·Published under the auspices of
The Netherlands Society of Psychiatry
and Neurology
as
Supplement no. 5 to the journal
Folia Psychiatrica, Neurologica
et Neurochirurgica Neerlandica

·POSTVACCINIAL
PERIVENOUS ENCEPHALITIS
A PATHOLOGICAL ANATOMICAL SILD ON THE PLACE OF POSTY ACCI\IAL
PERI EXO'S ENCEPHALITIS IN THE CROLT EXCEPHALITIDES
(THE DISEASE OF TURIBULL-LL'CHSCH - BASTI LASE)
ERNST DE VRIES
EMERITUS PROFESSOR OF NEUROLOGY AND NEUROPATHOLOGY
NEUROPATHOLOGIST, NEUROLOGICAL CLINIC, UNIVERSITY OF UTRECHT
THE NETHERLANDS
ELSEVIER PUBLISHING COMPANY
AMSTERDAM
LONDON
NEW YORK
PRIYCETON
1960

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·PREFACE The encephalitis that sometimes occurs following vaccination against smallpox has for some time been a subject of investigation in the Netherlands. After World War II, when it was possible for this rescarch to be resumed, I was invited to take part in the investigations by the late Dr. F S. Van Bouw dijk Bastiaanse, who had been a member of the Encephalitis Committee of the Netherlands Health Council since 1925 Tus invitation was a consequence of the institution of an Advisory Committee to the Health Organization T.N.O.- a branch of the Central Organization for Applied Scientific Research (T.N.O.) in the Netherlands with the investigation of the causes of posti accinial encephalitis as its object The support of this Organization, together with the opportunity to use the matenal in the Neuropathological Laboratory of the Utrecht University and the availability of the material previously collected in that laboratory, enabled me to carry out an investigation into the histopathology of postvaccinial encephalitis, the results of which are presented in this book. Acknowledgements are due to the staff of the Neurological Clinic of the Utrecht University, especially to the Director, Prof W. G. Sillesis Smitt, for their pleasant and helpful co-operation The discussions in the Health Organization T N.O have always been a stimulant to my work and I wish to express my gratitude to all who have taken part in the discussions I am also grateful to Mrs J L AM Zwanıkken for her assistance in reviewing the literature. I should also like to thank Dr Dorothy Russell for her help, he kind permission to use her laboratory enabled me to examine Di Turnbull's orginal slides on postu accınial encephalıtıs, which are kepi in the London Hospital Finally, I should like to pay tribute to the late Dr. F. S Van Bouw dijk Bastiaanse, by whose moving spirit the entire investigation has been guided since the first reports on postvaccinal encephalitis appeared L'trecht, September 1959 ERNST DE VRIES ·CONTENTS 1. 1 4 8 2. 12 3. 16 16 & 18 25 33 39 48 e Preface. Introduction Definitions Classification Material Postvaccinial microglia encephalitis a. General b Perivascular focal lesions 1. Foci 2. Earliest stages 3 Late stages 4. Influence of intercurrent diseases 5 Cases with the clinical picture of transverse myelitis c. Diffuse infiltration by glia cells d. Marginal ghosis Ganglion cells f Complicating actiological factors Summary Clinical postvaccinial cncephalitis different in pathology from microglia encephalitis Post-infectious encephalitis before and after the year 1923 b. Children under 2 years of age show no microglia encephalitis Revaccination cases and their pachological substratum d Development of another disease during the first sechs following vaccination e, The encephalopathic brain reaction following vaccination. f. Rare histological pictures Occurrence of microglia encephalitis and microglial perivenous reaction before 1923, and without preceding exanthematous disease a Introduction b Cases occurring before 1923 c Cases without preceding disease d Cases following other conditions or diseases Subacute case 56 57 59 60 63 66 67 73 82 с 99 102 300 5 ITO NO 118 120 130 e

·CONTENTS
VII
f. Relation of microglia encephalitis to disseminated
cncephalomyelitis
& Experimental pervenous encephalomyelitis
6. Discussion. The nosological entity of microglia encephalitis
Introduction
2 The clinical side
b The pathological side
c. The pathogenic side. Some further considerations
7.
Conclusions
List of cases from the literature, reviewed in the text
References
Index
130
131
134
13+
135
145
156
161
165
166
178

·No text on this page.

·Chapter 1 INTRODUCTION Postvaccinsal encephalitis still offers problems both as to its nosological place and its actiology and prevention or therapy. It has been our aim in the present article to group together the facts that patho. logical examination of many cases which occurred in The Netherlands from 1925 up to the present time can offer, and to add some data from the literature pertinent to our problem. The basic idea underlying the present investigation has been to bring together facts pointing to a separate nosological position of persvenous encephalitis in the group of para-infectious cerebral lesions and to avoid grouping them together with cases of a different pathology We therefore follow a principle opposed to the clinical method of grouping together, in the discussion of a disease, many borderline cascs The clinical syndrome, with us, should come in the second place, and the borderline cases should be divided, according to their pathology, into cases belonging to the disease under discussion, or to other diseases or conditions. The histological picture of perivenous encephalitis differs from the wellknown changes in inflammation of the nen ous system due to viral infection. It should also be distinguished from the para-infectious vascular reaction types, and it is at the same time different from the experimentally produced allergic reactions of the brain, a special group of which it sometimes resembles This work is an attempt, not to compare a clinical disease with a pathological picture, but to see whether a monomorphous reaction of the CMS is caused by as simple an aetiology as we can conceide Therefore, clinical postvaccinal encephalitis need not necessarily show an uniform hsstopathology We want to stress this fact Sometimes ·2 INTRODUCTION I on following vaccination, many times following measles or other exanthematous diseases, a pathologically different reaction of the C.N.S. is seen (haemorrhagic, or encephalopathic), a point which is not mentioned by many authors. B. Walthard and K. M Walthard (1958), in their article on encephalitis following vaccination, variola, measles or varicella, give the impression that the only type of cerebral reaction following these diseases is perivenous encephalitis, they then must accept the encephalopathic changes, found as the only changes in many cases, as a fulminant reaction. They do not mention other reaction types. For us it is precisely the occurrence of these negative cases which, in the future, must give us a better understanding of the "gemeinsame Auslosemechanismen” (H. Jacob, 1958, p. 692) in diseases of the C.N.S. and the complicating factors which can alter the primary histopathological picture. As a working hypothesis we accept for the present that perivenous microglial infiltration in a demyelinated area is caused by a specific factor, cither endogenous, or exogenous in origin. Il'e accept that in brology as well as in physics the same cause, acting on the same tissue must have the same effect. Van Bogaert (1950, p. 234) speaks of a standard form of reaction of the nervous tissue, determined by the tissue itself and independent of the causative agent. For us the character of this causative agent is as important as the endogenous constitution for the occurrence of pervenous encephalitis. If the specific factor were endogenous, it would mean a certain reaction type of the individual, as accepted by Scholz, H. Jacob and others. Probably this holds true in many cases when differences in heredity (van Bogaert, 1937; Sillevis Smit, 1952) or constitution exist. These latter are acquired by the patient during life (allergic sensitization, preceding brain diseases, changes in the blood-brain barrier, etc.). However, if the factor were exogenous, then the difference between perivenous encephalitis and other types would depend on a factor which might be a living agent or some kind of antigen or other toxic substance Perhaps we must not even think of a factor necessary to produce the pervenous type, but rather of the lack of a factor prohibiting this type of histopathological reaction to occur.

·INTRODUCTION 3 We wish again to stress the specificity of perivenous glial proliferation, because when for example haemorrhage occurs in postvaccinial encephalitis, this may be due not to the vaccination, but to another additional factor (c.g. bronchopneumonia or another infection) and is therefore not an essential part of the disease we are discussing (see Chapter 3, b. 4). Many authors do not differentiate between these pictures and then, when finding haemorrhages in one case of perii enous encephalitis, state that this belongs to the histological picture of this disease; a conception we do not wish to adopt. I will use, in the following pages, the name microglia encephalitis to separate this particular type from other pathological changes. This is necessary because, in many articles on postvaccinial encephaltis, no differentiation is made between this microglial type and embolic encephaltis, and certain vascular encephalopathies. Formerly they have always been grouped together and in statistics and tables no distinction was made, which, in my opinion decreases their value. The name pericenous encephalitis, coined by Spatz for the same purpose, is now used by many authors for cases of postvaccinial encephalitis chnically diagnosed before an autopsy could prove this diagnosis--or disprove it. Radermecker (1937). a girl recovered after encephalitis following vancella, six days after the skin eruption, but she was exposed to the sun the day before. This case may as well have been insolation, and the name perivenous encephalitis should not be used This name is also often used in the literature for circulatory disturbances. Zulch (1954) describes his cases 9, 10 and 11 as typical pericnous encephalitis, although no microglial proliferation is mentioned and the descnption points to a vascular origin of these foc: Moller (1949) uses the name pervenous encephalitis for many cases, including foci with central necrosis with a lymphocyte cuff (plate III, Fig E). It is for this reason that, in the subsequent study, the name microglial encephalitis will be exclusively used for cases in which autopsy proved this pericenous microglial ope of encephalins to be present. A further restriction is necessary to differentiate microglia encephalitis from those cases of disseminated encephalomyelitis in which perivascular foci of demyelination and microglial proliferation occur, ·INTRODUCTION but which show a marked reaction of the vessel walls, proliferation of histiocytes and plasma cells with often much larger lesions and fewer foci. The clinical course also differs; it may be subacute or recurrent. For these cases the name perivenous encephalitis is also often used (van Bogaert, 1950; Lhermitte, 1950) and, therefore, we prefer to use a special name for the material under discussion. In examining the pathology of the Dutch cases of postvaccinial encephalitis, our attention was soon drawn to the fact that infants under two years never showed the wellknown histological picture (de Vries, 1955), but they did show other changes which ranged from embotic encephalitis to encephalopathy. It also became apparent that microglia encephalitis is a separate disease recognised as new in 1923, which follows only a few (exanthematous) diseases and shows a sharply defined clinical course. These facts enabled us to describe many cases in detail, thereby helping to elucidate the many still dubious points, Definitions Our purpose in giving definitions of a number of terms used in the following discussion, is not to choose between those already in use, but only to circumscribe in which sense words are used here. Inflammation, as seen by the pathologist, is a complex reaction of an organ or part of it to damage caused by living or inanimate forces which can be present in vanous combinations and grades of action The name inflammation is of necessity more or less arbitrarily used, as a sharp distinction between inflammation and degeneration does not exist in biology We can describe certain changes seen in an organ as an inflammatory reaction, but whether we shall call the disease which causes these changes an inflammation depends not only on the distribution of the inflammatory changes, but also on the occurrence of other changes which could be more important in the general picture of the disease (c.g. degenerative diseases often show inflammatory lesions in some parts). I'hen we accept, in accordance with the general pathology, as necessary changes constituting an inflammatory reaction, ·DE FIXITIONS 5 proliferation, alteration and crudation, we again have difficulty when one of these factors is predominant, and another nearly absent. All grades occur in our histological pictures, but we have only few names to describe them. Thus encephalitis and encephalopathy do not have a sharp borderline and one author will group with the encephalitides cascs that another author calls encephalopathies (sec Radermecker's discussion of this point, 1958). We therefore fecl that, in the following pages, we should try to define sharply the inflammatory reaction as seen in the tissues from other reactions, but that a separation of an inflammation from a degeneration as type of disease will necessarily be vague. Globus differentiated between inflammation and inflammatory reaction years ago; it is also accepted by Jacob (1956). It will in the future be necessary to search for the role of the elementary processes acting together in an "inflammation", to judge of the value of this word in a given case. A difficulty arises in neuropathology, as one of the most typical elements of the inflammatory changes, rız. the polymorphonuclear leucocytes, function and behaviour of which in the tissues are rather well known, play only a minor rôle in the encephalitides which interest us now. About the function of the mononuclear small lymphocytes, however, very little is said in general pathology. This explains that we do not know whether the absence or presence of small lymphocytes in the tissues is important in grouping a certain picture with thc inflammations or not. If Ehrich (1957) is right that the lymphocytes play a rôle only in the reparative stage of tissue reaction, then they ought not to be regarded as a sign of inflammation. Link and Schleussing (1958) attribute an antitoxic reaction to the lymphocytes and think that they have some function in the assimilation and dissimilation of fatty products. Another difficulty in neuropathology is the role played by the microglia and other glial cells. Is hyperplasia of glia cells equivalent to the proliferation of mesenchymal cells in other organs? We will not discuss this point, but have mentioned it to demonstrate the difficulties that may arise when we try to grie precise definitions Continuing our discussion of the pathological side of our problem the name encephalitis will be used here to designate vanous types of ·6 INTRODUCTION reaction of the nervous tissue to damage, either by living agents or chemical substances. It is thought inopportune to give a very precise definition, as this must necessarily differ from definitions used by other authors and might cause more misunderstanding than it would clarify the subject. This implies that no sharp differentiation will be made betwcen encephalitis and encephalopathy. Also, in certain cases, a division into degeneration and inflammatory lesions will be difficult, and many histological pictures can be interpreted either as a degeneration or as an inflammation. In general we shall use the word encephalopathy when vascular changes, other than cellular exudation dominate the picture (but including haemorrhages), and degeneration when changes in nerse cells or nervc fibres prevail. But sometimes encephalitis may cover both these extremes of reaction to damage. Spielmeyer differentiated between primary and secondary inflammation, thereby introducing an aetiological factor in the histological definition. This is quite logical but very difficult to handle in any particular case with obscure aetiology. These words are cumbersome and will never come into general use. It is for this reason also that we cannot follow Ferraro, when he proposes to divide his material into cases of leucoencephalitis, when an infection is the cause; leucoencephalopathy, when caused by intoxication, and leucodystrophy, when degeneration is the cause. In many cases we cannot wait with a classification or denomination until the final word is said about the pathogenesis and aetiology and then, naturally, mistakes have already been made which it will be difficult to correct afterwards. We therefore prefer to use the names either without a sharp defimtion or by adding adjectives that will give them a certain meaning The tendency to use the word inflammation only for reactions to a living agent, 15 very widespread (Radermecker, 1956, p. 3), but most authors do not follow this use systematically because it is in contradiction with the original conception. The word microglial encephalitis, as pointed out, will be used only for cases in which autopsy shows perivenous demyelination with microglial proliferation in the demyelinated areas, without or with ·DEFINITIONS 7 only slight changes in the vessel wall, and together with other signs which will be described in detail in Chapter 3. Here, & grcat number of foci are present in the cerebral hemispheres, prevailing in the white matter. The word is therefore not used for the cases generally known as disseminated encephalomyelitis, with larger lesions, more tissue destruction and a different clinical course, nor for cases showing only the peris enous foci without the other characteristics, but sometimes together with other changes. Postraccınial encephalitis* comprises the cases, clinically following smallpox vaccination within about 4 wecks, showing a chnical picture of encephalitis. This group will therefore consist of cases of microglia encephalitis and other discases. When a Heine-Medin infection is activated by vaccination and encephalomyelitis follows, this also is postvaccinal encephalitis and, as perhaps constituting a risk of vaccination, worth to be included in our investigations. The clinical aspect of the use of the name encephalitis has to be commented on. The clinician regards encephalitis as a discase of a patient, and not as a reaction of a part or of one organ' Therefore there can be no absolute parallelism between the clinical diagnosis of encephalitis and the histological picture of changes in the CN.S. However, the inflammatory reaction in any part of the brain, found at autopsy, should direct the final diagnosis of encephalitis, when the changes are assumed to be primary and to constitute the most important part of the findings But when exudation and degeneration are secondary (rız. in fat embolism, salvarsan brain purpura, etc.) the name encephalitis should preferably not be used. The distinction of clinical encephalitis as a syndrome, from pathological encephalitis as a local histological change, is also made by Scholz and by Lhermitte (1950), and others When a patient shows fever, general brain symptoms, malaise (functio laesa), and when autopsy reveals oedema and hyperaernia of the bram, the diagnosis encephalitis seems clinically justified, although hustological cxamination may only show encephalopathic changes. * Postvaceimal when following smallpox vaccinador, posts accinal when following accinations in general, as the logical orthography, u will be generally used here ·8 INTRODUCTION The literature on postvaccinjal encephalitis gives numerous examples of cases clinically diagnosed as such but, at autopsy, showing pictures varying from pneumococcus sepsis to poliomyelitis or normal brains (Gins, 1931, and others). Many authors still group most of these pathological changes together as the pathology of one disease, in which we shall not follow them. When Comby (1935) states that all postvaccinial encephalitides in infancy constitute an indivisible group both clinically and actiologically, sciencc cannot profit by her documentation and discussion It is on the contrary the aim of the present study to try to delineate smaller disease units by dividing the large clinical group of post-exanthematous encephalitides into smaller units, each consisting of cases similar or identical in their pathology, clinical course, pathogenesis, and perhaps aetiology. Wc follow here the meth of H. Jacob (1954), who isolated from the large group of post-infectious encephalitides the diffuse lymphocytic encephalitis as a type with hitherto not fully known aetiology, but ultimately probably due to a certain combination of factors Posts accinial encephalitis is classified by various authors in different ways. Some, using the name para- or post-infectious disease, group together with the changes following infections, intoxications and general discase (Scholz, 1957; Kinnier Wilson, 19.40; Biemond, 1946). Pette (1942) groups it together with disseminated encephalomyelitis, multiple sclerosis and some forms of diffuse sclerosis under the heading. demyelinating forms of non-bacterial encephalitis. Verlinde (1947) groups perivenous encephalitis following measles, varicella and smallpox vaccination as one type of leucoencephalitides, whercas Globus (1932) and Hassin (1948) put it down as a separate unit in their system of encephaluudes. Classification A classification based mainly on the pathological changes was suggested by Spatz (1931) and later slightly modified by Halleri orden (1943) and van Bogaert (1950). A summary is given here. 1. Meningo-encephalitis (tuberculous, purulent, etc.)

·CLASSIFICATION 9 2. Mctastatic, embolic cncephalitis with muluple perivascular foci (in endocarditis, scpsis, etc.) 3 Polio-oncephalitis, diffuse, mainly telencephalic (demcntia paralytica, pan-encephalitis of Dauson-san Bogaert, etc, or the acute form of Pette-Doring) 4 Polio-encephalitis, mainly focal distribution (epidemic encephalitis, Heine-Medın infection; some authors include rabies) 5 Focal demyelinating encephalitis (multiple sclerosis; some forms of diffusc sclerosis; acute encephalomyelitis disscminata and neuropticomyclitis) 6. Multiple focal periicnous encephalitis (postvaccinial; postmorbillar; postvaricellar and some cases following other affections) 7 Polo-cncephalitis with glial nodulcs (typhus is a typical example; encephalitis japonica; St. Louis encephalitis; Russian springsummer encephalitis probably also belong in this group; perhaps some cases of Pette-Doring's pan-encephalitis) 8. Diffusc cncephalitis (African trypanosomiasis). Does dementia paralytica belong here or under 3? 9 As yet unclassified cases. I will add for the sake of conscience, and as seen from a clinical standpoint 10. Encephalopathics, with hyperacmia, ocdema, haemorrhages, degencration, oligodendroglial reaction, reticulo-endothchal proliferation, le, the so-called haemodynamic syndromc of van Bogaert (1947), Link and Schleussing (in Handbuch der Spez, Pathol Anat Bd XIII, 2, P 205, 1958) regard para-infectious encephalomyelitis of varying ongin as a separate group of leuco-encephalomyelitis. This brief enumeration sufficiently shows that no classification satisfactory to the clinician, the pathologist and the epidemiologist has hitherto been made whether this will be possible when the aetiology of these diseases is understood, remains to be seen For nosological purposes the word diffuse had better be discarded, as it is used sometimes meaning multiple (as in peris enous encephahtis ·10 INTRODUCTION I following vaccination, which consists of rather sharply demarcated lesions, with normal parenchyma between the foci). Otherwise the term diffuse must be reserved exclusively for changes such as seen in dementia paralytica. The names leuco- and polio-encephalitis do not imply an absolutely sharp localization in either of these structures; generally this distinction is only valid in the cerebral and cerebellar hemispheres, and it is then of a certain value for classification In the deeper structures, leuco-encephalitis of vaccinial origin is also widely present in the grey nuclei, as also in other diseases included in this group. Again, in poliomyelitis of the Heine-Mledin type, lesions in the white matter of the spinal cord and medulla oblongata are rather common. Our aim in the future must be to determine the pathological changes that are specifically found with a certain etiology, not only in post-infectious disease in general but also those connected with the more elementary aetiological factors. These can obtain in the individual, e.g. a certain degree of specific immunity to the infection; allergic disposition; acute or subacute reaction; general weakness; sensitization of the brain due to previous trauma or disease; coincidence with other vaccinations or seruin injections or diseases which often show nervous complications (e.g. whooping cough), etc. On the other hand, differences in the virus may be important: neurotropic strains; dose of virus at the side of invasion; portal of entry and perhaps mutants, with some specific characteristics. The medium in which the virus is transported may also play a certain róle. This brings us to a consideration of the value of slight deriatrons from the normal type. In a few cases of postvaccinial encephalitis, topical loss of groups of large ganglion cells is found; in others, the incubation period is much shorter or longer than is usual; large lymphocyte cuffs may be present, etc. In these cases we should not confine our. selves to saying that the case is atypical, or that there are complications, but we must look for the additional factors in the actiology or pathogenesis, as discussed abose. The course of the disease may be altered by high fever, by con- ·CLASSIFICATION 11 vulsions with focal destruction of nervous tissue or by marked hyperaemia with small hacmorrhages or with oedema of the brain. The changes found at autopsy in these cases should not all be ascribed to the primary disease! We believe that when all these things will be known, we shall no longer say that any kind of infection in the brain can cause any type of reaction, but that a certain combination of aetiological factors always induces the same specific reactions ·Chapter 2 MATERIAL The present article mainly deals with autopsy cases of postvaccinial cncephalitis that occurred in the Netherlands after 1925. With the cxccption of cascs 1, 2, 4 and 6, all were examined by the author, and of those 4 cases satisfactory descriptions were available. Fatal cases without autopsy and those of which no slides were available for study were excluded from the present study. The material therefore does not lond itself to statistical elaboration Only cases with an incubation period of 21 days or less arc considered, as it is generally accepted that perivenous postvaccinal encephalitis does not start beyond that period. Nervous diseases starting more than 3 weeks after vaccination, are either due to complications (purulent processes, etc.) or are independent of the vaccination. Perivenous encephalitis has not been found in cases with an incubation period exceeding three weeks (see, however, Chapter Vc, case de Busscher and Radermecker). A complete list of our cases is given in Table I (p. 13) The frequency of cases during the 34 years covered by this survey was unevenly distributed, this was partly due to external circumvery few vaccinations were performed after compulsory vaccination was stopped in 1930 Then the age of primary vaccination was lowered from about 5 years to the first or second year of life. In recent years, from 1952 onwards, more attention has been paid to cases of cerebral damage following vaccination which were clinically atypical, either with a very short incubation period, or with a different clinical picture. This explains why many cases of this period showed a pathology other than pervenous encephalitis. In addition, human material of other types of encephalitis could stances ·BEITERIAL 13 TABLE I DUTCH ALTOPSY CUES OF POSTI CCALL COVPLICATIONS INDITIIN IRTI P = Primary vaccination. R- Revaccin, Vaccini Seneralit * Microglia enc. -= Other patholog). baltor days Cau. Jlaroglia en ophalın Tror Death follo.cine CIN, dus T'accur. 1 1925 11 2 3 y. 5 y. 5 y. 12 1926 10 13 1 3 + 5 6 1927 12 16 20 16 19 21 59 1 12 5928 P. 1 P 1 13 (1 10 8 9 1929 10 3 y. 5 y 3. 4 y. 3 y. 5 y 7 y 13 Y 13 Y 13 y. 29 y. 4 Y 4 y 62 y 10 Y 14 9 13 6 P R R R R P 1 R P 15 9 16 18 7 12 1930 10 11 1940 [ 1 12 13 14 1S 16 17 18 19 20 21 22 23 24 25 26 27 28 6 mo. 2 ין 3 it 7 mo 20 8 mo, 5 14 1 85 9 mo IO mo 8 y TO mo 19+1 12 6 7 II 1942 19:14 1946 12 13 m 9 mo 29 ·14 MATERIAL, 2 Incubation days Microglia encephalutus Case No. lear Age Death following vaccin. days l'accin. 1947 21 3 y. 8 y. 9 y. 13 12 15 22 14 12 20 10 y. 8 mo 5 5 3 12 9 6 8 1918 1951 1 30 31 32 33 34 35 36 37 38 39 40 41 42 43 41 45 46 47 I 2 5 y 9 mo 19 y. 20 y 20 y. 21 y. 22 y. 26 y. 56 y 68 y. 20 y. 8 mo. 11 mo. 16 mo. ++ | | + + + + +11 | + + + + 13 P P р P P P P R P P P P R R R P P P P P P P 19 15 15 14 19 8 9 13 6 8 9 24 16 1952 17 12 8 8 9 48 10 IT 1954 7 mo. 9 mo 9 mo. 24 mo. 7 2 8 7 24 8 1955 10 20 1957 20 y. 49 50 51 52 53 54 55 56 57 58 13 9 IO TO 10 7 mo. 20 y. 20 y II mo 7 24 0 P P P R Р Р P P P P 7 24 13 5 18 59 60 61 4 mo 14 mo. 17 mo 7 mo 5 18 1958 I2 1955 12 62 1958 6 mo 5 5 ·MATERIAL 15 be used for comparison, as also a number of animal brains with various spontancous encephalitides, viral, bactenal or granulomatous. The experimental material consisted of some experiments, dating from carlier rescarch into the actiology of postvaccinial encephalitis, and some recent experiments Very little material of experimental allergic encephalitus was available for study, A considerable part of the extensive literature has been read, especially to search for abnormal pictures. But we arc aware that many important articles may have escaped our attention.

·Chapter 3 POSTVACCINIAL MICROGLIA ENCEPHALITIS a. General In the introduction it has been mentioned that the name microglia encephalitis will be used for those cases in which autopsy revealed the perivenous type of demyelination and microglial proliferation, excluding abortive cases and the fulminant cases of encephalitis in which only encephalopathic changes in the CN.S. are found after death Some of these cases, however, are grouped by their authors with the perivenous type (see Chapter 6, a). It is evident that only by narrowing down our concept in this way we can try to bring facts together for a final evaluation of the place of microglia encephalitis in the nosological system. It is not the purpose of the present article to give a complete description of the pathology of postvaccinial encephalitis This has been repeatedly done by many competent authors The principal aim of this article, however, is to discuss a number of details as found in the great majority of the Dutch cases, which have come to autopsy and which could personally be examined by us. In Table XIV (end of book) we listed the main facts of microglia encephalitis requiring discussion As demyelination is present in all, it has not been listed. One purpose of this table is to follow up differences in the histological picture in cases of short and long duration The cases are therefore arranged according to survival time after vaccination. The duration of actual nervous illness is given in Fig 18 (p. 135), which shows that there is no correlation between the duration of incubation and that of the actual nervous disease. The typical pathological changes of micrr lis encephalitis are the ·CENERAL 17 following Gmeal hyperaemia of the meninges and parenchyma present doubtful absent in the meninges 16 3 (Nos. 7,27, 33) in the parenchyma 21 1 1 (No 17) It is remarkable that this symptom of inflammation was equally found in the causes of early death and those of fate death, and was even suli present in case 5, in which the nervous sypmtoms and histolognal examination had shown that the patient was on his way to recover before a complication set in. It was sometimes thought that the congestion of the central veins of the foci was more marked in des of more prolonged illness. Dedema and suelling of the brain. General ocdema of the brain was seen in 2 cases (Nos. 41, 53) and a slight cerebellar conus without broadening of the consolutions was found once (No 45. The bruin weight may be found increased (No. 53). In this case the medi!... oblongata was very much enlarged and this ocdema and the side spread encephalitic foci in this region were the main causc of death in this patient (sec history of this case in paragraph b 4). Perivascular oedema was also found sometimes, although seldom, in the encephalitic ſoci. Aleningeal cellular infiltration was present in 24 out of 25 cases The intensity of this infiltration varied with different localizations, without any recognizable rule. The cells were small and large lymphocytes, and sometimes plasma cells were observed. Polymorphonuclear leucocytes occurred in three cases (Nos. 19, 39, 11), but only in two (Nos. 19, 11) in larger numbers. In these patients many congested blood vessels were found, filled with polynuclear cells, this evident represented an early stage of a pyaemic conditon or of purulent meningitis to account for the abnormal picture One of these patients Cellular infiltration of nene roots, as described by Turnbull and by Perdrau, or of the spinal ganglia (Perdrau, Pette), was not seen in had purulent cystites. our cases ·18 POSTVACCINIAL MICROGLIA ENCEPHALITIS 3 Case 39, mentioned above because of the number of polynuclears in the meninges, was somewhat different from the general picture; in some places the meninges contained many plasma cells and large lymphocytes, and a dense infiltration with glial cells existed in the underlying molecular layer of the cortcx Perivascular microglial foci could also be found in all cortical layers at these same places. Observed with low magnification, the picture resembled purulent meningoencephalitis, but the cell type was quite different and the ganglion cells remained normal in the foci (Fig. 1). Fig. 1. Complicating purulent meningitis Case 39 Inflammation of meninge, invading the cortex and spreading along vessels b. Perivascular focal lesions 1. Foci The distribution of the foci along the cerebral axis differs from case to case. In the cerebral hemispheres foci prevail in the white matter, oſten abounding in one lobe (occipital more often than other lobes), and are in most cases also found in the 5th and 6th cortical layers in the upper layers foci are rare and small, sometimes resembling glial ·19 PERIVASCULAR FOCAL LESIONS B stars in the cerebellum a cortical localization of the foci is extremely rare, and the name leucoencephalitis therefore seems justificd. But in all decper structures as well as in the spinal cord, a predilection for the white matter is less marhed F. Lhermitte (1950) points out that the density of myelinated fibres in the grey substance is probably the most important factor. In the white substance, however, the compact parts (corpus callosum, internal capsule, pyramids) are generally much less involved than the more loosely built structures. Finley (1950) thinks that the diameter and perhaps the function of the affected veins is the most important factor. According to him, the upper cortical layers do not show ſoci because they have only small veins, whereas the caudate nucleus, with a similar paucity of myelinated fibres, often contains foci around the large veins In one case examined in reference to this point (No. 53), however, the very rare foci in the caudate nucleus were lying in or adjacent to fibre tracts, perforating this grey mass. In a number of cases (e.g. our case 11) the spinal cord is seriously affected, whereas foci in the brain are scanty. This is especially marked in cases with the clinical picture of transverse myelitis, in most of which only few foci are found in the higher centres (sce b. 5). The opposite condition may also occur. The foci in the subcortical white matter of the hemispheres are found along the reins running towards the ventricle, t.e, the places where we also find the lipochrome pigment from ganglion cell degeneration remaining for a long time. Other places of predilection are the larger veins, running dorsally from the olives, and those dorsally from the anterior horns of the spinal cord, and the median and paramedian veins in the posterior column The subependymal veins of the lateral ventricles are also often the site of larger focs. Sometimes the localization in stem and cord is more or less symmctrical, but in other cases only one half of the medulla is affected (case 37), or we find one olive heavily affected, and the other quite free (case 3). The distribution of the foci is very irregular, a cross section of the cord or brain stem, or even of the subcortical white matter, often shows a mumber of foci lying rather close together ·20 POSTVACCINIAL MICROGLIA ENCEPHALITIS 3 whereas adjacent parts may be free or much less invol ed. As will be discussed later (case 38), this area sometimes seems to be a place of increased vulnerability, due to an older lesion, The total number of foci is generally very large. Their localization, especially when grouped together in larger numbers, is of course important as this may cause neurological symptoms. As Lhermitte (1950) points out, the localization in the deeper parts of the brain stem, in pons and medulla is often responsible for a fatal development, the oedema being perhaps even more dangerous than the microglial proliferation. When many foci are grouped in a small area there is a tendency to coalesce; but generally we can still distinguish the individual foci by which they differ from the larger foci of disseminated encephalo. myelitis Demyelination was present in all our cases and we did not find a conclusive difference in this respect between cases of longer and those of shorter duration. Our slides did not give any clear indication for a solution of the problem whether the microglial proliferation preceded the demyelination or was a reaction to it. Sometimes, however, the picture suggested that the cellular infiltration had been present before myelin changes became evident with our staining technique. But it is very well possible that the microglia is more sensitive to the earliest chemical changes of myelin degeneration than our staining methods are. This question is known to have arisen even in the earliest descriptions of postvaccinial encephalitis, and both views have had fervent advocates. In fatal cases, however, the histological picture is generally already complete; an answer to the question could be found in cases of very early death, or in cases of longer standing with development of new foci during the period of illness The occurrence of these new foci is denied by some authors, but we think there is evidence that this process actually takes place. Roizin and Kolb (1957) approached this problem from the histochemical side and reached the conclusion that there is some evidence of abnormal enzyme reaction to the lipid material before this can be detected by the usual histological techniques ·1. 21 PERIVASCULAR FOCAL LESIONS In our case 5, in which the encephalitis tended to healing, the lesions were rather small and the surrounding normal fibres camc closer together. It may well be that no marked demyelination is visible after complete healing The breakdown products of myelin degeneration were never very conspicuous. The foci never resembled a malacic lesion, with drops of myclin scattered cverywhere. Generally, Sudan-stainablc fatty substances were very scarce in the foci or their immediate surroundings but could be found in the sheaths of sessels at some distance, absorbed by granulc cells. P.A S.-stainable material was only present in the foci in very fine granules or drops. We therefore believe that the glia cells dissolve the larger part of the degenerating myelin by some chemical reaction, which cannot be traced with our staining technique. M. B. Schmidt (1914) explains this as adsorption of the fat onto proteins, which yields a soluble product. In the earliest stages the microglia cells did not contain vacuoles which, however, became evident in later stages (see below). It is therefore certain that the main catabolism of the myelin substance is primarily effected by the microglia cells. Subsequently, oligoglia and astroglia probably take part in this process. Little need be said about the axus cylinders. We found, as previously described by many authors, in some foci, all or nearly all axis cylinders intact, but a certain loss was as a rule visible, especially in larger ſoci The microglia cells are lying free in the parenchyma around the vessels, sometimes their nuclei are elongated and very irregular, and the plasma is also elongated, with many processes. Other cells are shorter and may show more rounded nuclei. The latter type is more frequently seen with the cells lying close to the vessels. As a rule, the cells lying free in the periphery of foci have smaller protoplasmic bodies than the more centrally located cells, but they may also show vacuolation of their plasma (Fig. 2). The origin of the microglia cells could not be determined with certainty, they are probably formed by amitotic division of the pre-existing cells I have never found conclusive pictures suggesting that multipotent vessel wall cells, infiltrating the tissue from the ·22 POSTVACCINIAL MICROGLIA ENCEPHALITIS 3 vessels, develop into microglia cells, as C. de Lange states (1943). On the contrary, in many smaller foci with microglia cells scattered diffusely in the parenchyma, the vascular walls showed no hyper- FIG 2 Microglia cells in a focus, showing vacuolisation of the protoplasın (X) Case 45. Nissl stain trophy, and no cellular infiltration of the Virchow Robin spaces extsted Microglial cuffs existed in all our cases, and generally they were found at all levels of the nervous axis The total number of foci was practically the same in cases of death shortly after vaccination and cases of longer duration. This indicates that the foci de clop at about the same time and that we can expect to find foci of different ages only in cases of short survival. Fatty granule cells were present in u cases, doubtful in 2 and ·PERIVASCULAR FOCAL LESIONS 23 abscnt in 8 cases. The earliest appearance was in casc to: 14 days after vaccination in the later stages their occurrence was constant and their number increased. These cells were most easily recognized by the vacuolated protoplasma in Nissl stains; often the Sudan reaction failed to give clear pictures. We gained the impression that the microglia cells in the periphery of a locus could show vacuolation of the protoplasm while still having the shape of rod cells (Fig. 2). Nearer the central vessel, the plasma processes became shorter and the nucleus tended to a spherical shape. An accumulation of round granule cells in the vessel sheaths, as found in malacic foci, was very rarc. In some cases the lat stain showed that no fat was present in the focus but that the csscl sheaths at some distance contained granule cells laden with fatty substances All granule cells originated from glia cells, there was no evidence that the mesodermal tissue also took part in their formation. Myelin lumps, as found in malacic foci and in fat embolism, were not present in our cases, evidently the myclin degeneration took place along another line of disintegration than in those diseases. No definite explanation of this can be offered. It might be possible that from the start the microglia cells were more activc in changing the myelin into soluble substances, or that myelin degeneration was more gradual But it is also possible (even probable) that other enzymes are active herc, and give another catabolic product than in malacia As already stated, material stainable with the PAS method for polysacchandes was present in the foci only in very small drops, and was also rare along the vessels. However, pink staining patches of 5-15 u were present in many fibre tracts, independent of the focal lesions It is not certain whether this must be considered pathological. Lymphocytes The small lymphocytes must be discussed in some detail because uncertainty about their function still exists We group here the cells with a small, round and darkly staining nucleus and very scanty protoplasm. In the dense cellular aggregates around vessels, it is always difficult to determine the size of the protoplasm and several cells included by us in the lymphocyte group may have been micro- ·24 POSTVACCINIAL MICROGLIA ENCEPHALITIS 3 glia cells in a stage before the nucleus enlarged, but after it had resumed the spherical shape. In the table we have listed separately the lymphocytc cuffs around vessels without microglial proliferation (giving a picture as regularly found in common virus encephalitides) and the microglial foci, with lymphocytes and without them. It is quite evident that simple lymphocyte cuffs were very rare in our cases. In case 9 the child was affected by whooping cough before vaccination took place; in case 37 typhoid and cholera vaccinations were given during the incubation period, and case II suffered from purulent cystitis several days before death. This suggests that the occurrence of lymphocytic infiltration is due to, or at least increased by complicating toxi-infectious conditions. Lymphocytes mixed with microglia in the foci occurred fairly regularly, but in several of these cases bronchopneumonia was the cause of death, or septicaemic conditions existed Comparing the number of foci without lymphocytes with the foci in which these cells were present, we gained the impression that the small lymphocytes are not an essential part in microglia encephalitis. They are not more numerous in the later stages than in the carliest stages, or the reverse, as stated by B. and K. M. Walthard (1958, p. 789). Large lymphocytes and plasma cells were sometimes noticed; this does not require special discussion. Polymorphonuclear leucocytes were rarely found in the foci. It was sometimes difficult to distinguish the very irregular nuclei of microglia cells from polynuclears but generally the latter cells have smaller nuclei. The round and well-defined protoplasma of the polynuclears, however, can easily be recognized in Nissi-stained sections when only haematoxylin-cosin sections are available, however, distiction may be very difficult. I ve that many statements confirming the presence of polymorphonuclears in foci of microglia encephalitis are due to this difficulty (e.g. Wiersma). We found them only once in our material; more often, however, in the meninges (3 times), but always in small numbers The central vessel is generally a vein of rather large diameter, and the impression is gained that the larger foci are lying around the larger ·B PERIYASCULAR FOCAL LESIONS 25 veins. Alicroglial proliferation is seldom found around an artery (case 3) and there is never a capillary as the centre around which microglia is arranged. We find, on the contrary, normal capillaries and smaller veins running through a focus without evident connection with it. The central vessel is generally filled with normal blood and the vascular wall shows no important changes However, in later stages or when destruction of the parenchyma is marked, some proliferation of the vessel wall can be found. This was also the case in No. 37, in which revaccination was given at the same time as injections against typhoid and cholera. 2. Earliest stages In the literature it is generally accepted (van Bogaert, Scholz, Lhermitte, Radermecher) that perivenous encephalitis de clops after an initial period of less obvious lesions of a more encephalopathic character. We do not think that the findings in our cases point in this direction. Since death from pervenous encephalitis generally occurs on or aſter the 13th day following vaccination (see Fig. 3), these very early cases were regarded by the authors as running a fulminant course. When discussing this question, we have to separate the cases in young children (under 2 years of age) from the older group, because in these young children pervenous encephalitis has never been observed and it would be illogical to surmise that only fulminant cases occur, with a pathology differing from the picture in more prolonged cases. The cases in young children therefore belong to a special group, which will be fully discussed in Chapter IV b, on children under 2 years of age. This also pertains to the case of Rohmer, Sacrez, Rohmer (1947), cited by Lhermitte. 1 2 3 4 5 6 Survival m days Number of cases 23. 10.9.202.22 411134 2 FIG 3 Survival time after vaccination in the Dutch cases of mucroglia encephalitis ·26 POSTVACCINIAL BICROGLIA ENCEPHALIT 13 3 The literature contains reports on 2 cases in older patients, described as fulminant cases of perivenous encephalitis, riz: a case by de Lange (1948) and a casc by Doring (1942). A case described by Wigand (1911), following the eription of rubella exanthema, is also regarded by the author as a very early case of periv enous encephalitis. Alany other cases have been described in which histopathological examination only showed encephalopathic changes; these were not considered carly stages of perivenous encephalitis, but regarded as another reaction in posevaccinial encephalitis Complete understanding of the nosological place of these so-called fulminant cases can only be attained by comparing them with the earliest cases of well-developed microglial encephalitis. We will give the data on the 3 aboiementioned cases, and compare them with 2 Dutch cases and the case described by Kokken (1937) (Tablc 11). Hassin and Geiger's patient also died on the 13th day after an illness of 31 hours, showing the typical microglial picture TABLE II DATA OF SO-CALLED FULMINANT CASES AND OF EARLY MICROGLIA ENCEPHALITIS Case -Age in years Incubation Death in days after racın 6 6 de Lange Doring IVígand 5 27 Encephalopathy 13 TO 13 3 after eruption exanthena 10 No 9 No. 19 Pertichous Enc 3 10 10 31 13 13 Kokken 17 Death from microglia encephalitis in the Dutch cases occurred on the sith to the 22nd day (Fig 3). Case C. de Lange. 1948 Girl, born 1313 41 Jother sullered from rubrbla cluring pregnancy in the family cases of Buerger's disease occurred The ·B PERIVASCULAR FOCAL LESIOXS 27 chuld was healthy; vaccinated (primary) on 20.5-47. On May 26th she was noted to be drowsy, then had a convulsion and died that same day. Autopsy about 36 h post mortem (Dr Straub) showed hypersemua of the organs; the thymus was too large for the patient's age. The hypophysis contained few basophilic cells, both eyeballs were atrophic. The brain showed general hyperaemia but nosnelling. At microscopic examination the meninges contained some mononuclear cells, diffusely distributed; many vessels perforating the cortex from the pia also had a slight increase of perivascular lymphocytes. In the brain the small round oligoglial nuclei were often arranged in rous along capillaries in the white matter or deep structures. There were no focal perivas. cular lesions and no demyelination along veins of the diameter generally affected in perivenous encephalitis. These oligoglial nuclei were ofteri surrounded by a small amount of protoplasm No microglial proliferation cxisted and mild destruction of myelin was found in some parts, where bacterial growth in the brain was evident. These bacteria were sometimes found around Vessels (which themselves did not contain the microbes) and in other parts in large areas of the deeper structures. The growth was evidenth prost mortem, but indicates an existing pyaemic condiuon The pathological changes found in this case point to a toxr-infectious condition, occurring shortly after vaccination and probably caused by some bacterial infection No changes were found which could suggest early perij enous microglia cncephalitis. Case Dīring 2, 1942 Male, 27 years, found dead 13 days after revaccination without any preliminary symptoms Autopsy failed to show any marked changes in the organs, except oedema of the lungs The brain showed the typical picture of encephalopathy oedema. lymphocytic infiltration and slight diffuse proliferation of the glia There was no microghal proliferation around the vessels but some was seen more diffusely in the parenchyma The meninges showed hyperaemia and slight lymphocytic infiltration Case Wigand, 1941 Boy, 10 years old, died 3 days after eruption of a measles rash 3 months earlier he had suffered from acute otitis On the third day after the eruption the condition aggravated, motor unrest and paroxysmal movements were noted, with eye muscle paralysis to the left Patient died the same das Autopsy showed an enlarged thymus, haemorrhagic pneumonia, infectious swelling of the liver spleen and kidney's The meninges were found normal, ·28 POSTVACCINIAL MICROGLIA ENCEPHALITIS 3 without signs of inflammation, Cuffs around vessels were found in the Virchow- Robin spaces, consisting of lymphocytes and plasma cells, with some degree of oederna, but without microglial proliferation or demyelination The sesse! walls were hypertrophic in some places. In his discussion Wigand states that the pathological picture is different from that in the perivenous type of encephalitis, and rather resembles the types found after whooping cough, influenza, etc. Although Wigand says that most cases of encephalitis following measles have a very short incubation period, he considers his case to run a fulminant course. Other cases may show the perivenous type of inflammation. Wigand thinks that status thymico-lymphaticus may have been a factor predisposing to hyperergic reactions and that haemorrhagic pneumonia is also a complication of the measles. According to Wohlwill, encephalitis following measles generally occurs in patients suffering from haemorrhagic pneumonia. These authors, as shown, do not discuss differential diagnosis in their cases. It is not clear why they do not group them with postinfectious encephalopathies, but rather with post-vaccinial perivenous encephalitis We will summarize two early Dutch cases (the data on a third child are insufficient) and add the case described by Kokken. It must, however, be borne in mind, in cases of early death, factors may be contributing to a quickly fatal course which are independent of the vaccination, and therefore might complicate the pathological picture. Case 9 A boy. 31 years old, was vaccinated (prunary vacc ) on August 6th, 1929, when symptoms of whooping cough were already noted and treated by 4 injections of antiserum On August 16th the child fell it with fever and had a convulsion during the night Vext day stiffness of the neck was noted; Babinski sign on both sides and a soporous condition with high feser (40.8”). He died the same evening. Autopsy of the body showed a normal pustular vaccine reaction, but was otherwise negatne The dura malet showed increased senson, the brain was hyperactic At tcroscopic examination the blood vessels were congested, a few red blood corpuscles were found in the Vircho-Robin spaces. Yo marked penvascular dedema was noied Vany blood sessels containted bacıllt, which had ·B PERIVASCULAR FOCAL LESIONS 29 in most places already left the vessels to be distributed in the parenchyma. Evidently this was a post-mortem phenomenon, but some foci were found in which polynuclears could be seen around the vessel The patient must have had Pyacmia before death The foct of pervenous encephalitus were typical in most places, consisting of an increase in glia cells, widely scattered in the parenchyma, generally without cellular cuffs in the Virchow-Robin space. This space was cften difficult to distinguish The nucle of the glia cells were round or oral, some had the typical irregular shape of the microglia nuclei The protoplasm showed many processes in various directions. In these ſoci derny clination was present only in the central parts. Xo foci were found with demyelination without cellular infiltration, but there were foci in shich slight cellular infiltration in the parenchyma existed around a vessel, without demonstrable loss of myelin In places covering the sulci, the meninges were infiltrated by small and large lymphocytes and plasma cells, many smaller vessels entering the cortex showed some increase in small lymphocytes in their sheaths This was most marked in the superficial cortical layers The vessels of the deeper layers and the white matter were generally normal in appearance The peris enous foci differed greatly in size, in the smaller foci the glia cells in the surrounding parenchyma were more menly distributed than in the larger foci, where a concentration close to the vessels was obvious. In these larger ſoci, more clongated and spindle-like nuclei were present than in the smaller ones. It is very suggestive to regard the larger foci as older than the smaller ones, and then the change in shape of the nuclei and their distribution around the central vessel are important factors in their des clopment. Lymphocytic infiltration was only very small or negligible Haemorrhages were not found in the hemispheres in this case, but around a few thrombosed vessels in the brain stem, erythrocytes were present in the Virchon-Robin space This is thought to be due to the complicating whooping cough Case Kokken This author described the following case in 1937. A boy, 10 years old, who suffered from whooping cough at the age of 5, and subsequently scarlet leser with otitis, showed some progressise mental deterioration He was revaccinated on 15 10 1936 with normal skin reaction and remained in good condition until 26 10 when severe headache started Next day general weakness developed, followed by sleep or a period of unrest Then coma came on, and he died on 28 10, 13 days after the saccination Pathological examination showed enlargement of the spleen, which was soft, haemorrhages in the lungs, ·30 POSTVACCINJAL MICROGLIA ENCEPHALITIS 3 but no important changes in the other organs The brain was hyperaemic. The meninges were slightly infiltrated by lymphoid cells In the brain a great many perivenous foci of microglial proliferation were seen, mostly very small but some of them already larger. Many of them resembled the embolic type of lesion in size and shape, but they consisted only of microglia cells without lymphocytes or polynuclears, and no vascular changes were found. The glia nuclei were mostly small and round, sometimes slightly elongated, irregular forms were also found, generally lying in an irregular prolaplass. Demyelination was already very marked, No fatty degeneration products In the corter a few glial nodules were found. Case 19 A girl, born 22 6 1930 was healthy before the primary saccination on 1.12 1910 Thepoxpustules des eloped normally, and the child was well until 13.11, when in the evening she became comatose and showed twitching of muscles. She had fever, and perspiration and salivation were increased. The C.S F. sample obtained on 24.11, contained 956/3 cells and Pandy and Nonne reactions were positive She also shoned meningeal irritation: stiffness of the neck and Kernig's sign No pareses were noted and the muscular tonus varied Gradually the temperature rose to 40.29 Respiration was irregular, the patient was sometimes cyanotic and she died on 1511, of oedema of the lungs Myoclonic twitching had been noted throughout the period of observation Autopsy of the body was essentially negative The brain showed some degree of hyperaemia, and was swollen, the brain weight, however, was 12865 At microscopic examination the meninges, covering the hemispheres, showed a marked infiltration with haematogenous cells, consisting in many places of a majority of polymorphonuclears. In other places small and large lympho cytes and plasma cells could be found in greater numbers No bacteria were seen. Many vessels, entering the cortex from the meninges, shoned hypertrophy of the wall and some slight periyascular infiltration by small round cells. These changes were also found in some vessels in the deeper cortical layers and in the white matter, in which stasis of the blood with clotting was sometimes also seen Then the architecture of the corter in some places was disturbed by widespread atrophy of ganglion cells; in the occipital cortex mort marked in the bottom of a fissure The threc phenomena mentioned (polynuclears in the meningcs, vascular wall changes and focal ganglion cell loss), do not pertain to the typical picture of peris enous encephalitis. They probably point to ·B PERIVASCULAR FOCAL LESIONS 31 complication by some other infection, and the results of circulatory deficiency with hypoxia due to oedema of the lungs IVc especially stress this, because the early death in this case, as in both preceding cases, is due to a complication and has no direct connection with the pathogenesis of microglia encephalitis In the sheaths of some cortical vessels, lipochrome pigment is present in phagocytes and one mesodermal scar was seen adjoining a vessel, probably an organized thrombosis of an artery; the surrounding tissue also contained old blood pig. ment. Nodata are available to determine the age and pathogenesis of these lesions He will now turn to the focal changes (material from the corte only was preserved). There are a great many subcortical perivenous foci, mostly rather small and sharply demarcated from the surrounding tissue The central vessel 13 enlarged, with normal endothelial cells or some hypertrophucd cells. A few plastia cells can sometimes be found in the Virchow-Robin space, whereas small dark nuclei are scattered in the parenchyma, their number, how cacr, is cry small. Probably they are small lymphocytes Polymorphonuclear leucocytes are not seen. The glial nuclei in the smaller foci are round, oval or slightly irregular, in the larger foci many more integular forms are seen, often suggesting very actue amitotic division Mitoses are very rare It is difficult to differentiate between oligoglial nucle and the round microglial nuclei, the size of the latter is more variable and generally the nucleus is darker, but often we cannot tell one from the other Demy clination in the foci is quite typical Summary The examination of these 3 early cases can be summarized as follows a. The microglial cuffs are already present on the eleventh day after vaccination; b They gradually increase a little in size and do not all start at the same time, but probably during a short period, c The microglia cells migrate from the tissues to the vessels and around these, increasing in numbers at the same time, mainly by amitotic division, d Small lymphocytes or other haematogenous cells play a minor rôle or are absent; there is no indication that they should precede the microglia cells, as stated by Lhermitte (1950) ·32 POSTVACCINIAL MICROGLIA ENCEPHALITIS 3 c. Demyelination is not found without microglial increase, whereas the latter may be starting before myelin loss can be demonstrated. f. General hyperaemia, slight perivascular oedema and some lymphocytic infiltration of the meninges are generally present. These findings are about the same as those seen in many cases of encephalopathy, but also in toxi-infectious conditions in patients dying from cerebral diseases. g. The carly death in thesc cases is probably due to the combination of perivenous encephalitis with other factors whooping cough, polynuclear exudate in the meninges, pyaemia in the agonal stage. Comparing the 3 microglial cases with the 3 cases called fulminating by their authors, it is at once evident, that Doring's case, with death on the 13th day, was not one of perivenous encephalitis, because the microglial changes should have been fully developed at that time but were absent in his case. The cases of de Lange and Wigand do not show any changes that could suggest early demyelination or microglial proliferation, but only the common changes seen in toxi-infectious conditions (this point will be more fully discussed in Chapter 4 on the Pathology of postvaccinial death without microglia encephalitis). In the 3 cases of very early death in microglia encephalitis, the localization of the focal changes was typical of this disease, and no affection of the upper cortical layers was found, which could point to the encephalopathic lesions, as found in the so-called fulminating cases of Doring, de Lange and Wigand Furthermore, death in the early microglial cases was not due to this disease, but to a complicating bacterial infection, and no continuity exists between the time of death in the fulminant cases and in true microglia encephalitis, which we should expect of the two differed only in the acuteness of the disease. We can therefore add to our summary: h. The early cases of microgla encephalitis show the fully developed histopathological picture. So-called fulminant cascs from the literature must be distinguished, and they are not preceding stages which-if life had not been terminated--would have developed into microglia encephalus ·B PERIVASCULAR FOCAL LESIONS 33 Lale stages The carliest cascs, described abouc, suggest that some specific factor acts from about the gth or roth day (or cven earlier?), causing changes which, in the first period, are gencrally not sufficiently senous to cause death, unless secondary infections are added as complications, or other noxious conditions are pre-existent. 3 The pathology of the final de clopment of pervenous encephalitis is well known Malamud (1937), v. Bogaert (1950), Lhermitte (1950), Scholz (1957), give the following as essential points: The gradual change of thc microglial syncytium into fatty granule cells, with accumulation of these around the central blood vessel and the effluent \cns. Generally the foci show a tendency to coalesce and finally the number of infiltrating cells decreases At the same time thc astroglia proliferates and may produce sclerosis which, however, is never as dense as in foci of multiple sclerosis. Some authors state that in the later stages lymphocytes are scarce or absent. Most authors agree that perivenous encephalitis is not an intermittent disease. Puntigam and Daimler (1950) found that, of g soldiers who had recovered from encephalitis after primary vaccination, not one reacted to reaccination with cerebral symptoms. Very few cases have been histologically examined long enough after recovery to allow of a clear insight in the final outcome Russel and Oddie (1928), in an article on a fatal case postvaccinial encephalitis, descnbe a child aged 9 years, dying 26 days after successful primary vaccination The incubation lasted about ten days and the clinical course showed cerebral symptoms with coma, lasting until death Autopsy showed swollen glomeruli in the kidneys, but no encephalitis The brain was hyperaemic, but no cellular perivascular cuffs or microglial infiltration was present The authors considered uraemia a more likely cause of death than encephalitis, which was definitely not found. This case is sometimes reported in the literature as an exampleof complete healing of encephalitis, but it is most improbable that encephalitis should have originally existed and have healed out in so short a time. Generally the hustological changes are still very marked aſeer 3 weeks.

·34 POSTVACCINIAL MICROGLIA ENCEPHALITIS Herckenrath (1935) described the case of a girl, 5 years old, who had been vaccinated without result in her first year and was revaccinated with goox result when 3 years old. She had suffered from a convulsion, when 2 years old and had varicella a month prior to the revaccination. On the 6th day following this, she vomited and again had a convulsion, which resulted in left-sided hemiparesis. A week after the vaccination, vaccine virus was cultured from blood and spinal fluid. The latter contained 10/3 cells but was otherwise negative She had more convulsions, but was considered well 2 months after the revaccination. The hemiparesis gradually disappeared but some speech difficulty remained She died from an intercurrent disease, 14 years after the revaccination. Microscopic examination revealed many fatty granule cells around the vessels in the white matter but no demyelination was found. This case, of course, is not conclusive, as the clinical picturc of postvaccinial encephalitis was not of the typical perivenous type; more probably it was the vascular, oedematous or haem agic type. Case l'an Bogaert 2, 1950 A girl, 9 years old, had at the age of 6 years diphtheria with polyneuritis. Tuo months later she suffered from measles, with encephalitic symptoms. diplopia, ptosis, nuchal rigidity and pain in the legs in addition, choreatic movements existed in the right arm and she showed a double Babınskı sign The C.S F was normal The child gradually recovered without sequelae, and died 3 years later from another type of acute encephalitis Histological examination showed no scars or lesions, caused by the post-measles encephalitis. Clinically, this had been a rather mild case but the diagnosis perivenous encephalitis seems justified. In his studies on post-measles encephalitis Malamud (1937, 1939) describes the brains of parents, dying 5 years and 4 years respectively, after recovery from the encephalitis. Both cases ran a serious course at first, with hemiplegia and mental retardation as late sequelae Aſalamud found, at pathological examination, perivenous demyelination still present in the typical distribution, with fibrous glial hypertrophy in the fucı and marginal in the spindl cord Microglia cells were no longer found The contradiction between the cases of van Bogaert and Herckenrath and those of Mfalamud, can be explained by more serious microglial lesions in the latter's cascs, or by a haemorrhagic complication. I'c will try to show in our material that both explanations may be true in one case or another, respectus ely.

·B PERIVASCULAR FOCAL LESIONS 35 When examining the literature and our own cases, ue feel that a distinction should be made betreuen patients dying from encephaltis and those cases, in which a complication has ansen, causing death a few days after the beginning of recorery from the original disease. Some differences in the histological pictures can then be easily explained. It is also interesting to recall that Grossmann and Humbert (1955) found E.E.G. changes still present a long time after clinical recovery from postvaccinal encephalitis. This probably indicates a rather slow scar formation and absorption of the degeneration products. Cases of about 3 to 4 weeks' duration have been described by many authors and only a short summary of some of these will be given here. Case Il'uersma 10, 1927. Boy, 5 years Primary vaccination. Incubation 12 days. Encephalitis ran normal course, condition improved but on 17th day fever returned, with increasing coma and stifịness of the neck. Death on 21st day Many polymorphonuclear cells were found in the pernascular infiltrations. Many microglial foci were smaller than in his earlier cases. It is very well possible that the chuld was already recovering from the encephalitis when an intercurrent disease caused a flare-up of the symptoms. This could also explain the polymorphonuclears found by the author. Case Suppan 6, 1937 Girl, 12 years Revaccination with normal skın rcaction. On the irth day fever and clinical encephalitis. Then Improvement unul the zoth day, when cardiac insufficiency de eloped and caused death on the 22nd day. Many loci without demyelination but with phagocytes and fatty granule cells Oedema of the brain. Typical microglial foci elsewhere. Evidently this patient was on the way to recovery when cardiac fatlure caused death. Case Perdrau 2, 1928, mentions that the foci were less cellular than in his case of shorter duration Case Laffer, 1939 Girl, 5 years. Three days after vaccination headache and abdominal pain, which were progressive l'omiled on 13th day, and became somnolent and hypertonic 3 days afterwards then she showed choreatic movements and remained in this condition until death on the 30th day, duc to circulatory collapse Autopsy showed oedema of the organs Foci with marked demyelination and loss of axis cylinders Coalescence of the foci. Many fatty granule cells in the foci and along the sessels No microglial syncytia Some fibrillary gliosis In addition, larger foci of destruction were found which, according to the author, should be considered vascular in ongin Subependymai

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·38 POSTVACCINIAL MICROGLIA ENCEPHALITIS 3 Fatty granule cells were definitely more conspicuous in the later stages, but were found occasionally on the rith day in small numbers and in only a few of the foci. We found no indication that granule cells should develop from connective tissue cells, as they do in malacic foci. Their phagocytic activity starts early in the process, and at a certam distance from the central vein. A migration of the already vacuolated microglia cells from the periphery to the central vein can be deduced from the pictures. The cells are finally found in the vascular sheath, taking the shape of rounded granule cells but often still showing the irregular form of their nuclei (as also stated by Greenfield, 1958). No evidence was found that these cells relay their breakdown products to other cells, as supposed by some authors. The smaller foci do not show granule cells of fat or fatty acids in the Sudan stain, but we may find elongated and irregular microglial cells with small vacuoles in the protoplasm. This probably means that part of the waste material in the foci is taken up by these cells, and broken down further to transportable products without a stage of demonstrable fat or fatty acids. In the larger foci the amount of degenerated myelin is greater than can be dissolved by microglia (and oligoglia?) and the well known picture of fatty granule cells results. I have the impression that here, as well as in other degenerative diseases, the invisible way of myelin breakdown is the more natural process (de Vries, 1958) which, only when insufficient, is aided by breakdown to stainablc fat products, which can be found for long periods lying at the site of the focus or along the larger veins. Summanging the observations on the late stages of the disease, we can say that the smaller foci probably disappear by a process of invisible myelin breakdown, without recognizable scar formation or remaining demyelination. These processes, however, become evident when larger lesions have been present. As will be discussed in the next paragraph, intercurrent diseases, often the cause of death in cases of longer duration, may add additional features to the histological picturc and, in cascs which ultimately recover, these changes may be the anatomical basis of clinical sequelae.

·B PERIVASCULAR FOCAL LESIONS 39 4. Influence of intercurrent diseases Repeatedly we have had occasion to point out that the occurrence of some peculiar histological picture coincided with additional aetiolo. gical factors Proof of a connection between these was difficult to give, but the possibility often struck us. This problem is closely connected with the possible influence, exerted by degenerative or toxi-infectious conditions, existing before the vaccination, on the outbrcak of nervous symptoms and their course and histological changes. This will be more fully discussed in paragraph f We will first discuss the occurrence of haemorrhages. Erythrocytes were occasionally found around dılated veins, but this was not thought to be important, because invariably these cells were quite fresh, evidently an agonal occurrence due to the marked hyperaeria There was no typical localization sometimes they were found in the cortex, sometimes subependymally or elsewherc In our case 9, the child had whooping cough when vaccinated. He also showed a few ring haemorrhages. Cases 38 and 37 both had scars from older brain lesions around the occipital horn, with haemorrhages in this region, and case 37 received other serum injections during the incubation period of the perivenous encephalitis. We also noticed in his brain old blood pigment around some of the intracerebral vessels, suggesting a healed, older lesion Case 41 had rather extensive hacmorrhages in the spinal cord, medulla oblongata, and pons, all were fresh and lying in the Virchow-Robin spaces This patient died of pneumonia on the 22nd day Finally larger haemorrhages were found in our case 53, which will be more fully discussed below. The five cases of our series in which haemorrhage was found, therefore, all show some infectious cause or predisposition which can have caused some damage to the vascular walls, resulting in diapedesis of erythrocytes The small haemorrhages are caused by an increased permeability of the vascular walls, as part of a nutritional disturbance The smaller foci, consisting of a few crythrocytes, are probably the result of stasis of the blood in the dilated vessels during the agonal stage of the disease They probably have no importance for our conception of the ·40 POSTVACCINIAL MICROGLIA ENCEPHALITIS 3 pathogenesis of the disease of the brain. However, it is known that a small amount of blood, lying outside the blood vessels, can disappear in a very short time without leaving old blood pigment or any reaction of the tissues. It is therefore possible that, when we find these fresh haemorrhages at death, others had already preceded them, We generally make a distinction between these haemorrhages and the so-called ring haemorrhages, although Nordmann (1957) and many others regard the latter as the result of more serious damage to the vessel, but with the same pathogenesis. Here the lesion of the vascular wall is of longer duration and partial necrosis of the perivascular parenchyma ensues, around which the erythrocytes assemble, while oedema and glial reaction can soon be seen in the periphery. This picture, which is well known in a number of toxic encephalopathies (salvarsan, etc.) and is also scen in haemorrhagic encephalitis following influenza and other infections, can develop in a very short time (1-3 days). When the glial reaction around the small haemorrhagic focus is large, the picture may simulate a microglial perivenous focus, as in our case 14 (sec Chapter 4c, Figs. 8 and 9). Also Fig. 5 of Crome's (1954) article on encephalitis during an epidemic of influenza suggests such a microglial focus. But very similar pictures can be seen in cases of fat chibolism, where certainly no toxic or infectious factor plays a róle Crome himself considers his case to belong to the group of infectious haemorrhagic encephalitis. We will now describe a case in which opucal microglial foci occurred besides Opical haemorrhagic foci. We think that the latter are due to concomitant bronchopneumonia. Case 53 A soldier, born May 16th, 1923, had no significant illness before his first smallpor vaccination on 7 8 1957. The skin reaction was normal Fever was noted 12 days later, and on 20 8 he was soporous, slightly delirious; he vomited and had some stuffness of the neck, he was then admitted to the Military Hospical* The pupils here equal and reacted 10 treht, No paresis of ocular muscles was found. Neurological examination showed slight general hypersensitivity, no motor disturbances but a positive Kernig sign. The spinsi . Thanks are due to the Director of the folitary Hospital in Utrecht for his kind permeson to use the case histors ·B PERIVASCULAR FOCAL LESIONS 41 Auid contained go3 cells per ml; Nonne and Pandy reactions slightly positive; protein 52 mg/100 ml, glucose 0 92%; gold sol and masti« cunes showed only very slight changes. An injection of y-globulin was given on the day of admission The EE.G, taken 21.8, showed bilateral A-activity and other changes, suggesting a pronounced discuse of the brainstem, with relatively intact cortex. As the temperature was 40.7°, hibernation was started with hyderginc, largactıl and cold compresses The respiration became difficult, but improved after tracheotomie Injections of penicillin and streptomycin were gyven, also cortisone and ACTH In the following days the condition did not improve: respiration was very difficult, with secretion of mucus and oedema of the lungs Gradually spontaneous respiration stopped and artificial respiration was started. Thc pulse rate increased and the patient showed cyanosis. The downward course did not react to any therapeutic measures and the patient died of heart failure on 278 Autopsy. There was some necrosis of the trachea, probably due to the tracheal cannula, with haemorrhages around it Then bronchiolitis and bronchopneumonia were found. These were probably due not to viral pneumonia but to a bacterial infection The lungs were very hyperaemic and oedematous. The other organs showed no important changes The muscles and the heart were normal at histological examination The brain weighed 16958 (1 month after death, fixed in formalın), the consistency was good The consolutions were broadened and the fissures less clear The medulla oblongata and pons were larger than usual and a cerebellar conus was also found Pia and brain were hyperaemic, and frontal sections showed punctiform haemorrhages. The detailed histological examination of this case may be interesting because of the long survival of the patient, due to the therapeutic measures Hibernation, tracheotomy and artificial respiration have probably kept this patient alive at least 3 days longer than in comparable cases in the past the chief histological conclusion was that microglial foci and haemorrhagic foci existed separately in thus brain and that they were seldom mixed We will start with a description of the haemorrhagic foci (Fig 4) The distribution was as follows No foci occurred in the cortex or central mass of the semioval centre. The corpus callosum shoved several haemorrhagic foci, especially in the genu and splenium None in the lateral radiations Internal * We thank the Department of Pathology for their kind permission to us the results of ther examination ·42 POSTVACCINIAL MICROGLIA ENCEPHALITIS 3 capsule very few, but external capsule some larger foci around large vessels The thalamus and lenticular nucleus were free, as were the substantia sugra and the subthalamic nucleus (Luys). Some were found in the mammillary body and hypothalamus, and a large accumulation was present in the pes pedunculi. T201427172 111 11416 to 2011 FIC. 4 Haemorrhagic encephalopathic foci in pedunculus, hypothalamus and corpus callosum. Complication in microglia encephalitis Case 53 The optic tract was not free from haemorrhages either In the pons and medulla oblongata we found some haemorrhagic foci, whereas the spinal cord only contained a few small focı The cerebellar cortex was not absolutely free and some foci were localized near the dentate nucleus in the subependymal white matter Localization in the subependymal glial zone was rare. Character of the haemorrhagic foci l'c can casily distinguish fresh and older lesions by the condition of the erythrocytes Sometimes, eg in the cerebellar cortex fresh erythrocytes were found lying around a small vessel, in its sheath and widels spread in the parenchyma Herc, no blood pigment was seen and the vascular or ghal structures showed no reaction and no necrosis In ·B PERIVASCULAR FOCAL LESIONS 43 the corpus callosum a small focus with well stained crythrocytes showed demyelination without microglial increase or other cellular response, and no blood pigment. In the older foc the erythrocytes were partly decolorized with vaque contours, and black pigment was present as finc granules. These foci showed partial demyelination, but cerahere myelin sheaths were still seen running between the accumulated blood Gla cells were increased in number, with round or oval nuclei, and some more irregular nuclei of microglia. Lymphocytes and polymorphonuclears were scarce. There was no microglial increase outside the demyelinated area, as is always found in the peri enous encephalıtıc foci (Fig 5) FIG 52 FIC 5b To compare haemorrhagic and microglia foci a Nissl stain. b Weil stain for myelin of same area in pons 1 and 2 haemorrhagic foci (in b the erythrocytes black),with sery little cellular reaction 3 Microglia focus around hyperaemic vessel ·POSTVACCINIAL MICROGLIA ENCEPHALITIS 3 A few ring haemorrhages with a necrotic centre were found in the cerebellum and in the mesencephalon. Two haemorrhagic foci u ere seen in the oblongata, probably connected with a vessel, showing stasis of the blood. Fatty granule cells were not found in any of these foci, but an astroglial reaction was evident in some of them. This descriptiore allows us to consider the haemorrhagic foci as dating from the later period of the disease (no granule cells, carly glial reaction) and differing in age. The haemorrhages did not take place in the older microghal foci, and their distribution along the nervous axis was different The pericnous microglial foct. Distnbution. In the spinal cord only a few foci were found, but their number increased orally and more foci were present at the level of the pyramidal Crossing. Then, in the oblongata and pons, a very Jarge number could be seen sometimes, as in the olises and the reticular substance, occupying nearly the entire field The cerebellar cortex was frec, as was the white matter, but the dentate nuclei contained a few large foci. In the mesencephalon all parts showed some lesions. Diencephalon and thalamus were rather seriously affected, as was the internal capsule, but the lenticular nucleus was nearly spared. In the corpus callosum several foci were seen, lying separate from the haemorrhagic foci. The centrum semiovale contained foci, mostly in the subcortical parts, the corter itself was nearly free. The structure of these foci is about the same as in the other cases. There are small foci with few, widespread microglia cells and without breakdown products or fatty granule cells and other, mostly larger foci, with densc cellular culls. These consist of lymphocytes and some plasma cells in the Virchow-Robin space and microglia, mixed with small dark nuclei, outside. Many microglia cells are developing into granule cells and some are found containing fine Sudan. stainable fat droplets This fat is also found in astrocytes and sometimes in vascular wall cells Many pictures suggest that cells are migrating from outside into the vessels and the nuclei of these cells sometimes have the typical dumbbelt shape of the macroglia, sometimes they rather resemble polymorphonuclear leucocytes. Many foci coalesce and seem to form larger ones, due to infiltration of microglia in the surrounding tissue But when ne examine these places in myelin-stained sections, it is evident that practically all the foci remain more or less separate, with a distinct central vessel, thereby still giving an image differing froin that of disseminated encephalo-myelitis The majority of the foci did not contain PAS-stainable material, although small droplets might sometimes be seen in the white matier, stained yellowish ·B PERIVASCULAR FOCAL LESIONS 45 brown with the counterstain, pink droplets were scry frequent, suggesting that some degeneration of myelin was widespread In addition to the described hacmorrhagic and microglial foxi, a more diffuse glial reaction was found in many places This could be a very mild form, as slight enlargement of the protoplasm of oligoglia and astroglia, without increase in the number of cells, more marked with hyperplasia of ghia cells. These diffuse infiltrations were sometimes found between perivenous foci, but in the corter they could also be seen in places where no foci were present. Rows of sinall round nuclei (oligoglia) along vessels were often encountered. They indocate some general reaction of the tissue. Glial stars or "strauchwerk" were not scen in our sections, Margmal glosis, one of the more characteristic changes in mucroglial encephalitis, was found in many parts in the subpial segion, it was slight in the spinal cord, more conspicuous in the medulla and only very slight in pons, higher parts and cortex. The cellular proliferation consisted, in the more thickly Infiltrated areas, of microglja cells, sometimes together with astrocytes, there was some degree of demyelination in other arcas ne gained the impression that this marginal gliosis was due to an increase of the small glia cells (astrocytes), forming the normal outer lining of the nervous system As this form of gliosis is a cry common form of reaction, og to meningitis, etc., it must not be confused with microglial marginal glosis, which is a rare occurrence in other diseases Subependymal ghosis was unimportant in this case, around the lateral ventricles it sometimes formed part of larger foci The choroid plexuses were normal The meninges shoned mild diffuse infiltration with some small and large lymphocytes and plasma cells Summary A man aged 20 years, with no important history of diseases, developed encephalitis 13 days after successful primary smallpor vaccination. Bulbar symptoms soon occurred, for which artificial respiration was started. He died of bronchopneumonia 20 days after the vaccination. Autopsy res ealed bronchiolitis and bronchopneumonia. The brain was oedematous and hyperaemic Microscopically, two types of lesions were found: the typical microglial pertvascular foci, with marked demyelination, and haemorrhagic foci with only partial demyelination and no or a mild glial reaction The distribution of these foci was different and no haemorrhages occurred in microglial foci. It is thought that the haemorrhagic foci were the result of the bronchopneumonia, and were not a part of the postvaccinial encephalitis.

·POSTVACCINIAL MICROGLIA ENCEPHALITIS 3 TABLE 117 CASES OF POSTVACCIVAL TRANSVERSE MIYELITIS Arranged according to age. Dixon's table not included Incubanon Author or Case No 12 15 Hausmann, 2 5 32 Soporous before onset. Recovered. Kaiser Zappert, 17 7 - Complete tranverse myelitis. Recovered Kaiser with sequelae Zappert, 19 7 14 14 Mild delirium, Stiffness of neck. Diplegia Total recovery. No II 7 14 15 P + + Kaiser Zappert, 26 7 - Paraplegia, anaesthesia, Healed. Henneaux Delcourt 8 - 16 P - Hereditary predisposition. Paraplegia; recoiered Kaiser Zappert, 7 9 Paraparests day following playing football 9 15 P+ + Death 20 days after accination Pette. 1936 R + Xo data of incubation. Landry syndrome. Jluluple foci in brain and cord. Resemblance to dessem enceph. myelitis Kramer 18 14 16 P. Started with meningitis Mage 14 R Recen cd other injections at same time, Afyelitis started day after running a race. Strobos - 16 P Worked on board ship until total transverse lesion Recovery sath sequelae. dc Busscher, Radermecker 20 - 28 - Vaccin against smallpox and typhoid, Morseback ride before onset of my chitis. Jutopsy showed mucroglia encephalitis. 19 No 33 12 12 5 20 20 ·B PERIVASCULAR FOCAL LESIONS 47 Incubation Luthor or Case. Vo Miller, Gounelle Miller, 3 21 Holbronk 20 10 HP Soldier Subtotal diplegia After one ). still sequelac 21 16 28 R-- On 16th day mild encephalitis and paresis of legs Partial recovery On 28th day total transverse lesion without encephal. 1ts. Recovered 7 P Soldier. Incomplete transverse lesion Sequelac lasted 2 scars. 26 10/12 R + + Syndrome of multiple spinal foci, and blindness Death after 2 mo 27 32 P + -- Soldier Vaccination and typh A + B. Repeated 9th day. 1oth day paresis during march Continued service unul 33.1 day 30 10 12 R + - roh da, hemiplegia with VII paralysis, then paraplegia I'robably Heine-Medin infection 30 - Vaccination and typh A B Total transserse lesion Rapid recovery with mild sequelac Diron Bakker Viller, 1 10 P This case therefore throws some light upon other cases, in which haemorrhages or other signs of vascular wall changes are found, and which are generally described by their author as another kind of lesion due to the same disease. We think that it is erroneous to attribute the changes under discussion to the vaccinia or the factors causing peris cnous encephalitis, but that they must be seen merely as a complicating syndrome A consideration of the pathogenesis of post- Vaccinial encephalitis should not, therefore, lay emphasis on these changes ·48 POSTVACCINIAL MICROGLIA ENCEPHALITIS 3 5. Cases wrth the clinical picture of transterse myelitis A number of cases are found in the literature, in which symptoms of transverse myelitis occurred shortly after vaccination, and it seems worth while to establish whether we have to consider them a special group. The typical anatomical changes of microglial encephalitis can be observed in the spinal cord in nearly all cases of postvaccinial encephalitis, most of which do not show transverse myelitis clinically. Symptoms of a slight affection of the spinal cord, however, arc mentioned in many case histories. From our Table XIV we learn that some affection of the spinal cord in postvaccinial encephalitis occurred in all cases in which this was examined by us, and that it was as widespread and as serious in the patients dying early after vaccination as in the cases of longer duration (only numbers 33 and 11 clinically showed transverse myelitis). However, the incubation time of the myelitis syndrome is not always the same as in encephalitis (8-15 days, see Table III and Fig. 6). The cases reviewed by Dixon (1914) are not included in our first table, all his patients were soldiers, most of whom had simultaneously received other serum or vaccinc treatment, and all continued their military training after vaccination. Nonc of them showed typical encephalitis. They probably form a very mixed group. As the pathology of none of these cases is known (4 had a fatal issuc), they cannot be classified, but it is evident that a myelitis, starting on the third or fifth day after vaccination, cannot have been the microglial type but must have been due to some other pathological change. Here again, as already said in discussing encephalitis, the clinical diagnosis does not run parallel with the pathological diagnosis. Clinical myelitis includes cases which histologically show necrosis and malacia, or hacmorrhagic inflammation, not to be mistaken for the encephalomyelitis we are discussing here. In the cases in which cncephalitis was agnosed, is is not preceded the spinal cord symptoms by 0-3 ·PERIVASCULAR FOCAL LESIONS 49 significant difference. As will be seen in Fig. 6, the incubation in several cases lasted longer than is found in microglia encephalitis (sec Chapter 6), but only one of these came to autopsy (de Busscher and 2 *6.8 12 14 16 18 20 22 24 26 28 30 32 FIG. 6 Incubation of postvaccinial transverse my ehitus Above the line the cases of myelitis without clinical encephalıtıs; below the line cases of encephalomyelitis Drawn linc incubation of nucroglia encephalitis. From the literature. Radermecker) and the others might well have been myelitis of a different pathology. The case of de Russcher will be presently discussed In one case (Baller, 1930), not included in Fig 6, the myelius was probably part of a Heine-Medin infection, and this casc is only mentioned here as it may focus our attention on the possibility that more cases in which no autopsy was performed, could have been acute anterior poliomyelitis, eg the case of Henneaux and Delcourt (1954) with 79% polynuclears in the spinal fluid, and Mſage's case (1937) with prolonged sequelae. Miller (1953) cites 3 cases of pohomyelitis among a total of 31 soldiers developing myelitis following Vaccination. The description of the sequelae after partial recovery is generally very brief, and does not allow us to form a definite conclusion about their pathology. Why is the incubation time in myelitis longer than in encephalitis? We could assume that early histological changes in the brain give risc to complaints sooner than lesions of the spinal cord, but it is also Possible that the lesions in the cord do not give the picture of transverse myelitis before they become either very numerous or coalescent, with some destruction of the nerious parenchyma (including the axons, which are always found intact longer than the myelin sheaths) Dedema may also be an important factor because the cord, due to the staff meningeal covering, will be compressed earlier and more seriously ·50 POSTVACCINIAL MICROGLIA ENCEPHIALITIS 3 by a developing oedema than the brain tissue, which can more casily expand. But this can only explain cases in which the incubation time is a few days longer than in the encephalitis. In 4 cases of our table, the incubation lasted more than 16 days, an explanation of which it is difficult to give, especially as the pathology is known only of de Busscher's case. Or the cases of our table, only 5 came to autopsy. In Pette's case no data are given on the duration of the incubation. The casc is not regarded by Pette as perivenous encephalomyelitis of the postexanthematous type, but rather as disseminated encephalomyelitis. It is possible that the cases in Dixon's table, with an incubation of 19, 28 and 32 day's respectively, also belong to this category. The two cases of our own series and the case of de Busscher and Radermecker, will now be discussed, Case 33. A boy, born 2 12 1936, had been healthy before vaccination on 2. 7. 1947 Pustules developed normally with rather marhed skin reaction. General malaise ensued 8 days after vaccination, and on 14 7 headache and dizziness with yoriting were reported This was progressive and stiffness of the neck was noticed the next day. No fever, but positive Kernig sign. CSF. showed increase in cells. There was some weakness of the left leg. On the 15th day paralysis of both legs and the abdominal muscles was noted, with retention of urine and facces At the same time swallowing becamc difficult and speech defective. He died with high fever on the 20th day after accination, Autopsy The brain was not hyperaemic but the meninges were. Macroscopically the brain did not show any abnormality, there was no swelling, no hactorrhage. The spinal cord showed no typical fori macroscopically, but in the and thoracic segment the gray matter did not clearly stand out. Alicroscopic examination In the spinal cord there was a great difference beturen the foxii. Some seemed to be in regression (thoracic II, ant. column), still with very marked demyelination but only few infiltrating cells These were not accumulated around the central vessel but were lying loosely in the parenchyma. There were no granule cells and the protoplasm was still well developed and showed many processes The nuclei were small and dark, irregular in shape microglia) in a somch har larger focus ne found some fati) granule cells ta the tissue and also sma)} astrocy 13 with clear, round or oval nuclei and a distinct nucleolus ·B PERIVASCULAR FOCAL LESIONS 51 Many farger foci showed the typical arrangement, but I crywhere lympho cytes were scarce or absent Granule cells were never found in greater numbers The cord at the lower lesels was not hyperaemic but some dillusc oedema was present, the perivascular spaces, however, were not dilated A very conspicuous change was widespread chromatolysis of the ganglion cells, which was most marked in the anterior horn cells but was also found in smaller cells of the posterior grey matter (Fig 7) Yot all the cells of one secuon were affected; normal cells with well deseloped tigroid substance might be seen near greatly swollen cells with only a small border of tigroid substance peripherally in the cellular body. Other motor cells were pycnouc or showed more general degeneration of the cellular body There was no neuronophagia or small-cell infiltration, as seen in poliomyelitis, and the axis cylinders of the anterior roots were well stained in their central part (inside the cord). This change was found in the lumbosacral cord and at the rith thoracic level, thor. Vi and 11, however, did not show these changes in the large nerve cells The significance of this ganglion cell change will be discussed in paragraph e. FIG 7 Chromatolysis of anterior horn cells Transierse myelitis in microgba encephalitis Case 14 Nissl stain Marginal gliosis was marked along the anterior longitudinal fissure in the lumbar and lower thoracic cord The pia of the lumbar cord contained few lymphocytes, except in the anterior ·52 POSTVACCINIAL MICROGLIA ENCEPHALITIS 3 fissure, where dense accumulation of cells was found Many were granule cells with sharply demarcated protoplasm, without processes but containing many vacuoles (in H.C. stain) and with a rather large and irregular nucleus, which often showed the curious forms found in the hypertrophic microglia of the perivenous foci. Some cells were smaller, not vacuolated, but showing the same tortuous and twisted nuclei. They must also be microglia cells, which have passed the pia-glia membrane before their nucler became rounded and smaller and the plasma was filled with breakdown products. The higher thoracic segments (VI and II) showed only slight changes, we found only a few foci and no demyelinated areas, without infiltration. Some veins had a cuff of small lymphocytes, mixed with morc irregular nuclei, probably microglia cells which had wandered from the parenchyma to the Virchow-Robin space. There was no marginal gliosis here, and chromatolysig of ganglion cells was also absent The cord was slightly more hyperaemic than in the lower levels. The oblongata contained no foci, no important changes were found in the ganglion cells or the subpial tissue The pons contained some typical foci around swollen veins in the midline, in the dorsal part of the tegmentum The cerebral cortex and subcortical white matter were free from foci in the frontal and insular regions, but the occipital lobe contained a number of perivenous foci, mostly localized in the vicinity of the ependyma. These foci ucre small, with little demyelination and only a few infiltrating cells. Some small lymphocytes were found around vessels, without infiltration in the surrounding parenchyma The pictures sere probably remnants of small foct which had nearly disappeared. Summary. A boy, 10 years old, became ill with gencral symptoms 12 days after successful vaccination. Cerebral symptoms were never serious, but 3 days later symptoms of transverse myclitis appeared, weakness of one leg having been noted before He died on the 20th day after vaccination. At histological examination only a sery mild aflcction the brain, brainstem and upper spinal cord was found, but severe affection of the lower thoracic and the lumbosacral cord existed All lesions had the typical character of perii cnous encephalitis; many already showed regression. In addition it was found that there was some oedema of the parenchyma; the vessels in the lower cord were empty (there was hyperaemia at the higher lesels), and marked ·B PERIVASCULAR FOCAL LESIONS 53 chromatolysis of a large number of ganglion cells. As this could not be due to an axon lesion, it was suspected to be hypoxic in origin. Case 11. A girl, 7 years old, was vaccinated with good result, for the first time on 4 9 1929 From the start she was not scry healthy, but neurological symptoms were not noted before 18.9 She was then somewhat soporous and had ſever. Next day hyperaesthesia was noted and wcakness of the legs, which was progressive until total motor and sensory paralysis existed The level of the lesion was diagnosed at the 4th or 5th thoracic segment. Patient died on 26 9 from purulent cystitis and bronchopneumonia, Autopsy. Only parts of the brain and cord wert available for examination; the mid-thoracic level was not available. The brain showed only a few lesions, these were small, with typical demyelination, but the number of microglia cells was rather small Evidently these foci had already partially healed. In the pons, many foci were found, most of them loosely built and in regression, with typical mucroglia cells, very few granule cells and active astrocyte proliferation. In these foci lymphocytes were rare or absent, but in the dorsal part some vessels were found with thick cellular cuffs in the perivascular space, consisting of lymphocytes, large lymphocytes and cosinophile leutocytes There was only a very slight glial reaction around these vessels, consisting mainly of hypertrophic astroglia At the thoracic level of the spinal cord, very severe changes were found A great many large foci were seen both in the grey and the white matter. Many still showed the oval shape of the perivascular distribution but large fields, laden with fatty granule cells, lay between them There was total demyelination in the central part, including both anterior horns, but some large ganglion cells were still in evidence Thick cuffs of small and large lymphocytes surrounded many vessels in these foci or in less affected parts. Polynuclears were rare at this level Along the anterior surface of the cord we saw marginal gliosis Proliferating astrocytes were found everywhere and the Holzer stain showed a very dense fibrillar network, especially well developed in the grey matter, Axis cylinders were still present, there was some loss in foci in the white matter and very marked loss in the anterior hornis Summary A 7-year old girl died of transverse myelitis, cystopyelitis and bronchopneumonia 22 days after successful vaccination. Encephalitis symptoms had been very mild Typical ſoci were found in the pons and a few in the hemispheres, all showing healing stages. In the spinal

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·B PERIVASCULAR FOCAL LESIONS 55 RUT le to explain the segmental clinical syndrome; the higher foci then would not have caused manifest loss of function. We need not wonder that, in cases diagnosed as postvaccinial transserse myelitis, only few foci are found in the brain because, with marked affection of the hemispheres, the patients are treated in bed and a soporous, or even comatous condition impedes examination of the function of the spinal cord This is well illustrated by the following case. Case 41, a girl of 22 years, became comatous 13 days after primary vaccination Before this, atary of the legs had already been noted, and 2 days later retention of urine set in She died of pneumonia, of about 36 hours' duration, 20 days after the vaccination The cord showed, especially at the lower levels, a great many foci, more in the white matter than in the grey horns Granule cells were abundant in some of these lesions, but absent in others, where the microglial proliferation was still intensive. As in our casc 33. ses cral anterior horn cells showed chromatolysis, although not as marked as in the other case. Here, therefore, lesions in the cord were not as serious as in the two other cases, clinical examination remuned unsatisfactory due to the mental condition of the patient, but would probably have revealed spinal cord lesion if examination had been possible Summing up the aforementioned cases, we can say that the lesions encountered in postvaccinal encephalomyelitis are also present in the cases with the clinical syndrome of transverse myelitis and, although abundant in some segments of the cord, can always be found in the brain also. Many of the foci in the cord are distinctly on the way to recovery, but some become more serious, with more marked destruction of nervous parenchyma without, however, developing into total malacia It is probable that oedema of the cord and hypoxia, due to this, play an important role in causing the symptoms of total transierse lesion We gained the impression, that fatty granule cells occurred in large quantities more often in the spinal cord (and oblongata), than in the cerebrum, as an expression of the more destructise character of the lesions in these parts Intercurrent infectious conditions (purulent pyehus, pneumonia) probably play an important role in this process but there is also reason

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·D MARGINAL GLIOSIS 57 authors. B. and K. 11. Walthard (1958) think that these ficlds always belong to some peris cnous focus. We cannot agree with this; the occurrence in the upper cortical strata pracnically rules it out; and the evidence of the large size of these foci scems also convincing. d. Marginal gliosis This is considered the second most important histological change in pcrivenous encephalitis because it is present in most cases and rarely seen in other diseases. Since Wohlwill's description in 1928, in a case of measles encephalius, general attention has been drawn to it and many authors have given accurate descriptions In our material subpial microgliosis was present in 20 out of 23 cases, but even in the others it might have been found if more blocks had been examined The subependy mal type was rarer but here too, examination may hasc been insufficient. Harginal gliosis is a proliferation of syncytial microglia cells in a very thin layer, directly underneath the pia mater. In the cortex, therefore, it occupies only the superficial part of the molecular layer. The cellular type is the same as that seen around the veins but a change into fatty granule cells is extremely rare. Even in cases of long standing this marginal ghosis still shows the syncytiał type. Demychnation is always present, but is rarely as marked as in the centre of perjvascular foci. Its distribution varied from case to case; most commonly it was found along the anterior median fissure of the spinal cord and laterally, dorsal to the anterior horns The subpial white matter of the oblongata, pons and mesencephalon were less often affected, and the cerebral cortex still less Qften, but not always, this marginal gliosis was continuous with a periv enous gliosis extending to the surface, and often the impression was gained that marginal gliosis was more frequently scen in places where perrvenous foci were found deeper in the tissues. However, we also encountered this marginal głosis without any penvenous foci at the same level of the cord (eg case 53) This is denied by Finley (1937, 1950) and other authors, i ho consider marginal gliosis to be a continuation of the pervenous foci But our Fig 8 shows a continuous zone of gliosis along both sides of the spinal anterior long- ·58 POSTVACCINIAL MICROGLIA ENCEPHALITIS 3 tudinal fissure, with only a few perivenous foci in the parenchyma. The small astrocytes of the most superficial layer and the astrocytes of the white matter may be increased in number; however, a fibrillaryglosis, resulting from hypertrophy of these cells, was not evident in our cases, We should not confuse the marginal gliosis described above with the reaction of the superficial small astrocyles found in cases of meningitis or other irritation. The nuclei of the microglial gliosis have the samc irregular shapes as in the perivcnous foci: elongated, tortuous, dumbbell-shaped, etc., whereas the astrocyte nuclei arc stained lighter, are round or oval, and generally somewhat larger. The protoplasm also differs: the astrocytes show the more regular spider shape, and do not form a syncytium as do the microglia cells. The occurrence and the importance of subependymal gliosis is more difficult to evaluate, because often a perivenous affection in these FIG 8 Marginal gliosis. Ant fissure of spinal cord. Continuous microglia layer, in many places without connection with peris enous foci. Case 39 Nisst stain ·E GANGLION CELLS 59 regions, where the seins run parellel to the surface, makes a distinction difficult. Here, too, irritation of the ependymal astrocytes may give pictures which can be easily interpreted as microglial proliferation. We found the subependymal microglial layer in 9 cases and subpial gliosis in 20, but only in 3 cases was it rather marked. In one case (No 45) we found subependy mal gliosis in the apex of the occipital lobe, surrounding a solid stall of cpendymał cells, without lumen e. Ganglion cells It is well known that the ganglion cells generally remain relatively intact in the perivenous foci although, especially in older lesions, some of them may show degeneration (eg case 37, a revaccination, in which some of the anterior horn cells show signs of tigrolysis). Some diffusc loss of cells in the cerebral cortex is rather often seen, but this is a vcry common finding at autopsy when a long agonal period preceded death (stasis of blood in the cerebral circulation and perhaps toxic influences) We already described the marked degeneration of anterior horn cells in two cases of transverse myelitis (No. 33, 41), not connected with focal microglial lesions (this chapter, par. b, 5). This was found in otherwise normal tissue (see Fig 7). Mild degrees of chromatolysis were also present in case 37 in the lumbar anterior horns, without neuronophagra Many typical foci were present at this level of the cord The patient had shown a weakness of the legs, at first suggestive of acute anterior poliomyelitis The same acute cellular degeneration was described by Pette (1936, p. 271), but in his case, following revaccination, a diſluse glial reaction existed in the anterior horn, as also in other parts of the transverse section. This case is considered by the author to be nearer to the disseminated encephalomyelitis, than to the perivenous type. The pathogenesis of this cellular degeneration is possibly vascular hypoxia, caused by oedema of the cord in cases of longer duration, and more serious destruction of tissue. Al} cases with this type of ganglion cell degeneration occurred in the spinal cord and in patients with severe clinical symptoms of myelitis Marsden and Hurst (1932) described a ·60 POSTVACCINIAL MICROGLIA ENCEPHALITIS 3 similar degeneration of lumbar anterior horn cells in a case of posto variolar encephalomyelitis; they also regard these changes as not belonging to the usual picture but the pathogenesis remains obscure. Considerable degeneration of the large cells of the substantia nigra was found in our case No. 40. Many cells were ill-defined and somctimes the pigment was lying free, no cellular body remaining visible. This, however, was also considered a reaction to the patient's un. favourable general condition (he had suffered serious brain lesions at a younger age). Similar conditions of the substantia nigra can be seen in postoperative hypoxia cases. Abnormal mitotic figures were described by de Vries (1954) in scicral cases of microglia encephalitis. They were found to be very numerous in one case, and less numerous in 6 other cases. Generally only a number of small, dark, basophilic granules are seen, lying in a white field, inside a large cell, but sometimes an indication of spindles, as scen in mitotic division, was found. They were considered to be an abnormality of unknown pathogenesis. Rarely we found them in other diseases, rız. in a case of typhoid fever and in tuberculoma of the thalamus. Similar pictures were described by Perdrau and Turnbull and McIntosh in postvaccinial encephalitis. Wohlwill (1928) described, in post-measles encephalitis, irregular basophilic granules in the anterior horn cells, which have lost their nucleus. Probably they belong to the same category as our findings. A description of similar bodies by Tinel and Bénard (1923) in a case of ascending myelitis, beginning 5 days after eruption of a rubclla exanthema, dently also belongs to this group. Il'yers * recently demonstrated sımlar nuclear changes in gliomata and discussed their relation to changes, experimentally caused by throurea injections. f. Complicating aetiological factors Factors which might influence the constitutional basis on which microglia encephalitis may become manifest, were seen in a number of cases This aspect of our problem has been discussed by many • Demonstraten in the Dutch Society for I'sychiatry and Trurukrey, 1938 To be published.

·F COMPLICATING AETIOLOGICAL FACTORS 61 authors and may throw some light on the pathogenesis of the process. fle will list below the cases which seem to be important in this respect. Of course, our material includes only cases coming to autopsy; whether the same holds true for encephalitis cases which recovered, cannot be stated by us, but it secms very probabie. in 3 cases we found evidence of preceding disease of the brain. No 37 showed marked fibrillar gliosis around the lateral angle of the brain ventricle, and phagocytes containing old blood pigment were localized along vessels in the white matter of the brain. The history gave no information about previous trauma or discasc. No. 38 showed a similar picture, but in this case the scar tissue around the posterior horn of one lateral ventricle was much more developed and extended further in posterior direction, where only a closed cp mal stalk was present This casc also showed old blood pigment in the shearls of deep cerebral vessels. No 40 had esen more important lestons. In the left frontal and temporal lobes, old malacic foci were found, with microgyria of the adjacent convolutions Only scar tissue was present; the lesion, probably traumatic, must have occurred early in life. No cause of this disease could be found Microscopically the encephalitis in this case showed, besides the typical picture, glial stars in the oblongata and degeneration of a number of cells of the substantia nigra. These 3 patients were all soldiers, and nothing abnormal had been noted in them, before the vaccination A hereditary predisposition was involved in one case, No 32, a girl, suffering from clubfeet A brother had spina bifida Endently we may consider this to be a case of status dysraphicus Hequired predisposition was found in the above 3 cases with old brain lesions, probably of traumatic orgin One patient, No 8, was still unable to speak at 4 years of age, no data were available to explain this retarded deselopment. Revaccination may be mentioned here, because in several cases an abnormal picture was seen We saw microglia encephalitis in 2 cases after revaccination (in which primary vaccination had been positise), and ın 26 cases after primary vaccination, which should be about the ·62 POSTVACCINIAL MICROGLIA ENCEPHALITIS 3 relation given also for the non-fatal cases. But of the cases of other cerebral affection following vaccination, seven followed revaccination and only 20 primary vaccination (of these 18 were 2 years of age or younger). This will be discussed in Chapter 4. Our cases of revaccination encephalitis were No. 12 and 37. The former had a typical skin reaction; in the latter the skin reaction came rather early, but was still quite typical. We saw no cases of transierse myelitis following revaccination, as described by Holbrook (1930), Gounelle (1930) and Perte (1936). Many patients may have suffered from other diseases, known sometimes to cause damage to the brain, but this was not noted down in our material. An allergic predisposition was not evident either in our cases. An important group is formed by the patients who, shortly before vaccination or during incubation, were subject to some noxious factor. No.9,3/2 years old, had whooping cough shen vaccinated and was treated by 4 injections, the last of which was followed by a convulsion; then the cncephalitis was noted, which lasted for only one day. Incubation had been to days (sec case description in paragraph b 2 on early cases). Angina, of course, is sometimes noted, but in our cases it did not secm to be an important contributing factor Greater importance should probably be attached to the simultancous injection of vaccines or antisera against typhoid, cholera, diphtheria or other diseases. This was only noted in our matcrial in one case (No. 37), but probably had been done more often without being recorded. It was the usual procedure in soldiers to give many injections at the same time. Especially worth mentioning is the possible influence of mental or physical strain shortly after vaccination. Case No. 45 was preparing for cmigration, which always entails much excrtion. A statistical analysis of the occurrence of postvaccinal encephalitis in soldiers, compared with adults of another occupation, might be worth while 10gc an idea of the importance of mental and physical strain in this group.

·SU 31 MARY 63 Physical strain was evident in cases 39 and 40, two soldiers, who made long bicycle trips on the 12th and oth day of incubation and who fell ill on the next day and the same evening, respectively. No. 39, dying 2 days after the outbrcal of the encephalitis, had a septic condition at autopsy, together with typical microglia encephalitis. It is interesting to mention the case described by Mage (1937), of myelitis de cloping the day after the patient participated in a race, and the case of Kaiser and Zappert (1938), of a boy de eloping myelvis the day after playing a football match, 19 days after vaccnation. It is rather difficult to evaluate the importance of the data given above. We should also bear in mind that in some cases (c.g our No 53 and 11) the history specifically states that no important diseases had preceded the vaccination and that the patient had always been of excellent health We also have to bear in mind the influence that cortisone may have in actrvating viral encephalitis (discussed in Chapter 4. d). In the literature, mention is made of the influence of endogenous or exogenous factors predisposing a person to posti accinial encephaltrs. Hutter (1930) mentioned constitutional and familial factors, Sillevis Smit (1952) also laid stress on the endogenous factors, André- Balrsaux (1953) gave several case histories to clucidate the importance of a nсuropathic predisposition, of trauma, etc. An allergic predisposition was noticed by some authors but was absent in many cases Summary The general picture of pers enous encephalitis, as described by most authors, was also found in our cases. It should be pointed out that the demyelinating microglial foci are only part of the changes seen in nearly all cases. A general mesodermal reaction of the meninges and, in some places, of the vascular wall, was explained as the expression of the systemic disease produced by postvaccinal encephalstis ·6+ POSTVACCINIAL MICROGLIA ENCEPHALITIS 3 We formed the conclusion that the typical perivenous foci are primary and not preceded by a vasculo-mesodermal reaction at the site of subsequent microglial proliferation. When the encephalitis is not complicated by other infectious) conditions, the disease is not fatal in the first stages of the foci; when death occurs early in the 'clinical course, we must admit that the glial proliferation has existed for several days. The later development and final absorption of the foci, of coursc, cannot be seen in autopsy material and has to be deduced from cises with death from intercurrent diseases, or after the original lesion has healed out. We reached the conclusion that the smaller foci disappear without leaving a scar or demyelinated plaque because the surrounding myelin fibres group together. The catabolic products in these smaller foci were broken down by the glia to soluble substances, and fat or fatty acids were seldom present. In the larger foci, however, we thinh that the bulk of decomposition products could not be entirely absorbeci in this way, and fatty granule cells derived from the microglia were found in larger numbers, transporting the material along the blood vessels, as also seen in other types of destruction. Astrocyte reaction in thesc foci can cause some degree of sclerosis. We think that, during the first days of the disease, now foci may develop just as an exanthema increases during one or two days, but this cannot be called progressive involvement. We found some indocation that microglial proliferation originated in the parenchyma surrounding the vessel oser some distance, and that these cells gradually concentrated close to the vascular wall and invaded the adventitial tissue. Increase of these microglia cells occurred mainly by amitotic division. Often the protoplasm was vacuolated, but no sudanophile substances could be detected When other diseases or affections occur in the course of postvaccinal encephalitis (e.g. bronchopneumonia, other vaccinations, cic.) the pathological pictures can be complicated, but this should be separated from the changes of microglia encephalitis. The picture of transverse myclitis may occur in patients in whom cerebral involvement is not serious. Microscopically, the same ſesions ·SUMMARY 65 are found as in the cerebrum, but more serious destruction of the parenchyma is often seen. This could be explained by the impeded circulation of blond and lymph as soon as oedema causes compression due to the stuff coucring membranes. The possible influence of physical exertion on the outbreak of symptoms is discussed.

·Chapter 4 CLINICAL POSTVACCINIAL ENCEPHALITIS DIFFERENT IN PATHOLOGY FROM MICROGLIA ENCEPHALITIS In this chapter we shall review cases of postvaccinial cerebral com. plications in which the autopsy findings suggested a process differing from the pathology described in the preceding chapter. It is important for an understanding of the occurrence of various reactions of the nervous tissue to study not only the typical cases but also the negative cases with other types of reaction. The fact that many authors do not pay much attention to this point hampers a general evaluation of the difficulties. A sharp distinction of the various changes found in cases of post-measles encephalitis, however, is made by Litvak (1947). Moller (1949) described these in post-infectious nervous involvement in children. These articles illustrate the importance of a carcful description of all cases coming to autopsy. In the course of our investigation it became evident that in some cases the picturc of complete microglia encephalitis was foc found but that perivenous foci with demyelination and microglial pro. liferation existed in the same brains with vascular reactions, although in separate foci. The pathogenesis of these perivenous microglial foci is probably closely related to the pathogenesis of microglia encep}1- alitis but we will group these cases together with the other cases to be treated in this chapter. A full discussion of their occurrence and pathology will be given in Chapter 6, a and b. Our material, a total of 30 cases, at once suggests that a division into some major groups can be made, which will be discussed in the next paragraphs. Special emphasis is also fad on the so-called encephalopathic changes, the place of which in pathology is still under discussion. Few cases then remain with a pathology differing from the usual pictures (discussed in pas ).

·POST-INFECTIOUS ENCEPHALITIS 67 a. Post-infectious encephalitis before and after the year 1923 It is generally accepted that the wave of postvaccinial nervous complications which attracted world-wide attention, started in the autumn of 1922, gradually increasing in severity until a maximum was reached around 1930 But it is also a well-known fact that nervous complications had been seen before that date and that many cases occurred in the 19th and 20th century which can now be clinically diagnosed as postvaccinial encephalitis. It will be my object in this paragraph to discuss the problem as to whether microglia encephalitis occurred cven before the abovcmentioned date, or whether this was really something new, as Spielmeyer (1928) wrote: "die postvaccinale Encephalitis und die Masernencephalitis sind etwas neues". The literature includes a number of cases referred to by many authors to prove that postvaccinjal encephalitis did occur before 1923. We shall discuss these cases below. A distinction between encephalitis and other cerebral complications following vaccination, was rarely made in the last century and in this century before 1925. Convulsions in young children, one of the most outstanding manifestations at this age, were for some authors enough to diagnose encephalitis, whereas others did not think it of sufficient importance to be mentioned. It is interesting that, according to Kaiser and Zappert (1938), an accumulation of postvaccinial complications occurred in Bohemia in 1802 Among 10,000 vaccinations of babies during that year, 31 were followed by severe convulsions, one by paralysis, one by a soporous condition, all starting 2-16 days after vaccination. Three children died of convulsions. In the years preceding and following 1802 complications were rare. In 1886, von Barlow described a case of haemorrhagic encephalitis in measles, Freud (1897) mentioned vaccinia as one of the causes of infantile cerebral paralysis Then (1900), according to Bastiaanse (1931), a case (boy, 6 years old) occurred following vaccination but here again convulsions and hemiplegia developed and this case is not accepted as postvaccinial encephalitis ·68 DIFFERENCE IN PATIOLOGY In 1903 a case occurred, described by van Bogaert (1937): a girl, 6 years old, developed poliomyelitis, following vaccination. In the same year complications arosc in the Netherlands (Bastiaanse, 1931), but the author did not diagnose them as cnccphalitis A case, described in 1904 by Brissaud and Brécy, of a boy aged 16 dying after 13 days of illness of unknown aetiology, showed multiple perivascular lymphocytes but no microglial proliferation. Some foci showed demyelination and the disease was diagnosed as nсuropticomyelitis. It certainly was not a case of microglial encephalitis, as is sometimes suggested in the literature. Comby (1926) described 3 cases, occurring in 1905, in which serious sequelac followed the vaccination. The age of the children was 4 months, 2/2 ycars and 18 months, respectively. In all cases convulsions and vascular syndromes dominated the picture. They do not resemble microglia cncephalitis but are quite comparabic to the material of younger babies, as given below (par. c). In 1907 Thausing described a case in which paralyses, resembling poliomyelitis, were still present three months after the onset. In 1929 Mader described a case occurring in 1912: a child, 21 months old, was vaccinated June 12th; from Junc 19th on he showed convulsions, becamc comatous on the 26th but gradually recovered Probably this, too, was an encephalopathy. In 1912 Gins (1934) observed a girl aged 18 months, developing convulsions on the 12th day after primary vaccination, from which shc partially recovered, remaining an idiot. He saw another child, 2 years old, in whom the incubation lasted 12 days; haemorrhagic encephalitis was found at autopsy Another wave of complications was observed in Holland in 1916 (v. ll'ayenburg, Koetser, Busch, and others) when, after more than 30,000 vaccinations and revaccinations, many cases of brachial or thoracic neuralgia occurred Sporadıc cases with the same symptomatology have been observed again after 1925, and are thought to be peripheral in origin These always followed rei accinations. It is evident that the cases rcferred to the paradigmata in the literature) dis not show the typical clinical picture, nor at autopsy the ·POST-INFECTIOUS EXCEPHALITIS 69 pathological changes of microglia encephalitis. In the literature I found only 4 cases occurring before 1923, in which microglial pro liferation in the parenchyma around blood vessels highly resembled microglia encephalitis (a further search of the literature might well disclose more cases). These cases will be discussed in Chapter 5; a short summary, however, is given here. 1. Turnbull and McIntosh (1926) described a case occurring in 1912, following vaccination. It is generally accepted in the literature as proof that peris enous encephalitis occurred prior to 1923. Krabbe (1913) published the case of a one-year-old child. The actiology was unknown; the child had not been vaccinated. 3 Marie and Tretiakoff (1921) described a girl aged 16, falling all on 30 11. 1918, with no known aetiology. 4. Tinel and Bénard (1923) briefly referred to a case of post-rubella cncephalitis, occurring in 1921 in a man aged 21. 2 It is the general opinion that nenous complications following acute infectious diseases have considerably increased in number since 1920- 1923. Gins ascribes this to the epedemic encephalitis of 1918-1921 which, when developing after vaccination, should in his opinion adopt a special symptomatology and pathology Other wellknown nervous diseases, eg acute disseminated encephalomyelitis, encephalopathies, etc., also increased in numbers (Gins, Bastiaanse, Lucksch, Turnbull and McIntosh, Bogaert, Scholz, Kaiser and Zappert). That the perivenous type of encephalitis did not occur before 1923 is stated by Spielmeyer and accepted by Pette (1936), who found no histological proof to the contrary in the literature, and also by Walthard and Walthard (1958) In measles Wohlwill (1928) stated that, before 1925, encephalitis following this disease was nearly unknown, but increased in frequency following the pandemic of Economo's disease. Vfusser and Hauser (1928) report the same condition in the US, wherc encephalitis ·70 DIFFERENCE IN PATIOLOGY following measles infection was formerly unknown, but was reported in 1927 in various States. C. de Lange (1943) gives r in 1,000 as an aterage for the more serious complications in the course of measlesma rate certainly much higher than before. Litvak (1947), who also estimates the number of measles encephalitis cases at that time at i in about 1,300, says that, during 1902-1924, only 2 of 2,000,000 cases of measles had cerebral complications in England. The nervous complications that followed vaccination before 1923 are discussed in a number of reports and articles. In 1902 a commission was formed in the Netherlands to report on the complications of vaccination against smallpox. Ninety per cent of the practitioners returned the completed questionnaire Following 21 million vaccinations, skin reactions and crysipelas 1 cre most common, then abscesses and other septic conditions. Meningitis occurred twice; in both cases the tuberculous type was diagnosed. No other cerchral complications are reported. Convulsions did occur but were not considered a complication of the vaccination, although some reports state that they occurred more frequently after vaccination than without it. Vaccination at that time in the Netherlands was done mostly in children aged 4-6 The English Report on l'accination (1928) notes that, from 1911 to 1925, 37 million vaccinations were done in chuldren under 1 year of agc, with 133 deaths, and 600,000 in older persons, with 15 deaths. Death was due to convulsions in 26 cases, to meningitis in 4 in hacmorrhagic encephalitis in 1 (in 1923) and to acute encephalitis in 1 (1923) In contrast to the above data, the dangers following vaccination increased after 1923 Bastiaanse (1931) states that in 709,918 primary vaccinations, 54 cases were reported with untoward complications which were certainly not posti accinual encephalitis, and an additional 59 cases which were probably not. The percentage of cases with a fatal nutcome was about 30. His material, how curr, is not uniform ind no definite conclusions Games Tore be me ·A POST-IXFECTIOUS ENCEPHALITIS 71 TABLE IN DEATII DLE TO PRAY ARY VACCINATION Tear Print. race Deaths Frequency 6 Dutch Commission English Report Dutch Report 1932 +1890-1901 1911-1922 1924-1928 incl. 2 500 000 3 700 000 70 000 133 38 1.416 000 1: 27 000 1: 21 000 The Dutch Commission excludes from statistics on death due to vaccination cases of tuberculous meningitis or activation of other discases, whereas these are included in the English statistics Another point which impedes conclusions is the difference in age at which vaccination was generally performed. A few words may be said about the significance of contulsions as a sign of post-infectious cerebral discuse. Convulsions followed vaccination in 1802 in Bohemia (Kaiser and Zappert, 1938) in a rather large percentage: 31 in 10,000 vaccinations (1:322), with 3 deaths (1 : 3,300). According to Julius (1938), convulsions were given as the cause of death during the first year of life of 1,011,493 children during the years 1931-1936, as high as 1916 ( 1543) The role of vaccination is not especially stated Bastiaanse found convulsions in his material of pathologically or clinically certain cases of postvaccinial encephalitis in 48 of 138 cases (+ 2.8). The English Report (1928, p.41) states "Convulsions are occasionally met with in the course of vaccinia as in other febrile conditions, but it was not unul 1923 that certain other manifestations appeared". The matenal discussed in this paragraph is rather suggestive of the following conclusions (see also Table XI, p. 141). (1) Typical fully developed microglia encephalitis following vaccination has not occurred before the autumn of 1922 Turnbull's case of 1912 is atypical in many respects.

·72 DIFFERENCE IN PATHOLOGY + (2) The pathological picture of perivenous microglial foci can occur sporadically following vaccination (1 case), rubella (1 case), or without definite aetiology (2 cases), and is also rarely met with, after 1923. without previous vaccination or other exanthematous disease. (3) Convulsions in young children apparently do not occur more frequently after 1923 than they did periodically before that date. They should therefore not be considered a danger inherent in postvaccinial encephalitis, which only occurred from 1923 on According to Marchand and Ajouriaguerra (cited by Rademecher, 1958) three main groups of convulsions should be distinguished: "Convulsions isolées fébrilcs" with a good prognosis without scquclae; "convulsions des spasmophiles" and "convulsions répétées", often progressing into epilepsy. There is, however, some evidence that an encephalopathic reaction following vaccination (haemorrhagic, lymphocytic, toxic) incrcased in frequency after 1923, especially in very young children. Death from microglia encephalitis still periodically occurs in the Netherlands when mass vaccination is performed (see Fig. 9), whereas death due to postvaccinjal nervous complications other than this type, continues to occur more regularly. The figure could cven suggest that the relation of encephalopathy to vaccination is much less important than it has been supposed to be. Microglia encephontis 1925 1930 1935 1940 Other pathology FC 9 Frequency of microglia encephalitis compared with cases with other pathology, in the years 1925 to 1957. Dutch autopsy cases From 1930 to 1939 vaccination was nearly stopped. In 1979 a non saccination lau was passa! In 1947 mass vaccination because of smallpor truprione in Tilburg In 1951 mass vaccination because smalfpor occurred in Breclado ·B CHILDREN UNDER TWO YEARS OF AGE 73 b. Children under 2 years of age show no microglia encepbalitis A systematic examination of the Dutch cases of postvaccinial complications has res caled the interesting fact that microglia encephalitis does not occur in infants in their first and second year of life. In a suney of the literature the same observation was made. A great number of cases have been reported but, whenever an adequate description was gnen, another type of pathological reaction was found Many of thesc cases were diagnosed as postvaccinial encephalıtıs; others as cncephalopathy and only in a few cases did the author especially note that they belonged to the peri enous type or were an initial stage of pern enous encephalitis. Sometimes other wnters interpreted these cases as such These cases will now be discussed in some detail (Turnbull, 8; Schurmann, 2, Doring, 1; Jacob; Baló, 4; Zulch, 10; Schlcussing). Case Turnbull 8. 1928. A bos, 3 months old, rell ill on the oth day following vaccination and died on the 25th day Turnbull considered this as a subacute case Pathological examination showed oedema and hyperaemia of the brain, no haemorrhages There is a cry diffuse mild increase of glua nuclei In the left pulvinar ne found a focus with oedema and old as well as fresh erythrocytes in the parenchyma but this was not per vascular. There was some hypertrophy of the astrocytes The lumbar cord showed periyascular oedema Fatty granule cells were present in the scssel sheaths in vanous sections and could be followed into the subarachnod space The haematorylin and msin stains showed no demyebration Turnbull groups this case together with his other cases (of older persons) as postvaccinal encephalitis We would now call it an encephalopathy, and it certainly does not belong to the microglia encephalitis group, as is sometimes contended in the literature Case Schürmann 2, 1928 A chuld of 11 months acqwred saricella ar about the time of vaccination It died 12 days later of bronchopneumonia The vaccmation pustules developed normally. On the 8th day the chuld had convulsions Autopsy showed fresh granulations on the mutral valve The meninges were slightly blurred at the base, the ventricles dilated Only one block was microscopically examined (probably paraffin embedding and haematory lin-eosin stażn) Schurmann mentions protoplasmic glia cell proliferation around the ·746 DIFFERENCE IN PATHOLOGY essels, but expressly states that the case had been insufficiently studied to use or a description. His first case, a child 6 years old, showed sypical microglia incephalitis, and Schurmann gives a very good description of it, using this case or his description of postvaccinial encephalitis Is glial hypertrophy occurs after small haemorrhages or around small, iccrotic foci, and as demyelination was not noted, the second case of ichurmann does not prove that microglia encephalitis can occur at i very carly age. ase döring 1, 1912. A child, 15 months old, was vaccinated 28.9 and fell ill on ,.10 with vomiting. 7.10 he had convulsions; the temperature rose, he became omnolent and died the following day. The spinal Auid shoned 74/3 cells. Lutopsy showed hyperaemia of the brain and mild lymphocytic infiltration of he meninges The parenchymal vessels were engorged with blood and sometimes urrounded by oedema. Some plasma cells could be found and lymphocyte ults were present around a number of vessels. Ganglion cells were found 10 c practically normal. Doring considers this to be an initial stage of perivenous encephalitis Ve cannot follow him here. Firstly, in older children dying on the leventh day after vaccination, the typical picture of demyelination nd syncytial microglia can be seen (niz, our case No. 9). Then the hanges in Dorings casc, as in many cases of encephalopathy with cath around thc roth day, were widely distributed in the brain, not i loci with large stretches of normal tissue between them. They arc /pical of encephalopathy and there is no proof that these changes hould have changed into perivascular microglial foci if the child had sed. We shall presently discuss the problem of fulminating cases jore extensively. A casc briefly mentioned by H. Jacob (1956, case 1), should be listed cre, although the description only states death at 8 months, following nallpox vaccination, with "Lymphocytärer perii cnoser Incephalitis uit laminarem Ocdem der U-Fasern und beider unteren Rinden. hichten". Probably this was not a microglia encephalitis b iscular accident. The name perii enous encephalitis is used by so for encephalo-myelitis disseminata Balo's case 4 is a child, 2 ycars old, who died 17 days after, ·B CHILDREN UNDER THO YEARS OF AGE 75 lion. Focal perivenous haematogenous cells were present; no microglia is mentioned, but demyelination was found. It is not certain that this might have been the youngest case of microglia encephalitis; it could well have been a haemorrhagic or embolic type A case described by Zulch, 10 (1954) as typical para-infectious peris cnous encephalitis certainly does not conform with the picture Spatz gave as typical when he coined the name, and in the sense it has been used by many later authors. A child, 16 months old, fell all following a common cold The child had not becn recently vaccinated Death on the 5 th day of illness. Histopathology showed predominantly lymphocytic pervenous infiltration and carly demyelination. The latter was probably caused by the oedema found in these cases. Schleussing (1953), in a preliminary communication, reports on 14 cases in children 6 months to 14 years old, with acute cerebral symptoms following vaccination in 4 to 16 days All cases showed serous exudation without demyelination or microglial reaction Schlcussing considers his cases to be an carly phase of perivenous encephalitis, but his findings are the same as in our cases in young children and we cannot accept his explanation. Table V gives a list of the autopsy data of 33 cases of Www 10 20 25 30 Days of incubation FIG 10 Incubation of cases of postvaccinal CNS complications other than microglia encephalitis Children o and I year of açe Dutch cases and the cases from the literature, mentioned in this treatise ·76 DIFFERENCE IN PATHOLOGY TABLE V CHILDREN L'\DER 2 YEARS OF AGF. POSTVACCINTAL DEATIE Cases from the firerature, with autopsy findings Author Death Inch days bation after months L'accin. 171 Clinic Pathology Turribull VII 3 to 25 Eckstein, 37 + 15 15 Report Vaccin. 26 Lawler Eckstein. 90 5 6 12 8 9 6 23 Gins, It Eckstein, 47 33 15 7 I! Oedema; hyperaemia; hacmirrhag. No gla prolif.; granule cells around cssels. Peruasc, cell. infiltr.; Diffuse cell infiltr.; Ggl cells degener. ated, Glia increased! Acute cerebral oedema. Bronchopneumonia, Oedema of meninges and brain, Oedema of meninges. No encephalitis TB meningitis. C.S F. polynuclears in brain perivasc, infiltration Hyperaemia; no encephalitis; CSF with pneuri cocci. Oedema of mchinges, no en cephalstis PneumOXOCCIC sepsis, no en cephalitis Ocdema, thromboses; To gha hypertr.; no demyelmatı Feri ascul, infiltrates. So macrosc, jesion of CSS Septic condition Singht entcephalopath changes Vo prists acc encephalitis Probably TB Eckstein, 99 7 10 7 8 8 7 7 9 Cins. 13 Gins. 14 8 8 10 Dolgopol 8 15 16 Excema accinja general 10 13 13 28 42 Granier Gatc x Bogacrt Eckstein. 101 12 10 3 ·B CHILDREYYDER TO YEARS OF ACE Bals 2 Eckstein, 95 Ceter). 2 Rohmer, Rohmet, 2 2 Bentolio, 3 Eckstein, 45 Donng, 1 Rettet Schürmann, 2 8 12 Bronchopneum. One haemat.-cols! Varicella; glua around scssels, 1 convulsion data 12 14 15 Thrombones of CK 1 and bands. 12 20 28 Noencephalitis, herinne 12 7 7 Vennus hyperaenu - negat 12 Oedema; hy!.. leucor or lympho Oedemi; hura. leuco- or lymphocytes 13 8 9 I'oliomyclatas 1. 10 Hyperacmua. (edde: - film. Brain nuci 15 7 10 Ilyperacmi, aedcytes perriscul more inte matter 15 Meningitis and when the proliferation 16 Focus in pains, diffuse 213 cephalus, not specified 18 26 28 Vaccinia gen. Haemorrhagic encephalitis Granier, Valette 18 14 23 Vaccinia gen. Haemorrhagic encephalitus 3 14 Epidemic encephalitis 20 6 13 Toxi-infect Ggl cells sery diffuse degener enteritis Glia diffuse hypertrophy, lessel endothelia swollen 73 Vaso-gluat prolifer, no demyelination 24 6 17 Oedema of brain, perivascul lymphocytes, plasma cells and polynuclears Fally granule cells, demy clination, no micro Jacob glia mentioned 24 8 to Lymphocytic infiltr : crsudutuse syndrome 27 11 15 Haemorrhagic encephalitis Bemiroglio, France de Vries Eckstein, Esser 18 Martinsohn Ball, Kaute ·82 DIFFERENCE IN PATHOLOGY + plications, E.E.G. changes indicating a subclinical cerebral affection but none of these occurred in children under one year of age. During a measles epidemic in Grecnland (Christensen & al., 1952— 1953) in a population without immunity (4,262 persons out of the total population of 4,269 acquired the discase) 6 cases of encephalitis occurred, all in persons 2 years of age or older. Sudden death in the prodromal stage occurred in 2 children out of 321 cascs; in older persons in about 0.6%, lie, about the same frequency, To summonize, we can state that the very young brain does not rcact to vaccination or exanthematous diseases with demyelinating foci and microglial proliferation, as the older brain sometimes docs. This is probably not due to an insufficiency of the glia. A different chemical constitution of the myelin may play a rôle, but cannot be the only factor. As there is no difference in the histological reaction of the very young and the older brain to viral infections, it is improbablc that perivenous encephalitis be caused by a sinus. Perhaps a sensitization to allergic reactions has not yet taken place. Most probably several factors act together to protect the infantile brain from the demyelinating reaction. In other respects, howei cr, thc baby brain can react in the same way as the more developed brain to typical neurotropic virus infections, to toxi-infectious conditions, to vascular accidents and hypoxía. It remains a point of further research whether the reaction to other demy clinating conditions in the very young differs from that in the older brain. c. Revaccination cases and their pathological substratum Many authors have published cases in which encephalius, following revaccination, showed a picture other than the expected perivenous type. But tl uas Bastiaanse u ho for the first time (1949, 1955) stated that, The literature has been restered by Mrs Znanıkken VD, in search fur autopsy Cars in which the skin reaction showed a partial Immunity About 1400 article were alable, And of several articles only brief references or abstracts could be obtained 11c feel certain that no case in which exact data about the skin reaction to the 12ccination and an accuralr autopsy report are given, has extaped our force 1 diagnose "typical prostracciat encephaltis" has been listed as insufficient for our purpose ·C REVACCINATION CASES 83 in all cases Anoun to him, in achich the skin reaction to the reaccination shoued parkal immunity, microglia mcephalitus n'as not found at autopsy and the incubation time and clinical course might also show diffcrences from the usual picture. That, however, microgla encephalitis has been found Gallowing revaccination, has been descnbed by a great number of authors. It is well established that revaccination, followed by eruption of normal pustules, can be followed by perivenous encephalitis, though in a much smaller percentage than after primary vaccination. We have examined 3 cases sllustrating this face, all of which showed normal pustular skın reaction to the revaccination, In 8 of our cases the skin reachon to the primary vaccination had been negative. We have included these cases in our revaccinanon paragraph, because many authors think that, even without a reaction of the skin, the vaccinia virus may invade the body and gne rise to the formation of antibodies (Eckstein et al., 1930). Van Bogaert says (1987) that, when encephalitis follows, the brain may take over the function of the skin to prepare immune bodies and that the encephalitis may be a manifestation of the disease vaccinia, localized in the brain, Rehsteiner and Wiesmann (1949) demonstrated antibodies to vaccinia in the serum of a child aged 14 ycars, who had not shown a skin reaction to the vaccination but developed encephalitis 10 days lates A case described by Eckstein, Herzberg, Kremmer (1930) seems rather conclusie A child aged 15 months is vaccinated without apparent result Vaccination is repeated 14 days later and an early skin reaction results five days later the child develops convulsions, fever and a soporous condition After injection of reconvalescent serum the chuld recovered wnhout persisting symptoms The authors state that, in other cases also, signs of immunity may follow an apparently unsuccessful vaccination The case described by Herckenrath (1935) (see Table VI, group 1, p 86), is perhaps also an example of this assumption, as pathological examination, two years after recovery, did not show signs of healed microglia encephalitis, ·84 DIFFERENCE IN PATHOLOGY and as the incubation was shorter (7 days) than usually secn in histologically verified cases. We have listed the cases of revaccination on which sufficient data were available (Table VI, p. 86), and divided these cases into 3 main groups: one with normal skin reaction the rcuccination; the second group with accelerated or very mild rcaction, and a small third group in which no data about the shin reaction could be obtained. The first group (I A-D) includes all pertinent Dutch cases and a certain number chosen at random from the literaturc (this number could be casily increased). Group II (I1 EH), with partial immunity reaction, comprises all cases in which sufficient data on skin scaction, clinical course and autopsy findings are given, from the Netherlands مدلهج'داود جمع و/flie | درامداد 12 مواد اولاد 21/Sys | IA с a a No coses G H F. 12 Incubation time in the groups of revaccinations.

·c REVACCINATION CASES 85 and from the literature. In the third group are listed the cases with insufficient data about the revaccination skin reaction Group Id When revaccination gives rise to a normal pustular shin reaction, a certain number of patients will react with postvaccinial microglia encephalitis. We have listed 11 cases The incubation time (see Fig. 12) is the same as in postvaccinial encephalitis following primary vacci. nation, the clinical course and the histopathological picture do not significantly differ from the well-known description of microglia encephalitis. No difference is noted between the cases with a positive and those with a negative shin reaction to the primary vaccination, Our number of cases is too small to make an cyaluation of the frequency with which encephalitis follows successful revaccination Probably the percentage is less than that following primary vaccination. Group I B Eight cases have been accurately described in which revaccination was done with good result and an ensuing encephaltis did not show the microglial type. A short description of each cate is given below. Several facts attract our attention The age distribution (Table VI) vanes much more than in primary vaccination; also the incubation time is irregular and the wide variety of changes found in the brain may lead to the conclusion that this is not an homologous group but merely a collection of cases of very different aetiology and pathogenesis Groups IC and D The groups C and D are combined here, because they show an irregular spreading of the incubation time They probably comprise cases of perivenous encephalitis together with cases of different pathology. The variation in incubation time resembles that found for encephalitis ·86 DIFFERENCE IN PATHOLOGY TABLE VI CASES OF REVACCINATION Case No. I. NORVAL PUSTULAR SKIN REACTION TO THE REVACCINATIOV A. Microglia encephalitus 3 P- 13 P + 19 P+ 12 No. 5 No. 12 No. 37 19 9 12 Turnb., 3 22 9 19 Chol, Typh. A + B inj. at time of revacc. Old blood pigment in brain. 14 Case of 11.1922 Blood in spin. flud Bronchopneum Myclitis, mening. encephalitis IO 20 Lucksch Sjov P- P 23 13 26 Blood W'ass + Clinic. poliomyelitas ascend. paral. Typical demyelination 12 $2 12 Thom Bras Kok. Zier. P + P P+ p7 10 16 14. Consulstons C.S F. 500 cells. 13 Mentally backward, 21 Had eczema, this infected Vare gen funincul Aficroscopically not quite typical 22 Death from heart failure Microse not typical Supp 1 2 I! B No microglia incephalitis Yo 42 6 26 62 No 18 P- 8 Diabores Embolic encephalitis 15 Clinic general paral? Sfichisc. dull changes 4 Death đuc to my adidas cric tyraft atrophy 56 8 ·C REVACCINATION CASES 87 Case Mu Sjov., 1 31 P+ 9 Herck 3 P- 6 11 No demyelin Thrombosis of veins. Inflamm of vessels and advertitia 139 Convulsions; hemipares Recovered. After 2 y. no sequelae found. 18 Haemorrh. enceph. Many small cells could have been microglia 13 Found dead Oedema of brain 16' Cerebral thrombosis Ramon 12 P- 12 Dor. And 27 39 13 12 C. Death wrthout autopsy report Kaut., 2 12 139 Mor, TO Mor, 2 ro Busch Eck ,49 12 No 44 68 13 13 20 Cerebral oedema; type of encephalitus doubtful. 17 Corna, convulsions. 16 Cores, convulsions. 8 Motor unrest 24 Bulbar paral, perhaps poliomyelitis. 19 D Recorated Mad, 2 11 P+ 6 Typical course, could have been perivendus encephalitis Probably penicnous encephaliti Sopor, vomiting, positive Babinski 2 P- TO 10 Mad., 4 Hooz Gort Siss Dene Goun, 7 57 29 9 9 P+ Complete recovery 21 16 Kaut 13 12 Xiyeltis, healed, Relapse 27 days after vacc., recovered Paralyses resembling ac, polio Partial Tecovery R partial reconery Paul 7 PL 2 ·88 DIFFERENCE IN PATHOLOGY Case No. Age in Frars Result primalry vaccin Incubation in days Surrical ajit t'accin, Comb., 16 19 8 Comb., 17 10 6 10 Lere. Mage Dunn 20 - 14 14 17 leningism, comia, pos. Babinski: pareses, recovered. 12 days after vaccin. subtotal paralysis; recovered. Paralyses of legs; after 13 d reconcred. Had typh. inj., clinical myelitis Vientally clouded; flacc. paral, after 6 mo still scquclae. Zoster 4 d. after onset enceph. Wicnincoencephalitis. Vaccin during typh. inj, series Parkinsonism. 21 Mado 60 8 Lcifer 20 10 II. TYVUNE SAIN REACTION TO TIF RFLACCIYITION E. Wrcroglia encephalitis No cases F Autopsy shou's another pathology 13 P + 13 No 13 No. 14 13 P+ 6 Yo, 15 29 7 15 Small number of foci, with polynuclears; no demy clination, Baemic lesion 9 Epilepsy from childhox! fmbecil Haemorrhagic Icsions. 16 Slasse dift semsclination, Pacman rhages, atypical myelin transpxit. 36 In cellul infiltrar., no demyelination Gth day ataxia, then delirium Encepha. Inpathy with haemorrhages Baron 28 No 56 21 P 8 Go autopy 1. }) }) 16 9 11 sih-9th day malarse, then paralyses Probably poliomyelitis.

·17 REVACCINATION CASES 89 Case No. H Recorated Berg Bak 6 7 10 30 Bas 5+ o BB 2 BB3 26 6 P + P + 17 BB+ IO P + 20 1. B.R 6 30 P + IO Myoclonia, sopor, later Parkinsonism Hemiplegia, then quadruplegia Probably poliomyelitis Zoster eruption, no other encephalitis syinpt Kernig pos , Babinski Rigidity of neck 25th d paralysis of arm Probably poliomyelitis Paralysis one arm, Rabinski pos. Possibly poliomyelitis. Convulsion, mentally disturbed, sequelae Probably enc myel dissem Paralyses with atrophy 9 mo in bed. Probably poliomyelitis Flaccid paralysis legs Probably poliomyelitis Kerng, Babinski One day mentally disturbed Heart bloc Next day recovered Convulsion, recovery Kernig pos , later, 26th d poliomyelitis 14th d zoster cruption and encephalitis Kecovery with sequelac V BBS 16 P+ 12 VB BIO 7 P + 7 8 v BB 12 Noord 35 31 P + 9 14 P- Eckst Jaub Wolman 5 26 22 P + P + 39 12 111 NO DATA ABOUT REVACCINATION REACTION 16 13 Car Gins Miller Strabismus, sopor, recovery 5 weeks, Haemorrhagic encephalitis Hemiplegia, aphasia After 16 mo focal epilepsy 22 3 ·90 DIFFERENCE IN PATHOLOGY + Goet. 14 9 9 Goet. Pette 12 11 Haemorrhagic encephalitis 16 Perivascular focal encephalitis Clinical Landry, Path resembling enceph, myelit. dissem 12 following primary vaccination, in cases in which microglia encephalitis was excluded by post-mortem examination (Fig. 19, see p 137). Group II E Microglia encephalitis in revaccination cases with immunc skin reaction. No such instance has been found in the Dutch material or in the literature. A search of the literature to this purpose was rather depressing, because very few articles gave sufficient data about the skin rcaction and the microscopic picture. Only one case from the literature (Baron, 1929) could be used in addition to the 4 Dutch cases of group F The assumption would seem justifiablc that, when a casc is considered interesting enough to be laid down in the literature, the author would mention the type of skin reaction to revaccination if it were not normal, and that therefore few cases could hasc escape! Our notice. 1l'c shall not try in this chapter to glc an cxplanation of the cry important fact that rcs dccination, when some degree of immunity is sull present, neier gives rise to microglia encephalitis but any discussion about the place of perit cnous eni cphalities will have to consules this fact, ·C REVACCINATION CASES 91 Group IF Five cases are grouped together, although their pathology is widely different The incubation time is mostly much shorter than in microglia encephalitis. Groups II G and H These groups need not be discussed in detail It is remarkable that in 7 out of 15 cases a well-known virus infection of the nervous system was activated: 6 cases of Heine-Mledin's discase and one of herpes zoster. Bastiaanse considered his cases 3, 4, 8, ro as post-revaccination encephalitis, but they showed the typical atrophic muscular paralyses of poliomyelitis, with serious scquclae. In 3 cases (Bastiaanse 2 and 12; Eckstein), an encephalopathic reaction must be taken into account. Case extracts (only cases in which autopsy was performed are given) Group 1 B. Case #2 Male, 25 years, known to have had diabetes for at least 5 years He had been vaccinated with good result against smallpox in early youth and was revaccinated 18.5 1956. The pox pustules developed normally He fell all on 20 5 with fever and general symptoms. Five days later coma came on Blood sugar 74 mg/100 ml with insuline the patient became mentally clear, but was in coma again on 27. 5 and died the same evening Autopsy showed slight leptomeningitis and multiple small fuck of poly. morphonuclears, often with cocci in the centre, lying around a small blood vessel of the white or, more rarely, of the grey matter Around these foci we can sometimes find a zone of demyclination with glial reaction Diagnosis embolic encephalius in a diabetic patient, following successful revaccination Case 18 (Bastiaanse 9, 1955) Male, 62 years Successful primary vaccination in youth, revaccination in 1901 and 16 8 1929, after which 3 small papules de veloped 23 8 mentally cloudy and drowsy, on the 28th somnolent, with nystagmus and positive Babinskt and Kernig stgns Increasing sonnolence and death on 31.8 Wassermann reaction in the blood 4+ Autopsy showed the weight of the brain to be subnormal 1050 g At microscopic examunavion muld ·92 DIFFERENCE IN PATHOLOGY perivascular lymphocytic infiltration was very diffusely present in the white and grey matter; rarely were abnormal cells seen in the parenchytila round these foci and no demyelination had taken place The condition of the ganglion cells was fairly good Larger foci did not exist Van Rijssel, who examined the case at autopsy, diagnosed it as an atypical general paralysis or syphilitic meningo-encephalitis, whereas Bastiaanse made a tentative diagnosis of encephalitis post revaccinalis. Case 43 Male, 58 years Reaccination 4. 5. 1951, with good shin reaction On 12.5 he developed high fever, and he died the following day from heart failure. The brain showed senile changes, no inflammation. Due to the late autopsy, changes in the ganglion cells are of no value. But death was certainly not duc to a cerebral disease Autopsy resealed acute myocarditis with scattered groups of polymorphonuclear leucocytes Case Sjörall , 1932, is grouped here, although the result of the revaccination is not expressly noted but is presumably positre 77:e pauent died on the cleventh day, after an illness of 2 days, The Inflammatory changes were limited to a perivascular aduentitial reaction and oedema, with occasional glial reaction Venous thrombosts was also found Demy clination is not mentioned The clinical course was stormy, and the histological changes did not show microclia encephalitis The case could not be interpreted as a very early stage because death cleven days after vaccination is not too carly for microgla encephalitis to be well dei eloped (eg our case 9) This case of Sjovall must le classifical as coxl-infectious encephalopathy Case Verchenrath, 1935 (same as Eckstein, Sioli, Ilerzberg, 1932). Chill, 3 years oldl, Primary vaccination when one year of age, without result. At 2 years she had a convulsion and at 3 years varicella. One month later resaccinations done (June 24th, 1931) On 30 6 vomiting occurred and she had another convulsion, after which hemiplegua was noted. Spinal fluid 10/3 cells, otherwise normal On the seventh day she had one more convulsion, then she de cloped a rash on the palms and soles. After ses eral more convulsions the chuld reconeted and two months after reaccination she was considered well, although with a slight defect of speech The chuld dred a year later of an intercurrent disease lutopsy showed no abnormality of the brain shich could be attributed 20 thie previous encephalitis Some atrophy of cells in the cortex and basal gangli1 s attributed by the author to another cause ·C REVACCINATION CASES 93 The case is listed in this group because I cannot accept the diagnosis perii cnous encephalitis here: the clinical course is quite different, short incubation time, cry protracted course, frequent convulsions, lasting sequelae. A vascular encephalopathic reaction scems more plausible and the ganglion cell atrophy could well be attributed to that discase. Case Rammox', 1935 Girl, 12 years of age, was vaccinated in her first year without result (no scans were found at autopsy) Revaccination with good result From the 7th day on she was ill, probably due to the vaccinia On the 12th day neurological symptoms developed, and death followed on the 18th day. Autopsy showed small-cell infiltration around vessels, punctate haemorrhages in the white matter, basal ganglia and lower structures This probably was a haemorrhagic encephalopathy, although the very short report cannot exclude microglia encephalitis with certainty. Case Dšreng 2, 1942. Male, aged 27, is found dead 13 days after revaccination, without any preliminary symptoms Autopsy failed to show any serious changes in the organs, except oedema of the lungs. The brain showed the typical picture of encephalopathy. oedema, lymphocytic infiltration and slight diffuse proliferation of the glia Doring believed this to be the carliest change of perivenous encephalitis and considered the case to have run a fulminating course Now we know that the fully developed picture of microglia encephalius can be found at autopsy within 11 days of vaccination The lesions in Doring's case are more widely distributed and different in histological details (lymphocytes are not the important part in microglia encephalitis). In a fulminating case of any diseasc, the lesions found at autopsy should be the first stage of what is also found in the more gradual development, but the picture in Doring's case is not a first stage or focal demyelination and microglial proliferation but the encephalopathic reaction of toxic- or post-infectious encephalitis The histological changes had probably existed for some time, and perhaps the patient had an epileptic fit or a heart attack during his sleep, which caused his death. H Jacob (1955), also regards Doring's casc, as not belonging to the group of pervenous encephalitis.

·94 DIFFERENCE IN PATHOLOGY Cası Anderson 9, 1942. Male, 39 years, vaccinated in infancy and again on 4. 7 1942. Several days later found semi-comatous. No data about the duration of liness are given. Autopsy showed cerebral thrombosis. Group II F Case 13 Male, 13 years old. Revaccination produced three small red papules, without vesicle formation. Neurological symptoms descloped on the 13th day. Death occurred 2 days later, Autopsy showed signs of general septicaemic infection; the white matter of the brain was invaded by post-mortem bacteral growth. Encephalitis foci were present and consisted in some places of perivascular accumulations of polymorphonuclear cells with necrosis of the parenchyma. In other places a diffuse glial proliferation was found. In the mesencephalon perivascular foci with small, round cells occurred; plasma cells and some large lymphocytes and slight microglial proliferation the parenchyma. Thrombosis of vessels was found in many places No pervascular demyelination could be found. Diagnosis: embolic septicaemic encephalitis following revaccination. Case 19. Female, 13 years. The skin reaction to the revaccination was cry mild; at autopsy (death occurred 9 days after vaccination) 4 scratches, covered with scabs, ucre seen The patient had epilepsy since childhood and was mentally backward. Sıx days after the revaccination she developed high fever with soporous condition, low tonus of the extremities and continuous Invitching of the hands The spinal flud came under normal pressure, with a normal protein value and cell count. Next day she had an epileptic fit, became somnolent and des cloped bronchitis. Death came on the 9th day after revaccination. Autopsy showed marked hyperaemia and ocdema of the brain, with many ſoci in the white matter, with perivascular lymphocyte culls, mixed with red blood corpuscles (Fig. 13). The ſoci were round, not elongated along the vessels and often po connection with a vessel could be found the parenchymo shone very slight microglial infiltration around the necrotic parts and a mild degree of demyelination, but many myelinated fibres ucre running through the frxus In other parts of the brain similar focy can be found (Fig. 14), but the distribution is not typical for pericnous encephalus the brain sitt is nearly csempe from changes, the cerebellar white manter, honescr, contains many laemorrhagic foci. This case is described by Querido (1930) as a typical case of postvaccinial cncephalitis, with very short incubation (6 days), dis such,

·C
RFVACCINATION CASF
95
Ti 13. Haemorrhagic creeplahtis
following revaccination. Pens: one
large and three small haemorrhages;
no glia proliferation, Case 14.
cresylviolet
I'vo, 14. llaemorrhagic encephalit
in myelin stain Case 14. IVeigert
Pal
it is often quoted in the literature. But Querido did not mention the
haemorrhagic character of many foci, the incompleto demyelination,
the shape of the foci (often round, not clongated), the abnormal
localization of the lesions and the unimportant glial prolforation In
our opinion, the casc cannot be grouped with microglia cncephaliti
but " a hacmortliagic encephalitis, possibly belonging to llurst's
acute hacmorrhagic leuco-encephalitis
Case 15. Male, 29 years Revaccination 26 9 1929 Three pustulas developed
within a few days On 3 lo he was mentally cloudal. The C.S.T. was founrt
to be normal Babinska sign positive Death came on 12 10 1929 Autopay

·96 DIFFERENCE IN PATIOLOGY # showed healed gastric ulcer, with perigastritis, fatty degeneration of ses cral organs; pleuritis. The brain is is markedly hyperacmic and showed samic haemorrhages around the lateral ventricles There was celema of the meninges The subarachnoid space showed localized mononuclear infiltration. Many of the smaller Vessels in the corter and the white matter were thrombosed. Many Vessels in the brain were accompanied by an increased number of oligochal nuclei. Aficroclial increase was not seen. Around some vessels lymphocytes in small numbers could be found, but this was not of great importance. The most outstanding change in this brain was the my clin degencral. tion especially in the white matter of the hemisphere, frontally more marked than elsewhere. In myclin-stained slides wc saw small, round, whitc foci, 30-100 H, sometimes appearing as cmpty spaces, sometimes containing a substance which still took the Weigert.Pal stain. There was no perivenous demyclination of the type scen in encephalitis following primary vaccination. A remarkable picture was seen also in the coreck, where numerous scssels słoned the same lipoid masses found in the foci of the white matter, staining grcy with thic Weigert-Pal, in their Virchow-Robin spaces. This substance was lying ſrce and was not taken up by phagocytes. It was evidently being transported to the subarachnoidal space, where it can sometimes be found around the entrance or exit of penetrating vessels. This type of transport of myelin degeneration products as also found in the brains of thrce monicys intraperitoncally injected by Verlinde et al. (1953, animals 145, 148, 165) with vaccinia virus and dead staphylococci. I have been unable to find any report on this curious type of myelin degeneration and transport in the literature. Case 56. Male, 21 years old, vaccinated in youth, scars hasc not howmer, brett obser\cd Revaccination 26 6 1937, gayca typical immune skin reaction, nolari 17 Three days later he was forced to swim, but turned out to be slightly atactic Afterwards he twice fell from his bicycle, complained of headach during the evening and was restless during the night. Early next morning he was found dead in bed. General autopsy showed serious vasomotor collapse, with hacmorthagic ocdemna of the lungs and oedema of the kidneys Tic brain weighed 1500 & and was slightly swollen At microscopic roamination, haemorrhages were found around the lateral entricies and in the cerebral white matter Furthermore, diffuse perivascular clema of the brain mar present, ·C REVACCINATION CASES 97 sometimes with a few small round cells and brown pigment included in place qytes in the sheaths of some icssels These changes were probably an carly stage of a haemorrhagic encephalopathy, death being due to the pulmonary condition Case Ngron 8, 1929 Female, 28 years, de cloped angina on 29 i 1939, the next day injection of 40 ml antadiphtheria serum 12 revaccination, dried scabs of which were still present eight days later, without surrounding skin reaction On 52, serum exanthema descloped, and soon disappeared again On 62 mild ataxi and progressive disturbance of speech were noted, and a soporous condition developed 3 days later Then the patient had ses cral epilepuc fits, and she died on 17 2 1929 Autopsy showed hyperaemia of the meninges and brain, with some haemorrhaces, but without signs of encephalitis The vessels were filled with polynuclear leucocytes, indicating a general tox-infectious condition No demyelination was found In this case thrce aetiological factors were present. the sore throat, the anti-diphtheria injections and the vaccination. It is probable that the combination of these toxious conditions caused the vasomotor collapse, which is quite different from a perivenous encephalitis, Case Brouwer, de Jongh, Rochal, 1933 In addition we will mention this case, in which revaccination may have played some rûle in the development of symptoms A motorcar driver, aged 27 years, was successfully vaccinated in his youth and revaccinated on 2 10 1939, showing immunity reaction On 31 10 he came into close contact with a patient with a haemorrhagic type of smallpox. He was then revaccinated on 511, again showing a very shaghi reaction A morbilliform exanthema was noted on nnt. it was diagnosed as a very light case of smallpox His condition improved but on 21 11, signs of transyerse myelitis descloped, soon increasing to total paraplegra, causing death due to decubitus on 27 1 1930 Pathological examination showed large my elatie fort with necrosis, marked demyelination, fatty granule cells, microglsal syncytia and fibrillar glial sclerosis Sinall round cells were present in the subarachnoidal space, but were rarely found around parenchyma vessels The ganglion cells were mainly intact Very few small foc were found in the oblongata and the pons, the cerebellum and cerebrum showed no changes The authors conclude that the lesions are typical of myelitis following smallpor. Whether the partial immunity and the revaccinations had ·98 DIFFERENCE IN PATHOLOGY any influence on the eruption, or des clopment of the myelitis, cannot be decided at present. Discussion The number of cases with an accurate histological description is too small for statistical cvaluation, but still some general conclusions may be drawn. (1) In the first place it is evident that microglia encephalitis is not the prevailing nervous complication follou'ing retaccination. In our group D, several cases may have been microglia cncephalitis but, as they recovered, their exact nature cannot be giien. At least 4 of these did not recover completely, but still showed neurological defects afier somc time. Most probably they do not belong to the microglial group. (2) The most outstanding conclusion, however, is that microglia encephalitis has not been observcd following rcvaccination when partial immunity to the vaccine still existed but that, when immunity had subsided, the cercbral reaction might be the same as that following primary vaccination. However, the picture may be rather irregular, as described by Pettc (1936, p. 271) in a girl, aged 12 ycars, in whom resemblance to the picture of disseminated encephalomcylitis existed (no data about the skin reaction or incubation time are given by the author). Then, the proportion of cases with ccrcbral reactions other than microglia encephalitis is much larger than sc are accustomed to sce following primary vaccination. (3) Clinically the wide variation in incubation period as well as the irregular course of the disease and the great number of cases recovering with neurological sequelac, are outstanding differences from the picture of microglia encephalitis seen aſter successful vaccination. (4) Then, we found that activation of another virus discasc is scen aſter revaccination as well as following primary vaccination (firinc- Medin, zoster, myocardius) (5) The number of cases in this section is too small to discuss the problem of the possible influence of cerebral complications when other serum injections or vaccinations had been given in the same period ·DEVELOPMENT OF ANOTHER DISEASE 99 (6) As far as we know, there is only onc report on traccination of persons who had encephalitis following a primary vaccination. Puntigam and Daimler (1950) report on 11 soldiers: none of them showed any nervous reaction following revaccination (7) Nenous reactions following revaccination have been inown for a long time. In 1916 an accumulation of cases of brachial neuralgia was seen by many physicians during an intensive vaccination canpaign in the Netherlands (400,000 revaccinations). Thoracic neuralgia also occurred and the chnical picture somewhat resembled Bornholm's disease but there were no relapses after recovery and the pains were not as scvere as those in the latter disease. The incubation time was about 14 days. This complication was also noted in 1929 (Koetser, 1929) and again only following revaccination. Women were more frequently affected than men d. Development of another disease during the first weeks following vaccination In this paragraph some cases will be discussed in which a well-known nervous disease started shortly after vaccination, suggesting some relation between its occurrence and the vaccine treatment. No 21 7 Months old, developed cerebral symptoms 20 days after vaccination She died many months later of pyacmia and septic meningoencephalitis. NO 12. Man, 26 years Revaccination, died 8 days later of embolic encephalitis (sce par,c} No 46 14 Months old, developed meningococcal meningius 8 days after vacunation, which ran a fatal course in 6 months. Then our attention should be drann to Cascs of poliomyelius starting after vaccination Our series shows only one case (No 23) in which the paralysis des eloped on the 14th day; the child died one week later The histological picture has typical in her case and also in the nervous system of a monkey injected with matersal from this patient ·100 DIFFERENCE IN PATIOLOGY + The histological and experimental cridence in this case proves that, here at least, the vaccination may have been a factor which made thic outbreak of the Heine-Mcdin infection possible. For this case we cannot accept the explanation which van Bogaert (1956) gives: that a former subclinical or mild poliomy clitis infection leaves a segment of the spinal cord more vulnerable, after which vaccination may cause symptoms reminiscent of recurrence of the poliomyelitis. The Dutch literature contains a number of articles on this subject, the results of which are summed up in Tablc l'II TABLE VII CASES OF POLIONYELITIS FOLLOWING VACCINATION From the Dutch literature Age of palent Incubafron dars duthor rear Burgerhout 1929 Bastiaanse 1929 Bastiaanse 1929 Bastiaanse 1929 Bastiaanse 1929 de Monchy 1930 no data giyen Clinical observation only. 6 y 17 Revaccin Atrophy of muscles and paralyses remained 10 y. 20 Revaccin. On 20th day convulsions hemiplegia. go y. 10 Revaccin. On 15th day pareses: remaining atrophy. 7 y. 7 Revaccin, Flaccid paralyses; rentaining atrophy. 27 mo ca to Paralysts of arm on which saccin, took place 9 Paraplegia, fore cases of polso in the tots. 30 y. lo First hemiplegia; later also paraplegi 16 14 Hemiplegia. Histological confirmation 9 mo 14 Histological confirmation 21 mo. 14 Clinical observation 21 Clinical obsersation 3ly. 21 Reaccin Transitse my click to pred of tiene Nieden Heidema 1930 Balker V Rijssel No 23 l'eraal Verjaal Verzaal 1930 1910 1940 1947 1950 1950 10 mo ·D DEVELOPMENT OF ANOTHER DISEASE 101 In other countries also, a number of cascs were described in which poliomyelitis developed shortly after vaccination. Some relation between the two is generally accepted. Miller (1953) reports on 3 cases. Uiberall (1950), however, did not find an incrcasc in polto. myelitis incidence following mass vaccination, Our material contains two cases (Nos. 43 and 55), in which death from acute (probably viral) miocarditis occurred on the gth and 10th days after successful vaccination, respectively. A discussion of this subject cannot be given here, as our work is mainly based on the cases with histological examination, and these are only a small minority, which does not permit of any conclusions. The extensive literature on this subject need not be discussed here. However, mention should be made of administration of cortisone before cxperimental or accidental viral or other infection. Wolf et al. (1952) found that monkeys, carrying Trypanosoma crust and injected, after cortisone treatment, with monkey brain and adjuvants, developed trypanosomal encephalitis, whereas animals treated in the same way but with no previous administration of cortisone, dit not show this disease. Then, monkeys that received intracerebral injection of Echo g virus at the same time with cutaneous vaccination (smallpox vaccine), did not show any sign of encephalitis unless they had previously received cortisone treatment, in which case encephalomy clitis of the poliomyelitis type developed (Verlinde, 1955) A case, recently described by Paul (1954), perhaps belongs in this paragraph. A child, 13 months old, had a severe convulsion 8 days after vaccination, and remained a spassic imbecile The mother and the child showed a positive Sabın test for toxoplasmosis, and Paul gives as an explanation that the toxoplasmosis was an important factor in the development of postvaccinial encephahatis But we think periv enous encephalitis never existed in this case. Perhaps it was the other way round, vaccination activating toxoplasma growth, perhaps it was a common toxi-infectious vascular reaction ·102 DIFFERENCE IN PATHOLOGY + e. The encephalopathic brain reaction following vaccination We have examined 22 cases in which death followed vaccination within 4 wecks, with a pathological picture showing the changes generally grouped together as encephalopathic. Many of these cases have already been discussed in the preceding paragraphs in another connection. They can be divided into 3 groups (sec Table VIII): I, those, in s hich clinically no encephalitis was noted; II. cases showing a convulsion without (other) signs of cncephalitis, and III. cases with clinical sympions of a brain affcction, often called encephalitis. The most frequent, and probably thc most important, is ordema of the brain manifested by increascd weight, swelling of the convolutions and widened perivascular spaces (sec Table VIII). Sometimes the pericellular spaces were also larger than usual. Ocdema was found in all cases of group II, starting with a convulsion and in most cases of group 1, but onlyinone of 3 cases in group III. In the last group, honcier, comprising cases with symptoms pointing to an affection of the brain, changes such as hyperaemia, slight cellular infiltration and early glial reaction were more constant than in groups I and II. The reaction of the brain parenchyma and its vascular apparatus is definitely morc marked in the third group than in the first ise groups, although the duration of the illness has also been very short in threc of them. The infiltration of the meninges and sometimes of the vessel shcaths was norer very important; generally only a few cells were found in die tissuc covering the cerebral sulct or in the cisternac. They consisted of small lymphocytes with rare large lymphocytes or plasma cells. Polynuclears were not important and the distribution in the meningers was not perisascular in the vessel sheaths in the brain, cellular infiltration was never very cvident, a few lymphocytes were found only in some cases. The degeneration of ganglion cells was quite conspicuous in a number of our cases but in very young children, and in the presence of cerebral ocdema, the swelling and vacuolization of the cortical cells can casily be due to post-mortcm changes for esen to swelling during the ·E TABLE VIIT POSTVACCINJAL EXCEPHALOPATITIC REACTION Dutch autopsy cases Case do Incubator, days Prom or relacc. raccination Saretzal after Age ENCEPHALOPATHIC BRAIN REACTION 4 mo + 675 8 - Ocdcmna - 20 + ti + + ++ #1 7 I Death usthout conical cerebral in olvement 58 O P + 13 con ulsion 5 w before death shock, exsiccated. 6 mo. 2 3 day all Morbilli evanth at autopsy. No cause of death, 49 7 mo found dead in bed. No preced. ing discase Body autopsy neg, 5 6 Malaisc 1 day. Then dead in bed Thymus pos 50 9 mo, 21 Malaise, circulat. collapse. Shoch Thymus pos. 4 lomo. +8 Chron cczema Vaccinia gener Sister vaccinated 7 1 + + 8805 22 8 mo - - + 11 1 oligo+ 2 - 1100 & + ++ + - + + - ++ + 103 ·10+ Ol35) Incubation, days I'rm of relact Laccination Suriu al after Pia hyperaemia Pra infiltration hyperaemia Parenchymal or perilascular Oedema, general Peritascular Haemorrhages ganglion cells Degeneration of Cha reaction $11 +1 - IF oligot # 1150 5 - !! + + - thrombi oligot 47 il mo. 8 I day feier. Dead in bed. Body organs nes. 59 14 10 5 5 Eiening fever. Morning dead on hech Thorax purpura. o 18 mo 18 18 Vaccinja gener. Tulminant death 53 20 ) 10 10) Tound dead in bed. Yo diacase. Autopsy myocarditis + 43 56 ) Tever. Nors subita. Autopsy myocarditis 61 7 1110, 12 + 12 No disease. Dead in bech Spleen infectious cond. 62 5 5 l'ound dead in bed. Aviopsy malformation of cerebellum DIFFERENCE IN PATHOLOGY + Goog ! -- + - -- 6 mo. + it - + + 11 Death after cont ulsions, uithout other clinical cerebral disease 34 ។ ព០ P+ 20 Yonal until convulsion, Subarachnoid hacmorr. nu). 5 Status epilepticus I # 1 990 g oligot $ ·51 9mo 8 84 ltad cold No dyscase before canyal Blood 24000 leucoc SF. & cells Thymus + 7 5th day fever it night convul. 24 Tener, consulsions, Death after few hours Polourus in pons- 1000 + + 11 + £ + 6 26 romo 37 I mo 24 + - It It + регі. vasc 52 24 10 to 70 Feier before convulsion. Later deep idiot Vascul. malacia of brain. No indammation found, brain weighed 1550 II Cerebral disease and histologual encephalopathy 36 9 mo 3 8 Progressive allness. Toxic, diarrhoea, restless. 48 16 RIO 10 Pru1 Father Nu Pochpustules oth day Illness 8 hours FXCEPHALOPATHIC BRAIN REACTION + + + ti + + + + + pers. Yanc. gla. star 35 5ły + + + oligo + 56 21 Y 6 P 6 fother rubella during progr. Malausc. convuls 6 hours later death 7 R 75 One day headache Dead in bed vasomotor collapse Hae. morrh pneumon Okl lain lesions 1500 K + olil + 105 ·106 DIFFERENCE IN PATHOLOGY first 1cchs of fixation in formalin solution) and should not be mistaken for a toxic effect on these cells. Demrelination was never found in thesc cascs and the reaction of the glia cells was very moderate, mostly consisting of some increase in the number of oligoglial nuclei, often arranged in rows along small vessels or in the direction of the nerve fibres. Four cases in which death could definitely be ascribed to a disease other than cerebral changes (group I, Nos. 4, 43, 55, 60) give the same histopathological picture as the others. Tuo of these dicd of vaccinia generalísata and two of myocarditis. The general toxic and infectious condition of these patients, therefore, was reflected in thcir nervous system by the same changes as found in the others A further interesting point is that no difference can be found better the early and the late cases. No. 20 had no aetiology other than vaccination and an enlarged thymus, and still the changes are of the same character and grade as in the others Therefore these changes cannot be sech as the initial stage of another discasc (microglia cncephalitis), is supposed by some authors, but they constitute a discase as such, giving the complete picture of the encephalopathic brain rcaction to toxin infectious conditions of the body. The question as to whether wc should speak of infectious changes or of post or para-infectious conditions seems to me an academic one, of only little importance for an understanding of the pathogenesis There is no sharp borderline between the ino; es on in a very mild general discase, the vasculoconnectic tissuc of the brain shows some changes; but thiese subside as soon as the general discase improves. Only those cases in which the brain symptoms and luistological changes do not disappear alich improvement of the general condition, should be called post. or parainfectious, and considered complications Our table shows one more interesting aspect. there is no clear difference belucen the groups without and those with contulsions. Thic consulsion is mostly foreceded by a short period of fever and malaise, which can be considered an expression of the developing ocdema of dic brain. "Ibis oedema was found in all cases of group II on which sufficient data were available. In case 57 the vaccination, donc 2 days prior to the ·E ENCEPHALOPATIIC BRAIN REACTION 107 fatal outcomc, cannot have been of much importance, but the findings of virus of poliomyelitis in the brain must probably lead us to the explanation that the viraemia caused a toxi-infectious condition resulting in brain ocdema and a consulsion. Whether the vaccination acted as an accessory factor remains open to discussion, it is certainly possible. Case 52, surviving the convulsion for 2 months, of course shows another histological picture because the serious damage caused by the anoxaemia during the convulsivc state (lasting about 2 hours) was evident at death. In the other cases, how cier, death came on too quickly for changes due to the convulsion to be demonstrable. Radermecker (1958) makes a sery careful analysis of convulsions during hyperthermia and also considers them to be non-specific cerebral reactions to general infectious processes The great number of patients who were found dead without important preceding symptoms being obsen ed by their surroundings, is astonishing We encountered this 6 times in small babies and twice in adults (No 55, a soldier with myocarditis; No. 56 found dead at night after he had complained of headache during the evening). Miller, 1953, also points out this sudden death, 3 of his patients (all soldiers on active service) died within 24 hours after the first symptoms. It is very kely that at least 2 of them, dying 2 and 5 days after vaccination, had an encephalopathy rather than peris enous encephalitis Doning also describes a man of 27 years, found dead 13 days after revaccination, with encephalopathic changes in the brain this case has been discussed in the paragraph on revaccination). We must consider the brain oedema in these fulminant cases, together with circulatory collapsc, to be the chicf cause of this spectacular course The fact that small babies formed the majority of our cases of encephalopathy is not astonishing when we realize that the cause of death is often general shoch, and that the brain oedema noted in most of these cases more easily develops in the very young brain than in the older brain Scveral cases had an cnlarged thymus, predisposing them to circulatory disturbances ·108 DIFFERENCE IN PATHOLOGY The encephalopathic changes discussed in this paragraph, of course, are not specific for postvaccinial disease, but are a icry common reaction of the nervous system to many toxi-infectious conditions. It is not necessary to describe these in detail but it might be north mentioning that the same changes of the brain can be found in patients in whom a nervous disease was not clinically present and who did not even show any nervous symptoms. This is important in our discussion, because we can more casily accept that the mild cerebral changes found in a number of cases after i accination are an cepression of the condition of vaccinia and the general disease following vaccination, and not a complicating brain diccasc. The difference in incubation time (as shown in Fig. 15) betseen these cases and those of microglia encephalitis, stresses this point further. A99 years Number of coses Age in years OI e non n 1) Incubation days Number Days D)... DOOD IT WORK Survivor in dors Number Days tanPX4 [16 15 Dutch cases of postiaccinal encephalopathy that come lo autot, We shal} describe one crise belonging to this calegnry No 5259, a chuid of 11 months, sell acutely !! with alxominal pain fiy which an oprtai *5 done the discase, hontier, was progressie and the thikel dieet alkut 5 d113 after the first complaints, without having shown neniowy symptoms Routine examination of the brain, howeser, shone scry marketi ordem: the brand weight was 1120 g. and, microcipically, fictivascular cerima nas al«? found.

·F RARE HISTOLOGICAL PICTURES 109 as well as spongious oedema of the cortex, sometimes with laminar distribution. Another change was diffuse hypertrophy of the walls of small vessels in the parenchyma Cellular exudate was not important Alcad or arsenic przsening was considered but could not be prosed Summansing, important histological changes in the brain uett found in a young child uith abdominal disease, urthout any dinical simptoms The literature contains many articles pointing out this important fact. Pagès (1952) divides the pathological changes in toxicoses of babies into 3 groups hyperaemia, sometimes with thromboses and haemorrhages; then, oedema of the brain and meninges and, thirdly, ganglion cell degeneration Annell (1953), in an article on pertussis in infancy, mentions that a psychopathy in later childhood can very often be caused by encephalopathic changes during the pertussis, which did not impress as important neurological symptoms at the ume She also mentions that these complications have increased in frequency in the third decade of this century That cerebral changes can be present without clinical symptoms is also demonstrated by Hodes and Livingstone (cited by Radermecker, 1956). They found that, out of 114 cases of measles without cerebral symptoms, 43 showed E.E G changes suggesting subclinical "encephalitis". f. Rare histological pictures Some cases showed a microscopic picture that could not be classified or brought under the well-known headings All occurred after revaccination, descriptions of these cases are gren in par c, (cases 13, 14, 15, 18) Bastiaanse put them together as revaccination encephalitis, but in our opinion they show too many differences, among each other and from other cases occurring after revaccination, to unite them in one group The greater complexity of the microscopic picture suggests a more complicated aetiology, in which the earlier primary vaccination probably plays an important role.

·Chapter 5 OCCURRENCE OF MICROGLIA ENCEPHALITIS AND MICROGLIAL PERIVENOUS REACTION BEFORE 1923, AND WITHOUT PRCCEDIXG EXANTHEMATOUS DISEASE A. Introduction In this chapter we shall review the occurrence of perivascular microglal proliferation in conditions other than those so far described. Many cases have bcen described in the literature as periscnous encephalitis or disseminated encephalomyelitis, often giving to these conceptions a rather broad pathological basis. It will be our aim in this chapter to divide these cases into a group, limited strictly to thic picture of microglia cncephalitis (+) as opposed to a less homogeneous group comprising cases differing from these in some points but all showing perivenous microglial proliferation and demyclination (+) and others with the characteristics of another rcaction ( - ). Wc presume that only by narrowing down our group in this way will rt be possible in the future to relate a certain pathology to definite actiological factors A discussion of the results obtained will txe postponed until the next chapter Alicroglial proliferation occurs in many discases, and we need tot describe these. Only when focal periyascu),ir infiltration is seen with this type of cells can the pictures resemble those of microglia enceph. litis. Some figures will illustrate this Fig 21, (p. 70) shows the lateral ·INTRODUCTION 111 FC 16a Fat embolism, microglia reaction around necrotic Centre, not spreading along the vessel Case 5336, death 7 days after trauma Nissi stain. FIG 166. To compare with a microglia encephalitis Focus along normal vessel Case 45 Nissl stain S.H.S. 1. Olidow LULLEL TIRRY ·112 OCCURRENCE OF MICROGLIA ENCEPITALITIS ws ganglion cell degeneration with neuronophagy is apparent (oint shown in the figure), and thick lymphocyic culls are present around many vessels without a microglial reaction. Demy clination is scarce or absent. Some degrce of marginal gliosis may be present (casc 23; girly months old; illness began 15 days after vaccination; three days later paralyses developed and, again 3 days later, a fatal outcome, In. oculation of spinal cord tissue into a monkey was positive for licinc- Medın virus). This microglial proliferation occurs in many different diseases of the C.N.S, and can easily be distinguished from the postvaccinial foci. Also, its distribution along the cerebral axis is quite different. Perrascular foci occur in a variety of discascs. Embolic cnccphalitis shous pictures, in which the glial proliferation is more often perivascular (Fig. 16 a, case of fat embolism, No. 3620, death y days afier trauma), but necrosis in the centre is generally present and the forcus is arranged also around very small vessels, not only the larger veins Demyelination is often incomplete. Often there is some haemorrhage in the foci (compare with 16 b, a typical focus of microglia cncephalitis). In mans toxi-infectious conditions foci can be found which resemble this type. Generally ocdema and changes of the vessel wall indicatc their true nature, and they will not be mistaken for microglial foci. In hoemorrhagic encephalapathy we previously described (Chapter 3, b, 4) foci of partial tissue necrosis of vascular origin, and the subscquent microglial reaction. These facı differ from microglia cncopha. les in that they are more rounded, much smaller (not infiltrating for into the parenchyma), showing only incomplete demyelination Thrombosis of the vessel or thickening of its wall is ofion present. In addition, the distribution of the foci can be different. In these cases we do not find marginal gliosis and rarely more diffuse glial proliferation. Differential diagnosis is far more difficult in cases whicrc, in addition to the changes opical of the disease, periteous foci of demyelination urth microglial proliferation cctur.

·INTRODUCTION 113 In the first place he must mention some rare cases of poliomyelitis, in which typical microglial foci were obserıcd. G. Peters (1938) and ollaret and Bertrand (1951) demonstrated these in the white matter of the cord and hemispheres. We obscen ed a similar picture in two monkeys which had recen ed an intracerebral injection of Echo g virus at the same time with cutaneous anti-smallpox vaccination (Fig. 17). FIC 17. Pervenous microglia proliferation in clinical poliomyelitis Monkey, injected with Echo virus Thalamus Nassl stain Both animals developed paralyses and autopsy showed the typical lesions of acute anterior poliomyelitis in the spinal cord, but also more involvement of the higher centres, especially the thalamus In these centres several typical pervenous foci of demyelination with microghal and polynuclear proliferation occurred, but the foci showed .

·114 OCCURRENCE OF MICROGLIA EXCEPHIALITIS 3 marked hypertrophy of the vascular walls and also infiltration by mesenchymal cells. Perivenous foci have been described in cases which also shoned other types of lesions; they will be reviened in the following para. graphs. In par. f, a short discussion is given on disseminated encephalomyelitis, to which group many of these cases belong. We will regard as positire signs of microglia mtephalilis: Perivenous microglial proliferation; Marked demyelination in these arcas; Less degeneration of the axis cylinders; Marginal gliosis by microglia cclls; Small or no lymphocyte cufls; Diffuse but not very'set cre glial proliferation in whitcand grey matter; Distribution in hemispheral white matter, in white and grey matter in the deeper structures; Sparing of ganglion cells in the foci. And we regard as negative signs: No necrotic centre in the foci; No or only agonal erythrocytic infiltration; No thromboses of essels; No coalescence to foci in which the original perivascular local. ization is not evident. The occurrence of these changes would point to another reaction type, probably to a complicating actiological factor. Table IX summarizes the cases with autopsy reports scferred to in the lucrature as perrvenous encephalitis, with the exception of prosevaccinal and post-measles cases (they arc scry numerous); not all post-rubella cases are included b. Cases occurring before 1923 The case reported by Brissaud and Brécy, in 1904, as ,,ncusomyélite optique", had multiple lesions 17th lymphocyte exudates, but no cells in the parenchyma (according to the figures); there were some hacmorrhagic foc: but it does not resemble microglia cncephalitis. 1: is referred to by some authors as a case of periscnous encephalomyelitis.

·B CASES OCCURRING BEFORE 1923 115 TABLE IX AUTOPSY CASES REFERRED TO AS PERIVENOUS ENCEPHALITIS IS THE LITERATURE (Shortly mentioned in the text) Author Tray Rating Aetrology + poliomyelitis poliomyelitts vaccinia 士土 feserish disease rubella no known cuiology HT common cold + vaccinia 28 d. earlier ? Peters Xollarcı, Bertrand Brissaud, Brécy Turnbull, Micintosh Krabbe Marie, Tretjakoff Tinel, Bénard Wohlwall Pette, 2 Grinker, Bassoe, 1 Müller De Busscher, Radermecker Van Bogaert, 2 Briggs Wigand Moller, 117 Falger Zimmerman-Yannet Van Bogaert Roeder-Kutsch Dagnelie, Dubois Swan Spiller McIntosh, Scarff Kramer, 7 Kramer, 8 Troup, Hurst Marsden, Hurst, 1 Warsden, Hurst, 6 Marsden, Hurst, 7 Brouwer, de Jong, Rochat 1938 1951 1904 1912 1913 1921 + 1921 + 1928 + 1928 1931 1923 1949 + 1950 1935 1941 1949 + 1913 ? 1931 1930 19H + 1932 1916 1903 1930 1951 1951 rubella – rubella rubella rubella Vancella varicella varicella varicella varicella + angina smallpox smallpor smallpor smallpox smallpox alastrim alastrim alastrim mild smallpor t 1930 1932 + 1932 + 1932 + 1933 + ·116 OCCURRENCE OF MICROGLIA EXCEPIIALITIS 5 duthor lear Rating Hetiology . 1941 + ? Schreuder, van Rijssel, Verlinde 1950 + Winkelman 191? Moller, 92 1919 Donohue Greenfield 1930 + Greenfield 1930 +? Demme 1930 Davison, Brock, 1 1937 Davison, Broch, 2 1937 Moller, 2 Crome 1957 Higier 1912 .. Rojas 1932 . Bassoc, Grinker 1930 +? or Stuart, Krukoran 1930 Uchimura, Shirah 1957 Jones 1958 Griflin, Rogers, Kernohan 19.18 Giedcon 1954 De Massary, Albcissar 1936 1949 + cowpor scarlet feuer Whooping cough parotitus influenza influenza angina --? common cold common cold common cold influenza rabics + anti-treatment rabics + treatment rabics-treatment rabics-treatment rabies-treatment rabies-treatment antityphoid inj. antityphoid ini subacute course 1. Turnbull and McIntosh (1926) described a case occuring in 1912 .I boy, 15 years old, was vaccinated 5 7.1912 No scars from previous vaccination were present, and the skin reaction took the course of a primary saccination On the 18th he became comatous, oculomotor palsy was noted the following day. On 22 7 the CSS contained numerous cells one third being polymorphonuclears He died from mucopurulent bronchopneumonia on 22. 7. Autopy showed degeneration of the kidneys and calcified mesenteric glands The brain weighed 11.48 g Subdurally and in the subarachnoid space, small haemorrhages were found. One cortical block and 5 les cls of the spinal cord scrc histologically examined The cortex showed hyperaemia, with lymphocytes and erythrocytes around a number of vessels Very little glial proliferation cíther in krey white matter and no demy clination, other than what could by attributed to per vascular oedema ·B CASES OCCURRING BEFORE 1923 117 In the spinal cord, at all levels, foci of demyelination were found perivascularly, with the typical longitudinal arrangement. Hon ever, microglial proliferation in these areas is sery mild, as also stated by Turnbull. The foci arc localized mainly in the white matter; in some of them haemorrhage was prescrit (thor. VI) and ocdema was conspicuous in a}} Turnbull mentions that the demyelination is more easily sech with the van Gieson stain than in Weigert-Pal-stained slides, which might mean that oedema nas more important than primary myelin loss. The picture cudently differs from microglia encephalitis in many points, but still the spmal ſoce show enough similarity with it to be of importance for a final explanation. 2. Krabbe (1913) published the case of a one-year-old chuld, who died 12 days after the onset of disease, which stanied with diarrhoea After 5 days he was restless, he develtyped diplopia two days later and had some ngidity of the neck. Symptoms changed in the course of the disease and he had con ulsions and tonic ngidity The spinal flud showed high pressure and a mild increase of mononuclear cells The brain showed hyperaemia, no meningitis. Microscopically the most interesting change was a focal perivascular increase in glia cells, with distinct plasma bodies The photograph seems to confirm that a pertvenous microglial focus is demonstrated here. There were no mononuclear or other haematogenous cells The distribution of these foci was mainly subcortical and deeper in the white matter Demyelination in the foci was typically perivascular In addition a few granule cells, laden with fat, were found in vessel sheaths and also there existed a mild, cry diffuse increase in small round glial nucler. Krabbe considers this case to be a sery carly stage of diffuse famulial sclerosis, and not an inflammatory condition The child had not been vaccinated, nothing is known about previous diseases*, A brother had a simular condition at the age of 2 years, but recovered. 3 Varu and Tretjakoff (1921) described a girl, 16 years old, falling it on 30 1 1918, with fever and eye muscie paralysis. A werk later paraesthesia and weakness of the legs developed and the disease ran an ascending course, with death on 1712 Nothing is noted about pres tous vaccination, no aetiology could be found Autopsy revealed inflammatory Iesionts, limited to the white matter of the cord, brain stem and centrum semiovale The lesions consisted Personal communicatton ·118 OCCURRENCE OF MICROCLIA ENCEPHALITIS 5 of foci of demyelination arranged perivascularly, oval or rather long in shape. They contained granule cells and glia cells. The ganglion cells were found in be intact. The authors do not discuss the pathology; to them it is one of the types of changes found in Landry's ascending paralysis, but the figuses are very suggestive ar perivenous microglia encephalitis 4. Tinel and Bénard (1923) briefly refer to a case of post rubella cucephalitis, Occurring in a man aged 21, in 1921. Death occurred on the 6th day after cruption of the cxanthema, 2 days after the first neurnlogical symptoms had appeared. In the spinal cord (other parts could not be examined) numerous small perivascular foci existed with total demyelination and cellular infiltration by mononuclear cells (called plasma cells) in the vessel sheaths and surrounding tissuc. All nerve cells were perfectly well presen al. The spinal Nuid had shown infiltration, mainly by polynuclear Icucocytes Thc figures given by Tincl and Bénard show a great resemblance to pcrivenous cncephalitis; the spinal fluid rcaction, however, and absence of glia cell proliferation, could indicate that embolic encephalitis cannot be excluded Thesc cases show some points of resemblance with our picture of microglia cncephalitis; honcver, only the cascs by Tinci and Ménard, and by Maric and Tretjakoff can be accepted as probably trur microglia encephalitis. c. Cascs without preceding disease Tlus paragraph contains cases, sometimes typical sometimes not quite so but with enough points of resemblance to be taken up in our discussion Case of Krabbe (1913), discussed abose Case of Varu and Tretjakoff (1921), discussed above. Case of Iloklzeill (1928). In acry short discussion Wohlwill schuinas this case with the picture of perschous encephalitis, frst le cincs not gile carugh details for its final establishment in a certain grup. Peste, case 2, 1928 One microphotograph of this rasc very much resembles per lenous microgha) proliferanon. The other pictures ·CASES WITHOUT PRECEDING DISEASE 119 indicate another type of cncephalitis, and the case is diagnosed by Pette as disseminated encephalomyelitis or acute multiple sclerosis. Grinker and Bassoe, case 1, 1931. Female, 23 years; 10 days after contracting a cold, nervous symptoms and fever set in, of which she died 6 days later. The symptomatology was that of myckes, with mental cloudiness. Death from bronchopneumonia. Leptomeninges and sacral roots were infiltrated by white blood corpuscles and fatty granule cells, Necroscs in cord, often around veins, coalescing and with many granule cells. Demyclinarion was marked. Hemispheres were not inoked The case has, according to Grinker and Rassoe, the same pathology as Greenfield's cases following influenza and postiaccinial or post-measles encephalitis Sull, according to us, there is a marked difference After 5 days of illness, microglia encephalitis does not show total necrosis with many fairy granule cells, and the perivascular and meningeal reactions are much less. It is comparable to our cases of transverse myelitis, in which secondary factors alter the picture. But it is not certain that a typical microglia encephahtis was the original disease Muller (1933) This case shows typical microgla encephahtis in the white matter of the cerebral hemispheres, but also shows many hacmorrhagic fact, with vascular thromboses and necrotic centre. Both types of foci show demyelination No meningeal affection; no marginal ghal proliferation and rather marked astrocyte proliferation in the foci are other points of difference with mucroglia encephalicis l'an Hasselt (1931). We mention this case, because it is sometimes quoted in the literature, although the description suggests an embolic or haemorrhagic type of encephalitis We cannot include this case in the microgla encephalitis group De Busscher and Radermecker (1949). This case has been reviewed in Chapter 3 b. 5 msetites) It showed typical microglia encephalias, starting 28 days after successful smallpox vaccination, together with typhoid vaccination As has been suggested by the authors, it seems more accurate to group it with the cases without known aetiolog) than with posts accinal encephalıns ·120 OCCURRENCE OF MICROGLIA ENCEPITALITIS 5 P'an Bogaert, cast 2, 1950. Girl, 9 years old, had mcasics 3 / cars bcſorc with cerebral symptoms, but recoi cred. Fell ill 14 days beforc death. with general symptoms, aſter which cercbral symptoms dacloped. Transverse myelitis with beginning decubitus. No infectious condition had been noted before the illness started. Pcrii ascular infiltrates in demyelinated arcas were found throughout the white matter of the hemispheres. No specification of the type of cells or of the appearance of thc Icsions in other than my clin-stained sections is given, but the casc is classified by van Bogaert as post-infectious encephalomy cliris, activated by some general infection and showing the same type as the child had shown 3 years earlier, following measles. d. Cases following other conditions or diseases 11'e give herc the short cxccrpts of the cascs mentioned in the literature as perivenous encephalitis, and regarded as cquivalent to typica postvaccinial cnccphalitis. arasles Typical microglia cncephalitis is well known as post-measles complication, but explanations of other histological pictures in clinical post-measles cncephalitis differ with various authors. According to many authors (Lhermitte, van Bogaert, l'erraro), other types of cncephalitis or encephalopathy can occur, but B. and K. M. Walliard (1958) bring these under the samc licading, cither as "Toxisch. perakut scrlaufenden Typus der fascrtiercephalitis" or as "Spula fàlle". Jacob (1936) also groups together the cases with different pathology As will be shown later, we think that a sharp distinction should be made here Vícasles 15 often complicated by haemorrhagic pneumonia or bronchopneumonia and this may cxpressed also in the reaction of the central nersous system. morc lymphocytic infiltration and sometimes hemorrhages in the foci. German measles, rubella Tie number of cases with autopsy report is scry small; we will give a short report on the cases that live ucen laid down in the literature ·D CASES FOLLOWING OTHER DISEASES 121 as penis enous encephalitis by their author, or in discussions on this subject. Case of Tinel and Bénard, 1923. Man, 21 years. Died 6 days after cruption of exanthema. Spinal cord examined, rei caled rather typical microglia my clitis, Case of Briggs, 1935 Boy, aged 10 years. Two days after exanthema cercbral symptoms set in, with convulsions and death within 24 hours Perisascular lymphocytes and leucocytes, other foci haemorrhagic. Yo microglial reaction The boy suffered of hacmorrhagic pneumonia. The case is evidently not one of microgha encephalitis, but a toxiinfectious process. Case of Iligand, 1941. Boy, aged 10. Had status thymico-lymphaticus and suffered from otitis Three days after eruption of cranthema nervous symptoms des eloped, then convulsions and death Brain swollen; vascular cuffs with lymphocytes, some plasma cells, histiocytes and polynuclears Vo cells outside the Virchow-Robin space, but some oedema No demyelination Evidently this is an acute vascular syndrome but no microglia encephalitis Case No 117 of Joller, 1919 Man, 20 years Four days after eruption of the rash, nervous symptoms came on; death after 3 days. Autopsy showed typical perrvenous proliferation of the microglia. Case of Falger, 1944 Woman, 26 years Exanthema 15 days after infection Cerebral symptoms one week later, and next day death in coma. Brain hyperaemic, perivascular cuffs with lymphocytes and gla, mostly in white matter Some vessel wall changes Description is insufficient for exact es aluauon but might have been microglia encephalitis. Varicella Or sıx cases which have come to autopsy se can ghe the following details Van Bogaert (1930) Girl, aged 12 Had angina, a week later Vancella eruption After one day cerebral symptoms, and death 18 days after the eruption The foci are not typical of microglia encephalitis but, as van Bogaert remarks, resemble those of acute multiple sclerosis.

·122 OCCURRENCE OF MICROGLIA ENCEPHALITIS 5 Zimmermann and H. Mannet (1931). Child, 13 months old. Fever three days after the outbrcak of the rash; next day a consulsion and death. Brain some oedema. llicroscopically, marked ganglion cell degeneration; petechial haemorrhages. In white matter foci around seins, with fatty granule cells and demyelination. No microglial proliſeration. Evidently an acute vascular encephalopathy. Dagnélie and Dubois (1932). Girl, 8 months. On 15th day after eruption cerebral symptoms started. Coma and death aficr 24 hours. Brain hyperaemic. Perivascular demyelination with sharp borders; some fatty granule cells; no other cellular infiltration. These 3 cases do not belong to the group of microglia encephalitis; two showed the typical lovi-infectious reaction of young children, and van Bogacrt's case belongs to a very different group The following casc, which we know only from references, seems to be positive. Roeder-Kutsch (194, description by Walthard, 1958). Boy, aged 7. Started with cerebral symptoms so days after the eruption and died 8 days later. The description and the figures have the typical ſcatures of microglia encephalitis. Suan (1946) Boy 6 years, had varicella and angina, and started 8 days after the onset with nerous symptoms, spasın, sopor, con. vulsions, with remissions and exacerbations. Died of bronchopneumonia 4 cehs after eruption of the exanthema. Clinical diagnosis was tetanoid chorca, as post-varicellar cncephalitis. Pathological cxamination showed symmetrical softening in the ncostriatum and more diffuse vascular and perii ascular lesions, with softcning and some demyelination Ganglion cells disappeared All forms of glia cells increased. Evidently we have a vascular affection, not the result of microglia cncephalitis .ippelbaum a al. (1953) briefly mention onc case, without gning details, shoking pensascular oedema and lymphocytes. Smallpor Cerebro-spmal symptoms follos ing smallpox are not frequent but, when they do occur, the discuse is often serious ·CASES FOLLOWING OTHER DISEASES 123 Spiller, case 2, 1903, 1929. Developed symptoms of myelitis and died about 5 weeks after smallpox eruption. Lesions mainly in grey matter, resembling poliomyelitis, but in 1929 compared with perivenous encephalitis. Description, honcier, not typical. Patient had septic condition. The case cannot be considered one of microglia encephalitis McIntosh and Scarf (1930). Child, 2 years old, showed perivascular demyelination, with cells in the space of Virchow-Robin but no microglial reaction. Troup and Hurst (1930). Van, 63 years, had alastrım, duration 37 days; total transı crsc myelitis, decubitus, cystitis, lung complication. Total malacia of lumbosacral cord, in higher centres gradually less set cre lesions. Around the latter often typical microghal foci, with demyelination, generally with lymphocyte cuffs The entire brain showed vessels surrounded by lymphocytes, but microglial foci were very rare, only in the higher centres. Varsden and Hurst, case 1, 1932 Alastrim epidemic to ycars old, death 14 days after the illness started Description typical of microglia encephahtis but severe degeneration of motor horn cells in lumbar cord Case 6 Girl, aged 7, died 9 days after onset of the illness. Typical lesions in the brain, spinal cord less markedly affected Rather thick lymphocyte cuffs. Case 7 Boy, 13 years, died one week after exanthema eruption, after an illness of 3 days Brain showed pernascular lymphocyte cuffs around many arteries and seins, and a few foci of demyelination with microglial reaction Brouwer, de Jongh and Rochat (1933) See also Chapter 4, c Man, 27 years Revaccinated during incubation of smallpox Had mild exanthema but continued his work, until acute transserse myelitis set in 5 days later Death 2 months after onset Main lesions in spinal cord, very few in oblongata, pons, basal ganglia, none in the hemispheres Demyelination is often pernascular, with lymphocytes and syncytial microglial increase, and many fibrillar astrocytes Some fatty granule cells The case can be considered one of microglia encephalıtıs, in which partial healing of many foci took place, whereas in others complications arose due to a septic condition ·126 OCCURREXCE OF MICROGLIA EXCEPHALITIS 5 Influenza, angina, common cold Greenfield, case 1, 1930. Jan, 37 years old, suffered from bronchopneumonia which improved in 18 days. After some cxcrcise hc developed the first symptoms of transserse myelitis the same ciening; he died 6 days later (with bronchopneumonia). Autopsy rci caled typical microglial foci in the cord and brain. Case 2. This case showed no microglial foci, only lymphocytic infiltration. The distribution in the cord was rather typical, but foci were absent in the brain and brain stem. As thc ccrcbral illness lasted 40 days, it is possible that microglial foci had alrcady healed, while the lymphocyte reaction remained much longer, A definire evaluation, therefore, is impossible. Demme, case 1, 1930. Man, aged 21, suffered from recurrent angina. Day after bathing in very old water, acute onset headache and meningeal symptoms with cranial neric involvement. Gradually spreading of paralyses and death from bulbar symptoms on roth day of illness. A rather large focus was found in thc oblongara, with central necrosis, probably not the result of many coalescent focs. Some vessels in the vicinity showed lymphocy te cuffs and microglial infiltration with demyelination, mostly around cry small cins or capillaries. The distribution is mainly in the oblongata; Iess in the pons and sell less in the mesencephalon. 77ic descriptinn and the figures suggest disseminated encephalomyelitis, or cien poliomy clinis, rather than microglia encephalitis. Daredson and Brock, case 1, 1937. Man, 37 years, died from decubitus and septic condition 41 days after a common cold, followed by cerebral insolement lasting 3 wechs. Clinically some improvement of the neurological symptoms was noted before death Jiany fryce of demyclination without cellular infiltration were found, often wills fatty granule cells and astrocytes. It is doubtful ushether tius case has been a partially lcaied microclia encephalitis or, more probably, a Iori-infectious yascular condition, Dazdsor and Brock, cose .. In this case the illness lasted 6 days, starting with general symptoms for 3 days The patient has an ·CASES FOLLOWING OTHER DISEASES 127 abscess in the prostate and inflammanon of the testicles. The brain was large, 1565 g, and showed many small round areas of demyelinatson, with lymphocytes, but without typical microglial proliferation, This was probably a case of tori-infectious vascular disease. foller, case 2, 1919. Man, 26 years old. Two wecks after a catarrhal infection acute nervous symptoms set in, with death following 2 days later Many focí were found in the CNS, mostly around paracapillary vessels No further description is gnen, but the case may be interpreted as microglia encephalitis Crome (1954) describes two cases of influenza with haemorrhagic encephalitis. Around some foci microglia can be seen. All types of lesions are considered by the author to belong to one group Rabies The pathology of rabies encephalitis is quite different from that of microglia cncephalitis (Schukni and Spatz and others), but two cases are on record in which rabses developed in the course of antirabies treatment and in which some microglial foci were found at autopsy. Higuer (1912) A girl, 12 years old, started antirabses treatment the day following a bite by a probably rabid dog Recened 5 daily snjections, then desisted because of fever Twenty days after the trauma, the first symptoms of rabies were noted; death within 3 days Animals injected with brain material died of rabies Pathology of rabres was found in the cord lymphocytic infiltration, Babes' glial nodules, but Negra bodies were absent In addition foci were found of, and photographs showed microglial probſerauon in the parenchyma around vessels, with lymphocyte cuffs 17 the Virchow-Robin space The description is suggestue, but not quite typical, of some perivenous microglial foci, nothing is noted about demyelination Rojas (1932) A man was bstten by a rabid dog and recened antarabies injections from the 23rd to the 38th day on the 37th day, the first changes of rabies were noted, he died on the 42nd day The clinical course had been typical, inoculations in animals were positie and Vegri bodies were found in the brain The inflammatory changes ·128 OCCURRENCE OF VICROCLIA ENCEPHALITIS occurred in the grey matter; the cerebral white matter was frec; Babes' nodules were present. Then other foci of peritenous microglial proliferation were found, without lymphocytes. Antirabies treatment Transverse my clitis, Occurring during antirabics treatment, or starting shortly after it, has been known for a very long time. In 1912, however, Pette distinguished 4 clinical types of nervous disorder, ris.: the myelitic type; the encephalitic type; the optic and the ncuritic typc. The main localization was in the grey matter; some foci shoned the typical perivenous microglial type. Bassoe and Grinker, case 1, 1930. Woman, 48 y cars, was not bitten by a dog. She had recened 14 daily injections of antirabies vaccine When symptoms of a Landry paralysis started. She showed no ccrebral symptoms. Death came on the 42nd day after the first injection, from decubitus ulcers and bronchopneumonia, Autopsy showed absence of foci in the brain, but cxtcnsisc destruction of the spinal cord, with lymphocyte cuffs, microglial proliferation, fatty granule cells and some demyelination The case differs from purc microglia cncephalitis in the serere necrosis of the cord and the absence of lesions in thic higher contres. Some perivascular foci, boncycr, are typical or perivenous microglia encephalitis, and the long duration and final toxic condition could explain some of the differences, Il'c think it is better to class the case as + because it shons rather important differences from our cases of postiaccinial transverse myelitis. Stuart and Krkorian (1930) Man, 24 years, was bitten by a stray dog. Vext day he started trcatment and after the ifth injection, symptoms of Landrv's paralysis set in. The discase #ds progressive until death on the 18th day after the trauma The spinal cord showed the typical lesions of subacute disseminated myelitis, well known as the most common complication of antırabicsomote l'chimura and Shirakı (1957) dese Japan 113 and They found no microglial foci, 1 cells demy clination and smaller foci in the STC) Arf ·CASES FOLLOWING OTHER DISEASES Jones (1958). Van, 58 years. Played with rabid dog. Received 14 daily injections. Two months after the first injection, acute onset with cerebral symptoms and hemiparesis. Death 16 weeks after first injection. Many foci of encephalitis were found, probably increasing in size. Jones compares his case with acute multiple sclerosis. Injections and caccinations (except smallpor and rabies vaccine) Cerebral damage following injections vaccinations is not very rare. Klinge (1914) reports on 45 cases in soldiers, who died as a result. Two cases were due to smallpor vaccination (with probably one case of perii enous encephalitis). The others followed antityphus, tetanus, diphtheria vaccinations, etc. Many articles have been published on this subject and the general opinion is that perii cnous encephalomyelitis does not occur in these Lhermitte, Walthard, Volland are of the opinion that typhoidparatyphoid injections sometimes cause other types of cncephalomyelitis, and this is also true for antitetanus injections (Czernely, cases. '950). We found only two cases, sometimes mentioned in the literature as erivenous encephalitis. Giffin, Rogers, Kernohan (1948) A woman, 21 y cars old, had recen cd 3 antityphoid injections four years prior to the present illness Following a new antityphoid injection, general malaise and leftsided herni. paresis started the second day and the condition grew progressively worse. Serious cerebral involvement started one month after the injection, and was progressive until death, 4 days later Large foci of softening were found in the right hemisphere and a great many small foci in other parts of the brain These showed demyelination with central necrosis and oedema and infiltration by fatty granule cells. There was no excessive glial proliferation The nature of thesc foci could not be determined, but it is evident that it is no microglia encephalitis. Giedion (1952) A soldier on active service received from 3 to 23 12 Inci , seven injections against cholera, typhord, paratyphoid, and was ·130 OCCURRENCE OF MICROGLIA EXCEPHALITIS 5 vaccinated against smallpox on the day of the last injection. On 24.12 fever and cerebral symptoms set in, and next day he was soporous. The condition was progressive until death on f. 1. Hlistas pathological examination showed haemorrhagic encephalitis with some lymphocytic polynuclear and glial proliferation, but no lesions of microglia encephalitis. The role of the smallpox vaccination is dubious and it seems unjustified to call this case haemorrhagic post. Vaccinial encephalitis. e. Subacute case In the literature we sometimes find the following case mentioned as a subacute case of perivenous encephalitis. De Massary and Albeissar (1936) describe a patient, 41 cars old, with progressive disease ending fatally in about 3 months. Clinically, mental and ncurological symptoms were gradually increasing, without acute onsct. No actiological factors could be found. Autopsy showed multiple foci of demyelination in the centrum ovale, mostly around vessels, with a marked increase in astroglia and oligoglia and some increase in microglia. The diagnosis of the authors was Schilder's discase, but in the discussion Bertrand pointed out a resemblance to postvaccinial encephalitis and to senile vascular changes in the hemispheral white matter. The case can probably be grouped with disseminated encephalomyelitis of a special type, but it is certainly no microglia cncephalitis. f. Relation of microglia encephalitis to disseminated encephalomyelitis The trend of this work has been to examine whether post-cxanthicmatous perii chous encephalus, as described by the early authors (Turnbull, Bastiaanse, Spielmeyer, Wohlwill, Spatz and others) and called by us microglia encephalitis, must be regarded as a unit with enough characteristic features to differentiate it from other cerebral rcactions A full discussion of this will be given in the next chapter. Microglia cncephalitis is one of the types of pcriicnous encephalar and we think that it should not be grouped together with other types, becausc pathological and aetiological differences exist.

·G EXPERIMENTAL PERIVENOUS ENCEPHALOMYELITIS 131 Microglia encephalitis is one of the demyelinating diseases, but here again it must be given a separate place. The cases of this group vary both in their clinical course and in aetiology and pathology, Microglia encephalitis is a disseminated encephalomyelitis but, as pointed out, ought to have a separate place in this group. We do not know yet which aetiological factors are important in causing the cerebral reactions of these various groups Probably some factors are the same but others are different In his excellent discussion, van Bogaert (1950) reviews a great number of borderlinc cases between perivenous encephalus, disseminated encephalomyelitis and multiple sclerosis, for which a similar but not identical aetiological factor is postulated. Van Bogaert lays greater stress on the constitution and on predisposing factors than on differences in actiology. It will be our task in the future to determine which factors cause special types of reaction, and which influence on these reactions is played by other factors. We might then be able to divide this great group of diseases into a number of syndromes, in each of which aetiology, clinical aspects and pathology can be defined. g. Experimental perivenous encephalomyelitis The importance of mulaple sclerosis, the aetiology of which has ever been a much discussed question, induced many investigators to try to solve this problem by the experimental route. Since more than a quarter of a century, many experiments have been conducted. Although the idea as a rule was to produce subacute or chronic cerebral reactions which, of course, are not apt to throw much light on our problem of acute postvaccimal damage, some experiments showed acute lesions, and it will therefore be necessary for us to establish a possible relationship with clinical postvaccinial encephalitis Many experiments were conducted on the basis of the theory that the demyelinating diseases were due to some allergic reaction of the brain, Another approach to our problem tried to reproduce the conditions supposed to act in postvaccinial encephalitis. Although it has not been possible experimentally to reproduce the picture of typical microglia encephalitis, part of this picture (perivenous ·132 OCCURRENCE OF MICROGLIA ENCEPHALITIS 5 microglial proliferation with demyelination) was sometimes encountered, The focal reactions in the experiments based on the allergic theory; are generally perivascular, with localization predominantly in the white matter. Vessel-wall changes and exudation of fluid and hac. matogenous cells predominate; central necroses and small liacmorrhages are a common feature. This, therefore, is comparable with the allergic reactions in other organs. Demyelination is often found. It is stated by all authors, that the reactions are not predictable, that the samc technique can cause various types of lesions and that very little is known about the factors governing these differences. A microglial reaction is often seen, caused by degeneration of myelin, and then fatty granule cells occur in large numbers. But the diffuse pcrii cnous microglial foci seen in postvaccinial encephalitis are rarely found. Lumsden (1949) describes these foci, running the length of some veins and without thick lymphocyte cuffs. However, he states that resselwall changes are nearly always present, generally with an increase in connective tissue of the adventitia, In their summing up of recent work on experimental encephalitis, Ferraro and Roizin (1954) state that the microglial rcaction is rarely seen in the subacute and chronic stages but belongs to the first stages. The other approach, mentioned above, succeeded once in producing a pervenous microglial reaction very similar to that secn in prosta vaccinial cases. Verlinde (1954) started a series of experiments in which smallpox vaccination of the animal was combined with injections of various substances (guanidine, phosphatase, etc.) or inoculations of other viruses. In the casc referred to, a monkey was vaccinated on the shin against smallpox and received an intramuscular injection of Columbia S.K virus, which was isolated from the stools and throat of a child diagnosed as suffering from postvaccinial encephalitis. The child was about one year old and had, 2 months prior to the vaccination, becn in places where poliomyelitis and other cases of meningn-cnccplialitis occurred. Ninc days after this procedure he had a convulsion, but recovered after treatment with ACTH and aurcomycin. Thic diagnosis: postvaccinial encephalitis, miglit be correct (not microglia encephalitis ·6 EXPERIMENTAL PERIVENOUS ENCEPHALOMYELITIS 133 but the encephalopathic type), but another explanation is also possible, nz,· that the vaccination activated an encephalitis by Columbia SK, virus. The animal developed neurological symptoms on the 7th day and died the next day. Histological cxamination revealed many lesions with demyelination and microglial proltferation around the veins and some lymphocytes perivascularly Some foci are quite typical, others are located in the upper layers of the cerebral cortex; some are abnormally compact Although the lesion is not a pure microglia encephalitis, the similarity of some of its foci is striking. This lesion was not reproducible: experiments with the same ingredients, or by vaccination and using other strains of Columbia S.K. virus, failed to produce the perivenous encephalitis. In the animals that died with neurological symptoms, polioencephalomyelitis was found, as sometimes also seen following injection of Columbia virus without smallpor vaccination. As far as a very short survey of the literature teaches us, the most frequent reaction of the brain to an experimental approach to the problem of demyelinating diseases is a vascular and circulatory change, and microglial foci without vascular reaction are rare, but they go in the same direction as following many infections diseases in man. Pure microglia encephalitis has not hitherto beenexperimentally reproduced.

·Chapter 6 DISCUSSION THE NOSOLOGICAL ENTITY OF MICROGLIA ENCEPHALITIS Introduction In 1950, van Bogaert wrote: "It appears as though the pericnous cncephalitis found in all these discases is a standard form of reaction in the nervous tissue". It will be the task of future research to find to which causes and conditions the nervous tissuc reacts by this standard form. According to the basic idea of the present study, we shall usc in our discussion mostly the cases in which post-mortem examination of the nervous system has been performed. Our principal aim has been to scc whether sharp distinction should be made botucen the discases with foci consisting mainly of vascular changes, enccphalopathic and hacmodynamic cerebral reactions and the discasc "postiaccinial encephalitis" in its morc restricted sense, with foci of demyelination with microglial proliferation Further, whether this latter discase should be separated from, or at least classed as a special type of, acute pcrivenous demyelinating encephalomyelitis Other diseases starting during the first 3 wechs after vaccination must also be considered, because some connection between their outbreak and the vaccination may exist, as found in embolic encephalitis and probably also in poliomyelitis These conditions will not cause difficulties in our cases syith autopsy, but the clinical course may very much resemble the picture of postvaccinial cncephalitis. I'c shall separately discuss the clinical and pathological aspects and then see whether any conclusions about the pathogenesis can be formed at this time ·THE CLINICAL SIDE 135 a. The clinical side The clinical picture of microglia encephalitis »s typical. The onset is acute with general malarse and ſever for one day or less, after which the cerebral symptoms become manifest Following a severe skin reaction to the vaccination, however, feser, headache and general malaise may often exist from the 6tk or 7th day on and sometimes merge into the oncoming symptoms of the cerebral complication. The exact day of onset of the encephalitis is then difficult to determine, and may be put one or two days too early. According to the main localization of the lesions, mental symptoms may prevail, or cerebral or spinal neurological irritation or pareses may dominate the picture. The course is always acute, reaching its acme in a few days, even running a fulminant course in several cases, death following one or two days after the first symptoms were noted (see Fig 18) In these Days 22 20 1Iness www.gy Incu. bation Age 3)Say..4+39.0332022017 Case No. FIG 18 Duration of incubation and illness of 28 cases of microgła encephalitis, arranged according to age No correlation is found between age patient and duration of incubanon and duration of survival tune after vaccination. Incubation varies much less than survival time cascs, as in the others, the autopsy shows the fully developed picture of microgua encephalıtıs rather than the vascular, encephalopathic pictures of toxic-infectious reactions (see par. b, A 2). Table I (p 13) ·136 DISCUSSION 6 also shows that there is no correlation between the day of onset and the duration of illness, nor between these and the age of the patient. When the discase does not run a fatal course, some improvement in the patient's condition can be scen, gencrally within a week. Some patients, surviving that long, may des clop complications which increase the risk of a fatal outcome. If the patient sunives, there is no chronic stage, nor do we sec scquclae or relapses. These point to complications or to another type of encephalitis (Chapter 3, par. b, 4). Only in cases of transversc myelitis may the damage due to oedema of the cord be rather serious, and may hypertonia or parcses last for a long time, This clinical picture can in many cases not be distinguished from other toxi-inſectious brain diseases occurring after vaccination or following many other conditions. We have pointed out that much misunderstanding has arisen when too much weight was given to the clinical picture and all changes in the brain, found in these cases, were grouped together as one discase (Lhermitte, Comby and many others). Incubatron tume The duration of incubation is a valuable point of differentiation between the various conditions. The carliest investigations on posivaccinial encephalitis have shown that the incubation lasted about 10--14 days and that exceptions were rather rarc. As the following figure will show, this becomes still more convincing when we compare the incubation in microgla encephalitzs (Fig. 19) A with B and C. giving the incubation of other cerebral complications in o to sacar old children and older persons, respectively. The number of cases in Fig 19 A is very small because only the cases with personal microscopic examination were used. Bursablesbasen been given by many authors, using a larger material of clinically diagnosed cases, and they show the same differchce between the typical cases in persons of 2 y cars and older, with a rather symmetrical biphasic cune, with the maximum at 12-13 days, and those cases with atypical course. The same liolds truc for the graphs pertaining in ·THE CLINICAL SIDE 137 Atheroglua encephorlys Dusch costs only coses 8 Other pathoody on 1 year old ofia want Other pathology 2 ytors and aktar 22 22 23 24 FIG 19 Incubation me of 3 groups of posssaccinal complications Autopsy Cases mentioned in the treatise Very young children, which show 2 very irregular dastribution, Cases following measles cannot be used, as the date of infection is uncertain and as the mode of infection and the amount of virus invading the tissues may vary much more than under the nearly experimental conditions of smallpor vaccination. In cases only clinically examined, shorter incubation time sometimes shown, but the history then often states that convulssons des cloped, or that serious sequelae remained which, for us, makes it probable that not macroglia encephalitis, but e.g, haemorrhagic encephaltis occurred. In one case (No 9) the incubation was given as 8 days, but this boy was already under treatment for whooping cough and, in addition to the vaccination on Aug 6th, had received injections against that disease on the gth, 11th and 13th day On that day he became all and Aug. 14th had a mild convulsion, following which cerebral symptoms became evident The convulsion may have had a 10x-infectious ongin, and the encephalitis perhaps started on the oth or even toth day after vaccination In other cases it may be difficult, when the history is incomplete, to ex aluate whether fever and headache are the ·138 DISCUSSION result of the vaccination with severe shin reaction, or alrcady the first symptoms of a cerebral complication. The graph of the incubatinn therefore tends to be distended to the left side, but is probably neier extended further than it really is. The difference besueen the first graph (A) and the second (B) is quite conclusive of the fact that microglia encephalitis is not a part of the general reactions of young children to toxi-infectious diseases but that it stands by itself. It is illogical to regard all these cases as running a fulminant course of a disease which has, in this age group, never been observed. Funthermore, the incubation period would then hase to be shorter than the usual incubation for microglia encephalitis, and not distributed at random over a period of 4 wechs. In Chapter 4, b it has been remarked that the histological picture of the cases ICpresented in Fig. 19 B is not the carliest change that could desclop into perii cnous microglial foci. Comparing the graphs 19 A and C, the same holds true. If these cascs were to be considered as earliest microglia encephalitis, the graph Cought to show the same variability cure as A, only shifted two or three days to the left, with the maximum at so days. The typical incubation time, therefore, is a strong argument in consider microglia cnccphalitis a separatc unit. Occurrence of microglia encephalitis compared uith other pathological changes, and occurrence in various diseases From the first appearance, around 1924, of postvaccinial encephallitis and the similar complication following measies, it was apparent that exanthematous discases play an important role. It is interesting to find out whether this also holds true for typical microglia encephalitis. It was known, of course, that other pathological changes also occurred Basuaanse (1931) found from his clinical studies that, following 709,918 saccinations, 138 cases of posts accinal encephalitis Orcurred, and 136 cases with other cerebral affections. Too often, houcict, an cncephalilis following saccination was called periichimus, without realizing that it might as well be something else.

·THE CLINICAL SIDE 139 TABLE X CASES OF POST INFECTIOUS NERVOUS COMPLICATIOVS Extracted from article by Moller, 1949 Enology Peru enous encephalitus Other pathology TO 6 2 2 Smallpox vaccination Measles Rubella Varicella Scarlatina Parotitis Whooping cough Pneumonia Dysentery Tooth abscess Otitis Tonsillitis Common cold 7 4 1 1 3 3 - 2 11 7 2 2 1 7 4 1 We will first discuss the interesting reports of Moller, on postinfectious nervous complications in Sweden, and then investigate our own material in this respect From the literature and from personal examination Moller (191 Insted a large number of cases, of which our Table X was mad Differentiation between microglia encephalitis and other forms pern enous encephalitis was not possible, but the table very clearl indicates in which diseases we may expect the microghal reaction to occur with more or less frequency In the column of perivenous encephalitis, the following cases are listed by Moller common cold, Moller 1949, otitis, Brissaud and Brécy, pneumonia, Idler, 1940, whooping cough, Moller, parotitis, Schenker, Wegelia, Donohue, scarlatina, Ferraro, 1944 Of these, we accept only 2 cases as microgla encephalitis (Moller, common cold and Donohue, parotitis) Several of her other cases do not even show perivenous microglial cuffs, according to her description The table clearly shows that a ·140 DISCUSSION 6 common toxi-infectious reaction of the brain is a more frequent reaction following most diseases, but is also very common after the four exanthematous diseases. From our study of the literature se made Tables XI and XII. Thesc show various interesting details (the distinction between microglia cncephalitis and perivenous microglial foci will be discussed in the next paragraph). Only following smallpox vaccination in persons of 2 years or older does the microglia reaction occur more frequently than the toxi. infectious reaction types. In all other conditions we find more cases of the other reactions than of microglia encephalitis. Here the occurrence of microglia encephalitis is only sporadıc: parotitis; influenza; anti-rabies treatment; cases without clear actiology, or very late after vaccination. We believe that these sporadic cases also occurred before the massive outbreak aſter 1923. Perhaps even the relative frequency of occurrence of microglia cncephalitis and other pathological changes has, for thic above cnumcrated discases, not changed significantly since that year, which would mean that the frcqucnt occurrence following exanthematous diseases really was new, which was the general impression of most clinicians and also stated by various authors for the pathological anatomy (Bastiaansc, Luchsch, Spiclmcyer). Looking at one special actiological feature, sc can make the following lists (Table XIII). It is at oncc evident that the occurrence of microglia encephalitis dnes not follow a random distribution but that some rclation between its frequency and the special type of infection cxists. Especially the fact that it des clops after pox virus infections inversely proportional to the scriousness of the disease, must be stressed. I'c could think of the influcncc of stress on the pathogenesis of these conditions. A possible explanation could be that, in the more serious discasc (small por, as opposed 10 alastrim or vaccinia), the adaptation reaction would lic stronger and therefore give an increased production of ACTII OF cortisone, which would suppress cruption of an cncephalitis Clinical data about the therapeutic influence of cortisone injections in the earliest stages of postiaccinial encephalitis, support this theory.

·A THE CLINICAL SIDE 141 TABLL XI AUTOPSY CASES DESCRIBED IY TILE LITERATURE AS PERIVENOUS ENCEPHALITIS Revaccination includes own cases. No case known + more than a few cases Nfuroglia encephalitis Pern enous mucroglia fora Toti-infections Encephalomyelits reachon dissem. Acura I - + 8 8 3 +++ 4 1 ++ + + 2 2 following vaccination Before 1923 following rubella without clear ctrology Primary vaccination, 2 y and older Revaccination with good pustules Primary Vaccination, o and I y old Revaccination with immune skin teachion Mild smallpox, alastrim, cowpor Hcavy smallpox Measles Rubella Varicella Parotters Rabies Rabies outbreak during antirabics treatm. antırabies treatment only Vaccination to typhus inj i month before onset Influenza, angina Pohomyelius Pertussis, scarlet rever Other vaccinations and injections Etiology unknown Experimental 4 1 17 +++ ++ 2 +++ +++ 4 ++ + + + + + + ·142 DISCUSSION 6 TABLE XIT PERIVENOLS EXCEPITALITIS CASES FROV TIE LITERATLRE GROUPED ACCORDIC TO PATIIOLOGY Condensed from preceding table. Only about 50% of the cases descnbod in the literature as peris cnous encephalitis are probably microgla encephaltis Macroglia Primous Other encephalitis microglia cuffs farholupy All cases except vaccination, measles, rubella, poliomyelitis, but including smallpur Same, but excluding also smallpor, varicella 13 7 20 8 5 12 TABLE XIII COMPARISOY OF THE FREQUENCY OF MICROGLIA ENCEPHALTIS AND PATHOLOGICAL CHINGUS I 7110 CROUPS OF EARLY RELATED PISEASES Jikroglia Peru enous Other encephalitis microglia cuffs pathology Cxanthematnus diseases +++ + + + Vaccinia, over 2 years old Measies Rubella Varicella 2 2 + 13 3 Por cirus infections Primary vaccination Revaccination, fox! pustules Juld allpox, COwyx, alastrim Fless smallpox Reaccination immunc reaction ·A THE CLINICAL SIDE 143 It is stated by some authors that postvaccinial encephalitis occurs more often in those countries in which anti-smallpox vaccination is regularly performed, and that in countries in which smallpox is endemic, the encephalitis is absent or very rare. We have no data pertinent to this question. A short discussion of cases following riaccination may follow here, but this has been more fully treated in Chapter 4, c, When reaccination is followed by a normal skin eruption, microglia encephalitis occurs less frequently than after primary vaccination, and other forms of encephalitis are relatively more frequent. When the skin still shows some immunity to the vaccinia virus, a typical microglia encephalitis has never been obsen cd but very irrcgular histopathological pictures may be scen, in which demyelination and microglial proliferation around vessels are sometimes present. We have at present no explanation for this phenomenon, but it is evident that the condition of partial immunity must have caused a sex ere change in the constitution of the body fluids or cells, by which the demyelinating factor cannot des clop or act as after primary vaccination. Another important point in the variations in occurrence of microglia encephalitis is the absence in children of o and 1 year of age. This has been fully discussed in Chapter 4 b, to which the reader may be referred. We pointed out, that the majority of the infectious diseases can attack children under 2 years of age as well as older persons, but that the two groups differ in sensitization and allergic reactions. The reactions seen following vaccination in these young children are of the common toxi-infectious type, occurring in all age groups and after a great many toxic and infectious conditions, probably in the young children not more frequently after vaccination than after common cold, angına, fever and the like. Our material is not large enough to calculate the importance of age as a factor in the eruption of microglia encephalitis (except for the first 2 years of life) It is often stated in the literature that children from 3 to 12 years should be more vulnerable to this discase, but the number of vaccinations in the different age groups vanes in many countries, which makes comparison rather difficult ·144 DISCUSSION 9 The same can be said about the geographic distribution. It is well known, that postvaccinial encephalitis is more common in western Europe than elsewhere, and that it is 'ery rare in tropical countries. Viberall (1950) found in Chile, among onc million vaccinations, only 15 cases of cerebrospinal complications. In New York, Greenberg and Appelbaum (1948) found, after 5 million vaccinations, 49 cases of encephalitis which were certainly not all of the perivenous type. There is also a wide variation in the frequency of periscnous encephalitis in different years (Gocters and Stechern, 1918; Falk, 1950, and others), which is also known for other discases (Greenfield, 1929, for mcasles); its bearing on our subject will be very difficult to understand. Bricf mention should also be made of subclinical cases, because sometimes the literature contains reports with the tendency to regard very mild cases of encephalopathy as subclinical peris cnous encephalitis. As far as our discussion is concerned, this pertains mainly to the cases in which death camc on without a clinical period of discase. An investigation of E.E.G. changes in persons without any clinical symptoms of a cercbral nature was done by van Wulfften Palthc and Puister (1956). They found that, of 40 healthy military mien, 14 showed a change in the E.E.G, talon in these subjects before vacci. nation and one half year later. None of them showed clinical changes, or developed subsequent postvaccinial symptoms. The authors come to the conclusion that the general vegetatic condition in these persons undergoes a temporary and reversible change in the sense of increased lability, In measles, Hode and Livingstone (cited by Radermecker, 1936) found an abnormal E.E.G in 43 of 114 cases without cerebral complications (none of thesc under one year old), suggesting what they call subclinical encephalitis Brown, Kirkland and Hein (1948) reported on the spinal fluid cxamination in 70 cases of parotitis: in 26 cases they found more than 10 cells, only 9 patients had mild cerebral symptoms (one case of meningo-encephalitis also had orchitis). They then cxamined the spinal fluid in 5 cases of measles in adults, and fuund 26, 14, 11, 2 and ·B THE PATHOLOGICAL SIDE 145 O cells, respectively. Only the patient with 26 cells had slight ccrebral symptoms. Cronemeyer (1957) found pleocy tosis of the CS.F. in 25% of measles patients and in 32% of varicella cases without any clinical ymptoms of nervous system affection. It is well known that infectious diseases attack the entire organism and not exclusively one or to organs, and it very difficult to state when a change in the spinal fluid is sufficiently maried to speak of a meningeal or cerebral complication That this may be present without Clinical symptoms may explain those cases, in which a rapidly develop ing cerebral oedema (in young children perhaps accelerated by status thymico-lymphaticus) may cause sudden death But nothing points, as far as our study has retraled, to a perirenous encephallis being al the origin b. The pathological side In our discussion of thus aspect or our problem we shall use the following scheme as a working hypothesis: l'accination against smallpox is followed by racania, which is a general disease of the entire organum This means that we can expect the reactions often encountered in toxi-infectious conditions A. (1) alsays more or less senous irritation of the reticuloendothelial system, which in the C.N.S can be seen as a very slight cellular increase in the spinal fiud, some degree of lymphocyte infiltration of the meninges, probably some hyperacma and perhaps some oedema. This may start at an early date (2) In few cases an exaggeration of this can occur, huch can be clinically diagnosed as encephalopathy or encephalitis, and pathologically as toxi-infectious changes of the vascular-mesodermal tissues, sometimes with ganglion celi degeneration. This probably also starts before the skin reaction is at its maximum Then we sometimes find another type of pathologal reaction, which we should sharply separate from the first B. In some aetiologically prabably very specialized instances (of as yet unknown ongin), ·146 DISCUSSION 6 (1) peritenous production of a myelolytic substance, which secondarily gives rise to microglial proliferation and some ocdema. Probably the microglial proliferation is partly also a reaction to the noxious substance which causes the demyelination. Clinically, this produces the picture of cncephalitis. (2) This inflammatory process causes fever and general symptoms and can also cause irritation of the reticulo-endothelial system of the brain, increasing the existing changes as noted under A. C. Finally we sometimes meet abnormal pathological reactions, which occur in rare instances and have not yet been classified. Others show a pathology belonging to other diseases (activation; purulent complications, etc.). These haic been discussed in Chapters 4 and 5. Ad. d. 1. It would at first sight scem impossible to get autopsy material from this group because when the child (or aduit) dies of this disease, it is already a cerebral complication and is placed by us in group A. 2. But a number of young children and cien adults sometimes died during, or shortly after, a convulsion, or were found dead in their beds without having shown ccrcbral symptoms bcforc. Il'e discussed this group in Chapter 4, e (sec Table VIII) and concluded that the very slight meningeal and vascular changes werc an cnccphalopathic rcaction to the vaccinia in individuals predisposed to this kind of reaction. Radermecker (1958) sums up a number of factors pre. disposing to convulsions. former brain lesions; infections, anoxia; constitutional vasomotor lability; disturbance of the haemateencephalic barrer, etc., to which we would add spasmophili. In many cases, therefore, convulsions arc a symptom not of cerebral disease but of a general discase. The point can bc illustrated by the following casc. Case. Vo 18 This girl *13s born 16. 10 50 and was healthy before vaccination on 24 " 52 Pustules desclopedt slowly, but were quite distinct on the oth day without hosser, redness of the surrounding skin On 3.2 she desclopeel sue fmer, somited at night, then became soporous and dial on the nth day after vaccination, with a temperature of 42', carly in the morning of 4 ? The general aulripsi showed a few infiltrating cells around a currinary artery; the ·B THE PATHOLOGICAL SIDE spleen was normal, whereas Iner and kidneys shoned a distinct reticular reaction with small-cell infiltration in the periportal spaces. The menunges were not contained i difuse increase of small fumphocytes with a few an also showed me vessels. The matic reaction of the rcticular is virus. The iy organs. The red in cases of ase but, when fTcction of the ns. ered as post-or reactions, the Jany patients, us but even two rs after vaccin. icephalopathic we can expect present in the iccination, and wain rôle in the a more serious ind of clectro- • the 6th to 8th both in cases it later develop sonstrates thai Ccination Was Icroscopic material ·148 DISCUSSION 6 apparent, the pathology showed more distinct changes of the same character as in the former groups. Still more conspicuous changes are seldom scen after uncomplicated primary smallpor vaccination, but are frequent after other vaccinations or infectious diseases (measles, scarlet fever, whooping cough, etc.). These changes, 17.2.: marked oedema of the brain with scrous or cellular perivascular infiltration, with haemorrhages and distinct esse) wall changes, sometimes with thrombosis of vessels, are the pathological expression of what is called the "hacmo-dynamic reaction" by van Bogacrt; the "syndrome malin" by Alajouanine; the "orage vasculaire" by Cathalca. Pagès (1952), describing toxicoses of babies, especially following cnteric discurbances, disa tinguishes several degrees of seriousness and says that in the most marked cases some glial increase (as also noted in our Table VIII) can be found. In a recent article Verhaart (1958) describes the histopathology of encephalopathy, in cases of severe cerebral symptoms, accompanying general diseases in infants and children. He stresses thc fact that the pathological changes are the same, independent of the actiology of the general discase, A differentiation of these histopathological changes into various types is not pursued in this study. However, we feel that in the future this will be necessary for a full understanding of the rcaction types of the nerous system. As mentioned Jacob (1955) isolated the group of acule diffuse ! mphocytic encephalitis as one reaction type, of which lic gives scieral examples. We wish to summarize here some conclusions of the important experimental work donc by Lumsden (1949). Lumsden divided the pathological changes occurring in guinca-pigs after injections of brain cmulsions and adjuvants, into four groups: (a) toric reactions; (b) sensitization; (c) an immunity reaction and (d) thc encephalito. genr effect He then finds that these 4 reaction types are not obviously associated, in fact, appear to be dissociated and need not cien occur in the same animals But in none of our cases, or in any description of cases in the literature, doute find an indicator that changes suggesting an rolls stage of enous murs. glia mcephaltus udt also present in the other reaction bpes.

·B THE PATITOLOGICAL SIDE 149 Even such authors as interpret their encephalopathic findings as first stages of perivenous encephalitis (de Lange, Lhermitte, Doring, a.o) expressly state that the actually present changes were of another nature. And we can add to this that they also showed another distribution in the C.N S., viz., involvement of the cerebral cortex as part of the picture. Some cases of more serious vascular reactions (haemorrhagic or embolic foci) may show pictures of perivascular demyelination and glial reaction which, at first sight, resemble microglia encephalitis. Fig. 16 shows a focus due to ſat embolism (a), as compared with a microglial focus (b). In (a) the focus is round, not elongated along the vessel; it has a necrotic centre and very little glial reaction, while fatty granule cells and myelin débris are still lying around (not clearly seen in the Nissl stain). The microglial focus (b), however, is oval with much wider distribution of glia cells and without the vessel-wall reaction or necrosis. In describing case 53 (Chapter 3, b) another example of the difference of the vascular foci was given. But am elongated microglial fori can hare another pathogenesis, which is illustrated in Figs 20—23, of a man, 42 years of age (No 5373), who had suffered a cerebral contusion 31 months before death. He was unconscious for about one hour after the accident and improved in the first week Then coma once more set in, due to a subdural haemorrhage, the remnants of which were found at autopsy. The condition was complicated by a fracture of the femur and des cloping decubitus He died of the septic condition, but had shown some dementia and urational behaviour Autopsy showed a thin covering of the inner surface of the dura with phagocytes, containing large amounts of blood pigment Some atrophy of the brain was found Subcortically at several places, demyelinating lesions, arranged around bloodvessels, with marked glia proliferation (see Fig 20-23) existed However, the myelin stain showed also one larger degencration, in which much iron pigment could still be obsened The smaller lesions did not show a positive iron reaction, but a small haemorrhage could easily be absorbed without pigment deposit Vearly all the aris cylinders have also disappeared in these lesions, which is uncommon in microglia encephalitis The vessels showed more changes and serous oedema was present in the smaller and larger foci and the infiltrating cells were partly large astrocytes, partly rod cells and small round glial nuclet There were no small lymphocytes, no polynuclears and very few granule cells, but some sudanophile granules were still present

·150
DISCUSSION
6
FIC 20. Traumatic destruction of
neric fibres; scicral perisascular
foci and onc large long lesion.
Case 5373. Weil stain.
Tic. 21. Same case as fic 20,
subcortical white matter; only
smaller lesions. It'cil stain.
The resemblance of these ſoci, due to confusion of thc brain, to the
truc pericnous microglial ſoci is cvident, but they differ cnough to
put them in a separate class This again stresses the necessity of
sharply distinguishing between microglia encephalitis and microglial
foci of different origin.
Diffuse ganglion cell degeneration, often most marked in the cerchrai
cortex but also present in losser nuclei (subst. nigra; inferior oliscs)
is also a common abnormality in toxic encephalopathic brain diseases
bul, .s tlus may be caused by a complicating bronchopneumonia and
is often rather difficult to cvaluatc in human material, it does not
generally add a valuable argument to differential diagnosis.

·B
THE PATHOLOGICAL SIDE
151
Ad B. Il'hich is the nosological place to be given microglia encephalitis?
In the course of our investigations, it became apparent that a division
of microglial proliferation into 2 types would be advantageous to our
understanding, namely: the complete picture of microglia encephalitis,
and the perivenous microglial foci without the other typical symptoms
or changes, but often combined with vasculo-mesodermal changes in
another localization.
In the first publications on this disease by Turnbull and Bastiaanse,
both in 1924, the idea prevailed that a disease entity existed, which
should be separated from other conditions but clinically showing some
FIC 22 Same case as fig 20, very
little cellular reaction Nissl stain
FIC 23 Same case as fig 20,
Iron pigment (black dots) around a
large vessel near the malacic foci
Gomor stain

·152 DISCUSSION 6 similarity to it. Later work showed that onc histological change, riz. perivenous microglial proliferation, also occurred in a number of other diseases and could be reproduced by experiment (Lumsden's fourth group). But thesc never formed a unit and therefore it is still necessary to differentiate thesc conditions. The cntity first described by Turnbull and by Bastiaanse, and described by Lucksch in his first publication (1924) as a change in the pathology of epidemic encephalitis duc to the presence of vaccinia virus, was called peritenous encephallis by Spatz. We used the name microglia encephalitis for the cases vcrificd by autopsy. Both names, however, do not cxpress exactly what is meant by them, because around cmbolic and haemorrhagic foci the microglia is also often increased and demyelination is present, and becausc differentiation from disseminated encephalomyelitis may be rather difficult. It might therefore be advantageous to introduce the name disease of Tumbull, Lurksch, Bastiaanse to the clmco-pathological disease entily sometimes following smallpor laccination and meales, and seldom occurring spontaneously or after other infections. The main idea underlying the necessity to make this distinction is based on the principle that we should try to determine the cause for crident differences of the reaction of the nervous system in various conditions, and not be content to spcah of intermediate types or transitions without trying to explain their pathogenesis. The pcrivenous microglial foci arc a typical rcaction of the nerous tissues to some noxious condition as yet unknown. This reaction occurs in a number of discases, the principal instances of which we rcvicucd in Chapter 5. The clinical side of this problem has been discussed in this chapter in par. a. As typical listopathology in microglia cncephalitis, wc mentioned (Chapter 5, P 114) the pervenous microglial foci with marketi demyelination and less destruction of the axis cylinders; the marginal gliosis by microglia cclls and sometimes morc diffuse glial increase in wintc and grey matter. Distribution of the lesions in the hemispheral white matter and in the wlite and grey matter of the deeper structures Then, sparing of the ganglion cells and small or no lymphocyte culls. As negative signs wc noted. no necrotic centre and no thrombosis of ·B TIE PATHOLOGICAL SIDE 153 vessels; rare polynuclears and no coalescence to foci in which the original perivascular distribution is no more recognizable This picture can be influenced by preceding brain diseases, an example of which may be mentioned here (case 38), in which an old lesion around the occipital horn of one lateral ventricle existed, with a dense conglomerate of ependymal cells and a broad zone of sclerotic tissue around it. This again was surrounded by a great number of perisenous foci, widely coalescent, but of the typical constitution and marked lymphocyte cuffs in the sessel sheaths. Some hacmorrhage had also occurred in this region. The impression was gained that the older lesion had left the tissues more vulnerable to the encephalitic process Van Bogaert gave an example of this kind of strong reaction in the spinal segment of a patient, who previously sustained a trauma of this part of the cord. Van Bogaert calls this a neuro-allergic reaction due to a kind of "memory" of the involved parts. The peris enous microglial ſoci, however, are known to occur in several diseases, often as a rare and minor detail (e.g. in poliomyelitis), or as an important part of the histological picture (disseminated encephalomyelitis). They are conform group d. of Lumsden (see above). In Chapter 3, f, we noted cases in which noxious factors might possibly have had some influence on the histological picture of postvaccinial encephalitis, Our material here is rather scanty and does not seem to allow of well-founded conclusions. We now have to consider microglia encephalitis in its relation to other encephalitrdes. Only the acute forms have to be discussed, either the acute diseases or the acute phases of more prolonged diseases (multiple sclerosis and others) From the histological angle, the lymphocytic encephalitides (as poliomy clitis), greatly differ from our disease. The inflammation attacks the grey substances more than the white matter, and ganglion cell destruction is the rule, myelin destruction exceptional. Then, infiltration around vessels is mainly by thick cuſis of lymphocytes and other mononuclear cells, mostly without a marked glial reaction in the ·154 DISCUSSION 6 surrounding tissue. Around the focal lesions in the grey matter, microglia cells oſten proliferate, together with astrocytes. Honeser, they are not grouped around venules or cins, Licn the first authors writing on postiaccinial cnccphalitis stressed the differences from epidemic encephalitis, at that period the best known type of nonpurulent inflammatory reaction of the C.N.S. Only few authors (Gins, 1931, 1934) tricd to explain postvaccinial encephalitis as an epidemic cncephalitis with a reaction of the nervous tissuc, changed by the presence of another virus. The group of so-called nodular encephalılides (riz. typhus cnccplatitis, St. Louis encephalitis) differs from the post-exanthematous group in the size and distribution of the foci. There we find nodules of glia cells, mainly microglia, of round shape, not connected with vessels and localized both in the grey matter (cortex and decper structures) and in the white substancc, or even predominantly in the grey matter. Marginal gliosis is unimportant and demy clination is not part of the picture, but vessel-wall changes and infiltration of the meninges with cellular curls and more diffuse infiltration can be very marked. The embolic encephalides (e.g. thosc duc to haemolytic streptococci, listeria, also to fat droplets, ctc.) also give another picture. Flere, the capillaries are often infected and ball-shaped masses of polynuclears, often mixed with other phagocytes, are lying in the various tissues There may be necrosis of nervous tissue, with necrosis of the nerve fibres (myclin and axis cylinders) and a glial reaction to this, consisting partly of microglia and partly of the other types of glia cells. Sometimes we find a scry small central focus with larger microglial proliferation, as demonstrated in Fig. 16 of fat embolism, or often seen in haemorrhagic encephalopathy (fig. 13). But the difference from typical microglial pernicnous foci is generally casily clcmnn. strated and the other findings of microglia cncephalitis arc annars absent in these cases. More important, however, is a discussion of the disseminated encephalorrychnis group We can best understand these by considering microgla encephalus to be onc cxtrcmc of a larger group of pathological ·155 THE PATHOLOGICAL SIDE changes, probably the result of various combinations of a number of pathogenetic factors similar, but not the same for the various clinical types or discases Alultiple sclerosis and the large single foci of Schilder- Foix's encephalitis periaxialis, are examples of other extremes. But this does not mean that each type loses its individuality and could not be considered a disease entity. On the contrary, when enough arguments can be brought forward to separate microglia encephalitis from the other forms, our conception of the pathogenesis and aetiology can be more firmly established and clarified Probably the number of pathogenetic factors acting together in microgla encephalitis is smaller than in other forms of encephalitis and we therefore called it (1955) the most monomorphous type of encephalitis that occurs. The large number of foci and their obligatory distribution around cins of medium and large size at once distinguishes this type from the acute changes in multiple sclerosis and disseminated encephalomyelitis, in which a focus may start around a small vessel but then increases without following the vascular territories Also the lustopathology is different, because microglia encephalitis shows only a slight reaction of the other tissues (mesodermal and other glia cells), whereas these are generally quite evident in the aforementioned diseases But in these cases typical microglial foci may sometimes be found (sce Fig 158 of Pette, 1942, in a case of acute multiple sclerosis), pointing to a similarity in the pathogenesis of these foci in both diseases. Then the other histopathological changes (eg the marginal gliosis) are not a part of disseminated encephalomyelitis. The very acute course, the high percentage of fatal cases and the recovery of the others, without scar formation, are outstanding characteristics for the entity called microglia encephalitis. Very few cases occur with multiple foci of pervenous demyelination, in which the myelin stain shows great resemblance to the postvaccinial encephalitis But a more chronic course and marked mesodermal cell increase point to another nosological placc However, we mentioned in Chapter 5 (Table XI) some cases, which we classed with microglia encephalitis with an aetiology differing from the usual onc At the present time they cannot be classed definitely and these erceptions ·156 DISCUSSION 6 will not detain us from placing microglia encephalitis as an entity in the nosological system. When we tackle the problem of the relation of microglia encephalitis to other encephalitides from an actiological angle, we can at once say that the pathology differs from the diseases caused by a known virus. In the first group (Heine-Sicdin; lethargic encephalitis; rabies; herpes encephalitis; zostcr) the difference is quite evident, as it is in the group of spring-summer encephalitidcs (Japan B; Australia; St. Louis, ctc.). Finally the encephalitis in other virus discascs (Armstrong choreo-meningitis; encephalomyocarditis; encephalodermatomyositis; rare cases of encephalitis due to Corsachic virus) differs widely from our picture, No known virus causes changes in the brain, comparable to microgira encephalitis. Thc encephalitides caused by other living agents do not cause any dilficulty in differentiation from microglia encephalitis, because thic acute inflammatory changes generally consist of very marked in. filtration by polymorphonuclears and lymphocytes of various kinds, localized in the Virchow-Robin spaces or in nervous parenchyma, when this is markedly degenerated or even necrotic. We have rcached the conclusion that microglia cncephalitis is not directly caused by a living agent, but that another mechanism must play some rôle in the production of the histopathological changes. On this point, we agree with the majority of the authors and! naturally our thoughts are going in the direction of an allergic pathan genesis but, before discussing hus, we wish to see on which pathological details a discussion can be, or must be, based. c. The pathogenic side. Some further considerations in our discussion 1c have opposed the vascular processes mainly occurring in the walls of and around capillaries and small vessels, to thc perii enous processes occurring partly in the l'irchos-Robin spaces and mainly in the parenchyma around these. The first reaction is typical of thic toxic processes caused by heavy metals, organic substances and bactcnal toxins and of the usual experimental procedures to produce allergic encephalitis, ·157 THE PATIIOGENIC SIDE C The second, the perivenous type, follows exanthematous diseases and those experimental procedures which have either used white matter of the brain as antigen or in which vaccinia virus was introduced into the animal. This poses the question: What is the role of the lens in this process? Is it the special type of vessel, or the space around it that is of importance? The similarity of the subpial gliosis with the picture of the pers enous foci strongly suggests the same function, which in the former system must mean either absorption from the CS.F or excretion into it, or building up a shield against noxious substances This would bring us to the assumption that the perivenous localization of the foci points to a greater importance of the contact with the perivascular fluid than with the vessel itself This theory is supported by the fact that foci are never localized around capillaries, which do not have a perivascular space, and seldom around arteries in which this space is smaller (as seen in perivascular oedema!). The preference for the larger veins running directly to the surface (eg in the posterior column of the spinal cord, the veins dorsal to the olives, etc) then easily finds an explanation The marginal gliosis is not especially localized in places with overlying large pial veins. We have also compared the frequency of affected veins in the more compact parts of the white matter with that in the more loosely built parts, but have not found a conclusive difference (although the corpus callosum, cerebral peduncles, optic tract and pyramids are generally little affected) No definite solution can at present be given, but it may be remarhed that the pervenous spaces in the brain are generally sites of predilection for oedema, and also for accumulation of fatty granule cells in processes of degeneration These cells may be found a long time after a malacic accident, still lying in exactly the same places where demyelination and microglial proliferation occur in perivenous encephalus. Also, in chronic atrophy of the brain, we find widened peris enous spaces filled with clear fluid, with the same localizauon. Perhaps the structure around these veins is less dense than in other places and can be more easily distended This distension is also ·158 DISCUSSIOX 6 necessary in hyperacmia, because the increased flow of blood in the arteries is due to the increased rate of flost, in the capillarics to a grcater number of capillaries filled, but in the icins it must be duc to grcater distension of these vessels. Continuing this line of thought, we might suggest that processes which start with a toxic action on the vessel wall can primarily affect all the vessels, larger and smaller ones, whereas processes starting with a disturbance of the perivascular fluids (in the Virchow-Robin space, or even in the parenchyma) would, by preference, talc place around the medium-sized cins. We could also suggest that the veins arc the places of predilection, because high molecular substances cannot be absorbed by the capillaries, but have to be broken down to low molecular ucight and that this is done in the Virchow-Robin space, which does not exist around capillaries (Farquhar, 1957, and others). This mighi byc important when we consider this cncephalitis to have an allergic basis (Boyd, 1947, antigens cannot pass the wall of the seins). The subpial marginal glia could likcwisc aid in transporting sub stances directly to the arachnoidal spaces, after breaking them up into substances of lesser molecular scight. The disturbance of the enzymic processes of this kind of glia would then causc degeneration of the myelın (Roizın; Huszak, 1958). The demyelination is always focal and must thereforc lase its cause locally. This could either be a chemical substance, diffusing from the pernascular space into the parenchyma and acting directly on the myclin, or a substance or agent acting on the Oligodendroglia. Microscopically, hower cr, changes of the oligoglia, except slight hypertrophy, are not found in our preparations. In our slides, demy clination and microglial proliferation occur together Yo focı of cither one or the other can be found, but nc alrcady said that 10 our opinion the demyelination is not caused by microghal proliferation, but that both probably are the result of some noxious agent. Scholz remarked, that microghal proliferation gnes far beyond what is generally seen in small necrotic foci, and only part of this probably " ·159 THE PATHOGENIC SIDE с must be regarded as a reaction to the myclin decomposition products. Iselin is a rather labile chemical substance, reacting to a number of conditions by chemical changes of which swelling and lessened stainability by our usual techniques are most easily recognized. The oedema around a tumour (Greenfield) or in hyponia (Scholz) may cause a serious change in our myelin-stained slides, although probably much of the substance is still present. The reaction of the surrounding ghal tissue in these conditions varies with actiolog. Oedema round a tumour often does not cause microglial proliferation and onls slight slıgoglial hypertrophy. In a malacic focus, howeser, the microglia will react by the formation of fatty granule cells. Well known is also the metachromatic myelin breakdown in some groups of leucodystrophy. Von Hirsch and Peiffer (1955) distinguish two main types of catabolic products, the sudanophile substances and the prelipids, and suggest specific changes in the various lipidoses. In this respect too, perivenous encephalıus therefore has a separate place in the histopathological pictures and it is not preposterous to suppose that this special picture must have a special biochemical cause, differing from what we know in other conditions The breakdown of myelin to a substance of low molecular weight is necessary because myelin, which is absorbed into the blood, gries rise to the formation of iso-antigens. Although a discussion of the theory of an allergic pathogenesis of the peris cnous encephalitis is outside the scope of this treatise, some words must be said about it, because the picture we consider the typical histopathology of microglia encephalitis differs in many points from allergic inflammation in other organs. Here, the reaction is primarily vascular, with proliferation of the wall, ocdema and cellular perry ascular infiltration by mononuclear or polynuclear cells, which 13 only the minor part in microglia encephalus and may even be enurely absent. Also, the absence of cosinophils in the latter, is stressed by nearly all authors However, a number of other symptoms and signs point in the direcuon of an allergic reaction the incubation ume of g-- 14 days; the very short period of outbreak of the symptoms, followed by ·160 DISCUSSION 6 recovery or death; the therapeutic influence of ACTH; the affection of only a small part of the population; the great influence of differ. ences in constitution (previous vaccination; influence of other discascs or injcctions; influence of stress, etc.); the focal character of the lesions; the monomorphous character of the uncomplicated cases; the fact that perivenous foci can be cxperimentally produced by methods generally causing allergic reactions, although these arc combined with the usual vascular changes. Even thc fact that microglia encephalitis does not occur in young babies points in the same direction, when wc bcar in mind that experimental allergic encephalitis cannot be produced when brain from new born animals is used, in which normal myelin de clopment has only started, and the brain of the very young child diſſers in my clin composition from the older brain. This brings us to the supposition that some process, not the well-known allergy but somcthing akin to it, in some way is responsible for the development of microglia cnccphalitis following exanthematous discases.

·Chapter 7 CONCLUSIONS 1. The clinical disease postvaccinial encephalitis comprises several pathologically different diseases of the C.N.S., which often cannot be distinguished before an autopsy reveals their nature. Thus acute anterior poliomyelitis, occurring shortly after vaccination, has been repeatedly diagnosed as postvaccinial cnccphalıtıs until autopsy showed its true nature. 2. One of the clinico-pathological diseases following smallpox vaccination is called penvenous or microgla encephahtıs It is characterized by the following facts. It occurs following smallpox accination and a few other exanthematous diseases, and very rarely fter other diseases. It has an incubation period of 9-15 days (with one possible exception of 28 days), runs an acute course and, when no complications occur, leaves no sequelae (except when myelitis is the main localization), It has sery rarely been noted before 1923, it does not occur in children under two years of age, and is absent in patients in whom revaccination results in immunity reaction of the skin It has a very specific histological picture, differing from encephalitis caused by a living agent and from the usual reaction of the CNS 10 tovi-infectious conditions. The name microglia encephalitis is used in this treatise for those cases in which histological examination verified the existence of this 3 Smallpox vaccination can also be followed by other nerous complications with clinical symptoms and pathological changes similar to those following other infectous diseases of these, encephaspecial type ·162 CONCLUSIONS 7 lopathy and convulsions are frequent in young children; hacmorrhagic encephalitis is sometimes seen in children and adults. 4. Smallpox vaccination may also influencc (stimulate, activate?) thc outbreak of other virus discases (herpes encephalitis; poliomyelitis; cpidemic encephalitis; myocarditis). 5. Microglia encephalitis occurs relatively more often after vaccinia than after measles, and rarely after rubella and varicella. It is extremely rare following other discases or occurring without clear aetiology The occurrence in por virus affections is ins erscly proportional to the seriousness of the disease: not observed after typical smallpox; sometimes found after alastrim or very mild smallpox and rather often after vaccinia. 6. The incubation period in microglia encephalitis following revacci. nation is the same as when following primary vaccination. No clear accelerated reaction can be found. But when revaccination is followed by another pathology, the incubation is showing a wide range of dispersion as is also seen when primary vaccination is followed by the toxi-infectious reaction types. 7. A fatal clinical course depends on the main localization of the process in the brainstem, pons and oblongata rather than on the number of foci and the incubation time. It is independent of the seriousness of the skin reaction to the vaccination. 8 When microglia encephalitis runs i ſulminant course, the histopathological picture has already fully descloped. We find no indication that a vasculo-encephalopathic reaction should have preceded this. Cases of fulminant death in which only changes of encephalopathy are found, should therefore not be considered cry carly or incipient cases of pervenous encephalitis. 9. The foci of perivenous microglial proliferation arc always distributed along the cntire nerous axis, but they may be more numerous in the hemisphere or the deep ganglia, or pons and oblongata, or in the spinal cord. Localization chiefly in pons and oblongata is probably the most dangerous to ifc. The pinal cord is affected in all cases, but symptoms of transierse ·163 CONCLUSIONS certain myelitis are generally not conspicuous shen the cerebral symptoms dominate the picture. Death in these myelitis cases often comes on after a longer illness than in the cerebral cases and is mostly due to complicating diseases (decubitus; purulent infections, pneumonia) When the patient suryacs, sequelac may be present for a certain period 10 Following smallpox vaccination, we can expect a number of patients to have subclinical signs of cerebral (or spinal insolement, which could perhaps be diagnosed by EEG and albumin or globulin changes in the C.ST. This has been demonstrated in measles and parotitis, and E E.G. changes after vaccination point in the same direction. We could regard these patients 25 sensitized in some way and therefore more vulnerable to exogenous factors, to which they might react with the development of an encephalitis. 11. The pervenous type of clinical postvaccinial encephalitis consists of slight diffuse pia infiltration by lymphocytes, marginal ghosis and focal demyelination and microglia cells, lying in the parenchyma around veins Small lymphocytes are found in nearly all cases in small numbers and, therefore, probably belong to the picture Other cell types, as polynuclears and crythrocytes, are not a part of microglia encephalitis. The presence of these blood cells probably always points to other factors (as bronchopneumona, other serum injections, lowered resistance of the brain due to earlier disease or trauma) acting at the same time. 12. The myelin degeneration is not observed with our staining technique before glial hypertrophy is evident, but there is reason to believe that some degeneration of the myclin has taken place, the microglial proliferation being partly a rcaction to this The breakdown of the degeneration products of the myelin can obtain in the smaller foci by a chemical change into soluble substances, which are then transported to the circulation However, in the larger foci the amount of catabolic material is larger and a change into fat and fatty acids occurs, which can be found by Sudan stains 13 Marked oedema 15 an outstanding characteristic of mucrogla encephalitis, although it was very evident in a feu Cases not ·161 CONCLUSIONS 7 It is on the contrary very much in cvidence in cases of cncephalopathy, whether following vaccination or toxi-infectious conditions. 14. When patients suffering from postvaccinial microglia encepha. litis die from bronchopneumonia or from other complications, histological changes (haemorrhages, thromboses, tissuc necrosis) may be found, which do not belong to the picture of the original discasc. 15. The perii crous microglial foci are a special reaction type of the nervous system, which is the most important pathology in postexanthematous microglia encephalitis but may be occasionally met in other conditions, of which poliomyelitis must be mentioned in the first place. But pictures highly resembling thesc foci can also be cncountered in embolic and hacmorrhagic cnccphalitis, following contusion of thc brain, and other discases. 16. A sharp division should be made between the pericnous microglial foci and the vascular toxi-infectious foci, which fall into a different class of reactions The border between microglia cncephalttis and disseminated encephalomyelitis is less sharp, and cases occur in which histopathological examination does not allow a decision as to the group to which a case belongs. 17. Cases of cocephalitis following sevaccination are often not so monomorphous as those after primary vaccination. The clinical coursc and the pathology may shon some differences, which are more marked when a low degree of immunity still exists. 18 Thic rôle played by the veins in the demyelinating process is still unknown; a suggestion is given that the width and function of the pervenous space might be more important than the circulation of the blood in these vessels. 19 Post-exanthematous microglia cncephalitis is probably not directly caused by a virus or other living agent but is due to marc complicated interaction of fugh-molecular substances, formed by conditions which in some points resemble allergic processes. Because the name perii cnous or microglia encephalitis, com. prises more than is originally meant, it is proposed to introduce the nanie drcase of Turnbull, Luchsch, Bastiaanse, for the special type rumise ribed here. 20 ·LIST OF CASES FROM THE LITERATURF, REVIEWED IN THE TEXT . t28 120 34. 120 12 68 . 36 • 101 • 118 98 . . • 127 • 122 122 33 Page Page Andreson, 1972 123 94 Varsden, Hurst, 1932 Pald (H), 1931 de Massary, Albeissar, 1936 230 Baron, P, 1929 123 97 Ale tacosh, Scarff, 1930 Bassor, Grinket, 1939 Muller (91 and 2), 1919 175,127 van Brgaer, 1930 Muller (117), 1919 t21 van Bogaert (2), 1951 Muller, 1933 119 Bnges, 1935 Mulligan, euburger, 1912 Brussaud, Brery, 1994 Paul, J, 1934: Brouwer dr Jongh, Rocha, 1933 97 Petre (2), 1928 de Busscher, Radermecker, 1919. st. 119 T'etic, H, 1936 Comby, J 1926.. 91 6.8 Querido, I, 1930 Crome, 1951 Rammow, 1935 93 Darnele, Dubou, 1932. Roeder Kutsch, 1914 Davison, Rrock (1 and 2), 1937 126 Rojas, 1932. +27 Demme (1), 1930 126 Russell, Oddie, 1928 Donohue, 1941 125 Schreuder, Rijsel, Verlinde, 1930 - 124 Doring (1), 1942 74 Schurmann (2), 1928 73 Donng (2), 1942. 92 27,93 Sjovall (2), 1932 123 Eckstein er al, 1930 83 Spiller, 1993 Faiger, 19+ Stuart, Ankorian, 1930 Giedion, 1952. 129 Suppan (6), 1937 35 Giffin ef al, 1918 129 Suan, 1946 Cins, 1912 68 Thathing, 1907 Greenfeld (1 and 9), 1930 6. 118 · 126 Tinel, Benard, 1923 Grunker, Bassoe (1), 1931 119 Troup, Hurst, 1930 123 Flerckenrath, 1935 69. 16 34. 92 Turnbull, McIntosh, 1926 Higice, 1912 73 127 Turnbull (8!, 1928 Jacob (1), 1956 128 74 L'chmura, Shurakı, 1957 Jones, 1938 129 Verlinde, 1955 Kokken, 1937 29 Walihard, 1930 Krabbe, 1913 69, 117 Hegelın, 1935 Kramer, 1951 33 124 Hortsma, 1927 de Lange. 1943 Hagand, 1941 17. 121 de Lange, Ca. 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·INDEX Alastrim, 12+ Allergy, 80 ANDRÉ-BALISAUX, G., 63 Angina, encephalitis following, 126 AVELL, A. L, 109 Ascariasis, 36 Astroglia, 33, 58 - subependymal, 58 -, subpial. 58 Death, sudden, in babies, 107 Demyelination, histopathol., 158, 159 - invisible breakdown, 38 Discase of Turnbull, Luckich, Bassiaanse, 152 Diros, G. J., 48 DORING, G., 25, 107, 118 DUBOIS, R., et al., Bt BAKKER, S P., 49 BARLOW, T. vo\, et al., 67 BARON, P., 90 BASTIAANSE, F. S. VAN BOUWDIJK, 67, 70, 82, 138, 140, 151 TOCAFRT, LVA., 2, 25, 33. 56, 83, 131, 134, 153 BRISSAUD, E., et al., 68 BROWN, J W., et al., 144 Cerebrospinal fluid, 14 Children under two years, 73 CHRISTENSEN, P. E., et al , 82 Chromatolysis of ganglion cells, 51, 55 Cold, cnccphalitis following common, 126 Cosby, J. 8, 68, 136 Commission, Dutch, on vaccination. 70 - English, on vaccination, 70 Complications, 35, 40 -- postinfectious, 139 Contusion cerebral, 1.49 Consulstons 67, 71, 106, 146 Cortisone 10 (RONFMEYER, L', 145 LOGAR, G. 19, F., 80 LIRICI, W'. E.. 5 Llectroencephalography, 144 Encephalitis, acute diffuse lymphocytıc, 8, 148,153 , classification, 8 - embolic, 112, 15: -, epidemic, eg -, microglia, actiology, Go, 61, 156 -, allergic predisposition, 62 carlier brain diseases, 61 - heredity, 6! -, mental, physical strain, 62 -, norious factors, 62 characteristics, 114 clinical picture, 131 coalescence of focs. H complications, 35.fo - date of onset, 37 definition, 3.6 --, demyelination, 20, 38 carliest stages, 25 -, electroencephalography, 141 -, foci, 37 Sulmın course, 35, 32.78.93 -. ganglion cells. 59 genkaphic distribution, 141 glicis, marginal. 45. 57 haemorrhage in, 39, 40, +7 -, incubation time, 135 1). IT Idol , 81 Dead hund in bed, 107, 146 ·INDEX 179 Hacmodynamic reaction, 18 Hacmorrhages, 39, 40, 47 HASSELT,J H. V4N, 119 HEYNEAUX, 3, 4 el., 49 HERCKENR 4TH, B, 83 HSASCHI, THE VON, et al, 159 Hope, « al , rog, 144 HORTEGA, P DEL RIO, 79 HUTTER, A , 63 Hyperaemia, 17 - nitul stages, 74 - late stages, 33 mononuclear mfiltration, 17, 23, 37 --, myelitis, transverse, 48 - rosological place, 356 --, oedema, 17, 49 - pathogenesis, 47 - polymorphonuclears, 17, 24 -, subacute case, 130 subclinical cases, 147 use of this name, 3, 6 nodular, 254 -, peruaxual, 155 - peris enous, 3 -, post-measles. 34, 36, 66, 67, 69 - postvaccinal, 7 -, use of this name, 5 Encephalomy chius, disseminated, 130, 154 experimental, 131 Encephalopathy, 78, 102 - definition, 6 -, haemorrhagic, 112 Immunity, partial, to vaccination, 83 Incubation time, 135 Influenza, encephals is following, 126 Injections, nervous complications aſter, 129 latcrcurrent discases, 39, 55 Jacos, H, 148 KAISER, M, et al, 63, 67 KEMKES, I al, 81 Kidneys in vaccina, 147 KLS CE, F, 129 Fat embolism, 112, 149 FERRARO, A, et al, 6, 132 FNLEY, KH, 19, 57 Fulunant cases, 25, 32 LANDE, C DE, 25, 128 Leucocytes, polymorphonuclears, 13, 24 LEVADITI, 3 C, 80 LHERMITTE, F. 19, 33 136, 148 LITVAK, A M. 66 Lurer in accia, 147 LUCKSCH, F, 140 LUUDEN. CE, 132, 148 Ganglion cells, 59 Ganglion cell degeneration, 102 -- -, diffuse degeneration, 150 Geographic distributori, 144 Grus, H A, 68, 154 Glia reaction, diffuse, 45, 56 Gliosis, subpial, 157 Groots, 3 11,5 Granule cells, Catty, 23, 38, 55, 157 GREENBERG, J G, et al. 144 GROSSMANN, H., et al. 35, 81 MADER, 4, 38 MAGE, J. 49, 63 MAGID, at al, 81 ALALAMUD, N, 33 NARCI4ND, L, Ha!, 72 MARSDEN, J P. I al , 59 MCI TOSIE, J. 60 ·180 INDEX Vieasles, encephalitis following, 120 Alicroglia cells, 21 -, origin, 79 -, vacuoles, 37, 38 MILLER, H. G., 101, 107 Mitosis, abnormal, 60 MOLLARET, P., et al., 113 TOLLER, I , 139 Multiple sclerosis, 155 NILSSER, J. H., et al., 69, 81 Myclin, degeneration, 96 --, transport, 96 in young children, 80 My clitus following smallpor, 97 - transicise, incubation, 48 -, rôlc of oedema, 54, 55 Myocarditis, 101 -, cause of death, 147 Rabies, antirabies treatment, :28 -, encephalnis following, 127 RADCRUECKER, J., 25. 546 REUSTFIER, R., et al., 83 Reticulo-endothelial system, 145 Revaccination, 02, 109, 143 - after primary saccination with encephalstys, 33 -- as actiologic factor, 61 Rod cells, 56 Roizin, L., et al, 20 Rubella, encephainis followins, 120 Neuralgia, thoracic, 68 Neuro-allergic reaction, 153 NORDVIN, MI, 40 Vuclear distort, amitotic. 37 Scarlet fever, cncephahtis following 124 SCHMIDT, M. B., 21 Scholz., 1., 25. 33. 158 SIT LEVIS SMITT, W.G., 63 Smallpox, encephalis following. 123 -, my clutis in, 97 Seart, I., 3, 151 STIELVFYER, W, 6. 67. 546 Status thumicolymphaticus, 145 Stress, 140 Subclinical cases, 144 Substantia nigra, degeneration, co Syndrome malın, 148 Ocderna, 17, 49. 102 influence on myelin, 159 Pagrs, P 3103 Parotius, encephalitis following. 125 l'auhuenesis, allergic 156. 159 PALE J 101 Priti 11. 59. 69, 98. 155 PERDRAL. J R 60 PATERS (113 Polarhus, acule anterior 49, G, THESENO, 68 TISEL, J., . al., 6.0 Toxoplasmos's, 101 Transition (ypes. 154 TUR\33212, 155 L'CMLRA, Y., et al., 81 LIBERALL, I., tai, 141 - microglia in 10 113 1 TIF al 33 Vaccination, nerous complicat313811 aftet, 129 Vaccins2, 145 Vancells, encephalitis kulkon ing. 121 Teios, röle of, 157, 158 QE KIIX 144

·INDEX
181
VERITAART, W.J C, 148
VERLI\DF, J. D., et al., 96, 101, 132
Virus, Columbia SK, 132
VRIES, L. De, 60, 81
I\'IGID, H1, 23
Wyildi, E, 81
WOHLWILL, F, 57, to
WELFTES PILFE, I ' VAN, et al,
1
\\YFRS, HJ G.60
WALTILARD, B, dal, 2, 57, 129
WAYENBURO, G. A. M. V4, 68
Whooping cough, encephalitis
Following, 1244
ZIWERYNY, H Met al , 81
Zilch, K. J.3

·CLIXICILIYD PATHOLOGICAL REMARKS Periusus infection when vaccinated. Had in agunst this Hartwithsary from hyperaemic sessels I fex ring harm thaga Bacteria in nurlu laulry 39 h post mortem) oth day consulsion Pa 50°. plynuclears, thick infiltrate. Iarket cornical cellent and were in lih to 6th lazers Piramidal cells stuit in subcortical white matter Jans rod cells in curter, diffusely, Sudan fat along Vessels Small (ori, but very dense. Cihal stars Marginal glosus as thuk microph? masses Dexoneration of subst nigra Csr many cells I cry compact fixes Old lipchrome pigment along vessels in cortex Atrophs around prat horn or ener Iosily fresh hacmnrthages round seseral vessels. In thor Ford sorte glial stars Many foci in cortex, small and large, pervasc Markellarce-cell menuncia Foci compact, rather small and nell defined roci ratified, distributed far in the tissues Many microglial granule cells Ibnormal mitotic ditsions Temp down to normal, then bronchopneumonia Foci centrally denar, rul cells iery diffuse in cortex L'prxr layers free Foci rarified, far in ISSUES ...danih cuma (serum tract's Thupus-cholera ini at time of sace and twice later Om Www mementin sosel sheaths Convulsun onth day Custais Sormal temp Last 5 dass, cumpl 4* si dra! I.1 of different age, 12th day crebral symptoms sgth day transserse muselitus expler (Irum.de Iysis of ant ben cells in spinal cord Here also typical lew tu. Fresh sty throrites in Torchon-Rotun apate in patis abknza in far * without microglia Chromatolyus of an horn cell in spiral and Swelling of bran Fori of haemorrhagic encepluadaris spurate from the TNT* Status dysraphicus 1918 pururata Starting purulent menungıta' Genelum cell rate: 1 pinal cord

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