an instance of lethargic enceph- alitis. A subsequent examination of the man and the development of facial paralysis proved that my supposition was correct. Dr. Sachs: You are willing to believe that just as there are 58 ACUTE EPIDEMIC ENCEPHALITIS some cases of lethargic encephalitis where there are chiefly eye symptoms, it may be that some exhibit chiefly ear symptoms? Dr. Friesner: Yes. There is one thing I would like to ask. I have stated in my conclusions and have called these cases "polio- encephalitic " cases. I wonder whether it is not more correct to call them "polyneuritic." When I looked to see in what category I could place these cases, I examined the divisions in your book and I found that they fitted only into what you called the"poIio- encephalitic cases," but it seems to me these are nerve lesions, not nuclear lesions, and I wonder whether "polyneuritis" is not correct or "mononeuritis." Dr. Timme: May it be central? Dr. Friesner: I do not know. There have been very few cases reported of total deafness of central origin. I never have heard of them in anything like an inflammatory state such as one gets with encephalitis. Dr. Dana: You mean you do not get total deafness in one ear from a central lesion? Dr. Friesner: There are a few cases reported with tumor on one side and an abscess on the other, or tumor on one side and hemorrhage on the other, in both lobes. Dr. Dana: I mean a nuclear disease of the cochlear nerve. Is that not called deafness in that ear? Dr. Friesner: I am not aware of any such case. I do not think we can differentiate between a nuclear disease, causing true deafness, and a nerve disease that is a true neuritis. Dr. Strauss: What other disease could cause these symptoms if not encephalitis? Dr. Friesner: The subsequent development of this one case, of which I speak, and which came to me with total deafness, could not be caused by anything else than encephalitis, but, this opinion may be due to my faulty observation when he came to me. All I was able to determine was that he was totally deaf in one ear, and that it had occurred but four days previous to my examination. That is all he had — total deafness. The static laby- rinths on both sides were perfectly normal. The first case, and I am depending on your word, was lethargic encephalitis. Dr. Sachs: Could any other disease have caused it, or do you know of any other disease? Dr. Friesner: Not as regards the first case. SYMPTOMATOLOGY 59 Ocular Manifestations (Ward A. Holden). The eye symptoms noted in one hundred consecutive case histories of epidemic encephalitis at Mt. Sinai Hospital are as follows: A. Opticus Symptoms. Blurring of the optic discs in 4, papilledema in 1. B. Oculomotorius and Abducens Symptoms. 1. Ptosis. Of both eyes in 45, of one eye alone in 1 1 — 56 patien ts in all. 2. Extrinsic muscles of the eyeball. Paresis or paralysis of both external recti in 17; of the right external rectus alone in 14; of the left external rectus alone in 13 — ^44 patient s in all. Paresis or paralysis of both superior recti in 1, of both in- ternal recti in 4, of the right internal rectus alone in 1. Paresis of both internal and both external recti in 2. Paralysis of all muscles supplied by one 3d nerve in 1. Paralysis of conjugate dextroversion of both eyes in 2. In all, weakness of the oculomotor muscles that would give rise to diplopia in 56 patients. Nys W^rnriK in 32 patients. 3. Pupils. Irregularity in 15, inequality in 20. Sluggish- ness_or_absence of light reflex in 35 patients, in 13 of whom the convergence or accommodation reflex was sluggish also. The irregularity and inequality of the pupils in 28 of the 35 cases were in eyes with sluggish pupils, so that irregularity and inequality not associated with sluggishness were noted but 7 times. 4. Accommodation. Weakness of accommodation in both eyes in 1. C. Facialis Symptoms. Weakness of some or all of the muscles supplied by the facialis of both sides in 24, of one side in 49 -3 patients in all. The most marked divergence from these percentages is in the carefully studied 8 cases of Barker, Cross and Irwin 60 ACUTE EPIDEMIC ENCEPHALITIS (Amer. J. M. 5c, cliv., 2-3). They found partial ptosis in 3, sluggish pupils in the entire 8, and weakness of accom- modation in 4. Their reports on the recti muscles are less specific. The percentages in the thirty histories reported in Tilney and Howe's book " Epidemic Encephalitis," are similar to the Mt. Sinai Hospital percentages except as regards the recti muscles. Tilney and Howe found the internal rectus paretic more frequently than the external. Opticus Symptoms. There was noted in 4 patients at Mt. Sinai Hospital a blurring of the optic discs and in one a definite papilledema. The earlier reports on encephalitis referred in many cases to blurring of the discs. But we recognize that a slight edema and a reddening of the discs due to dilatation of the capil- laries, with overfilled and perhaps tortuous retinal veins, is a fairly common condition when the general circulation is sluggish. In such cases a subsequent examination is made and if the condition remains unchanged we do not regard it as a beginning papilledema and we are strengthened in this belief when the patient complains not of headache and vomiting, but merely of cold feet. It is possible that some of the cases of blurred optic discs reported may have had but little significance. True papilledema was noted in 1 Mt. Sinai Hospital patient and was found in 1 of the 20 at the Neurological Institute. The latter patient, a child three years of age, had meningeal symptoms, paresis of both external recti, paresis of the right facialis and right hemiparesis, with papilledema of two and a half dioptres elevation in each eye. She made a complete recovery. In another case with papill- edema, verbally related, there was found at the autopsy an extensive subcortical hemorrhage in the parietal region which had caused hemiplegia. True papilledema then is a very rare symptom of enceph- alitis and seems to occur only where there are unusual com- plications. This papilledema is doubtless the result of SYMPTOMATOLOGY 61 increased intracranial pressure in most cases, although in some cases it may be due directly to meningitis. 1 Oculomotorius and Abducens Symptoms. Inflamma- tory changes have been found widespread in the brain, but with great frequency in the brain stem, consisting of edema, hemorrhage, proliferation of neuroglia, circumvascular exu- dation of leucocyte-like cells, and degeneration of ganglion cells. The meninges also are frequently inflamed. From this it is evident that there may be pressure upon the nuclei of the ocular nerves, upon the supranuclear and infranuclear fibers — direct and association — and upon the trunks of the nerves at the base of the brain. This pressure may be transi- tory or permanent, slight or destructive, or even alternating and recurrent. It is obvious that clinically one must find in this disease all degrees of muscular palsy and all possible combinations and varieties of palsy of the third and sixth nerves, with changes from week to week. 1 C. P. Symonds in a paper on "Optic Neuritis in Encephalitis Lethargica," Lancet, Dec. 18, 1920, after describing four cases studied at the Johns Hopkins Hospital, gives as one of his conclusions the following statement: "In the association of optic neuritis with acute disseminated myelitis we have an instance of involvement of the optic nerves in a diffuse inflammatory process affecting the nervous system, which is analogous to the association of optic neuritis with encephalitis lethargica." In Archives 0/ Ophthalmology, vol. xl, No. 6, and vol. xliii, No. 3, I described five cases of optic-nerve affection in acute disseminated myelitis. In this disease the affection of the optic nerve is a localized inflammation about certain blood-vessels in the nerve. There is, as a rule, no elevation of the disc and there ensues a partial or general pallor of the disc, with marked disturbance of vision. In 3 of the 4 cases in which visual tests could be carried out I found a lateral hemianopic defect in the field of one eye only, which seemed to me characteristic of the disease, and in one case an excessive concentric contraction of the field of one eye. The reports of optic-nerve disturbances in epidemic encephalitis lethargica with which I am familiar, including those of Symonds, show little in common with the optic-nerve disturbances I have seen in acute disseminated myelitis. Therefore, until anatomical proof to the contrary is presented, I prefer to regard the optic-nerve disturbances of epidemic encephalitis as being chiefly of the papilledematous type due to increased intracranial pressure, rather than of the retrobulbar inflammatory type, as Symonds would seem to suggest. 62 ACUTE EPIDEMIC ENCEPHALITIS In general, in this disease, we find a disinclination to use the eye muscles or a quick fatigue and return to the position of rest after using them, even when there is no well marked paresis. In this, as in many disturbed mental conditions, the patient may dislike to look up and may simulate paralysis of upward movement unless repeated tests are made. Ptosis. In the lethargic state the patient may lie with his eyes closed in the position of rest and often cannot be urged to keep them open, or even to open them wide for a moment. This may be due to a mental disinclination, to photophobia, to a dread of diplopia, or to a spasm of the orbicularis palpe- brarum muscles, as well as to weakness of the levators. When he can be urged to open his eyes a difference in the width of the palpebral apertures may be seen or a drooping of one or both upper lids may be noted, but except in the unusual cases of complete third nerve paralysis, complete ptosis is not likely to be present. In other cases the eyes are kept open, but winking is infrequent. Forcible closing of the eyes often leads to a marked tremor of the lids, for tremor is a very constant symptom of encephalitis. When one eye has been kept closed a few days to prevent diplopia, its palpebral aperture will be narrower than that of the other eye when both are opened. One can easily realize that the question of ptosis in a given case may admit of a variety of answers. Ptosis was noted in fifty-six of the Mt. Sinai Hospital patients. Extrinsic Muscles of the Eyeball. Certain brain affections have rather definite paralyses of the ocular muscles which are pathognomonic. Thus after diphtheria there may be paralysis of accommodation on both sides without pupillary distur- bances; in botulism there may be ophthalmoplegia interna on both sides — that is, iridoplegia and dilatation of the pupil with paralysis of accommodation ; in polioencephalitis superior the two internal recti are first paralyzed and later often one or both external recti; in destruction of one ab- ducens nucleus there is conjugate paralysis of dextro- or sinistro-version of the two eyes; in red nucleus involvement there is loss of upward movement of the eye; and with SYMPTOMATOLOGY 63 exudation at the base of the brain both sixth nerves or both third nerves in some or all of their branches may be affected. In epidemic encephalitis almost all of these paralyses are found. And if there is anything at all characteristic it is the frequent association of ptosis with paralysis oj the external recti. In the Mt. Sinai Hospital group there were twenty-three patients in whom paralysis of one or both external recti (without accompanying paralysis of internal recti) was associated with ptosis of one side or both. This is a combina- tion of third and sixth nerve affections that is rarely met with in any other disease. The fourth nerve doubtless is affected at times in enceph- alitis, although paresis of the superior oblique muscle has not been noted in any reports recalled. This may be because a paresis of the superior oblique might easily be overlooked in a lethargic patient, and even in a mentally alert patient it might escape notice when masked by more obvious palsies of other motor muscles. There is a curious condition, of whose pathology we are ignorant, known as paralysis of divergence. In this condition there is neither paralysis nor spasm of the recti muscles and the mobility of each eye is normal, but the eyes are converged on a point some 15 cm. away and see single at this distance, while at greater distances there is homonymous diplopia in every direction of the gaze. The etiology of this condition is obscure and the lesion is supposed to lie in a purely hypo- thetical divergence center. It has been seen in midbrain tumor and in uremia. This paralysis of divergence was one of the earliest symptoms in a patient with encephalitis, and two colleagues have said that they had found the same condition in encephalitis patients, so probably it is not very rare if care- fully sought for; and study of the cases in which it is present may lead to our better understanding of the condition. 1 1 In some cases, paralysis of divergence has either preceded or followed paralysis of one external rectus, suggesting that the site of the lesion in this condition lies near the abducens nucleus. It would be natural to assume that there is a break in the association 64 ACUTE EPIDEMIC ENCEPHALITIS The course of these palsies is not uniform ; often they dis- appear in a few days, sometimes they are permanent, some- times they are recurrent. In general we may say that diplopia disappears early, ptosis later, and pupillary anomalies and weakness of accommodation last of all the eye symptoms, many months after the onset. Nystagmus. There may be the slight nystagmus of asthenic states or the pronounced nystagmus of organic brain disease. Very frequently too there are the nystagmoid twitchings in the direction of action of a muscle that is par- etic. One variety of irritative spasm that has been described to me is a lightning-like oscillation of the two eyes, without parallelism of action, coming on at intervals when the eyes are in the position of rest. These different varieties have not been differentiated in our figures, but nystagmus was noted in 32 of the Mt. Sinai patients. Pupils. In 35 of the 100 patients there was ^defective light reaction of the pupils, often with irregularity and inequality. As a rule in encephalitis the sluggish pupils are small or of medium size. They differ from the pupils of cerebral lues only in the greater frequency of an accompany- ing defective convergence reaction. The characteristic pupils of cerebral lues are seen also at times with tumors and non- Iuetic inflammations in the brain stem. In encephalitis this symptom is very common, Barker finding it in every one of his reported cases. tract between the abducens nucleus of one eye and the nucleus for the internal rectus of the other eye. However, we believe that the impulse which turns both eyes to the right arises from the right abducens nucleus. And if this impulse were sent from the abducens nucleus in normal measure to the right external rectus and incompletely to the left internal rectus the result would be divergence of the two eyes and not the convergence which is found in these cases. Could we assume that the impulse which turns the eyes to the right arises from the nucleus of the left internal rectus, an interruption of the association fibers in the longitudinal fascicle would prevent the full impulse from reaching the right external rectus and thus lead to convergence of the eyes. But since this assumption seems untenable, our attempts to solve the problem with our present data are purely speculative and vain. SYMPTOMATOLOGY 65 This is not the place to discuss the mechanism and manner of production of the Argyll-Robertson pupil, but it is hoped that study by neuropathologists of these brains with inflam- matory changes still fresh may solve some of the unsettled problems. In lues, if there is a paresis of accommodation there is also dilatation of the pupil and iridoplegia — an ophthalmoplegia interna. A peculiarity of encephalitis pupils is that in many cases there is a paresis or even complete paralysis of accom- modation without dilatation of the pupil — in other words there is a normal pupil or an undilated Argyll-Robertson pupil plus the paresis of accommodation that formerly we saw as an isolated symptom in diphtheria alone. This paresis of accommodation in encephalitis, furthermore, is usually bilateral, whereas in lues it is mostly found in one eye only. The characteristic features of the sluggish pupil found in encephalitis then are, first, the great frequency of accompany- ing defective convergence reaction, and second, the association often with paresis of accommodation without dilatation of the pupil. Accommodation. Accommodation may be apparently nor- mal by the tests, yet the patient may not be able to maintain it for a length of time, that is, there is quick fatigue of accom- modation, or there may be various degrees of actual loss of accommodation. When there is actual loss of accommodation the hyperopic patient, who is accustomed to overcome his hyperopia by exercising his accommodation, finds that his dis- tant vision has suffered as well as his near vision. And the emmetropic patient finds that he can read print only with great effort and by holding it at arm's length. This paresis of accommodation may easily be overlooked in the bed patient, but the ophthalmologist finds it frequently in the convalescent. Facial Symptoms. The facial palsy is for the most part slight and often limited to the lower branches. It is rarely sufficiently pronounced to give rise to Iagophthalmos or even to cause difficulty in closing the eyelids. 66 ACUTE EPIDEMIC ENCEPHALITIS Since the eye disturbances of encephalitis are sometimes of early onset and then the most annoying of the patient's symptoms, the ophthalmologist may be the first physician to be consulted and in times of epidemic he may from the eye symptoms alone, if lues can be excluded, make the diagnosis. The following questions submitted to Dr. Holden before the commission, together with answers to them, are here reported verbatim. Dr. Sachs: I would like to ask Dr. Holden whether he attaches any importance at all to the irregularity of pupillary contour that has been observed in these cases. You make a distinction; I believe you stated that the contour is irregular but with a sluggish pupil, just as though you associated those two things in some way, or are they in any sense independent? . Dr. Holden: I think we all feel that the pupil of cerebral lues, for example, begins with irregularity and inequality and is followed by a sluggishness of light reaction. These pupils seem to me to fol- low fairly well the model of the Argyll-Robertson pupil in its incipiency. The irregularity in equality was noted in but 7 cases in which there were no sluggish pupils, nor sluggishness of light reaction. !Dr. Dana: Was there any case of sympathetic paralysis? Dr. Holden: I have not found any notes of these. There is a record of one ol the Philadelphia neurologists who reported a case of what he termed bilateral sympathetic paralysis. In other words, he had the slight narrowing of the palpebral aperture and the contracted pupil which we have as symptoms of the disturbance of the cervical sympathetic, and he regarded this as being unique in this disease as occurring on both sides; as a rule it is not ob- served. Now, as an ophthalmologist I would rather question the accuracy of his observation. I was not at all sure that his diagnosis was correct. Dr. Sachs: I think we have all seen some of those cases that should probably have gone in the first instance to the oculist. Tell us something about the length of time which you know that the ocular palsies have persisted in these cases. Have they been chronic? SYMPTOMATOLOGY 67 Dr. Holden: Many of the cases that I saw in my office, of patients who came with the eye symptoms first, were afterwards sent to hospitals and were lost to my observation. I cannot answer that question definitely. Dr. Barker: Dr. Holden has not said much about the fourth nerve. Was it involved in these cases, or does it usually escape? Dr. Holden: There was no note of the fourth nerve involve- ment in the Mt. Sinai Hospital cases. I have not observed it myself. Naturally, in bed patients, the fourth nerve involvements are difficult to make out. I have no doubt it has been involved in a good many cases, but this does not appear in the statistics. Dr. Hall: Could the small pupil be due to a sympathetic paralysis? Small pupils are quite common in encephalitis. Do you think it is an irritation of the oculomotor? Why is there miosis? Dr. Holden: My theory about all these pupils, the luetic pupil and the others, is that there is an irritation to begin with which causes an irregular contraction of the sphincter muscle. First we have an irregularity and later a small pupil. I cannot see any reason for dragging the sympathetic into these cases. Dr. Hall: Dr. House of Oregon has spoken especially of weak movements of both eyeballs — inability to do much of anything with any of the eye muscles — what might be called a sluggish eyeball as contrasted with sluggish pupils. What would Dr. Holden's idea be of the lesion that could cause such a phenomenon as that — sluggish eyeball, where all the movements are paralytic. Dr. Holden: I think it is rather difficult to say except that I regard a certain number of those cases as purely mental such as we have all noticed in examining patients in the hospital; for instance, that it is very difficult to get almost any of those patients to look upward, and in ^these encephalitis patients it is very difficult to get them to look aside sometimes. I have to give tests to be sure that the patient has not paralysis. Of course, in the cerebellopon- tile angle tumors we find what we may term a disinclination. The patient requires a good deal of urging to turn his eyes to the right in the case of right tumor. It is difficult, I think, to distinguish between the cases of mental disinclination and those in which there is actual nerve weakness. Dr. Dana: Referring to the sympathetic again, did not Dr. Cadwalader report other symptoms which belong to cervical sympathetic paralysis, like sweating and reaction of the pupils, etc.? 68 ACUTE EPIDEMIC ENCEPHALITIS Dr. Holden: As I remember it, the report was about thirty lines long only, and I do not remember that he mentioned other symptoms. Dr. Patrick: You spoke in rather a cursory way of the possi- bility of various varieties of the spasm of the ocular muscles as well as the paralysis. Might I ask if you have seen ocular spasms in these cases and to what extent? Dr. Holden: After I had written this paper I crossed out "spasm" and then I put it in again, because there were some cases reported of the spasm of the orbicularis. I think some of these cases might come under the head of "spasm." I have not seen any other. Dr. Sachs : Have you seen what we have described as cogwheel movements of the eyeballs? Have you been struck by the jerky movement of the eyeball? We thought that the expression "cog- wheel" movement would about express it. Dr. Holden: I think I have. CONCLUSIONS OF THE COMMISSION Mode of Invasion. Members of the Commission are of the opinion that no dogmatic statement can be made at the present time as to the exact mode of invasion of the infective agent. The suggestion, therefore, that the mucous membranes are the seat of primary involvement, the infection then ex- tending along the lymph paths must be accepted with re- serve; also the statement that nerve palsies are related to the primary and original site of infection. While the importance of the lymphatic system in the extension of inflammatory affections of the central and peripheral nervous systems is now well recognized, the blood-stream is no less important. In any investigation of this question, therefore, the hematogenous, as well as the lymphogenous, factors should receive consideration. The statement was also made that the more highly organ- ized cells of the central nervous system are more subject to the ravages of the disease. SYMPTOMATOLOGY 69 The Commission is of the opinion that while the general principle may be recognized, that the higher the degree of organization of the nerve cell the greater its vulnerability, this does not apply to infections of the type under considera- tion. Here other factors must be considered and especially one which is rather obscure at the present time, namely, the elective affinity of certain bacteria or their toxins for certain groups of nerve cells. Special Clinical Type. It has been the custom in the classification of all general infections of the central nervous system to designate special clinical types in relation to anatomical structures, e. g., cerebral, cerebellar, spinal, etc. Strict anatomical divisions in general infections of the nervous system are always arbitrary and the type is rarely so definite as its name would indicate and is often only indica- tive of a predominant symptomatology. This appears to be true of the so-called cerebral and cere- bellar types of encephalitis. These types are not only rare, but where they do occur they are associated with other focal symptoms which blur the purity of the clinical picture. In some cases the cerebellar symptomatology is to be ascribed to lesions involving the cerebellar connections in the midbrain rather than to the cerebellum itself. Basal Ganglia Group. One of the striking clinical features of this disease has been the involvement of the corpus striatum with the development of symptomsof paralysis agitans and of chorea as pure clinical types or in combina- tion. The relationship of chorea, choreo-athetosis, dystonia, and paralysis agitans to the corpus striatum has been shown by a number of studies in recent years. Their occur- rence in connection with the predominantly brain stem involvement of epidemic encephalitis is therefore not surprising, although practically unknown in other types of infection of the central nervous systems, as, for example, epidemic poliomyelitis. Of special interest is the occurrence of symptoms of both paralysis agitans and chorea, prac- tically in pure form, which would appear to favor Ramsay 7 o ACUTE EPIDEMIC ENCEPHALITIS Hunt's conception of the two striatal systems, — the one motor, for the control of automatic and associated move- ments (pallidal system) ; and the other exercising an inhibi- tory and coordinating function (neostriatal system). It is to be hoped that careful studies in the future, includ- ing serial sections of this region, will throw additional light on these important questions. Chapter III SYMPTOMATOLOGY: SYMPTOMS REFERABLE TO THE SPINAL CORD AND PERIPHERAL NERVES THIS portion of the section on symptomatology of epide- mic encephalitis concerns the coincidence of this disease in parts of the central nervous system other than the enceph- alon, and the Commission submits clinical and laboratory observations as follows: The report of Dr. Henry A. Riley of New York, upon spinal types of the disease, and the report of Dr. Foster Kennedy of New York, upon peripheral and radicular types. Also, the report on laboratory findings, of Dr. Walter M. Kraus of New York, and of Dr. Irving H. Pardee of New York, gives the serology of the spinal fluid and blood in epidemic encephalitis. Spinal Types of Epidemic Encephalitis (Henry A. Riley). This form was late of recognition being considered first as an aberrant form of poliomyelitis associated with somnolence. Only the increasing number of cases made it evident that there was a distinct form of spinal involvement of epidemic encephalitis. Pure examples of any one form or type being almost unknown, only the predominating picture determines the label to be applied to the disease. Figures by Wechsler show that out of 864 cases, 44 cases were described as myoclonic, 29 as radicular, neuritic or neurologic, 24 as meningitic, and 1 as dorsal poliomyelitic, a total of 121 cases. On account of the loose description and terminology, only 23 cases can be considered as spinal, these being myelitic, paraplegic and ventral poliomyelitic. 71 72 ACUTE EPIDEMIC ENCEPHALITIS The forms of epidemic encephalitis which are apparently mainly spinal in character may be divided into two groups: i. The ventral poliomyelitic form. 2. The transverse myelitic form. The ventral poliomyelitic form may be divided into two sub-groups : a. The irritative type. b. The paralytic type. Rarely seen as clear-cut entities, these merge one into another; the paralytic type is often the end result of the irritative. The irritative type may clear up without any permanent defect; the paralytic may develop full blown. Irritative Type. The literature is not clear in definite distinguishing features in motor disturbances, observations being mixed and conflicting. The character of movement is the criterion by which the level of the disturbance may be identified. a. The cortical level is distinguished by the movement being a purposeful synergized movement, presenting elements which distinguish not only the cortical pattern and concept, but also the collaboration of the cerebellum in the movement; for example, the movement displayed in Jackson- ian epilepsy. The arrangement of the Betz cells and the ventral horn cells makes the cortical type of movement a synergized movement, and not an aimless contraction of independent muscles or muscle fibers. Such cortical stimuli are incapable of bringing about myoclonic or fibrillary contractions. b. The striate level is distinguished by the movements which we know as the choreas, the athetoses and the mobile spasms. The underlying feature being the automatic asso- ciated type of movement, we can differentiate these from the spinal level of motility. c. The cerebellar level need not be considered, for we do not have any definite type of abnormal involuntary movement from stimulation of the cerebellum. SYMPTOMATOLOGY 73 d. The spinal level of movement characterizes the myo- clonic and the fibrillary manifestations of epidemic encepha- litis. Such contractions at most produce a movement of a single muscle, and at their least produce a movement of a single muscle fasciculus. They are simple purposeless irregu- lar movements. The coarse myoclonic movements are twitch- ing, exceedingly rapid in rate, irregular in rhythm and variable in extent. At times slow vermicular movements have been observed, probably due to the stimulation of connector neurons in the spinal gray and the resulting correlated activity of several neuron groups. The myoclonic form was often preceded for several days by radicular pains and the interval may indicate the time necessary for the infective agent to spread from the roots to the parenchyma of the cord itself. Paralytic Type. The paralytic type of the ventral polio- myelitis form, closely resembles that seen in poliomyelitis; in fact, of itself it is indistinguishable from that disease. The history and concomitant phenomena establish the differential diagnosis. The transverse myelitic form of epidemic encephalitis is similar to the transverse myelitis seen in other forms of spinal disease and varies with the site and extent of the lesion. By some it has been considered not as a definite type but as an accidental occurrence in the course of a typical spinal encephalitis, the result of hemorrhage or thrombosis. Occasional xanthochromia may substantiate this view. CASE REPORTS Case I. An irritative type from the service of Dr. Foster Kennedy at the Neurological Institute, New York City. Onset seven weeks before admission, with pain and soreness spreading from the head to the entire body; retention of urine, transient diplopia, insomnia and tremor. Fixity of facial expression; coarse tremor of upper and lower extremities, transient cogwheel in flexing forearm, brief jerky 74 ACUTE EPIDEMIC ENCEPHALITIS movements of the toes and feet and myoclonic contractions of dorsal muscle groups in the thigh. Abdominal myoclonus. Deep reflexes sluggish, abdominals absent, no pathological reflexes. No sensory changes of note. Slight external rectus weakness on the right side. Laboratory examinations negative. Case II. A myoclonic fibrillary type. Onset with pins and needles sensation, then pain in left instep, which was sharp, localized and stabbing. This spread to right leg, and then subsided and was followed by twitching movements in calves, thighs and abdomen. Patient delirious, hallucinating with expansive tendencies for some time. Could not walk on heels or toes. Gait was steppage. Cerebellar function normal. Left knee-jerk strong; right knee jerk weak. Ankle reflexes absent. Abdominal reflexes present on right and doubtful on left. No pathological reflexes. Muscle strength dimin- ished in abductors of thighs both sides. Adductors of thighs, left, affected more than right. Extension and flexion of feet very weak. Atrophy of left thigh and calf. Sensory: Some change over right L5— S5; left L2 — S5. Right pupil larger than left with normal reactions. Case III. A transverse myelitic form from the service of Drs. Frederick Tilney and Hubert S. Howe at the Presbyterian Hos- pital, New York City. Onset with dizziness, diplopia, headache, left facial paralysis. Right ptosis. Reflexes of upper extremity, active; of lower extremity, absent; no abdominal or pathological reflexes. No movement of lower extremity except slight flexion and extension of the toes. Tone much reduced in lower extremities. Level at T2 — 4 with secondary level at S2 for all types of sensation. Slight papillitis in each eye, pupils equal, regular and central, both sluggish to light and accommodation, left more than right. Right ptosis, right eye immobile; left eye, deficient internal rectus. Partial left seventh. Straw colored spinal fluid, otherwise laboratory examinations were negative. Following lumbar puncture the patient developed a total transverse lesion at the level of T2, complete paraplegia, retention of urine, pneumonia and death. No autopsy. SYMPTOMATOLOGY 75 The following questions submitted to Dr. Riley before the Commission, together with the answers to them, are here reported verbatim. Dr. Sachs: I would like to ask Dr. Riley this question: Have you seen paralytic spinal types which you could at the time diag- nose as due to the virus of epidemic encephalitis and not to that of acute poliomyelitis? I mean, if you had not seen them just at the time of the epidemic, was there anything about those cases to help you at the time to differentiate between the paralytic type of anterior poliomyelitis and the type that is due to the epidemic encephalitis? Dr. Riley: I think the drowsiness and the cranial nerve systems would be very valuable in differentiating. Dr. Sachs: That is, nothing in the spinal? Dr. Riley: I do not think so. Dr. Timme: Dr. Riley, may I ask whether you had any reason at any time to believe that in the ventral poliomyelitic type there were also involvements of the intermedio lateral tract in which the sympathetic cells were either entirely per se involved or in addition to the anterior horn cells? Dr. Riley: I do not think I have seen any cases that showed that. Usually there was some motor disturbance in connection with the anterior horn manifestations, but I have not seen any- thing of that alone. Dr. Timme: Would you be willing to include in your classifica- tion the addition of symptoms that would be due to such dis- turbance of the intermedio lateral tract? Dr. Riley: I think they should be, but they rarely are in the ordinary routine examination. Dr. Timme: You think they should appear? Should the classifica- tion include that? Dr. Riley: Yes, I think it should. Dr. Dana: I would like to ask Dr. Riley if he is sure that that last case as reported is a case of encephalitis Iethargica. I do not see how that can be a certainty. It is just with a group. Dr. Riley: The history of some drowsiness, and the cranial nerve symptoms which were quite marked in that case, — both sides were affected, one more so than the other, — and with the other spinal manifestations, the case could hardly be placed anywhere else. 76 ACUTE EPIDEMIC ENCEPHALITIS Dr. Dana: That is not making a diagnosis. How can you ex- clude some sort of a mixed infection? It is so entirely different in its course from perhaps ioo cases of epidemic encephalitis. Dr. Riley: I think that was just the characteristic thing about the disease, as we saw it, that it did not follow any outline. Dr. Dana: That is just the point I think has been too greatly emphasized — the characteristics of exceptional cases. I have seen cases over and over again, and they have a physiognomy that is quite characteristic and distinct. They do not always run to these bizarre forms. You have them and then immediately you form a new type without any post mortem evidence of it. Is there on record, for example, a case like the one you have described — very marked sensory symptoms in which there has been a post mortem which has shown that the case was surely encephalitis? Dr. Riley : There was another case at the Presbyterian Hospital which was autopsied and showed a symmetrical diminution in the size of the cord and also hemorrhages and destructive processes in the midbrain, etc. It seemed to be quite typical of what we recognize as epidemic encephalitis. Dr. Dana : I am not saying that this is not so, but I am reading a good many of the papers and listening to them, and it always seems as though they were trying to show another bizarre case, and emphasizing extraordinarily unusual types. Moreover, I don't think the cases have always been worked out so as to exclude absolutely some other infection or some mixed infection in those cases. Dr. Sachs: There is one other point I would like to have some information upon for the benefit of the Commission. I may not have understood you correctly, but did you not make a point that in spinal types, we will say, of acute poliomyelitis, there were never cases resembling a transverse myelitis? Dr. Riley: If I did make that positive, I ought to qualify it somewhat. Dr. Sachs: I remember distinctly, at the time of the epidemic of acute poliomyelitis, having seen such cases which were really typical transverse myelitis. The only evidence that we had that they were of this nature was the unusually rapid recovery, very much more rapid than in any other diseases we had ever seen. I should be glad to know whether from your study of the litera- ture you found that there was no basis for the diagnosis of epidemic SYMPTOMATOLOGY 77 poliomyelitis in these cases, whereas I believe you say there were some in this epidemic. That is, I understood you to claim that there was no reason to suppose that in the epidemic of poliomyelitis any cases of acute transverse myelitis occurred, which could be classified as due to that epidemic, whereas you did think there were some such cases occurring during an epidemic of encephalitis. Dr. Riley: Yes, that is true. We got that impression from the literature and also from some ot these cases. For instance, this last one only developed a transverse myelitis picture after a lumbar puncture, and that is the reason I said that some had con- sidered the transverse myelitis forms as simply the result of an accident in the course of epidemic encephalitis — as a hemorrhage or thrombosis, etc., not as a pure type of disease. Dr. Dana: Then you do say that possibly these definite trans- verse myelitis pictures may be accidental? Dr. Riley: Yes, I do not know myself; I am quoting. Peripheral and Radicular Types (Foster Kennedy). It is only for the purpose of presentation of different clinical aspects of epidemic encephalitis by different observers that we have divided with some arbitrariness the disease into different clinical groups. A clinical discussion, under these circumstances, therefore, must begin by a disclaimer that a type is ever a disease of its own genus, and by an assertion that it merely represents a variety in which the virus has fallen with some greater incidence on one part of the body than on another. Of the circumstances which go to permit this variety of form we know little; naturally, disease pic- tures will vary with the structure affected, and variety in such pictures following nervous lesions is furthered, because from lesions of the nervous system we may have either obliterations of normal functions or release of functions nor- mally controlled by centers higher in the neural hierarchy. It is probable that variety of clinical form in epidemic encephalitis is often produced by variety of virus or by a constant virus varied by appearing in different evolutionary guises. However this may be, it is certain that the peripheral 78 ACUTE EPIDEMIC ENCEPHALITIS nerves and spinal roots are affected in encephalitis to a considerable degree. Spinal Root. Abrahamson says that in 60 per cent of his cases unmistakable signs of radiculitis were present. This is a higher figure than has been obtained in the series at Bellevue Hospital; we have been slow, however, to ascribe to root or peripheral infection subjective symptoms unsupported by objective phenomena. Nevertheless, in some cases, the dis- tribution and character of the pains have forced us to the same conclusions; jn a few others, sensory changes similar to those found in tabes dorsalis have been present; in a small number there have been localized atrophies of muscles such as would occur from involvement of contiguous anterior roots. Cranial Nerve. Palsies of single cranial nerves are not uncommon, the seventh and third nerves being those most usually affected. It should be pointed out that the involvement of the seventh nerve in most of our cases has not been accompanied by any defect either of the fifth, eighth or sixth nerves, a consideration which would exclude the possi- bility of the lesion being in the pontocerebellar angle or in the nucleus of the facial nerve in the pons, and would compel observers to explain the facial palsies in these cases by a lesion of the seventh nerve in its parenchyma. Peripheral Nerve. Not only were single cranial nerves picked out for damage by the infection, but occasionally single peripheral nerve trunks were involved in similar fashion. An interesting example of this was seen in a riveter who in April of this year began suddenly to have sharp lancinating pains in the arms and shoulders accompanied by much weakness in the upper extremities. When examined, some three weeks after the beginning of these symptoms he was found to have a noticeable loss of power in both serratus magnus muscles, the right scapula being winged on raising the arm on that side. The patient had diplopia, heavy sweat- ing, slowness of emotional initiative and a mask-like facies some four weeks after the development of his peripheral nerve symptoms. It is at least an interesting speculation SYMPTOMATOLOGY 79 whether this man's occupation as a riveter imposing reiter- ated violent exertion of his serrati and notably of the right muscle could have had any determining effect on the inci- dence of the disease on the long thoracic nerve. Symptoms. Several observers, notably Pardee and Barker, have described cases of severe girdling pains beginning in the cervical region with persistent hiccough and de- scending to the lumbar region and lower extremities. None of their cases had any objective sensory losses, but all had a pleocytosis in the spinal fluid. It is remarkable that herpetic manifestations were not more frequent among such patients; only one of the Bellevue Hospital group had herpes, and that was confined to the left auricle and external audi- tory canal and was associated with a complete left facial palsy of a peripheral type. A geniculate ganglionitis was in this case the presumptive lesion. Polyneuritis. Instances of indubitable polyneuritis on an encephalitic basis are less common in the experience of the workers in Bellevue Hospital and the Neurological Institute than are the radicular types or those in which isolated nerve trunks such as the facial are alone involved. J. D. a watchman, aged fifty-three, formerly a coachman, a man who had never drunk more than an occasional glass of beer, in August, 1920, began to suffer from severe burning pains in the calf muscles, with tingling in the toes and progressive weakness in the legs. He became unable to walk and at the same time had severe headaches and felt very ill. He had a constant pyrexia of about 2°F. After two weeks the same symptoms as had been in the legs were felt in the arms which gradually weakened. A month after these developments he began to see double, his pupils became unequal and sluggish to light, the left face became paresed, the facial expression grew mask-like, he sweated exces- sively; the sleep mechanism was reversed, that is, he was drowsy by day and wideawake by night, the pulse was persistently about 125, and the sugar content of the spinal fluid and its cell content were greatly increased. There was atrophy in the intrinsic muscles of both hands and fibrillary twitching in all four limbs. All deep 80 ACUTE EPIDEMIC ENCEPHALITIS reflexes were abolished. There was excruciating tenderness in the calf muscles and abolition of the sense of position in the feet and hands with consequent sensory ataxia. There was no weakness in speech or swallowing. Micturition was slow and difficult, but there was no incontinence. This man is making a slow recovery (December, 1920). This case and two others in the Neurological Department at Bellevue Hospital remarkably resembled those reported before the American Neurological Association by Dr. Foster Kennedy under the caption "Acute Infective Neuro- nitis." In them, however, it was unusual to have a cerebral symptom complex, though autopsy examination revealed inflammatory lesions in the peripheral nerves, spinal ganglia and cord and cortex as well; lesions which for the most part, however, diminished as one ascended in one's ex- amination. These cases occurred as a minor epidemic among soldiers in the field and were accompanied by fever and other evidences of a general infection. In some few the posterior spinal roots were especially affected, so that root zones of grossly altered sensibility were easily demonstrated. A constant feature of these soldiers was the peripheral paralysis of one or both sides of the face, a feature commonly but by no means constantly seen in the American cases of epidemic enceph- alitis. In connection with these cases, however, we must consider those cases of acute polyneuritis which occur as a complica- tion of malaria and of enteric fever and scurvy, and perhaps especially those recently described by Farnell in which a staphylococcal gastro-enteritis was promptly followed by acute polyneuritic symptoms with not infrequently fatal results. All these diseases differ from similar conditions found in the encephalitic epidemic in degree rather than in type, but make manifest that disease pictures are sketched and colored more by the varying nature of the structures attacked than t>y the specificity of the invading virus. SYMPTOMATOLOGY 81 The following questions submitted to Dr. Kennedy before the Commission, together with the answers to them, are here reported verbatim. Dr. Dana: Did you have any radicular cases, purely sensory — I mean with intercostal neuralgia and herpes? Dr. Kennedy: We had one case I mentioned of herpes in which the left face was completely paralyzed with herpes in the external canal, a very definite case which I think was no doubt a geniculate ganglionitis. There have been no other cases of herpes in my experience. One of the cases I describe here had a very definite sensory ataxia with loss of sense of position in the arms. He had other cerebral manifestations of encephalitis Iethargica. He had diplopia, mask-like face, heavy sweating, etc. Dr. Barker: Is it your impression that those cases described as infectious polyneuritis by Bradford and others during the war come under this group? Dr. Kennedy: I saw those cases, Dr. Barker, and they had the appearance of it, but they had no lethargic manifestations at all, none of them. They had all the evidence of a general infection, but they had no evidence of a midbrain infection. There was one patient I saw whom I have not mentioned in this little abstract — a child who in February of this year came down with vomiting and severe gastric pain, abdominal pain, and a torticollis; saw double and began to lose power in the arms and legs, so much so that the torticollis was of spasmodic nature. There was complete loss ot power in the arms and legs in that child and that power fluctuated. There was complete loss sometimes and then tor three weeks afterwards there would be a little return of power and then there would be another increase in the abdominal pain and the power was gone again. Both the parents and the doctor told me that it came, as it were, in waves; that almost every four weeks from February until now there was a little remission, but gradually the waves of the involvement of loss ot power of the child became less, and the child is now considerably recovering. The recovery between each attack was a little bit more than the next wave would put it back, so that now in December the child is able to walk again and has lost a good deal of its paralysis, but not all. There is a great weakness of the neck muscles so that the head is thrown forward; the knee-jerks are not returned yet; the ankle-jerks are returned. 82 ACUTE EPIDEMIC ENCEPHALITIS The same condition of rapid wave-like attacks of the disease was seen during the war. I would examine a soldier at eight o'clock one night and find definitely that he could not feel below the midthigh, and I would find twelve hours later that he could feel only below the ankle — a condition which I could not understand. I noticed that one of the pathologists suggested that the essential lesion in some of these cases was an edema, flooding the nerve tissue and inhibiting conduction. The clinical manifestations that I have seen in some of the encephalitis cases and in those cases to which you refer, Dr. Barker, made me believe that they might be explained by an edematous phenomenon, and of course one would point out in that connection that sclerosis very often behaves in a similar fashion. Dr. Barker: Might I ask also if there have been sensory forms due to neuritis with spontaneous pains as a characteristic feature and taken by the practitioner at first to be infectious arthritis or myositis, often referred to orthopedists? Dr. Kennedy: I have seen those cases, but I do not think I have seen them having that sad conclusion. Dr. Weisenburg: I would like to ask if Dr. Kennedy has seen cases in which the pains were limited to certain parts of the body only? For example, I had one patient to whom the pains were limited to the parts above the line of umbilicus and never below. Dr. Kennedy: We have a patient in Bellevue Hospital at present whose pains are confined to the arms. That woman became affected in February of this year and she has complained of pain ever since. I can't find there are any objective changes oddly enough in all that time in her arms, but she complains of excruciating, burning pain down the arms in the lower segment distribution. Dr. Dana: How are you going to exclude, as the cause of these so-called radicular pains and paralyses, the conditions of the spinal cord or of the cerebral tissue itself? Why do you say a person has a shoulder pain or facial pains? Facial pain may be ophthalmic pain, may it not? Dr. Kennedy: Facial pain might be an irritation easily enough of the nucleus of the fifth nerve. Dr. Dana: Is there any way of differentiating between so-called radicular pains and paralyses and edematous conditions of the anterior or posterior horns of the spinal cord? SYMPTOMATOLOGY 83 Dr. Kennedy: No, sir, I do not think so. There is evidence that hemorrhages have been found in the posterior ganglia in some cases. That being so one argues that certain other clinical cases which correspond to them in type may have some of the lesions. Dr. Patrick: You spoke of a case ot hiccough. I should like to inquire whether you know that that was a real hiccough — or a spasm of the abdominal muscles? I believe, Dr. Kennedy, you quoted that from someone else. Dr. Kennedy: That is Dr. Barker's case. Dr. Sachs: Has anyone as yet seen the cases of hiccough that are reported as being connected with epidemic encephalitis? Dr. Timme: We will ask Dr. Barker to answer. Dr. Barker: Let me say that I have seen 2 cases of hiccough, described by the practitioners, lasting a long time, and they seemed to be definitely those of epidemic encephalitis. Several epidemics of hiccough were reported as occurring at the same time as the epidemic of encephalitis. One such case was examined roentgen- oscopically, and there was no movement in that case other than contractions of the abdominal muscles. That was an abdominal muscle hiccough rather than diaphragmatic, but that is the only case I know of trying to differentiate. I rather think these hic- coughs are associated with the epidemic. Dr. Timme: Perhaps Dr. Hunt could answer something from his observations in his myoclonic types involving abdominal muscles — whether that is an intensive type of this form. Dr. Hunt: In none of my cases was there anything that simu- lated a hiccough. It would have been very defective observation that would have interpreted any of the movements as related to hiccough, but I could imagine that with a very rapid, definite, rhythmical movement of the upper abdomen it might simulate the real hiccough, but that was not so in my cases. The Serology of the Spinal Fluid and Blood in Epidemic Encephalitis* (Walter M. Kraus and Irving * The material for this article was obtained from records of certain New York Hospitals: Bellevue, Mt. Sinai, The Neurological Institute, New York, Presbyterian, Roosevelt and St. Luke's, and from the following physicians: James B. Ayer, Boston; Lewellys F. Barker, Baltimore; Peter Bassoe, Chicago; Josephine B. Neal, New York; Harry C. Solomon, Boston; Walter F. Schaller, San Francisco; E. W. Taylor, Boston, and Lloyd J. Thompson, Boston. 84 ACUTE EPIDEMIC ENCEPHALITIS H. Pardee). The subject matter which we present has, for the sake of clearness, been divided into three parts; the first contains a review of the literature, the second data, based on the 245 case reports obtained from the foregoing sources, and the third, a section devoted to differential diagnosis by means of the blood and spinal fluid serology. Review of the Literature. Until the publication, in 191 7, of the description of the first cases of epidemic encephalitis in Vienna, no reliable statistics of the changes in the blood and spinal fluid in this disease were obtainable. At this time, von Economo 1 gave an account of the clinical and laboratory findings which we shall consider the first accurate data on the subject. He pointed out the following changes in the spinal fluid: An excess of globulin was found and the spinal fluid cell counts ranged from normal to 43. The fluid was clear and, in some cases, under pressure. The only group of observations which were not mentioned by von Economo concerned changes in the quantity of sugar in the spinal fluid. His observations on the colloidal gold curve were summed up in a sentence. No curves were given. In this country, curves were first published by Josephine B. Neal 2 in September, 19 19. She mentioned the abnormal changes and the similarity to those curves found in acute anterior poliomyelitis. Follow- ing this, observations on the occurrence of syphilitic and paretic types of curves were made by Bassoe, 3 Brill and Benson, 4 Davis and Kraus, 5 and Archambault. 6 1 Von Economo. Encephalitic Iethargica. Wien. klin. Wchnschr., 1917, xxx, 581. 2 Neal, Josephine B. Lethargic encephalitis. Arch. Neurol. ey Psychiat., September, 19 19, ii, 271. 3 Bassoe, P. Epidemic encephalitis (Nona). J. Am. M. Assn., April 5, 1919, Ixii, 971. 4 Brill and Benson. Lange reaction in epidemic encephalitis. J. Lab. &° Clin. Med., June 20, 1920, v, 113. 5 Davis and Kraus. The colloidal gold curve in epidemic encephalitis. Am. J. M. Sc., 1 92 1, clxi, 109. 6 Archambault, La Salle. Choreo-athetoid and choreopsychotic syndromes as clinical types or sequelae of epidemic encephalitis. Arch. Neurol. & Psychiat., November, 1920, iv, 484. SYMPTOMATOLOGY 85 The foregoing gives an idea of the chronological order of the description of the spinal fluid findings. The following paragraphs will be devoted to a detailed account of the spinal fluid and blood findings given in the literature. A. Spinal Fluid: Appearance. In the greatest majority of cases, observation records a clear, colorless fluid. Bloody fluids have occasionally been found, in fact more commonly than could be accounted for by the puncture of a vein. A xanthochromiac appearance has been extremely rare. Pressure. The pressure of the spinal fluid varies from normal to a considerable increase. Cell Counts. In spite of the fact that von Economo in his original description made note of a pleocytosis, the French, who had studied the matter carefully during the years 19 18- 1919, had come to the conclusion that a normal cell count was a rule and of diagnostic importance. It was not until December 10, 19 19, when Benard 1 reported a case with pleocytosis, that doubt was thrown on the invariability of normal spinal fluid cellular content in epidemic encephalitis. The absence of pleocytosis before this date, as noted by the French, was not found by the British and American ob- servers. The latter published cases seen in 19 19, in which there appeared more than the normal number of cells. The cells which appeared in the spinal fluid were always predomi- nantly of the mononuclear type although polymorpho- nuclear increase up to 15 per cent had been found in many cases. The impression gathered from the literature is that the number of cells may vary from normal to an increase of several hundred. Globulin. The discrepancy between the report of the French, who noted an absence of globulin in the early cases of the epidemic, and the English and Americans who had 1 Benard, R. Le Iiquide cephalo-rachidien dans I'encephalite Iethargique. Paris med., June 5, 1920, x, 474. (This article contains a thorough review of the French literature up to June, 1920. References from the literature of other countries are also given.) 86 ACUTE EPIDEMIC ENCEPHALITIS reported its presence in increased amounts, is a parallel to the reports on the cell counts. In general, it may be said that an increase in globulin occurs in the majority of cases. Sugar. No report of the amount of this substance was made until the end of 1919. From that time until the present, the French have published fifteen observations on the amount of this substance in the spinal fluid. These varied from 0.067 per cent to 0.106 per cent, averaging 0.085 per cent. It would seem, therefore, that the amount of sugar in the spinal fluid, wherever it has been reported, has exceeded the normal quantity. Wassermann Reaction. This has been found negative in the spinal fluid whenever it has been reported except in syphilitic cases. Colloidal Gold Reaction. Von Economo commented briefly on the reaction of colloidal gold solutions as follows: "The gold-solution reaction shows no typical elevation of its curves." This implies that some changes existed. B. Blood: The white blood counts, as reported in the literature, reveal a variation from 3,000 to 25,000, the average being about 15,000. Slight polymorphonuclear increase is the rule. The remainder of the blood picture is normal. Obser- vations on the blood chemistry have been scattered and incom- plete. The blood Wassermann reaction is reported negative. THE EVIDENCE OF CASE REPORTS The general statistics in Table I give a numerical summing up of the case reports on which we base our data. Table I. — numerical summing up of case reports Number of cases 245 Number of spinal fluid cell counts 260 Number of spinal fluid globulin determinations. 214 Number of spinal fluid sugar determinations 12 Number of spinal fluid colloidal gold curves 120 Number of spinal fluid Wassermann tests 185 Number of blood Wassermann tests 161 Number of blood polymorphonuclear counts 171 Number of blood differential counts 153 SYMPTOMATOLOGY 87 A. Spinal Fluid: As a rule, the spinal fluid shows con- siderable and important changes in epidemic encephalitis. These are extremely variable, not only in different cases, but also in the course of each case. The most characteristic changes are: 1. A clear, colorless fluid. 2. An increase in the pressure of the cerebrospinal fluid when withdrawn. Fig. 6. Variation in the number of cells in the spinal fluid. 3. An increase in the number of mononuclear cells. 4. An increase in the amount of globulin. 5. An increased amount of spinal fluid sugar. 6. A negative Wassermann reaction. 7. The presence of bodies producing a change in the color of a solution of colloidal gold (Lange reaction). 88 ACUTE EPIDEMIC ENCEPHALITIS i. Appearance. The fluid is, in most cases, clear and colorless. Occasionally bloody fluid is obtained. 2. The Pressure. As would be expected, the pressure of the spinal fluid is sometimes very much increased. Here also no rule exists, and, though this hypertension is frequent, it is not universal. 3. The Cell Count. Table II indicates the minimum, maximum and average number of cells during each of the first Table II. — number of cells in the spinal fluid Weeks Minimum AVEEAGE Maximum' Cases I 2.0 633 160.O 20 2 0.0 71.0 540.0 71 3 0.0 373 200.0 38 4 0.0 28.2 222.0 44 5 1.0 21.3 70.0 24 6 0.0 25.7 100. 26 7 1.0 21 .0 101 .0 \2 8 2.0 l6.2 48.O 10 9 0.0 13.0 32.0 4 10 5.0 8.0 14.0 3 11 4.0 40.0 40.0 1 12 2.0 15.2 33-0 7 Months 4 4.0 40.2 108.0 9 5 6 3-0 32.0 6l.O 2 7 2.0 1 8 2.0 2.5 3.0 2 9 10 11 \2 13 21 . . . 2.0 1 24 . . . 30 1 S YM PTOMATOLOGY 89 Table III — A. number of cells in the spinal fluids at various weeks INCLUDING REPETITION OF CELL COUNTS* 4 IOO 70 IOO 5 3 40 50 70 g 160 90 160 64 2 5 2 1 38 28 20 15 5 8 10 8 9 I I I180I 1350 J 45 25 10 18 32 26 100 40 40 120 (.30 1 I 540 1 26 '50 r50 270 1 >5 I 25 149 . I 22 1 16 18 IS) 1 16 U3 37 7 44 2 I 2 46 6 ISO 200 4 6 20 20 122 2S 27 29 / 30 1 IOO 30 30 43 45 50 / 54 1 160 56 70 7 1 72 80 103 190 2 (0 200 270 6S0 114 18 18 20 SO 31 4& (50 I 75 60 104 134 170 s 43 19 36 r 3 3 6 30 6 6 30 1 4 ° 1 6 1 42 1 6 46 f 6 I 57 1 7 1 8 ( 1 4 1 11 1 97 • 33 ( 8 * 4 48 14 14 i IS 1 5 9 8 9 9 3 5 | 10 ) IS 22 14 66 16 30 48 32 1 78 1 16 21 l"l 1 1 1 r IS 28 40 1 12 1 4 3 1 1 28 10 5 18 24 5 25 7 13 30 101 30 S No observation 28 30 IOO 30 35 40 ( 2 1 35 6 40 » 66 18 95 222 * Except where repetitions occur, the figures are arranged in an ascending order. Brack- eted figures indicate several observations on the same case and in the same week. 9 o ACUTE EPIDEMIC ENCEPHALITIS Table III — B. number of cells in the spinal fluids at various months including REPETITION OF CELL COUNTS* Months 24 4 /3 ^5 [ 3 6 61 7 l9j 10 5 14 5 is 8 98 22 100 108 * Except where repetitions occur, the figures are arranged in an ascending order. Bracketed figures indicate several observations on the same case and in the same week. twelve weeks and during the fourth to twenty-fourth months of the disease. The graph in Fig. 6 presents this in a different way. It may be seen that, on the average, more cells are found during the first three weeks of the disease. The value of this in individual cases is diminished by the varia- tions in the number of cells in each week. An idea of this may be had from an examination of the columns showing maxi- mum and minimum number of cells for each week and also from Table III. The number of polymorphonuclear cells may be as great as 15 per cent. Fluctuation in the number of cells occurs during the course of the disease. When there is a remission, the cell counts may increase. 4. Globulin. The globulin is usually increased to a mod- erate degree (in 72 per cent, of the cases). However, since this is not always true, its diagnostic value in individual cases is lessened. The presence of globulin is not always paralleled by the presence of cells or a positive colloidal gold curve. 5. The Sugar Test. The majority of the tests have been done at Bellevue Hospital since May, 1920. No estimates were given in case reports outside of New York. The number of estimations is insufficient to enable us to draw any but tentative conclusions. However, those figures which we have, show, without exception, values above normal. S YM PTOM ATOLOG Y 9i The sugar content of the spinal fluid has been tested in 12 cases. It has ranged from 0.062 per cent to 0.095 per cent (Table IV). Table IV Sugar Content of Spinal Fluid in Twelve Cases Mon Week 3 3 6 9 9 4 4 4 4 5 5 10 * Observations on the same case. Percentage of Sugar in the Cerebrospinal Fluid 0. 082 O.O75 0.068 O.062 O.O94 O.065 O.080 O.O94 . 092 * 0.070* O.063 O.O95 6. The Wassermann Test. This was negative when reported. 7. The Colloidal Gold Curve. This has been found changed in 100 out of 120 cases (83 per cent). The type of curve varies considerably, as Figure 7 shows. There is a tendency toward elevation of the left-hand part of the curves in the later stages of the disease, but this is not constant. Positive curves were found as late as the twenty-first month. Eleva- tions of the right end of the curve alone were not found. The tendency is to a color change in the high and medium concentrations of spinal fluid. Changes in the low concentra- tions do not occur alone, but may occur when the medium and the high concentrations are altered. B. Blood: Normal values for red blood count and hemo- globin have invariably been found. Leukocyte counts have varied from a minimum of 4,500 to a maximum of 32,000, Q2 ACUTE EPIDEMIC ENCEPHALITIS the general average being 12,000. Figure 8 shows these relations in graphic form. Maximum, minimum and average percentage of polymor- phonuclears are shown in the graph in Figure 9. This will J * 4 * ^ 4 *. va '^ 4 ^ A * 5a 4 HI A H 4\ A H }A i I -£ 4 4 Jk *4i « J 14 Curves j 1 U 1 * J ■ 00 i A « v| ^ 4 it & J 4 j ■* H H fe 1 -6- 4 * ^ N « ^ ^ *" A 4 4 H 4 4 1 1 1 1 H =l ~ 4 ^ 4 1 0) v . 4 < - ^ d CO 1 c A * 4m 1 4 1 < 1 < ^ 4 I 4 A 1 4 5 ex 1 1 ^ 4 I 4 + 1 i 4 4 4 < ■ ^| A t 4 1 i < I . A 1 ^ 1 5 J 4 1 * -« * 'o U serve to emphasize the extent of the variations in the various stages of the disease. The number of observations on the chemistry of the blood are too few to enable us to draw any conclusions. SYMPTOMATOLOGY 93 Weeks/ X 3 Max Auev. liui No.of Cases /3 6/ 24 2f /3 /£" f £ & / O ^ Fig. 8. Variation in leukocyte counts in the blood. Weeks / Z 3 4- )*%* Fig. i i. Lumbosacral portion of the spinal cord (Case 3). The membranes are slightly infiltrated; the subarachnoid space shows on the left a congested vein; the anterior and posterior horns exhibit a number of infiltrated vessels; the number of ganglion cells in the anterior horns is normal; the ependyma cells of the central canal are proliferated (a magnifying hand-glass will show the details better). (Toluidin-blue stain, X 16.) (Bassoe and Hassin, Arch. Neurol. & Psycho-Path., 1919, ii, p. 16.) and large nononuclear cells, the latter of doubtful endo- thelial or mesothelial origin. These cell infritrations are typically seen to be confined to the vessel walls, the Virchow- Robin and perivascular spaces. There is general agreement 11 1 62 ACUTE EPIDEMIC ENCEPHALITIS that this type of pathological process is most intense and most extensive in the gray matter of the basal ganglia, midbrain, pons and medulla, and the cervical cord. The > f • * v it, 9S3 ft , •} v jf '» «* i . %' * /* . * > . • *# > ■ t, >** &b «■ V &• ".*.' Fig. 12. Tegmentum of pons. Ag. Aqueduct of Sylvius. Toluidin blue, X 65. Three types of lesions are shown: perivascular infiltration, diffuse infiltration of the nervous tissue, and proliferation of the subependymal neuroglia. (Bassoe and Hassin, Arch. Neurol, tf Psycho-Path., 1919, ii, p. 11.) region about the aqueduct of Sylvius is most affected while the severity of the process lessens cephalad and caudad. The vessels are described as affected in a patchy manner, some intensely infiltrated, some normal in appearance. The vessels MORBID ANATOMY 163 of the gray matter are chiefly involved while those of the white are by no means immune. In the same territory, and frequently in apparent connection with the above described infiltration, occurs, in almost every case, the second most striking type of lesion, namely, diffuse infiltration of the nervous tissues. The same types of cells are here seen scattered through and intermingling with the fixed cells and •a, ,'. ^» '* Fig. 13. Hemorrhage into the perivascular space of His, region of thalamus. This is the type oi hemorrhage commonly observed in this disease. (Tilney and Riley, Neurol. Bull., 19 19, ii, p. 127.) fibers constituting gray and white matter. Not infrequently large mononuclear phagocytes are found in these terri- tories, and with special stains free fat droplets are here visible. This diffuse infiltrative process is usually described as being most intense in and near the substantia nigra. It is interesting and important to note that, with rare exception, polymorphonuclear leucocytes are not present. Hemorrhage, as has been stated, is not regularly noted in the gross appearance. Microscopically, hemorrhage into 164 ACUTE EPIDEMIC ENCEPHALITIS the perivascular space of His is seen frequently; rarely, however, does it spread from this locus into the nervous tissue. While hemorrhage may occur from vessels showing && ' m-^9' * Fig. 14. Midbrain, X 720: diffuse infiltration with plasma cells and lympho- cytes. (Wegeforth and Ayer, J. Am. M. Assn., July, 19 19, p. 21.) perivascular cell infiltration, this is not necessarily so. Nor is hemorrhage associated with any marked degree of vascular disease, as indicated by minimal changes in the intima and elastica, and almost total absence of thrombosis during the MORBID ANATOMY 165 acute state of the disease. Where hemorrhage into the par- enchyma is seen, it is usually not accompanied by reaction of the surrounding glia. Fig. 15. Midbrain, X1060. Mononuclear phagocytes and plasma cells in white matter. Death twenty-nine days from onset of symptoms. (Wegeforth and Ayer, J. Am. M. Assn., July, 1919, p. 23.) Changes in the Nerve Cells and Neuroglia. In discussing changes in the nervous tissue itself, nerve cells, nerve fibers and neuroglia, there is considerable difference of opinion. This is but natural, considering the difficulty in adequately estimating abnormalities of these structures. The majority 1 66 ACUTE EPIDEMIC ENCEPHALITIS of writers evidently have not studied these tissues with thor- oughness; hence our knowledge of parenchymatous lesions depends upon the reports of a very few careful workers. The nerve cells unquestionably show relatively little evidence of degeneration considering the severity of the pathological process. Intense generalized destructive pro- Fig. 1 6. A destroyed ganglion cell from the subthalamic region surrounded by plasma cells. (Toluidin blue, X 1200.) Neurophagia is absent in many of the cases reported; it is more likely to be seen in cases of several weeks duration. (Bassoe and Hassin, Arch. Neurol. & Psycho-Path., 1919, ii, p. 14.) cesses throughout the brain or the spinal cord have not been described, and only rarely have focal degenerations of large extent, as seen in certain other types of encephalitis, been observed. In areas of greatest inflammation, nerve cells appear apparently intact in the midst of extensive mono- nuclear cell infiltrations. In the neighborhood of such terri- tories minor changes, such as chromatolysis, are usually MORBID ANATOMY 167 described. However, isolated examples of cell destruction, chromatolysis, swelling of the cell, excentricity of the nucleus, absence of neurofibrils, satellitosis, and even neuronophagia are described in areas of intense infiltrations. In territory free from the striking changes of the disease, such as the cerebral cortex and cerebellum, nerve cells of all types are usually found to be normal or to present minimal degenera- "0 « ,.'tn, : • **HL Fig. 17. Hypoglossal nucleus. Many of the nerve cells appear normal, but some are degenerated. The nucleus was infiltrated with ameboid glia cells. (Tilney and Riley, Neurol. Bull., 1919, ii, p. 127.) tive changes; however, complete degeneration of the smaller pyramidal cells and of Purkinje cells, with or without neuronophagia, occurs. Neuroglia cell proliferation is said to be very considerable in and about areas of intense cellular invasion, and about vessels presenting marked perivascular infiltration. In the cortex and subcortex, also, diffuse neuroglia proliferation of the small cell type is evident in proportion to the amount of nerve cell destruction. Multinuclear forms are not described, 1 68 ACUTE EPIDEMIC ENCEPHALITIS nor is there evidence of neuroglia fibril formation on a scale to warrant comment. Microscopic Changes in the Meninges. Pia and arachnoid may be normal. Usually, however, besides greatly engorged Fig. i 8. Pial vessels during the acute stage. (Resorcin-fuchsin, X 60). The elastic membrane in the form of solid rings is very clear. In the acute stage the intima also is normal or only slightly affected, vascular lesions being almost confined to the adventitia. (Bassoe and Hassin, Arch. Neurol. & Psycho-Path., 1919, ii, p. 7.) vessels, already noted in the naked eye examination, the layers of the pia and the reticular network of the arachnoid are separated and in the interstices are numerous red cor- puscles and large mononuclear cells. In the depths of the sulci intrapial extravasations of red corpuscles are occasion- MORBID ANATOMY 169 ally observed. Except in these latter areas polymorphonuclear leucocytes are lacking. Summary. The locus of the most intense reaction is a mat- ter of general agreement. The brain-stem bears the brunt of the attack in almost every case. That the gray matter in gen- Fig. 19. Basal ganglia. Medium-sized vein showing thrombosis and calcareous degeneration of its walls. (Zeiss 16 mm. obj. Comp. ocular No. 4.) From a case dying four months following the acute attack. The patient was a young woman, and it is unlikely that the lesions in the vessels which were widespread should be attributed to other cause than the preceding encepha- litis. (Buzzard and Greenfield, Brain, 19 19, xlii, p. 330.) eral is the seat of greatest inflammation is certain, but that the cranial nerve nuclei are especially affected has not been apparent in all cases. The inflammatory process is not by any means limited to the gray matter, either of the brain or spinal cord. There is agreement that the pathologic process concerns primarily mesodermal structures, that infiltration of the i 7 o ACUTE EPIDEMIC ENCEPHALITIS smaller vessel walls and their true perivascular spaces by lymphocytes, plasma cells and large mononuclear cells is constant; that diffuse infiltration of the gray matter chiefly, but also of the white, is usually present. Also constant, but less striking, are changes in the ectodermal tissues, degenera- tive changes in the parenchymatous elements, with associ- ated proliferation of neuroglia cells. The changes observed in nerve cells and neuroglia, while most intense in areas of infiltration, may also be seen apart from any inflammatory foci. There is agreement also that the blood-vessels, while universally engorged, remain relatively intact (until very late in the disease), as evidenced by almost total absence of large or frequent hemorrhages, thromboses and microscopic evidence of degenerative or proliferative processes in their walls. The meningeal reaction is also constantly minimal in degree. Microscopical Changes in Nerve Roots, Cranial Nerves and Dorsal Root Ganglia. Examination of the cranial nerve roots has been carried out especially by Burrows. In each of three cases (two of them typically lethargic and one poly- neuritic) he found lesions in several of the cranial nerves, the 2nd, 4th, 5th, 6th, 7th, 8th being affected. The lesion is described as a perivascular lymphocytic infiltration and an interstitial infiltration of the nerve fibers by lymphocytes. Perivascular infiltration of the optic nerve was observed by Mills and Wilson and of the 12th nerve by the writer. There is almost nothing written on the subject of spinal nerve roots and root ganglia, an omission of importance in view of the fact that in poliomyelitis the ganglia so fre- quently show marked changes. Microscopical Changes in Cases oj Long Duration. A case of four months' duration reported by Buzzard and Green- field showed marked change in the pathological picture. The vessels had irregularly thickened walls, frequently with calcareous plaques. The lumen was often closed by fibrous or fibrinous occlusions. This was true of the vessels of the cortex and meninges as well as of those of the brain-stem. MORBID ANATOMY 171 Neuroglial proliferation was marked. Perivascular cell infil- tration was likewise present and the nerve cells showed a minimal amount of damage. Von Economo has published the report of a patient dying a year and nine months after the onset of the illness. In this case the vessels showed thickened walls and thrombi, and the neuroglial proliferation was marked. Pathology in Relation to Clinical Types of the Dis- ease. With the original conception based upon the first de- scribed cases of von Economo and Netter, lethargic encephali- tis must necessarily be accompanied by lethargy, oculomotor palsy and perhaps other cranial nerve affection, and a patho- logic picture was presented which was considered , pathog- nomonic. It was not long before cases with very different clinical picture presented themselves — epileptiform, chorei- form, hemiplegic, polyneuritic forms. One would a priori think that entirely different pathological lesions, both as to type and as to distribution, would be required to account for such diverse and contrasting clinical pictures. On the contrary, examinations of the records of published cases, including most if not all of the clinical types of epidemic encephalitis, fail to show great variation in pathology. Certain irregularities as to distribution do occur, but it appears that the same pathological lesions varying some- what in proportion are constant findings. So that whatever the clinical type, the pathological picture described in the first section of this paper is pretty certain to be found with modifications only as to intensity and locality of the different types of lesions. Certain of the clinical findings and clinical types of the disease are readily explained on the basis of the pathological changes noted. The cranial nerve palsies occurring in the common forms of the disease are readily explained by the marked infiltration in the nuclei, with or without destruction of nerve cells; in some cases a second possible explanation for the palsy has been shown in the infiltration of the nerves 172 ACUTE EPIDEMIC ENCEPHALITIS themselves. In the hemiplegic and apoplectic forms, conflu- ent petechial hemorrhages, either in the subcortex (Buzzard and Greenfield, 2 cases; Boyd, 1 case), or in the peduncle (Wilson) have adequately accounted for the symptoms. Cases with excessive meningeal symptoms have been shown to reveal profound congestion, frequently with considerable pial hemorrhage, and at times excessive mononuclear cell infiltration of the pia (Da Fano, Neal, Schwartz). The an- terior poliomyelitic forms have been adequately explained by appropriately placed inflammatory reactions in the spinal cord (Calhoun). While necropsies on psychotic, choreopsychotic, delirious, catatonic, myoclonic and paralysis agitans types have been recorded, and some of the reports are carefully prepared, there is not enough distinctive in them to warrant drawing conclusions as to the explanation of the peculiar symptoms. In fact, any of these reports might pass as descriptive of a typical lethargic case. Most reports have evidently been com- piled with no especial reference to a pathological explanation of clinical syndromes. But even when this has been attempted no distinctive differences appear to have been encountered. For example, Bassoe, commenting on the pathology of two personal cases of the delirious type, says: "It will be noted that essentially the changes are the same as in the ordinary lethargic form." The following questions submitted to Dr. Ayer before the Commission, together with the answers to them, are here reported verbatim. Dr. Sachs: May I question Dr. Ayer especially with reference to one statement which he made, which I think was a striking one? I think we ought to ask whether any gentleman here has had autopsy findings in these cases and whether we are actually going to accept it as a fact that in this disease the cortex is the part least involved. Dr. Ayer: That has been universally so. I have not seen a single case where the cortex was said to be involved as much MORBID ANATOMY 173 as any other part, and it is always involved very much less; in many cases the cortex is negative. I would like to qualify that remark a little. The cases are not always differentiated patholog- ically, but all types have fallen under the pathological hammer. One would expect to get more cortical changes relatively, but this has not been the case. With all the types that may have died from bulbar lesions taken into account, they all look about the same and there is little to choose in them. Dr. Sachs : The important inference would be that the Iethargy has nothing to do with the cortex. Dr. Ayer: That is one problem that might be called physio- logical pathology, perhaps. We do not know much about it. There is this tremendous engorgement of the vessels, and many of the symptoms, such as delirium, may be due to pure engorgement of the vessels. That is a thing we have no means of checking up. And so this fluid state — the cerebrospinal fluid and the blood — may play a large part which when we look at it pathologically, we cannot judge. All we can say is that in every case the one thing that stands out is the engorgement of all vessels especially at the base of the brain. Dr. Tilney: Is it not also true that the investigation of the cortex has been thoroughly inadequate and will not justify any comparative statement at the present time? Merely pieces of cortex have been taken here and there, and we can not guarantee any statement as to the relative cortical involvement. Dr. Ayer: As a rule one or two pieces are examined, and then the cortex is put down as negative. Very few articles have really as yet adequately covered the whole brain. Dr. Prince: Has serous infusion in ventricles ever been found? Dr. Ayer: The ventricles almost always have been normal in size and have been found to contain the normal amount of fluid. Detailed Pathological Report of the Brains of Five Cases and the Spinal Cord from Two of These Cases (William G. Spiller). Changes in the Cerebral Cortex. The pathological changes in the paracentral lobules were slight in all five cases; there was slight infiltration of the pia with mononuclear cells, and some of the Betz cells showed distinct chromatolysis, but in most of the cases these cells could hardly be considered abnormal, especially as the 174 ACUTE EPIDEMIC ENCEPHALITIS necropsies were not done very soon after death and formalin hardening was employed. There was little infiltration of the cortex with mononuclear cells. Neuronophagia was distinct. On the whole the changes might be regarded as relatively insignificant. The findings in other parts of the cerebral cortex were similar. Changes in the Basal Ganglia. The basal ganglia were examined in their lower portion. Much infiltration with mononuclear cells of lymphocytic type and plasma cells was found in all five cases, and the collections of cells were greater in some places than in others. In two cases the infiltration was less than in the other three, and one of these two was a case of the myoclonic type. The condition was like that in the cerebral peduncles but was less intense. In one case the ependymal cells showed an extraordinary appear- ance in one place; they were proliferated and massed one upon another. The infiltration in the case of the myoclonic type was diffuse and not nearly so intense as in some other cases. Changes in the Cerebral Peduncles. In four cases the lesions in the cerebral peduncles were intense, but they were slight in this region in the case of the myoclonic type. The intense infiltration of lymphocytes and plasma cells was not only about the vessels but in the tissue where no vessels could be seen, also in the pia between the crura and especially about the pial vessels, but not in the crura. These escaped almost entirely although the infiltration in the tegmentum came close to the crura. This explains the absence of paralysis of the limbs. The nerve cells near the aqueduct including those of the oculomotor nucleus on each side showed considerable chromatolysis, but little displacement of their nuclei. The cellular infiltration was by no means confined to the area about the aqueduct. Small hemorrhages occurred but were not intense. In one case a small area, oval and sharply defined from the surrounding tissue, of a light brown color by the Weigert hematoxylin stain, was found just above the innermost part MORBID ANATOMY 175 of the substantia nigra. In a nuclear stain this area was seen to consist of loose glial tissue from which the nerve fibers had disappeared, leaving small holes. This area contained many large cells with large nuclei, probably they were the corps granuleux (fatty granular cells). This area represented the late stage of a focus of inflammation and resembled by its appearance and sharp delimitation in a striking degree one of the sclerotic patches by the Weigert stain in a case of multiple sclerosis. Only one such sclerotic patch was found and in only one case, but its discovery suggested the possibility of multiple sclerosis developing after epidemic encephalitis. It seems remarkable that only in the case of the myoclonic type little cellular infiltration was found in the cerebral peduncles. It is believed that this condition will be deter- mined in all cases of the myoclonic type. There was some lymphocytic infiltration near the aqueduct but the intense perivascular infiltration of the other cases was absent. The cerebral peduncles were affected in a case of the myo- clonic type studied by Winkelman. Changes in the Pons, Medulla and Cerebellum. The findings in the pons and medulla were similar to those in the cerebral peduncles, and it is noteworthy that they were intense in this region in the case of the myoclonic type, as well as in the others, and much more severe here in the myo- clonic case than in the cerebral peduncles. The infiltration was especially intense near the floor of the fourth ventricle, and this probably explains the sudden death with bulbar symptoms so common in this disease, which also occurred in the case of the myoclonic type. The pyramids and pia were little affected. Very little alteration was found in the cerebellum. Changes in the Spinal Cord. The spinal cord was obtained in two cases only, and unfortunately not in the case of the myoclonic type. In one of the two cases the cervical region was missing. Moderate infiltration of lymphocytes and plasma cells was found in the pia and about the vessels of the 176 ACUTE EPIDEMIC ENCEPHALITIS cord substance, and also at some places within the cord without apparent association with a vessel. The nerve cells of the anterior horns did not show any pronounced altera- tion. In one case there was an extraordinary number of corpora amylacea in the thoracic region, and the patient was not advanced in years. The noteworthy finding in this study was the slight involvement of the cerebral peduncles in the case of the myoclonic type when the medulla oblongata showed severe cellular infiltration and the basal ganglia also, though less severe than the medulla oblongata. Sudden death occurred in this case. Also the area of degeneration in one case resem- bling that of multiple sclerosis; the peculiar heaping up of ependymal cells in one case; the escape of the pyramidal tract in all the cases, and the slight implication of the cerebral cortex. In no case were there found extensive hem- orrhages such as have been seen in other forms of inflamma- tion of the central nervous system. The following questions submitted to Dr. Spiller before the Commission, together with the answers to them, are here reported verbatim. Dr. Tilney: In selecting the paracentral lobules, was there any special reason for confining the examination of the cortex to that part of the brain? Dr. Spiller: No, only that the paracentral lobules are the most satisfactory for routine study and I have always taken them for that purpose. They contain the largest nerve cells of the human body, are the easiest to study, and give us more conclusive evidence as to what the findings may be. Dr. Tilney: Did the medullary substance show any changes? Dr. Spiller: No; not anything very significant; the findings were rather insignificant. I do not know any reason why I should not say that it was Dr. Copeland who took a piece of this brain, could not find anything that was very striking, and thought it was not a case of epidemic encephalitis. He told me, and other well known pathologists told me, in another case they found in the kidneys quite sufficient to explain the symptoms, but the lesions MORBID ANATOMY 177 in those two cases in the basal part of the brain were as typical as anyone could wish to see. Dr. Tilney: Nearly everyone has made some statement in reference to chromatolysis. The degree of chromatolysis seems to be a point of debate. Dr. Spiller: I think chromatolysis is debatable under all circumstances. When the matter of chromatolysis first came out in the literature of twenty-five or thirty years ago, I remember working in a laboratory and being shown changes in the nerve cells which were gotten in nicotine and strychnine and various forms of intoxication. When you consider the methods of harden- ing — these were not done immediately after death — one must be extremely cautious in accepting any judgment in regard to these final cell changes. Chromatolysis occurs so very readily. I do not think it is a post-mortem change, but one must not attribute too much to chromatolysis. I did not find in any of these the blowing up of the cells or the marked eccentric position of the nucleus— none of those changes which are so very striking and of so great pathological importance. Dr. Tilney: With relation to the hemorrhages described, were they entirely extravascular, perivascular or in the Virchow-Robin spaces? Dr. Spiller: They were around the vessels and in the vessel walls. They were never very numerous or intense in the sections I had an opportunity of studying, and did not get out into the tissue very much. Dr. Tilney: Did the sclerotic patch described in the cerebral peduncle have many features in common with patches of multiple sclerosis? Dr. Spiller: It looked exceedingly like multiple sclerosis, and when I examined it with an acid stain which characterized these patches so clearly in multiple sclerosis, I could not have told. Even under a nuclear stain it had the appearance of a sclerotic patch. But we cannot conclude that such a patch is going to proliferate or is going to produce further symptoms. I look upon it as a scar and I would not, therefore, attribute too much to it. If such a patch or such patches are found in other cases, they will have very great significance. There is a possibility that following epidemic encephalitis these patches from areas where there has been intense infiltration may become numerous, and 12 178 ACUTE EPIDEMIC ENCEPHALITIS possibly even the neuroglia may proliferate and we may have, though I have not seen any such cases nor heard of them, a typi- cal picture of disseminated sclerosis resulting from lethargic encephalitis. Dr. Tilney: Is it your opinion that there is any possible relation of epidemic encephalitis to multiple sclerosis? Dr. Spiller: I do not know of any relation between them. The subject of multiple sclerosis is now undergoing somewhat of a change in regard to our opinions of it. In the past few years I have reported a case where there was certainly a proliferation of the neuroglia, and I could not believe in a view formerly held that it was merely the replacement of destroyed tissue. It was certainly an active process going on. I could see where these new neuroglia cells like an advancing army were going into the more nearly normal tissue of the brain. In the spinal cord the lesions were more advanced and there was nothing of that. No human being, I venture to say. could have seen in the spinal cord anything differing from any ordinary case of multiple sclerosis; but in the brain it was certainly the neuroglia in the active state. I see no direct connection whatever between multiple sclerosis and epidemic encephalitis. Dr. Hunt: Are there any lesions in the nerve roots to explain the radicular types ol the disease? Dr. Spiller: In regard to the involvement of the root, how can the cervical nerves escape if all about them is infiltrated with cells? They are involved more or less, but I have not had enough cases to study in which the spinal cord was affected. I have not seen sufficient indications in the spinal cord roots to justify any conclusions of decided infiltration of the roots of the spinal cord. Dr. Sachs: It is conceded that there are no large hemorrhages in these cases, but I would like to ask Dr. Spiller whether he would recognize a distinct difference between these cases — this process and the process we formerly acknowledged to be the pro- cess of acute hemorrhagic and acute encephalitis? Dr. Spiller: No, because I think these cases are sometimes spoken of as acute hemorrhagic and acute encephalitic. I reported a number of years ago a case of myoclonic type of poliomyelitis where the hemorrhages in the anterior horns were very numerous, that I should regard as a type of hemorrhagic infiltration, but in these *cases_the hemorrhages had to be hunted for in order to MORBID ANATOMY 179 be found. They did not strike the eye on first looking at the sections. They were small collections of red blood corpuscles. Dr. Taylor : Admitting neuronophagia, is there any fundamental difference then except in degree between this lesion and the lesion of poliomyelitis? Dr. Spiller: A most interesting subject. I really would be in great doubt if I had a section presented to me. I think some- times clinically we are in great doubt. I had a patient who came from, the coast of Maine at the time there was an outbreak, and I thought it was a case of lethargic encephalitis; later I began to believe it was poliomyelitis of the basic gangliar type. I believe you do not get in the spinal cord the changes in encephalitis that you get in poliomyelitis, and you have a point of distinction. But if you take a section of what you suspect to be a basilar form of poliomyelitis, I do not see how under the microscope you could say positively it was a case of lethargic encephalitis and not poliomyelitis. I myself would not, I am sure. Dr. Patrick: You say that in the case of acute bulbar paralysis you could not tell it in looking at the section. Could you distinguish it from poliomyelitis? Dr. Spiller: You would expect to find changes in the spinal cord which are characteristic in the acute cases. In looking merely at the bulbar part, I should not be able to tell it, I am afraid. Dr. Taylor: Does it not bring us back to the original idea that encephalitis and poliomyelitis are presumably due to the same cause and are essentially the same lesion with different localizations? It seems we are going back to the original idea. In other words, are we not making again unnecessary distinctions between these lesions which may be essentially the same, simply differing in localization rather than in kind? Dr. Spiller: There is a great deal in that idea, and yet from investigations of Dr. Strauss and his co-workers there are going to be other means of establishing that the two diseases are not necessarily the same thing simply because the lesions resemble one another. Histologically, they are certainly very close. Dr. Prince: In rapid cases what is the common cause of death? Dr. Spiller: In one case a man came to me who had the myo- clonic twitchings and jerkings. I thought he was in no particular danger and was probably going to get well. I was startled to hear when I went to the office the next morning that he had died at 180 ACUTE EPIDEMIC ENCEPHALITIS five o'clock. I found that his medulla oblongata was the seat of intense infection, and I am inclined to think these sudden deaths are due to the involvement of the medulla oblongata. Dr. Prince: What is the common cause in general though in rapid cases? Dr. Spiller: I should attribute these sudden deaths almost invariably to the oblongata. It is hard to answer that otherwise. The complication is there. In a number of these cases there are serious kidney troubles, and I do not know if it is not from the kidneys. I should not be able to answer that. Dr. Ladd: Did you note any difference between the pathology of the venules and arterioles? Dr. Spiller: That is a point emphasized a great deal by foreign writers. It has been generally acknowledged that the veins are more involved than the arterioles. It is not always easy in a small arteriole to say positively whether it is a vein or arteriole. I have had dfficulty in determining that. Changes in the Endocrine System (Hubert S. Howe). Histological examination of the glands of internal secretion in epidemic encephalitis was undertaken to ascertain if any alterations were to be found, and if so whether they had any bearing on the course or manifestations of the disease. The material consists of four cases that were under observation prior to death. The autopsies were made shortly after death. The material was fixed in Zencker's solution and the blocks imbedded in paraffin. Sections were stained with hematoxy- lin and eosin. Histological examination was made of the thyroid gland, adrenals, the pituitary body, gonads and pancreas. THE THYROID GLAND Case I. The alveoli were of all sizes and filled with colloid. The lining epithelium was cuboidal. There was very little inter- stitial tissue and in places this appeared hyalinized or even colloid- like. In the interstitial tissue were a few localized collections of small cells with dense pyknotic nuclei. The vessels were greatly congested. MORBID ANATOMY 181 Case II. The thyroid was small, soft and symmetrical, and grossly normal. Microscopical examination showed the vesicles of average and about uniform size, filled with pinkish staining colloid. The cells were cuboidal and for the most part lined the acini in single rows. The blood-vessels were not congested. Case III. The thyroid was of normal size, and on section showed normal colloid material. Microscopically, the vesicles appeared of average size, filled with a pink-staining homogenous colloid and lined by a single layer of cubical cells. There was no increase in the interstitial tissue and but moderate congestion of the blood- vessels. Case IV. The thyroid was of normal size. On section there was a slight decrease in the average colloid content. Microscopically, the acini were small and for the greater part lined with a single layer of epithelium. The interstitial tissue was increased and contained areas of hyalinization. THE ADRENALS Case I. The capsule was of average thickness. The cells of the cortex were well preserved and normal; the medulla showed moderate congestion. Case II. The adrenals were equal, small and flat. They con- tained considerable fat in the cortex with a broad inner zone and a small amount of white medulla. Microscopical examination showed the cortex to contain much lipoid. At the junction of cortex and medulla were several large collections of round cells. In the reticular cortical zone was considerable Iipochrome pigment. The medulla was broad, taking the chromaffin stain. Case III. The adrenals presented a yellow cortex and a deeply stained pigmented inner zone. Microscopically, the glomerular zone was poor in fat, while the glomeruli of the vesicular zone were evacuolated. The whole gland was markedly congested. Case IV. The adrenals, though grossly normal, microscopically showed thickening of the capsule and hyalinization. In the medulla the blood vessels were congested. THE PITUITARY BODY Case I. Pars Anterior. The reticular arrangement was not very apparent as the cells were large and entirely filled the acini. 1 82 ACUTE EPIDEMIC ENCEPHALITIS The blood sinuses were dilated and congested throughout the entire lobe except for one area. The cells were predominantly basophilic. Those around the periphery were more intensely so, but even in the center they were more numerous than other types. The cells were polygonal with well defined outlines. The cytoplasm was finely granular. A few contained one or two vacuoles, usually in apposition with the nucleus. The nuclei were generally large, irregularly spherical, with a well defined reticulum in whose meshes were numerous chromatin granules. There were usually two or three large irregular chromatin masses mainly toward the center of the nucleus, and many smaller ones principally at the periphery. In one portion the gland stood out in contrast to the surrounding tissue. While the blood sinuses were congested in other portions, here only a few small capillaries were seen. The connective tissue stroma was swollen, edematous and fragmentary. The cells were of uniform staining and faintly basophilic. They were swollen and poorly outlined with frayed and irregular margins. The cytoplasm was coarsely granular. The nuclei were frequently pyknotic or occasionally swollen with large clear spaces between the chromatin network. In some instances there had been a rupture of the nucleolar membrane and a breaking up of its substance. Here and there were masses of protoplasm without nuclei or cell outlines. This entire area had the appearance of an early stage of coagulation necrosis from deficient blood supply. Pars Intermedia. The cells were mainly faintly basophilic and arranged in form of large vesicles filled with colloid. Pars Nervosa. The neuroglial cells appeared normal. Some of the fibers contained a brownish pigment. Case II. Pars Anterior. The capsule was of normal thickness and throughout the gland the reticular arrangement of connective tissue was well marked. The blood sinuses were moderately dilated. The cells had no definite arrangement but formed irregular groups. Many were shrunken and in the center of the acini, not in apposition with their walls. The central cells were almost entirely eosinophilic, those at the periphery were basophilic. The cells were of average size with well defined outlines and a single deeply stained nucleus in the center. Scattered throughout the anterior lobe were many large eosinophilic cells with a granular cytoplasm. These, were more prevalent around the periphery where they frequently were the only cells in an individual acinous space. Throughout the medial MORBID ANATOMY 183 portion of the gland they were rarely seen. The vascular sinuses were dilated. No hemorrhages or thromboses were seen. Case III. Pars Anterior. The connective tissue stroma appeared normal. The vessels were dilated and congested. The cells were mainly basophilic at the periphery, distinctly acidophilic in the center. Neutrophilic cells were scattered throughout the section but were in the minority. The eosinophilic cells were of average size with finely granular protoplasm containing no vacuoles. The nuclei were spherical and deeply stained. They contained a chromatin network and granules but were opaque. The baso- philic cells were smaller than the oxyphilic with less clear and more irregular margins. The cytoplasm was more coarsely granular and contained occasional vacuoles. The nuclei were large and translucent with a chromatin network and granules. Two small vessels were thrombosed with what appeared to be platelet thromboi. Many cells around these vessels were necrotic. In some areas there was an accumulation of loosely granular cytoplasm with no nuclei or remnants, in others the nuclei remained while the cytoplasm was disintegrated. Some nuclei appeared normal, others were fragmented and degenerated. The pars intermedia contained many spaces filled with faintly basophilic colloid. The pars posterior was normal. Case IV. Pars anterior showed marked congestion. Micro- scopically the reticular stroma was normal. The vascular spaces were dilated and many contained a homogeneous hyaline material. The cell staining reaction was mainly basophilic, but the central cells were mostly neutrophilic with a few scattered oxyphilic. Most of the basophilic cells were large and deeply stained. The cytoplasm was finely granular and rarely contained vacuoles. The margins were ill-defined. The nuclei were large, irregularly spherical or oval, occasionally sausage-shaped or triangular. They contained a well marked chromatin network supporting dense granules. No thromboses or necrotic areas were seen. The juxtoneural epithelium and posterior lobe were missing. THE GONADS Case I. The testicles were normal. Case II. Testicles. The left was soft and congested. The right, also soft and somewhat smaller than the left, was slightly adherent 1 84 ACUTE EPIDEMIC ENCEPHALITIS around the epididymis to the parietal layer of the tunica vaginalis. Microscopically there was no spermatogenesis and practically all of the elements were absent, only the sustentacular cells and debris remaining in most of the tubules. The basement membranes were normal. The interstitial cells contained considerable brown pigment. Case III. The testicles were apparently normal in the gross. On histological examination spermatogenesis appeared imperfect. Many pyknotic nuclear fragments were seen, with well preserved mitoses and apparently normal spermatis and spermatozoa. Case IV. The ovaries showed some old and some more recent corpora Iutea. Microscopically, there were a few semi-replaced corpora Iutea. Otherwise the entire ovary had been replaced with fibrous tissue. THE PANCREAS Case I. The pancreas was congested but otherwise grossly normal. Microscopically it was normal except for a few large circular open spaces which may have contained fat. Some had a thin hyaline membrane lining. Case II. The pancreas was grossly and microscopically normal. Case III. The pancreas was reddish, with marked congestion of the blood-vessels. The glandular tissue had a glossy, digested appearance. On microscopical examination the acini were decreased in size; the cytoplasm of the cells appeared vacuolated. Only a few of the islands of Langerhans were evident, many being replaced by fibrous tissue. There was increase of interstitial tissue replacing many glands and giving the tissue a fibrous appearance. In areas this connective tissue appeared necrotic. The blood vessels were sclerotic and many were obliterated. Among the clinical manifestations of the disease which might be interpreted as endocrine disturbances are profuse sweating, weakness, low blood pressure, menstrual disturbances, impotence and metabolic disorders resulting in increase of weight. It seems probable that further study will show these disturbances as dependent primarily on lesions in the nervous system, or the direct effect of disease toxins on the individual secretory organs causing altered functions without distinct histological changes. MORBID ANATOMY 185 SUMMARY CONCERNING ENDOCRINE GLANDS With the exception of the anterior lobe of the pituitary, there were no definite pathological alterations in the glands of internal secretion. In the pars anterior of the pituitary two kinds of altera- tions were observed — a predominance of basophilic cells and areas of focal necrosis and capillary thromboses. The normal histological variations in the anterior lobe of the pituitary are marked and the significance of the prepon- derance of the various types of cells is little understood. It seems unlikely that there could be sufficient interference of function in the pituitary body to cause the lethargy of epidemic encephalitis. The focal necroses and capillary thrombi are somewhat similar to the condition found in the liver in typhoid fever and in some cases of sepsis. Here, as in the liver, the collateral circulation is so extensive that it is difficult to believe that capillary thrombi could impair the circulation sufficiently to induce necrosis. It seems more probable that both changes result from the circulating toxins. These necroses were not prominent in the specimens studied and it is doubtful if they were sufficient to cause much alter- ation in the function of the gland. So that, while the altera- tions described in the pituitary are definite, there is at present no evidence that they are important or influence the course or manifestations of the disease. To reach definite conclusions concerning the changes in the internal secretory organs in epidemic encephalitis, many more cases must be studied. The following questions submitted to Dr. Howe before the Commission, together with the answers to them, are here reported verbatim. Dr. Tilney: Were the pineal or chorioidal glands examined in any of the four cases? Dr. Howe: No, only those I mentioned. Dr. Tilney: Did the appearance of the medulla of the adrenal suggest any marked departure from the normal? 1 86 ACUTE EPIDEMIC ENCEPHALITIS Dr. Howe: No, the medulla of the adrenal appeared normal. In one case there was an increase in the lymphoid tissue between the medulla and the cortex, but that is normal and we paid no especial attention to it. Dr. Tilney: In the pituitary body, did you find any dispro- portion in the basophilic and the acidophilic cells? Dr. Howe: That, of course, is a difficult point to answer. I have never seen two pituitaries that looked exactly alike in any condition, and while as a rule the oxyphilic cells predominate and the basophilic cells are largely at the outside, in these cases all of them I examined seemed to be in a greater proportion than is usually seen. I do not know that you could say it was abnormal, but I think you would term it unusual in appearance. Dr. Tilney: Sometimes in inflammatory conditions of the pit- uitary, there is an invasion of the posterior lobe by aciniform collections of basophilic cells. Did you find anything of this kind in the pars infundibularis? Dr. Howe: No; that appearance was not found in any of the four cases. Dr. Tilney: Concerning the residual lumen, did that contain any increase or decrease of colloid substance? Dr. Howe: All of these cases were adults. I think the youngest was thirty-eight and the oldest fifty-three. I think one was fifty and another fifty-one, and there was considerable colloid, but I think not more than is usual in patients of this age. Dr. Tilney: Do you consider the thrombosis of the pituitary vessels to be specific of this disease? Dr. Howe : I do not believe we know enough about the appear- ance of the pituitary in acute infectious diseases. As a rule the glands are not saved. It is quite likely that this does occur in other acute infectious diseases. Dr. Tilney: Is it your opinion in these cases you have examined, that the thyroid, adrenals, pituitary, pancreatic and other endo- crinic elements play no very important part in the symptoms or pathological appearance of the epidemic encephalitis? Dr. Howe: I think all that you can say in answer to that point is that if there are alterations they are largely functional rather than histological, and that you cannot determine by a study of this kind, because the glands really appear quite normal except for some minor changes. MORBID ANATOMY 187 Dr. Timme: Did I understand you to say that the patient showing pituitary thrombus had lethargy as a symptom? Dr. Howe: Yes; the patient with the thrombi had a period of lethargy about three weeks before he died. Dr. Timme : Do you know the immediate cause of death? Dr. Howe: In the second case I am sure it was due to respira- tory paralysis. Dr. Taylor: You would not say there was anything specific in any of these lesions, and would call this research therefore negative? Dr. Howe: I have never seen thrombi in the anterior lobe of the pituitary in any other condition, and I have never seen it described in the literature. But I do not think we know enough about it as yet. Dr. Taylor: Has Dr. Howe seen cases with great increase in weight? Dr. Howe: Yes, I have. I remember one patient very distinctly, a young girl of fourteen who had acute encephalitis with a Parkin- sonian residuum, and her greatest weight before was 107 pounds. In six months after this period she gained so as to weigh 149. I have seen one or two others of marked increase in weight. But I have not been able to study that patient thoroughly yet, and do not know whether she presents any other pituitary signs. I know that menstruation came on during her first illness and has pro- ceeded regularly ever since. The only cases of impotence that I have seen have been in patients having the paralysis agitans type. I have seen that occur several times. Dr. Timme: Have you seen any cases in which there has been marked pigmentation to the extent of bronzing the entire body? Dr. Howe: No, I have not. Lesions Outside of the Central Nervous System (William Boyd). It would appear that encephalitis Iethargica must be regarded as a general infection with special localization in the central nervous system. It is possible, however, that in many cases such localization never takes place, and that the patient suffers merely from some mild febrile disturbance the nature of which is never recog- nized. 188 ACUTE EPIDEMIC ENCEPHALITIS Changes in the Serous Membranes. Petechial hemor- rhages in the serous membranes identical with those found in conditions of septicemia occasionally occur. In three cases in a series of sixteen autopsies widespread petechial hemor- rhages were observed scattered over the epicardium, the pleura on both sides, the peritoneum and both surfaces of the diaphragm. The condition was so striking as to suggest at once the possibility of a septicemia, but the brain findings were those characteristic of encephalitis Iethargica. In two other cases there were small hemorrhages under the endo- cardium. Microscopic Changes in the Kidneys. The kidney was examined in eight cases and in every instance showed changes which appeared to be distinctly pathological. The kidney lesions were of two main types, vascular and tubular. The vascular changes consisted in intense congestion of the capillaries. This was most marked in the straight vessels of the medulla, many of which were so distended as to produce narrowing of the lumen of the collecting tubes. In places hemorrhage had occurred from these distended vessels into the tubules. Occasionally the vascularity in the medulla was so great as to suggest the edge of an infarct. Both the glomeruli and the intertubular plexus showed a moderate degree of congestion, and a few red blood cells could be seen in the capsular space of some of the glomeruli. The above description is that of a severe example of the condition, but minor degrees of intensity were constantly present. The tubular lesions were degenerative in character, and resembled those of the nephrosis described by Volhard and Fahr, or the tubular nephritis produced by such an irritant as corrosive sublimate. The cells to suffer most were those of the convoluted tubules and the ascending limb of Henle. In every case there was a marked degree of cloudy swelling, and in a few instances the nuclei had disappeared and the cells were completely disintegrated. The contrast between the con- MORBID ANATOMY 189 voluted and the collecting tubules in the more marked cases was striking in the extreme. It must not be thought, however, that the collecting tubules escaped entirely in every instance. In several cases the lining cells were crowded with yellow granules. As these were most abundant in areas where hemorrhage had oc- curred, it is probable that they were of the nature of blood pigment. In one case the cells of the collecting tubules con- tained granules which gave a fat reaction with Scarlet R in frozen sections. The convoluted tubules in this case, although profoundly degenerated, gave no fat reaction. An additional lesion was observed in one of the cases with widespread petechial hemorrhages in the serous membranes. Most marked in the boundary zone between the cortex and the medulla although to a lesser extent elsewhere throughout the cortex, there were found collections of small round cells with a few polymorphonuclear cells. These strongly sug- gested a focal infection, and the appearance was not unlike that of a suppurative nephritis. Appearance of Homogeneous Hyaline Bodies in the Central Nervous System. A change worthy of note was the presence of numerous spherical, homogeneous hyaline bodies, resem- bling the corpora amylacea found in the prostate and other organs. These bodies were found in severe cases, in the young as well as the elderly. As a rule they were of uniform size, but occasionally showed variations in diameter. The center was darker than the periphery, but there was no definite nucleus. Concentric striations could be made out in many instances. In one case they were present in the cerebrum, basal ganglia, midbrain, pons, medulla and cord, but not in the cerebellum. Although present in both giay and white matter throughout the brain and cord, they were most numerous at the surface, around the aqueduct of Sylvius, and under the floor of the fourth ventricle. The bodies stained blue with thionin, pale blue with hematoxylin, blue-black with iodine, but not at all with van Gieson. They are probably products of degeneration, similar iqo ACUTE EPIDEMIC ENCEPHALITIS to the colloid bodies found in old age. They appear to be due to neuroglial degeneration. They are certainly not derived from ganglion cells, for they are as numerous in the white as in the gray matter. Lesions in the Brain Produced by Lead and other Poisons Contrasted with* those of Epidemic Encepha- litis (George B. Hassin). Non-suppurative inflammations of the brain generally termed encephalitis may be caused by infections or intoxications. The infectious group is mainly represented by general paralysis and epidemic encephalitis; the toxic group by intoxications such as lead or arsenic. In both these large groups of non-suppurative inflammation of the brain there are to be found parenchymatous (or better, ectodermic) and interstitial (or mesodermic) changes. Ectodermal Changes Contrasted. The ectodermic changes, that is to say, those of the neuroglia and ganglion cells, do not exhibit any specific pathologic features, being practically alike in the epidemic and the lead varieties of encephalitis. In both forms there is present an excessive number of glia nuclei, which may be somewhat increased in size and possess a visible rim of cytoplasm. However, in both large proto- plasmic glia cells, myeloclasts, myelophages as well as various types of gitter cells are absent. As to the changes in ganglion cells and nerve fibers, the former are represented by chromatolysis, neuronophagia, satellitosis, and accumula- tion of fat-like substances. In short, the parenchymatous changes are degenerative in character. Mesodermic Changes Contrasted. Of much greater signi- ficance are the mesodermic^changes to be found in the vessels and the pia-arachnoid. In epidemic encephalitis, the vessels are much infiltrated, chiefly with lymphocytes and plasma cells, the infiltration frequently transgressing the perivascu- lar spaces and invading the parenchyma itself. The latter is frequently covered with dense foci of hematogenous elements, mixed with many glia cells, totally obscuring the parenchyma. Such dense infiltrations do not occur in lead MORBID ANATOMY 191 encephalitis. Here the vascular changes are mainly repre- sented by proliferative phenomena. Thus, there^jmay, be hypertrophy of the endothelial cells of the capillaries with an abundance of intensely stained protoplasm; there may be proliferated and hypertrophied fibroblasts; there may be an abundance of new-formed capillaries in the shape of buddings or off-shoots; the vessel walls may be thickened, etc. In short, all the various stages or phases of proliferation or new formation of capillaries may be encountered in toxic encephalitis, but not in the epidemic variety. The vascular changes in the epidemic form are confined principally, though not exclusively, to the midbrain, while in the toxic variety the changes above described are almost universal. They affect every portion of the cerebrum and cerebellum including the pia-arachnoid and its spaces. The latter structures show particularly noteworthy changes. In lethargic encephalitis they consist of mild infiltration with lymphocytes and plasma cells while in lead encephalitis, especially in early stages, the cell infiltration is much more marked, in fact may be enormous, always combined with great wealth of vessels, both pre- and new- formed. The pial infiltration elements, in lead encephalitis are more numerous, the mesothelial cells, polyblasts and fibroblasts being especially conspicuous. There are also many other elements mostly ill-defined and frequently packed with pigment granules. Such conditions ultimately lead to a general hyperplastic state of the pia-arachnoid, especially on the base of the brain, in the region of the optic chiasm and around the cerebellum. The prevalence of proliferative mesodermal changes fully justifies the name "productive" encephalitis which Bonfiglio proposed for such conditions, while the infectious variety should be termed "infiltrative" encephalitis. How- ever marked and important the vascular changes in the cerebral substance, those of the pia-arachnoid and the sub- arachnoid space*are of greater significance. Special attention should be paid to these structures in pathologic studies of 192 ACUTE EPIDEMIC ENCEPHALITIS typical and atypical brain lesions, for they may reveal changes even when the brain tissue proper appears normal. The following questions submitted to Dr. Hassin before the Commission, together with the answers to them, are here reported verbatim. Dr. Taylor: Would you consider it possible that changes you describe as distinguishing the toxic encephalitis from the epidemic might be due to the time element? Would it be possible that if the encephalitic process could be studied, for example, years after, we might find proliferation of vessels? Do you think, in other words, there is a specific difference? Dr. Hassin: It is absolutely specific in the cases I studied. I had three; two were chronic cases of ten months duration, and these pictures are taken from an acute case of five weeks duration. Dr. Tilney: In your Case 3 you state that only the pro- ductive changes occur in the more chronic cases of lead encephalitis. Would you consider it necessary to take into account the possi- bility of the influence of time here? Dr. Hassin: In pial acute cases there are only proliferic changes. The "productive" type of encephalitis is typical for brain lesions caused by lead poisoning. Dr. Taylor: Were your lead poisoning sections taken from animals, experimental matter or fatal cases? Dr. Hassin: From fatal human cases. CONCLUSIONS OF THE COMMISSION Material. It is the opinion of the Commission that while much knowledge has been gained from the pathological ma- terial already obtained, the number of cases subjected to autopsy up to this time is nevertheless too small to permit of any final deductions concerning the pathology of epidemic encephalitis. Furthermore, the Commission feels that the pathological material thus far investigated has not been studied with sufficient thoroughness to permit of more than an outline or sketch of the entire pathological process of the disease at the present juncture. This is especially true of the MORBID ANATOMY 193 cerebral cortex and for that matter of the brain stem and spinal cord. Intensive studies by means of appropriate differ- ential stains upon specimens treated in serial sections will afford the most reliable basis from which to draw definitive conclusions. The investigations of lesions in parts other than the ner- vous system and particularly in the endocrine organs like- wise comprise studies upon cases much too limited in number to warrant ultimate deductions. The contrasts between the histological changes due to epidemic encephalitis and histological changes caused by other inflammatory toxogenic factors, although appearing in some instances to be well defined, are not yet sufficiently established to warrant a statement that there is a complete specificity in the pathological process of epidemic encephalitis. The total number of cases up to December, 1920, in which there have been necropsy observations is 113. For purposes of histological comparison and topographical orientation, not more than 50 of these cases are available. No single case has been examined with the completeness of technical detail or anatomical comprehensiveness entirely satisfactory from the pathological standpoint. The results of experimental pathology, although of much interest and very Suggestive, are yet too meagre to Contribute measurably to the conception of the morbid process of the disease. Gross Pathology. Upon inspection the dura mater has shown no constant lesion. The pia-arachnoid is often edema- tous but quite as often shows no pathological changes. The surface of the brain is congested, sometimes intensely so. Free blood may be seen in the sulci but massive pial hemorrhage is rare. The convolutions may be somewhat flattened. The lesions are most intense in the midbrain, pons and medulla, least in the cerebellum. The ventricles are usually normal in size and appearance and contain cerebrospinal fluid of normal appearance. The ependyma, 13 194 ACUTE EPIDEMIC ENCEPHALITIS usually smooth and glistening, is occasionally slightly rough- ened. The meninges and surface of the spinal cord in many cases resemble the cerebral meninges and surfaces. Microscopic Changes in the Central Nervous Sys- tem. Histologically the essential changes in the brain and spinal cord are: a. Cellular infiltration chiefly affecting the small veins and, to a less extent, the larger veins, arteries and capillaries. The infiltrating cells are small and large mononuclear lymphocytes and plasma cells. The infiltration is largely confined to the Virchow-Robin and perivascular spaces. It has its greatest intensity in the gray matter of the basal ganglia, midbrain, pons, medulla and spinal cord. The white matter is not entirely immune. b. Hemorrhage which is usually microscopic and confined to the perivascular spaces of His is also a prominent feature. There is an almost complete absence of thrombosis, and if hemorrhage occurs into the brain substance it is accompanied by a reaction of the surrounding glia. In some cases spherical, homogeneous, hyaline bodies resembling corpora amylacea appear in the affected areas of the central nervous system. c. Cellular Changes. The nerve cells and their fibers show relatively little evidence of degenerative change in proportion to the severity of the pathological lesion. In areas of the most intense changes the nerve cells often manifest some degree of cloudy swelling, chromatolysis, disintegration of the neurofibrils, satellitosis and neuronophagia. The neurog- lial cells show marked proliferation in areas characterized by pronounced changes in the nerve cells or in the more intensely hemorrhagic foci. Microscopic Change in the Meninges. The pia- arachnoid may be normal. Usually the pial vessels are engor- ged. The pial layers may be separated and the pial reticulum distended with numerous red corpuscles and mononuclear cells in the interstices. In the sulci intrapial extravasations frequently occur. MORBID ANATOMY 195 Microscopic Changes in the Nerve Roots and Dorsal Root Ganglia. In some cases the cranial nerves have been found to be the seat of a perivascular lymphocytic infiltra- tion and an interstitial infiltration of the nerve fibers by lymphocytes. Evidence is still lacking concerning the involve- ment of the spinal nerves, nerve roots and dorsal root ganglia. Fundamental Microscopic Changes in Acute Cases. The essential histological alteration in all acute cases almost universally appears to involve primarily the mesodermal structures with infiltration of the walls of the smaller vessels and the perivascular lymph spaces with lymphocytes, plasma and large mononuclear cells. Microscopic Changes in Cases of Long Duration. Chronic cases usually differ histologically from acute cases. After a duration of several months the vessel walls thicken and frequently contain calcareous plaques. The Iumina are frequently closed by fibrous or fibrinous occlusions. Peri- vascular infiltration is still present and neuroglial prolifera- tion is more pronounced. Microscopic Changes in the Endocrine Organs. The only alteration which may be of pathological moment in the endocrine system is the occurrence of focal necrosis, capillary thrombosis and a predominance of basophilic cells in the pars anterior of the pituitary body. This was observed in two cases only. The thyroid, adrenals, pancreas and gonads (testes and ovaries) were found normal in all the cases examined. The Commission is not disposed to attach much importance to the pathological chahges in the pituitary body and feels that altogether too few cases have yet been examined with re- ference to the histological state of the endocrine organs to make any statement regarding the pathology of these organs in epidemic encephalitis tenable. The most that may be vouchsafed is that from limited findings the evidence of pathological alteration seems almost negligible. 196 ACUTE EPIDEMIC ENCEPHALITIS Reports on the condition of the pineal and chorioidal glands are thus far not forthcoming. Lesions Outside of the Nervous System, a. The serous membranes have been found to be affected by changes resembling the conditions of septicemia. Petechial hemor- rhages have been observed in the epicardium, pleura, peri- toneum and both surfaces of the diaphragm. In several cases small hemorrhages were found under the endocardium. b. The kidney was also found to present pathological changes which were vascular and tubular. The vascular changes consisted of intense capillary congestion with scattered hemorrhages. The tubular lesions were degenera- tive in character, resembling those of nephrosis described by Volhard and Fahr, i. e., the tubular nephritis produced by such an irritant as corrosive sublimate. Lesions of Epidemic Encephalitis Contrasted with Those Produced by Lead and Other Poisons. It is note- worthy that while ectodermal changes are very similar in lead encephalitis and epidemic, the mesodermal changes in these conditions are quite different. In epidemic encephalitis the vessels are much infiltrated, this infiltration frequently invading the perivascular spaces and the parenchyma. This degree infiltration does not occur in lead encephalitis, which shows mainly proliferation of the endothelial cells of the capillaries and thickening of the vessel walls. The vascular changes in epidemic encephalitis are more closely confined to the midbrain; whereas in lead encephalitis the changes are almost universal throughout the brain. Chapter VII BACTERIOLOGY AND ANIMAL EXPERIMENTA- TION; FURTHER STUDIES IN PATHOGENE- SIS, IMMUNOLOGY AND PHYSIOLOGI- CAL FUNCTIONING THE material presented in this chapter consists of reports of various contributors, namely, additional reports by Drs. Leo Loewe and Israel Strauss of the Laboratory of Mt. Sinai Hospital, New York City; of further remarks by Dr. William Thalhimer of Milwaukee; of the report of immunological distinctions of encephalitis and poliomyelitis by Dr. Harold L. Amoss of the Rockefeller Institute; of immunological studies by Drs. Marcus Neustaedter, John H. Larkin, and E. J. Banzhaf of New York; and finally of certain physiological interpretations of the function of the nervous system in respect to those diseases by Professor Frank H. Pike of the College of Physicians and Surgeons, New York City. Cultivation of the Virus (Leo Loewe). Early in the work it became evident to Loewe and Strauss that the virus of the disease resides in the nasopharynx. The filtrate of a profuse nasal discharge from a patient was injected subdur- ally into a monkey. Paralysis of both hind legs followed in seven days and cleared up in two weeks. Lumbar puncture revealed increase in cells, — up to thirty-five lymphocytes per cubic millimeter. This monkey was subsequently shown to have acquired an immunity. Further investigations were carried out along this line with human nasopharyngeal washings. It was also found experimentally that the virus is excreted through the nasopharynx. The inoculation intra- cranially into rabbits of filtrates of nasopharyngeal washings has become a method of diagnosis. As noted on the chart it 197 198 ACUTE EPIDEMIC ENCEPHALITIS is a method which has given a positive result in 16 out of 21 cases, or 77 per cent. There are cases of encephalitis which do not present the classical symptoms of the disease, and it is in such cases that rabbit inoculation has been especially valuable. The test was positive in one case of relapse. Results seem to point rather conclusively to the nasopharynx as the portal of entry of the infection. Inoculation of spinal fluids into monkeys and rabbits has demonstrated that the virus is present in the fluid especially in those cases which show an increase in cells. The inoculation of spinal fluid into rabbits for diagnosis in conjunction with the nasal washing method has been employed. Sixty rabbits were so injected with spinal fluids from 28 cases. Lesions were produced in 23 animals, thus establishing the diagnosis in 1 7 of the 28 cases, or 60 per cent. To control this work nine nasal washings and twelve spinal fluids from various neurological, medical and surgical cases, preferably surgical, to rule out the possibility of contact infection, were inoculated. The results were entirely negative. Two of the control spinal fluids were from poliomyelitis cases. Three of the nasal washings were from influenza cases. That the disease is at times a general infection is attested to by our positive inoculations with blood. In establishing a diagnosis of encephalitis in animals we have been guided by symptomatology, the pathological picture and cultural studies. The histological and cultural studies have been of most value. The lesions in experimental animals are similar both in degree and localization to the well-recognized lesions in the human cases. Throughout our extensive animal experimentation we have never met the spontaneous production of the characteristic lesions. We have resorted to the intravenous inoculation of both virus and culture in several instances in order to demonstrate a selective affinity of the virus and culture for the central nervous system. One experiment is particularly striking. In attempting to obtain a specific serumtin the sheep a number of intravenous injections with killed cultures were ANIMAL EXPERIMENTATION 199 given and then a fairly large dose of a virulent culture was injected. After a period of four weeks the sheep developed symptoms of a meningoencephalitis, to which it succumbed in eight days. Spinal puncture showed eighty-five Iympho- ***** ^ : Fig. 20. Human brain. Focal infiltrations with mononuclear cells in the puta- men (lenticular nucleus). cytes per cubic millimeter. An intense encephalitis was present. The other organs showed no abnormalities. The classical picture was produced in a series of rabbits by means of intracranial and intravenous inoculation with saline emulsions and Berkefeld filtrates of this brain. The organism 200 ACUTE EPIDEMIC ENCEPHALITIS was recovered from the original sheep brain and from several of the rabbits of the series. These experiments are being prosecuted for subsequent publication. The materials, after preliminary cultivation on the usual Fig. 21. Human brain. Mononuclear cell infiltration in the Virchow-Robin and perivascular spaces of vessel in the tegmentum of the midbrain. media to rule out contaminants, were put in the tissue- ascitis fluid medium, perfected by Noguchi. Anaerobic con- ditions were assured by the use of kidney tissue, by sealing with petrolatum, and later by the addition of glucose. It should be emphasized that the secret of success in this ANIMAL EXPERIMENTATION 201 method is the use of a suitable ascitic fluid. The organism is a minute filtrable Gram-positive coccus appearing in diplo- forms, chains and clumps. It stains best by prolonged con- tract with methylene blue, Giemsa or polychrome methylene Fig. 22. Monkey brain. Edema, necrosis and adventitial infiltration of ves- sel in cortex. Animal injected intracerebrally with emulsion of brain of monkey successfully inoculated with infected human brain (Loewe and Strauss). blue. Morphologically and culturally, the organism found by us resembles that found by Flexner and Noguchi in poliomyelitis. The organism has been isolated in pure culture from the following materials. 202 ACUTE EPIDEMIC ENCEPHALITIS i . Human nasopharyngeal mucous membrane removed at necropsy. The organism has been recovered in pure*culture from Berkefeld filtrate of nasopharyngeal mucous membranes from 8 fatal cases of epidemic encephalitis. Out of eleven Fig. 23. Monkey brain. Cortex showing perivascular infiltration of mono- nuclear cells. Animal same as that pictured in Fig. 22 (Loewe and Strauss). attempts, eight or, 73 per cent have been successful. The organisms have been carried as far as sixteen generations in artifical cultures without animal passage. The later strains proved pathogenic for animals. Control cultures of filtrates ANIMAL EXPERIMENTATION 203 of nasopharyngeal mucous membranes of seven patients dying of other conditions have all been sterile. 2 . Berkefeld filtrates of human nasopharyngeal washings of 23 cases, typical and atypical, were cultivated with positive roe S'-Si CO S CO • •<*> o > to toJO *--< o a < an co~C3 O "O o £ o c V rO w CO, +J ° i fl — co bD a r/i Z -q E 3 t/j < £ e J <*^» «! s ro cj o S < z ►»< . O co Hh o3 z .2 1 3 - O Oj 00 M 00 O *N <0 1 ro VN ro "~Tn K O NO t^ CI "O O IN On VN O 13 | W> O CO >-H ON O M ro CN <* 1 M HH 5 HH 1 M ^ 1 CN a CJ HH CN rq 00 hH ^ VN V\ H bC CO )- CO (U . 4-> fe 4 - > > O a H CO < JD 00 .si J HH CN 1-1 c3 oo >-< oj M tN vo 00 [\ u "+3 o3 '1 z .CO Si J !_j ,_] < 1 1 1 00 1 VN CO C ■P 1 VN r 1 CN X O d O 03 O O CO Cj d O O — — — 'co*0 ■3 ON CD c a co — — CO < CO a3 Ih +-> +-> 3 O 3 > Q s X -0 x) co -a w X) XI +-> +-> aj oj e3 t d o3 « 03 O "o O O oj O O u u ■« T3 1- CO Ih Ih cj (U CJ CJ 1) CJ CJ CJ CJ 4-> CJ • CJ >> >-j >> O >3 +-> >i >, CJ O O b , , ^3" J3 O aj g s < O Q 1 hJ CO 1 CO a eo 3 to 05 CO s .2 ~5 CO ■ — 1 ^ ^ > ^ 3 s £ UJ ANIMAL EXPERIMENTATION 21 I of Infectious Diseases, September, 1920. In connection with our animal experiments, we wish to bring out that we have not only produced typical lesions in animals with cultures derived from virus of various kinds, but we have also been V / v • at Fig. 31. — Rabbit brain. Section of midbrain inoculated intravenously with organism (Loewe and Strauss). able in many instances to recover the organism from the brains of animals so injected and also to produce lesions in animals injected in the same manner with control cultures. Immunological studies are now in progress. These include complement fixation studies with both bacterial and virus 212 ACUTE EPIDEMIC ENCEPHALITIS antigens, and neutralization experiments. Neutralization of both virus and culture by means of convalescent serum from cases of epidemic encephalitis has been successful. Both natural and acquired immunity in animals were demon- - * . / V. * . >•* • ■ > " ■* - *• *** 'S^.*\ v-*v . » . « -:% •> '/ - ,* *T* vv j • ■ • ,• ***** * m, '-Mr ♦*!.* »««. % ^** . rf «* % 4, »*M **■ »«&* •!!*>* Fig. 32. — Rabbit. Section of spinal cord inoculated intravenously with or- ganism. Same animal as that pictured in Fig. 31 (Loewe and Strauss). strated. A peculiar phenomenon is chain formation when organisms are grown in convalescent serum, analogous to the so-called Pfaundler phenomenon with typhoid bacilli. From the experimental work outlined above we wish to state that epidemic encephalitis is due to a living specific ANIMAL EXPERIMENTATION 213 infectious agent, different from that of poliomyelitis. This stand recently has been indorsed by both Levaditi and Harvier, and Mcintosh and TurnbuII. Fig. 33. — Monkey brain. Section of midbrain inoculated intracranially with organism (Loewe and Strauss). Bibliography 1. Strauss, Hirshfeld and Loewe. N. York M. J., 19 19, cix, 772. 2. Loewe, Hirshfeld and Strauss. J. Inject. Dis., 1919, xxv, 378. 3. Loewe and Strauss. J. Am. M. Assn., 1919, Ixxiii, 1056. 4. Loewe and Strauss. J. Am. M. Assn., 1920, Ixxiv, 1373- 5. Loewe and Strauss. Proc. New York Path. Soc., 1920, xx, No. 1-5, 18. 2i 4 ACUTE EPIDEMIC ENCEPHALITIS 6. Loewe and Strauss. J. Inject. Dis., 1920, xxvii, No. 3, 250. 7. Levaditi and Harvier. Compt. rend. Soc. de biol., Par., 1920, Ixxxiii, 354; also 1920, Ixxxiii, 385; Soc. med. des hop. de Paris, 1920, 179 and 583; also xliv, 876-880. 8. McIntosh and Turnbull. Brit. J. Exper. Path., 1920, i, 2; also 1920, i, No. 5, 257. 9. Ottolenghi, D'Antona and Tonietti. Policlin., Roma, 1920, xxvii, No. 39, 1075. Cultivation of the Virus (Israel Strauss). The criticism has been made that experimental inoculations with foreign material have produced lesions in rabbits. The foreign material which we have used, as shown in Dr. Loewe's paper, has consisted largely in filtrates; at times in emulsions and at other times in cultures. This is not foreign material in the sense in which pathologists use the term. The amount used is very small. The filtrates are nothing but filtrates of saline solution. The emulsion, of course, is a foreign substance inoculated into an animal, but you will note that in many instances we used controls — that is, we inocu- lated emulsions from the brains of individuals dying from other diseases, and never once in our experience did we find any lesion in these rabbits. We have also inoculated the spinal fluids of cases suffering from diseases other than epidemic encephalitis, and again never once in all the rabbits we have used have we ever found any lesion. We have also used the nasal mucous membranes — filtrates of people suffering from diseases other than encephalitis, and again never found a lesion. The rabbit has been found to have diseases, especially diseases of the vessels similar to arteriosclerosis, which has negatived the work done in the production of arteriosclerosis in rabbits, but I know of no other lesion of any importance that has been found by experimental workers in rabbits, especially when using careful methods, which is like that produced by our inoculations. When we presented this paper before the Society of Pathologists of New York City, not a single individual among ANIMAL EXPERIMENTATION 215 W*^f\,W^^^ Fig. 34. Rabbit brain. Cortex of cerebrum showing focal infiltration with round cells in proximity to vessel showing mononuclear cell infiltration of the adventitia. Rabbit injected with same inoculum as animal pictured in Figs. 29 and 30. 2i6 ACUTE EPIDEMIC ENCEPHALITIS the highly trained technical men present made any objection on this basis. In his discussion of our paper before the Academy of Medicine in May, Dr. Flexner who had failed to reproduce the disease in monkeys or rabbits described some inoculations made with a view of determining whether a lesion similar to encephalitis could be produced in a rabbit by using other organisms. He succeeded in producing a perivascular infiltration, by the use of an attenuated strepto- coccus viridans, but he admitted at that time that the lesions produced by us could not have been produced by a streptococcus viridans because we were competent enough in our bacteriological methods to have isolated a strepto- coccus viridans had such an organism been present in any of our fluids. Levaditi and Harvier have produced in rabbits the typical lesions of encephalitis Iethargica by inoculating rabbits with emulsions from the human brain. They have found that they could inoculate a monkey with the "virus fixe" obtained from the rabbit inoculations. They also succeeded in pro- ducing the disease in guinea-pigs, and what is of great importance when you consider this question of foreign material, they had produced the disease in rabbits by inoculating a rabbit in the sciatic nerve with the virus fixe and also by intraocular inoculation. They have confirmed our work in transmitting the virus from the nasal pharyngeal mucous membrane of human beings into rabbits, and they found out, as we had found out, that not only was the nasal mucous membrane infective for rabbits but the virus could be recovered in the nasal mucous membrane of rabbits that had been infected intracranially; in other words, that this was both the method of ingress and also of egress. They had also preserved the virus in the testicle of a rabbit for a number of days and they found, interestingly enough, that the retina of animals was also infectious. Their conclusions were that this was a filtrable virus to be preserved in glycerine and was effective for both rabbits and monkeys, and can be rendered a virus fixe by repeated ANIMAL EXPERIMENTATION 217 +-> £,' 218 ACUTE EPIDEMIC ENCEPHALITIS inoculations. In a personal comment by Levaditi he stated that his cultural work had not been extensive enough to give any results, and furthermore that he was having trouble with the serum which he was using. It may interest you to know that he sent us his virus and that we have cultivated the organism out of his virus and have it now in the fourth generation. In England, Mackintosh and TurnbuII have succeeded in producing the disease in a monkey by intracranial inocu- lations of the emulsion of the human brain, and also, again of importance regarding this criticism regarding the use of foreign material, by inoculation of a monkey intraperiton- eally. In both cases their monkeys came down with lesions which Mcintosh and TurnbuII describe as characteristic pathologically. Lastly, Mcintosh alone has recently published an article in which he states that he has produced the disease in a series of rabbits and also a monkey, and, interestingly enough, also describes the characteristic lesion in a monkey which developed a spontaneous infection. The monkey having been in contact with the monkey which he had inoculated, came down at a period of incubation comparable to the period of incubation of the monkey inoculated. There is as yet no confirmation of our work on the organ- ism. We are dealing here with a new field of bacteriology, the field of filtrable organisms. Some years ago Foster isolated a filtrable organism from cases of common colds, and in Foster's article there is a footnote which is of a great deal of significance. He states that he attempted to do this work after reading Noguchi's description of his method, but he found he was unable to isolate the organism. He went to the Rockefeller Institute, and he states that in order to do work of this kind one has to study under the master himself, because the work is so difficult technically and is open to so many pitfalls that it is only by personal instruction, he thought, that one can acquire the method. His work so far as I know has not been confirmed. ANIMAL EXPERIMENTATION 219 '*■ >%•''■' W, '»4<& iff' 'JfryV»x&fij& <& " * " '*. 220 ACUTE EPIDEMIC ENCEPHALITIS The next piece of work on filtrable viruses is that of Flexner and Noguchi, who have isolated an organism from cases of poliomyelitis. The confirmation of their work has as yet not been general. Yet we personally believe that the organism isolated by Flexner and Noguchi is the etiological agent of poliomyelitis. It is interesting to note that Bradford and Wilson in their studies of infective encephalitis during the war probably had the virus and isolated it. Then they made cultural studies which Arkwright criticised because he found that the organ- isms were not in pure culture, and they admit in the Ark- wright article that they were probably wrong in assuming that they had the organism in pure culture. We believe our- selves that they probably did have the organism; but, as Arkwright had proved, it was not in pure culture. They made this error very likely because of their unfamiliarity with the method. Our work is the latest that has been done in the study of filtrable organisms. We are indebted extremely to Noguchi for having shown us the way and the method. The finding of this organism does not in itself mean as much to us as does the fact that we feel that we have in our work placed upon record for bacteriologists and pathologists for the first time completely the fact that there is a filtrable organism as a cause of disease. The following questions, submitted to Drs. Loewe and Strauss before the Commission, together with the answers to them, are here reported verbatim. Dr. Dana: Will you be good enough to tell us or explain the reasons why Dr. Amoss and his group of workers did not get the same results as you did? Dr. Loewe: His results are practically as inexplicable to me as to the gentlemen gathered here. I can merely say that in order to straighten out this difficulty an invitation was extended to Dr. Amoss to come up and work with us. He found it difficult to do this, ANIMAL EXPERIMENTATION 221 so we attempted to compromise by having him run duplicate experiments with our materials and with our filters and by having us to run duplicate experiments with his filters and his materials. In other words, we feel that his negative results may be due to failure to obtain the same amount or the same quality of materials that we have obtained, or we feel that he may have used a certain type of filter which we have not used. I feel that is the only expla- nation, and we would welcome Dr. Amoss coming up and working with us in order to straighten out the difficulty. 1 may say that our animal experimentation numerically far exceeds his, so far as he cited it at the Academy of Medicine, and in all our inoculations we were aware of a 50 per cent immunity in rabbits, and we therefore used series of animals. We did not spare animals or spare materials. I do not think he had as many autopsies as we were fortunate to have. We had twenty-four, and as I said, we used over 600 rabbits and over 40 monkeys. Dr. Sachs : May I ask you to make some statement as to whether in your own experiments you have had any distinct failures and what the proportion of failures has been? Dr. Loewe: I believe I mentioned that with every individual material inoculated we had so many positives and the remainder were negative. That varied with the different materials. In spinal fluids our inoculations were less than with nasal washings; with the brain they were less than with nasal washings, etc., and our cultural work proportionately. Dr. Dana : I am requested to ask what the difference is between the filter used by Dr. Amoss and by yourself. Do you know? Dr. Loewe: I haven't any idea. In the beginning of the work I can merely say that we used a Berkefeld filter, but owing to the exigencies of the war, etc., we were unable to obtain the original Berkefeld filters later and we therefore used the domestic filters which we found satisfactory in a certain proportion of cases. We tested our filters carefully and discarded as much as 75 or 80 per cent of a given lot; before using a filter we were careful enough to test it out against the usual test organisms, and when they proved satisfactory to us we continued our experiments with those par- ticular filters. Dr. Taylor: In what respect do you regard your organism as related to that of poliomyelitis? In the first place do you regard it as a specific organism or possibly as a different strain of the organism which presumably is the cause of infantile paralysis? 222 ACUTE EPIDEMIC ENCEPHALITIS Dr. Loewe: We feel that the two diseases are distinct; just as there are groups of streptococci and pneumococci there are groups of organisms with different pathogenic characteristics. Culturally they are the same or practically the same, with slight differences which do not amount to much because we may find differences in cultural biological characteristics in a given organism and given strain at different times; but from our neutralization experiments we feel that the organism is specific. In other words, we have formed neutralization experiments with convalescent serum with both virus and culture, and we have protected animals by bring- ing the culture in contact with the convalescent serum for a certain length of time, injecting new animals, of course, and controlling it with injections of virus alone into the animals. Dr. Taylor: In your animals you not infrequently got lesions pathological to a certain extent and clinical signs which were analogous to infantile paralysis, didn't you? Dr. Loewe: We got paralytic conditions. Dr. Dana: Was there any other case of apparent contagion? With regard to the contagiousness of the disease, you spoke as though one animal appeared to acquire the disease through contact with another, did you not? Dr. Loewe: I believe Dr. Strauss mentioned the literature on that subject. We personally are not prepared to say that we have had any contact infections, but Mcintosh describes a distinct contact infection, an infection which can only be ascribed to con- tact. In other words, the incubation period between the original inoculation and symptoms in one monkey and the symptoms in another monkey one would only ascribe to contact infection. I may say that all our experimental animals were isolated and kept in cages apart from normal animals, and there was no possi- bility of contact infection. Dr. Neustaedter: In what percentage of cases in monkeys did you have anterior horn lesions and in what percentage purely cerebral lesions? Dr. Loewe: I cannot state the percentages. I can only recall two animals in which we got distinct lesions in the spinal cord, and even in those two animals there was no destruction of the anterior horn cells. As I say we are carrying on a minute comparative study of these animals which we are prepared to publish at some ANIMAL EXPERIMENTATION 223 subsequent date, but I feel sure we will not find the lesions of poliomyelitis in our experimental animals. Incidentally, I do not believe anybody has been able to produce the lesions of poliomye- litis in rabbits, as we pointed out. Marks, of course, has inoculated rabbits with poliomyelitis virus and subsequently brought down monkeys with them, but he himself claims, and rightly so, that the rabbit in his case merely acted as a host for the virus. Dr. Strauss: I want to call attention to one part of the work which Dr. Loewe mentioned and which is new and extremely signifi- cant. It may have escaped the attention of the Commission. That is the intravenous inoculation of this organism and the remarkable thing that it showed a selective affinity for the brain. These animals died after an intravenous inoculation. Now regarding this contact infection which Dr. Dana has asked about, Dr. Loewe has for- gotten to mention something of which we are not exactly certain as yet. As we stated, we have kept our animals isolated with one exception. The sheep that died after intravenous inoculation was in the same pen with another sheep, and this second sheep has died, and our autopsy of this second sheep showed us nothing but a marked degeneration of the liver. The brain, however, has not been studied, so we are not yet prepared to state whether this second sheep has come down with encephalitis or not. We are anxiously awaiting the results ot the culture studies of that sheep's brain because it may be that we likewise have got a contact infec- tion. That is the only instance in which two animals were kept close beside each other. While this one was dying, the other sheep was beside it and the food was not separated. We are not yet prepared to say but what we may have an example of contact infection there. Dr. Thalhimer: It is my privilege to present to you some cultural and experimental studies of epidemic encephalitis. The main value which these results might have is that they are con- firmatory of the work which have been reported by Dr. Loewe and Dr. Strauss. From the central nervous system material from 4 fatal cases of epidemic encephalitis has been available — spinal fluids from 3 cases which I have completed the study of myself, and from a fourth spinal fluid the results of which I heard by letter yesterday. Two oi these fatal cases were of the fulminating type that died within thirty-six hours. One of the spinal fluids was from one of the fulminating cases; one was from a convalescent case of 224 ACUTE EPIDEMIC ENCEPHALITIS thejethargic type — a nurse who was sick in a hospital in Chicago. The third spinal fluid was from a lethargic soldier at the Waukesha Hospital for Soldiers near Milwaukee. Virus from the central nervous system from these 14 cases has been injected into rabbits and has produced the disease — has produced the microscopic lesions of the disease, and this virus has been carried through ten series of animals. From the central nervous system an organism has been recovered and this organism is filtrable and has all the cultural and other characteristics which have been described and has been carried through from twelve to fourteen generations. Rabbits inoculated intracranially with these cultures have come down with the disease. The organism has been recovered from their brain. A large number of animals inoculated with the virus at various stages of its passage have been cultivated and the organism has also been recovered from their brains. More recently guinea-pigs have been used — inoculated intracranially both with virus and cultures — have come down with the disease, have shown a micro- scopic lesion and the organism has been recovered again from their brains. The fourth spinal fluid which I just heard from was obtained from rather a peculiar case. The animal was inoculated intra- cranially and died fourteen days after inoculation, and I have also heard that sections of the brain showed a typical microscopical lesion. In other words, the results reported by Drs. Loewe and Strauss of the filtrable virus obtainable from the central nervous system of spinal fluid have been confirmed in the laboratory at Columbia Hospital, Milwaukee. A filtrable microorganism has been grown from this material on the perfected medium of Noguchi. This organism has been injected into animals, has reproduced the disease, microscopic lesions, and this organism has again been recovered from the brains of these animals. Immunological Distinctions of Encephalitis and Poliomyelitis (Harold L. Amoss). The means of dis- tinguishing epidemic poliomyelitis and lethargic encephalitis, which has not yet been applied, relates to the point whether the serum of convalescent cases of lethargic encephalitis can neutralize the virus of pliomyelitis. This fact is readily determined experimentally by the method described by ANIMAL EXPERIMENTATION 225 Amoss and Eberson. 1 The principle of the test lies in the power of a neutralizing serum, when administered intra- spinally, to prevent the development of poliomyelitis in the monkey following the intravenous injection of a large dose of the virus. The blood serum of 4 cases of lethargic cencephalitis was used in the test, one from a patient convalescent in the fifth week of the disease, the second in the fourth month, the third in the fifth month, and the fourth fifteen months after the attack. The tests were controlled by two experi- ments in which the same procedure was followed, except that one monkey received intraspinal injections of normal human serum and the other intraspinal injections of polio- myelitic serum from a monkey which had had experimental poliomyelitis nine months before and recovered with residual paralyses. The virus of poliomyelitis used came from a strain which had been passed from monkey to monkey many times during the past nine years and which, between passages, had been preserved in 50 per cent glycerol in the ice box. Before starting the tests, this virus was passed through three normal monkeys in order to determine its virulence. 2 The certain infecting dose for intracerebral injection was found to be 0.25 c.c. of a Berkefeld filtrate of a 5 per cent suspension of the nervous tissues containing the virus. The infecting power of the virus when given intravenously is shown in the following preliminary experiment. A monkey received at 5 p.m. an intraspinal injection of 2 c.c. of normal horse serum. The following morning 50 c.c. of a 5 per cent suspension of fresh virus were given intravenously. Five days later the animal was weak in both legs and excited. Both arms were paralyzed on the sixth day and the monkey died on the seventh day. Autopsy. Microscopic lesions of experimental poliomyelitis were found. 'Amos, II. L., and Eberson, F. J. Exper. M., 1918, xxvii, 309. 2 All intracerebral inoculations were made under ether anesthesia. 226 ACUTE EPIDEMIC ENCEPHALITIS In making suspensions for intravenous injections the tissues used must be fresh. Accordingly, a monkey prostrate from an intracerebral injection of 0.5 c.c. of a suspension of the virus six days before, was killed with ether and autopsied at once. A 5 per cent suspension of the cord and medulla was prepared for immediate injection. Series 1 Experiment 1. Macacus rhesus A. Normal human serum con- trol. March 11, 1920, 5.50 p.m., injected intraspinally 2 c.c. of fresh normal human serum. March 12, 2.30 p.m., injected intra- venously 50 c.c. of a 5 per cent suspension of fresh poliomyelitis nervous tissue. 2.50 p.m., intraspinal injection of 2 c.c. of fresh normal human serum. The intraspinal injection of 2 c.c. of normal human serum was repeated daily for three days. March 18th, excited; slight head tremor and left facial paralysis. March 19th, prostrate. March 20th, etherized when moribund. Autopsy. Microscopic lesions of experimental poliomyelitis. Experiment 2. Macacus rhesus B. Immune poliomyelitic serum. March n, 1920, 6 p.m., injected intraspinally 2 c.c. of serum from a monkey which had had experimental poliomyelitis nine months before and had recovered with residual paralyses. March 12, 3 p.m., injected intravenously 50 c.c. of virus suspension. 3.25 p.m., intraspinal injection of 2 c.c. of poliomyelitic immune monkey serum. The intraspinal injections of 2 c.c. of immune monkey serum were repeated daily for three days. The monkey remained well. Experiment 3. Macacus rhesus C. Serum from convalescent case of lethargic encephalitis. March 11, 1920, 6.05 p.m., injected intraspinally 2 c.c. of serum from Case 1, aged thirty-one years, who was in the fifth week of well-defined lethargic encephalitis with general disturbance of the functions of the central nervous system and involvement of third and seventh cranial nerves. March 12th, 3.30 p.m., intravenous injection of 50 c.c. of virus sus- pension. 3.35 p.m., intraspinal injection of 2 c.c. of encephalitis serum from Case 1. The intraspinal injection of the encephalitic serum was repeated daily for three days. March 17th. Animal slow and weak. March 18th. Found dead at 9 a.m. Autopsy. Microscopic lesions of experimental poliomyelitis. ANIMAL EXPERIMENTATION 227 Experiment 4. Macacus rhesus D. Serum from convalescent case of lethargic encephalitis. Mar. 11, 1920, 6.10 p.m., injected intraspinally 2 c.c. of serum from Case 2, aged thirty-four years, three months after definite attack of lethargic encephalitis in which there was general disturbance of the function of the central nervous system, involving the third and seventh cranial nerves and spinal motor roots. March 12th, 4 p.m., intravenous injection of 50 c.c. of virus suspension. 5 p.m., injected intraspinally 2 c.c. of convalescent encephalitis serum from Case 2. The intraspinal injection of 2 c.c. of encephalitic serum was repeated daily for three days. March 18th. Excited and ataxic. March 19th. Pros- trate. March 20th. Etherized when moribund. Autopsy. Microscopic lesions of experimental poliomyelitis. Series 2 The second series of tests carried out at a different time was controlled by an experiment in which normal human serum was used for the intraspinal injections as in Experi- ment 1. The procedure in this series was the same as in Series 1, except that normal horse serum was used for the preparatory intraspinal injection given the day before the intravenous injection of virus. The same strain of virus employed in Series 1 was again tested for infecting power and used in this series. Experiment 5. Macacus rhesus E. Normal human serum con- trol. May 18, 1920, 4.10 p.m., injected intraspinally 2 c.c of nor- mal horse serum. May 19th, 12 m., intravenous injection of 50 c.c. of virus suspension. 12.25 p.m., injected intraspinally 2 c.c. of normal human serum. The intraspinal injection of normal human serum was repeated daily for 3 days. May 23rd. Monkey excited; both legs weak. May 24th, complete paralysis of both legs and right facial paralysis. May 25th. Died. Autopsy. Microscopic lesions of experimental poliomyelitis. Experiment 6. Macacus rhesus F. Serum from case of leth- argic encephalitis. May 18, 1920, 4 p.m., injected intraspinally 2 c.c. of normal horse serum. May 19th, 11.30 a.m., intravenous injection of 50 c.c. of virus suspension. 11.55 a.m., intraspinal injection of 2 c.c. of serum from Case 3, aged twenty-eight years, 15 228 ACUTE EPIDEMIC ENCEPHALITIS taken four and a half months after acute onset of lethargic en- cephalitis. The patient's illness began with dizziness, disturbance of vision, vomiting and fever, and he gradually became stuporous. Later paralyses referable to the seventh and spinal nerves ap- peared. The intraspinal injection into the monkey of the conva- lescent serum was repeated daily for three days. May 26th, monkey had paralysis of both arms and shoulder muscles. May 27th. Died. Autopsy. Microscopic lesions of experimental poliomyelitis. Experiment 7. Macacus rhesus G. Serum from case of lethargic encephalitis. May 18, 1920, 4.20 p.m., injected intraspinally 2 c.c. of normal horse serum. May 19th, 1 1 a.m., intravenous injection of 50 c.c. of virus suspension. 11.25 a.m., injected intraspinally 2 c.c. of serum from Case 4, aged twenty-four years, who had devel- oped lethargic encephalitis fifteen months before and was still under observation with residual ptosis and partial paralysis of left side of face and left leg. The intraspinal injection into the monkey of the convalescent encephalitis serum was repeated daily for three days. May 24th, monkey had double ptosis. May 25th, shoulder muscles paralyzed; arms and legs very weak; head tremor; animal almost prostrate. May 26th. Died. Autopsy. Microscopic lesions of experimental poliomyelitis. The experiments here reported show, the two diseases can be distinguished through the power of blood serum under certain circumstances to neutralize the virus of poliomye- litis. The blood serum of convalescent cases of poliomyelitis whether in man or monkey possesses this neutralizing power, while the blood serum of recently convalescent cases of epidemic encephalitis is devoid of it. On the basis of the distinguishing characters described, it is regarded as desirable at the present time to hold epidemic poliomyelitis and epidemic encephalitis as integrally distinct affections. The latter also may be infectious, yet the main lesions of poliomyelitis are present in the spinal cord, and of epidemic encephalitis in the midbrain. The following questions submitted to Dr. Amoss before the Commission, together with the answers to them, are here reported verbatim. ANIMAL EXPERIMENTATION 229 Dr. Tilney: Would you be good enough to discuss a little more in detail why you selected the in vivo method in preference to the in vitro? Dr. Amoss: The in vitro method depends upon the following experiment. You take 2 c.c. of the serum and add to it 2' m.l.d.'s of your virus; let it set in the incubator for two hours and over- night in the ice box, and inject the whole mixture in the monkey. If you will take a series of these — I have done I think 20 at one time, using the same serum — say, using 5 monkeys on one serum, you will find that some of the monkeys come down and some do not. Whether it is a question of hydrogen-ion concentration or whether it is a question of the variation in the immune bodies, one can't tell. So they are not clear-cut experiments. Some of them will come down and some will not. Another thing — normal human serum will sometimes neutralize in vitro, but normal human serum never neutralizes in vivo. Dr. Barker: Keeping in mind the possibility that the virus of encephalitis might be a modification of the virus of poliomy- elitis — the modification going so far as to involve also production of diphenyl bodies — is there anything known in immunology that would correspond to that possibility? Dr. Amoss: There is only one analogy which occurs to me now. I do not know if there are any others. If you take a pneumococcus type 2, pneumococcus type 2 serum will agglutinate pneumococcus type 2 in the sub-groups A and B. Pneumococcus type 2-A will not agglutinate a type 2 but will agglutinate only type 2-A, and so monotypical type 2-B will agglutinate only type 2-B and will not agglutinate type 2-A or type 2. That is the only group. It may be that it is perfectly possible from that analogy that enceph- alitis might be the more inclusive from an etiological stand- point and that poliomyelitis might correspond to type 2-A or type 2-B but I do not believe it. Dr. Timme: Dr. Thalhimer, would you like to put any questions to Dr. Amoss regarding the various discrepancies or findings in your respective work. Dr. Thalhimer: I do not think there are any questions that can be put at this particular time. The state of affairs is that there were simply two series of experiments done — on the one hand in a number of different laboratories with positive results with microscopic lesions and with the recovery of an organism, and a 2 3 o ACUTE EPIDEMIC ENCEPHALITIS series of experiments by Dr. Amoss of the Rockefeller Institute with negative results. I do not think there are any questions coming up between the two at present. I think the only thing that is indicated is that with this divergence a suggestion is in order that these two series of workers in some way come together and com- pare their technique and compare their results, and see if there might not be between them in a technical way some differences which can be eradicated. The work has got to stand or fall as it becomes more generally verified or not, and I think that the immediate thing to be done — being as there are sufficient number of people interested in this disease to come to these meetings — is to ask Dr. Amos if he will attempt to come together and go over this with Dr. Strauss or myself, and see if we cannot evolve some- thing which is worth while in an experimental manner. Dr. Sachs: May I ask Dr. Thalhimer whether he knows if encephalitis immunity studies have begun? Dr. Thalhimer: Yes, the immunity studies have been begun at Mt. Sinai Hospital. Dr. Sachs: There is a question handed in here: Is it true that the disease complex of poliomyelitis cannot be reproduced in rabbits while an encephalitic process of encephalitis Iethargica can be produced in some animals. Dr. Amoss: It is a question whether or not poliomyelitis has been transmitted to rabbits. Rosenauer and Caven thought that they were able to transmit the disease to rabbits, and Marks about eight years ago thought he had been able to transmit poliomyelitis to rabbits. However, in view of the findings in normal rabbits which I reported a while ago, and in view of the experi- ments by Clark and some of the rest of us at the Rockefeller Institute, I do not believe that anybody has ever transmitted poliomyelitis to rabbits. We have taken young rabbits, as young as you can inject them and let them live, and we have gone further and given them massive doses of x-ray so as to reduce their lymphocytes. Now we know that if you ray monkeys so that the lymphocytic curve comes down about 200 to 600 round cells per cubic millimeter, those animals are much more susceptible to poliomyelitis, but not so rabbits. So I think it is not established that rabbits will take experimental poliomyelitis. lMMUNOLOGICAL r STUDIEs"oF^EpiDEMIC ENCEPHALITIS AND POLIOMYELITS (MARCUS NeUSTAEDTER, JOHN H. LaRKIN ANIMAL EXPERIMENTATION 231 and E. J. Banzhaf). It is a well established fact, as was shown by Flexner and Lewis, Netter and Levaditi, Roemer, and Anderson and Frost, that serum of patients recovered from poliomyelitis neutralizes virus of poliomyelitis in vitro and also protects monkeys from the disease when injected with such a mixture. It is also known that normal human serum does not as a rule neutralize the virus. Following are the protocols of experiments : Experiment 1. March 6, 1920. Maccacus A was injected intra- cerebrally with 0.5 c.c. of a mixture ot poliomyelitis virus and serum of patient Miriam S., aet. 16 years, three months after recovery from lethargic encephalitis, prepared in the following manner: 0.125 c.c. of a 5 per cent suspension of brain and cord of a monkey that died of poliomyelitis, obtained through the courtesy of Dr. Amoss from the Rockefeller Institute, were mixed with 1.25 serum of the above patient and incubated at 37 for two hours and kept in the refrigerator for twenty hours. Result. The animal remained well without any visible ill effects until April 21st, when it was found dead. The autopsy showed that the cause of death was tuberculosis. Control. Maccacus B was injected in the same manner with 0.5 c.c. of a mixture of the same virus and in the same proportion with normal adult serum prepared as above. Result. The animal became paralyzed on the eighth day in the right upper and lower extremities but survived until October when it was anesthetized and autopsied. Experiment 2. May 18, 1920. Maccacus E was injected intra- cerebrally with 1 c.c. ot a mixture of equal parts of a 5 per cent suspension of Rockefeller Institute poliomyelitis virus and serum of patient Dawe J., aet. 30, recovered from lethargic encephalitis since February 20, 1920. This mixture was incubated at 37 for 1 hour and 20 minutes and kept on ice for ig}i hours. Result. The animal remained perfectly well until August 25th. Control. Maccacus D was injected in the same manner with 1 c.c. of a mixture of equal parts of the above virus and normal adult serum prepared as above. Result. May 24th, the animal found ill sitting in a corner of the cage; May 25th paralysis in all four extremities and muscles of the 232 ACUTE EPIDEMIC ENCEPHALITIS neck; shallow respiration. Anesthetized and autopsied. Macro- scopical and microscopical changes characteristic of poliomyelitis. Experiment 3. June 22, 1920. Maccacus F injected intraspinally with 4 c.c. of a mixture of equal parts of a 2}^ per cent suspension of virus of monkey D and serum of Dr. G., aet. 55 years, suspected of having had lethargic encephalitis, still having a paralysis of facial nerve with complete reaction of degeneration. This mixture had been incubated at 37 for 2 hours and kept on ice for 22 hours. Result. The animal remained well up to November 5th. Control. Maccacus G was injected as above with 4 c.c. of the same virus mixed with equal parts of normal NaCI solution, and incubated as above. Result. June 28th, the animal ill, refuses food. June 29th paralyzed in all four extremities and muscles of the neck. Anesthetized and autopsied. Macroscopical and microscopical changes typical. Experiment 4. October 8, 1920. Maccacus K was injected intracerebrally with 1.5 c.c. of a mixture of equal parts of an 8 per cent suspension of poliomyelitis virus of Maccacus E and serum of patient from Dr. Foster Kennedy's service in Bellevue Hospital, who had recovered from lethargic encephalitis. The mixture was incubated for 2 hours at 37 and kept in the refrigerator for 22 hours. Result. The animal suffered no ill effects and is well today. Control. Maccacus L was injected with 1.5 c.c. of a mixture of equal parts ot the above virus suspension and serum of a normal adult, prepared as above. Result. October 14th, animal very ill; left upper extremity par- etic; October 16th., both hind limbs paretic; October 19th, animal recovered from pareses and is well today. Experiment 5. October 28, 1920. Maccacus M injected intra- cerebrally with 1.5 c.c. of a mixture of equal parts of a 10 per cent suspension of poliomyelitis virus of Maccacus E and serum of patient Mary S., aet. 16 years, from the service of Dr. Foster Kennedy at Bellevue Hospital, and originally observed and described by Dr. Tilney as Case IV in his book, "Epidemic Encephalitis." The patient is at present in the neurological service of the City Hospital. This mixture was incubated at 37 for 2 hours and kept on ice for 22 hours. Result. The animal remained well. ANIMAL EXPERIMENTATION ^33 COMPARATIVE RESULTS IN NEUTRALIZATION TESTS OF POLIOMYEILTIS VIRUS WITH SERUM OF PATIENTS CONVALESCENT FROM POLIOMYELITIS AND LETHARGIC ENCEPHALITIS Monkeys Injected Result Flexner and Lewis 5 poliomyelitis virus + human con- valescent polimyelitis serum 3 poliomyelitis virus + human sus- pected poliomyelitis serum 7 and 9 injections of poliomyelitis virus + normal human serum of adults and children 4 protected 1 paralyzed, living 1 protected 2 paralyzed and died 3 paralyzed and died 3 protected 1 died, no paralysis and no poliomyelitis lesions Netter and Levaditti 4 poliomyelitis virus + human con- valescent poliomyelitis serum 1 control, poliomyelitis virus + nor- mal salt solution 3 poliomyelitis virus + human con- valescent poliomyelitis serum 1 control, poliomyelitis virus + nor- mal human serum 4 protected 1 paralyzed and died 3 protected 1 paralyzed and died R< 3 poliomyelitis virus + human con- valescent poliomyelitis serum 1 control, poliomyelitis virus + nor- mal salt solution 3 poliomyelitis virus + human con- valescent poliomyelitis serum 1 control, poliomyelitis virus + nor- mal new born infant serum, intra- cerebrally, and 5 c.c. pure virus in- traperitoneally 2 controls, poliomyelitis virus + nor- mal new born infant serum 3 protected 1 paralyzed and died 3 protected 1 paralyzed and died 1 slightly paretic, recov- ered 1 paralyzed and died Anderson and Frost 1 poliomyelitis virus + human con- valescent poliomyelitis serum 10 poliomyelitis virus -f- human sus- pected poliomyelitis serum 10 controls, poliomyelitis virus + nor- mal human serum 1 protected 7 protected 1 paralyzed and died 2 paralyzed, survived 3 protected 7 paralyzed Authors' cases 5 poliomyelitis virus + human con- valescent lethargic encephalitis serum 4 controls, poliomyelitis virus + nor- mal human adult serum 1 control, poliomyelitis virus -f- nor- mal salt solution 5 protected 1 paralyzed and dying 1 paralyzed, survived 2 paretic, recovered 1 paralyzed and dying AH sera were Wassermann negative. 234 ACUTE EPIDEMIC ENCEPHALITIS Control. Maccacus N was injected in the same manner with 1.5 c.c. of a mixture of the above virus suspension and equal parts of serum of an eighteen year old laboratory helper, who claimed never to have been ill. Result. November 2nd, the animal was ill and paretic in the right upper extremity and showed also a slight hypotonia in the right lower extremity. The same condition prevails today. Experiment 6. In order to establish whether the protection afforded the animals was due to the use of the convalescent enceph- alitis serum, Maccacus E was injected intracereb rally with 1 c.c. of a 5 per cent suspension of brain and cord of Maccacus G on August 25th, about three months after the initial injection. Result. August 31th, the animal was found paralyzed in all extremities and dying. Macroscopic and microscopic changes were characteristic of poliomyelitis. All sera used proved Wassermann negative and the serum of a different person was used as a control in each experiment. Five monkeys were completely protected from polio- myelitis by sera of patients convalescent from 4 undoubted cases and one suspected case of lethargic encephalitis. The results compare favorably with the results of other investigators in the neutralization experiments of polio- myelitis virus and convalescent human poliomyelitis sera. It is concluded from these facts that there is a close point of contact between lethargic encephalitis and poliomyelitis. BIBLIOGRAPHY 1. Flexner and Lewis, quoted by Peabody, Draper and Douchez. Monograph 4, of the Rockefeller Institute, 1912, 16. 2. Netter and Levaditti. Compt. rend. Soc. de biol., Par., 1910,617,855. 3. Roemer. Die epidemische Kinderlaehmung, Berlin, 191 1. 4. Anderson and Frost. J. Am. M. Assn., 191 1, Ivi, 663. The following questions, submitted to Dr. Neustadter before the Commission, together with the answers to them, are here reported verbatim. ANIMAL EXPERIMENTATION 235 Dr. Dana: Why will you not draw some conclusions? Dr. Neustaedter: I believe that before we could draw any definite conclusions two other things ought to be done, which I am in process of working on. One is to test out the spinal fluids of so-called lethargic patients with poliomyelitis virus for complement fixation. I have been doing that for the last few months in frank cases but I have not sufficient number to draw any conclusions. Results are so far very encouraging. Another experiment that I want to make and that I spoke to Dr. Strauss about some time ago was the antipoliomyelitis horse serum that neutralizes virus in much greater proportions. That is, the poliomyelitis horse serum neutralizes poliomyelitis virus in proportions of one to two; two of virus to one serum. 1 want to cross the experiment and try the virus of encephalitis, as they have, and neutralize that with our serum which we know neutralizes in every instance, without exception, poliomyelitis virus. When I have those three factors together I believe it will give us greater encouragement to draw conclusions than at the present time. Dr. Dana: As I understand it, you state that the serum from convalescent encephalitis cases neutralized the poliomyelitic monkey. Do you infer from that that the diseases must be very closely identical? Dr. Neustaedter: I would say there is a close contact between the two. I would not say anything further than that. I believe there is a close contact between the two; whether it is another phase or what it is, I am not prepared to say. Dr. Dana: May there not be many other infectious diseases the convalescent serum from which might do the same? Dr. Neustaedter: That has been tried, as far as I know, again and again, and never succeeded. Dr. Dana: You could say that some other convalescent serum than that of encephalitis or poliomyelitis neutralizes the virus of poliomyelitis, couldn't you? Dr. Neustaedter: Other infectious diseases such as measles, scarlet fever, etc., have been tried and did not do it, but we do know that from the results of other investigators the serum of socalled normal people has neutralized the virus, and in my ex- periments here two controls became ill but recovered. So you see normal human sera also contain some principles evidently that protect the monkey to a certain extent. 236 ACUTE EPIDEMIC ENCEPHALITIS Dr. Patrick: In the case of the physician, how long had this physician had the facial palsy before you saw him? Dr. Neustaedter: A week. Physiologic Knowledge as Related to Syndromes of Epidemic Encephalitis (Frank H. Pike). On our hypothesis of localization, a lesion of any particular group of cells should produce a definite effect. One asks whether or not these lesions in encephalitis are of the nature of deficiency lesions, the effects being such as one might get from excision of definite parts of the nervous system without inflammatory conditions or irritating conditions afterward, or whether these are of the nature of irritative lesions. Some years ago Stewart and Pike in animal experimenta- tion tied off the blood-vessels to the brain for a short period of time, say eight to ten minutes, and observed the effects. There were convulsions and rigidity which might persist for three or four days. In case of recovery these would grad- ually pass off. These cases were done aseptically and con- ditions verified at autopsy. At that time at least no changes were found which suggested encephalitis or meningitis. In these cases as was shown afterward there was always a chromatolysis. The cells were diffusely stained and this change was found at times to persist for days after recovery. The question was raised as to whether the chromatolysis itself might have been sufficient to account for the rigidity, and perhaps for the convulsions. It seems to be pretty sure that some agents at least which act injuriously upon nerve cells or nerve fibers will increase their excitability. It is known, of course, that there is an action current produced at every beat of the heart, yet the phrenic nerve on the left side runs right in contact with the pericardium. There is no twitching of the diaphragm ordinarily. The threshold of stimulation of this phrenic nerve is too high to be excited by the action current of the heart. Yet by decreasing the oxygen supply, by decreasing the blood supply of this phrenic nerve, it is perfectly possible to demonstrate that the ANIMAL EXPERIMENTATION 237 diaphragm on the left side twitches at each beat of the heart. It seems, therefore, pretty sure that there are conditions which will increase the actual excitability of nerve fibres and also of nerve cells. Now, until we know more of the effects of toxins upon nerve cells, one must, if he keeps within the limits of veracity, be extremely brief. Many of the claims that have been made for a specific action of toxins upon various parts of the ner- vous system are not very well founded. The effects, or the supposed effects, of pneumonia toxin, which is probably the most prominent, and perhaps also diphtheria toxin has been shown to lie in the end organs perhaps more than in the central system. One point perhaps is the relation of the ectasis of the blood to the lethargy. Experimentally, of course, we can reduce the blood supply to the brain to almost any desired degree. It is perfectly possible to tie up both carotid and both vertebral arteries in a cat or a dog, and most dogs will live after that, but during the period of associated lethargy we often find that there are convulsions. We find great respiratory disturbances as well, and within the last two years we have found that in every case of this kind which we tried experimentally there are characteristic changes in the carbon dioxide and oxygen concentration of the blood. Just as soon as one reduces the volume of blood flowing through the brain, just so soon will one reduce the concentration of carbon dioxide in the blood and increase the concentration of oxygen. From this point of view then, if ectasis is the only thing concerned in the production of lethargy, one would expect certain respiratory changes, and also certain circulatory changes. When the nerve cells are uninjured and one simply reduces the blood supply, there is a prompt rise in the sys- temic blood-pressure, and we have shown also that the usual relation exemplified by Marey's law in the high blood- pressure and low heart rate may be departed from here. We get a dissociation of response. We may get a rapid heart rate along with a high blood-pressure. Stasis may in part 238 ACUTE EPIDEMIC ENCEPHALITIS account for this lethargy, particularly in view of the peri- vascular infiltration which has been described, but one should be inclined to attribute a part of this lethargy at least to some other cause. The muscular rigidity in some cases at least departs some- what from the conditions we get experimentally. Sherrington and others have shown that in lesions of the cerebrum we get a typical rigidity of the muscles, a decerebrate rigidity. This affects the extensor muscles. In some cases of epidemic encephalitis there is a pretty general rigidity of extensors as well as flexors. This would seem to differentiate the effects in encephalitis, so far as our experimental knowledge goes, from the effects of a pure cortical lesion. It has been somewhat difficult for one to see just how a lesion of the endocrine system could produce such opposite effects as have been described. One can hardly see, for in- stance, how a low blood-pressure and profuse sweating might be due to the action of adrenalin since the action of the sweat gland is due to the sympathetic nervous system. It has been shown experimentally, as it had previously been postulated clinically, that there is a cortical mechanism for the secretion of sweat. One would like to know whether in these cases in which profuse sweating has been observed the lesions seem to be more of the cortical type or whether they were confined to the region of the aqueduct, as seems to be the rule. We are inclined to think that we have an irrita- tive process here as exemplified by the muscle tonus, and by certain of the other disturbances, namely, that of the sweat glands. One or two observations which have been made on animals might be mentioned. A dog developed the disease known as distemper among dogs, but there was a recovery. There was a twitching of all four limbs persisting even during sleep at times. This continued for about twenty-five months after the attack. There was a similar dog up in the Harvard Laboratory where there was this same twitching of the muscles, but it was more severe. Experiments were done to ANIMAL EXPERIMENTATION 239 see where some of these movements came from. The first thing was the exposure of the lumbar cord and the sections of the dorsal roots of the spinal nerves on one side. If these things were due to afferent impulses a section of the dorsal roots should have some effect. Perhaps the twitchings were somewhat decreased for a week or two, but they returned again, and people who saw the dog and who did not know on which side the nerve roots had been sectioned were unable to tell any particular difference in the two sides. Fol- lowing that was extirpated a motor area on one side. If this was due to cortical irritation, extirpation of the motor area should have some effect. The dog died of hemorrhage in a few hours, but in the time the dog survived, one couldn't see that there was any marked effect on the twitchings on the two sides. It seemed to be distinctly due to something outside of the cerebral cortex. The following questions, submitted to Professor F. H. Pike before the Commission, together with the answers to them, are here reported verbatim. Dr. Sachs : I would like to ask Dr. Pike whether the movements of that dog resembled in any way such movements as we have described here as following encephalitis? Were they of the chore- atic or myoclonic type? Dr. Pike: I think from the description I have heard, and from some cases I have seen, they are very much like those. They are very general; they involve even the jaw muscles. You could hear the teeth click. And there was some respiratory change. At times the breath would come in gasps. At first there was some weakness of the muscles of the limbs. The dog was unable to go up or down stairs unassisted, but that passed off in time. The dog became able to draw a sled with two boys on it. I couldn't notice any difference in the general intelligence or general habits. Dr. Barker: Dr. Hohman mentioned a case in which there was rhythmical myoclonia. The rate of the myoclonic contractions was in a definite ratio with the respiratory rate. I think he referred to some work of Dr. Pike's suggesting that this meant that rhythmical myoclonia must have an origin in the medulla oblon- gata. Can you give us any data on that? 240 ACUTE EPIDEMIC ENCEPHALITIS Dr. Pike : It is only in cases of considerable respiratory difficulty that I have observed any movements outside of the respiratory movements under experimental conditions. Many of these symp- toms which have been described, seem to me to point to an involve- ment of the medulla. In experimental work on the cerebellum or any region around the fourth ventricle one must be extremely cautious to avoid pressure or irritation, even though it be slight, of the floor of the fourth ventricle. I am in doubt yet sometimes as to the actual effects of cerebellar lesions. I am not sure that they are uncomplemented by effects on the floor of the fourth ventricle. In cases of increased excitability of nerve cells which one might possibly have in this disease of encephalitis, there is of course a possibility that some of these muscular movements might arise during respiration and be associated with respiratory movements. I don't think we have any definite proof. CONCLUSIONS OF THE COMMISSION The Commission feels that the evidence submitted before it on the bacteriology and pathogenesis of epidemic encepha- litis, together with the incidental additions brought out in the questionnaire, while not entirely conclusive as to the specific nature of epidemic encephalitis and its productive organism, yet is of the greatest weight. The work of Drs. Loewe and Strauss, confirmed by Dr. Thalhimer and by many European investigators, notably Levaditi and Harvier, Mcintosh and TurnbuII, and Ottolenghi, D'Antona and Tonietti, seems to the Commission to merit high commendation as having established apparently the closest relationship between organism and disease. The negative attitude was not one which pointed out errors of technique or fault in material or error in conclusion, but only inability to reproduce the same effect. And there is, it seems to the Commission, room for this discrepancy in the lack of using material obtained by different methods, and by the use of presumably different filters. The commendable attitude of the investigators in desiring to remove their differences by the respective use of each others' material and technical apparatus, lends hope that unity of conclusion will soon eventuate. BIBLIOGRAPHY Abrahamson, I. Prevalence of infectious lethargic encephalitis. N. York M. J., 19 1 9, cix, 879. Abt, I. Acute non-suppurative encephalitis in children, J. Am. M. Assn., 1906, xlvii, 1184-1188. Achard, L. E. La diversite clinique de I'encephalite Iethargique, Bull. Acad, de med., Par., Feb. 2, 1920, pp. 106-111. Alexander, J. B. Cases resembling epidemic encephalitis occurring during the influenza epidemic. Brit. M. J., 19 19, i, 794-795. Alexander, M. E., and Allen, H. E. Lethargic encephalitis: Report of cases and analysis of literature, Arch. Neurol. & Psychiat., May, 1920, p. 485. 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