encephalomyelitis the clinical pathologist · many years, between the attack of encephalitis...

J. clin. Path. (1956), 9, 1.

ENCEPHALOMYELITIS AND THE CLINICALPATHOLOGIST *

BY

J. G. GREENFIELD

Twenty-one years ago I had the honour ofaddressing this Association in a short Presidentialaddress and I then chose for my theme the oppor-tunity which clinical pathology gave for studyingthe natural history of diseases. This old term"natural history" recalls Gilbert White's immortal"Natural History of Selbourne." It distinguishesstudy by observation of naturally occurring bio-logical phenomena from study by planned experi-ments and thus well describes the special field ofthe clinical pathologist. Just as Gilbert Whitedescribed not only the form and colour of birdsbut also their habits of feeding, nesting, and migra-tion, so the clinical pathologist studies a diseaseas a whole, its aetiology, its clinical, biochemicaland haematological manifestations, and, finally, insome cases, the changes which it produces in theorgans of the body. For many of us this last studyhas such a special fascination that we tend, as wegrow older, to devote ourselves more exclusivelyto it. But, if in our earlier work, we looked atdiseases from the broader point of view of theclinician and clinical pathologist, we shall be lesslikely to lose sight of these wider aspects when wespecialize.

It is in this broad manner that I ask you toconsider the natural history of encephalomyelitis.

This group of diseases is fortunately rare inBritain. We owe this partly to our position as anisland and partly to our climate, which is seldomwarm enough to make our indigenous mosquitoesvery active or to encourage other forms of bitinginsects such as wood ticks. As a result we arealmost free from insect-borne forms of encepha-litis. The only exception is the occasional humancase of louping-ill. The only virus disease of thenervous system which has caused much troubleis poliomyelitis and even this disease seems to bediscouraged by our climate and only in rare sum-mers approaches anything like epidemic propor-tions. When therefore the occasional case ofencephalomyelitis turns up it arouses little interestand we may be satisfied with this general diagnosisand make no attempt to trace the type of disease.

* Foundation lecture delivered at the 55th general meeting of theAssociation of Clinical Pathologists on September 29, 1955.

B

In looking at the natural history of any diseasewe must learn from the past. I should like there-fore to say something of my own experience withthis group of diseases. This goes back to 1917when I saw my first two cases of encephalitislethargica, in a convalescent military camp. I wasacting then as a physician, and was very puzzledby the peculiar lethargic, sleepy state of the patients,who one minute appeared to be in deep coma andthe next minute were answering questions intelli-gently and again quickly slipped back into deepsleep. Nowadays neurologists would probablyattribute this symptom to lesions in the hypo-thalamus, but at that time we knew next to nothingabout that region of the brain. I made a post-mortem examination on one of these cases andfound nothing except a congested brain. We hadno facilities there for cutting sections, but whenthe epidemic spread to London I soon had as muchmaterial as I could handle.

Several points of interest arose in the examina-tion of the cerebrospinal fluid of this disease.

(1) The striking disparity between the high cellcount and normal or only slightly raised proteinwas emphasized first by the French. In the Lon-don cases the cell count was almost always purelylymphocytic, but in the short Sheffield epidemic of1923, which reached its peak after the disease hadalmost disappeared from London, polymorpho-nuclear leucocytes were common in the cerebro-spinal fluid, in which they might form over 40%of the cells, as well as in the cerebral lesions.

(2) The French also found in the cerebrospinalfluid abnormally high glucose percentages, such as100 mg. per 100 ml. or more. I never satisfiedmyself that this was constant or, when present,significant. At that time the methods in generaluse for estimating glucose in small amounts ofbody fluids were crude and the values they gavewere probably higher than the normal, which hadbeen estimated for the cerebrospinal fluid veryaccurately by Mestrezat in 1912.

(3) In the earlier years of this epidemic gold solexaminations were rarely carried out on thecerebrospinal fluid, but those who used this test

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J. G. GREENFIELD

found that it commonly gave positive results. Insome of the later cases strong reactions of paretictype were found. I believe that this is fairly com-

mon in many forms of encephalitis, especially insubacute cases. The gold sol reaction has a specialimportance in a subacute form which has recentlyattracted our interest and of which I shall speaklater.The histology of encephalitis lethargica is

described in all the textbooks and I shall refernow only to points which are sometimes omittedfrom these descriptions.

(1) Von Economo (1931) described under thename of " Neurophthoria " the damage whichnerve cells undergo in encephalitis. He describes

"isolated ganglion cells showing varying degreesof cell degeneration, varying from slight tigrolysisto swelling and hyalinization of the cell protoplasm.shifting of the nucleus to the periphery of thecell, pallor and disappearance of the nucleus, ex-

tending to the formation of ghost cells."

These changes in the neuron are found in all

forms of virus encephalomyelitis. Einarson (1949),who has studied the changes in nerve cells in polio-myelitis, finds in the early stages "chromatolysiswith dissolution and diffuse disappearance of theNissl bodies " and eccentricity of the nucleus. This

goes on to vacuolar breakdown of the cytoplasm

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FIG. 1.-Encephalitis lethargica with a 20-day history: substantia

nigra showing severe destruction of pigmented nerve cells with

scattering of melanin pigment free in the tissues (toluidin blue).

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FIG. 2.-Japanese B. encephalitis: cerebellar cortex showing a glialshrub in the molecular layer in relation to the dendrites of a

Purkinje cell which has disappeared. (From a section from thecollection of the Armed Forces Institute of Pathology, Washing-ton, through the kindness of Dr. W. Haymaker.)

and degenerative shrinkage and disappearance ofthe nucleus and nuclear membrane.

"The contour of the cell assumes an irregularragged appearance, the cytoplasm becomes struc-tureless, frequentlv with relativelv increased acido-phily, before it disappears altogether as a cellshadow, or is destroyed by macrophages."The early chromatolysis may, however, be rever-

sible, and the return of function in limbs paralysedwith poliomyelitis is probably due to a recovery

of this kind.(2) In encephalitis lethargica, in cases dying in

the acute stages as well as in cases of post-encepha-litic Parkinsonism, disappearance of cells of thesubstantia nigra is shown by the relatively in-destructible melanin granules which are left freein the tissues (Fig. 1). Or a ring or nodule ofphagocytes may be the only evidence that nerve

cells are destroyed. In the cerebellar cortex inJapanese B. and Russian spring-summer encepha-litis, and sometimes in poliomyelitis, loss of

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A.C.P. PRESIDENTIAL ADDRESS

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FIG. 3.-" Subacute sclerosingleucoencephalitis " in a girlof 20: cortical nerve cellshowingAlzheimer'sfibrillarychange. (Case reported byDr. J. A. N. Corsellis.)(Bielschowsky's silvermethod.)

Purkinje cells may be assumed from the collec-tions of microglial phagocytes which are spreadalong the remains of dendrites in the molecularlayer, an appearance which German writers call" glial shrubs " (Fig. 2).

(3) I have mentioned the loss of cells in thesubstantia nigra in post-encephalitic Parkinsonism.What is less familiar is that some of the remainingcells, both there and in the locus coeruleus, showfibrillary tangles or whorls similar to those foundin Alzheimer's disease (Fig. 3). Hallervorden(1933, 1935), von Braunmiihl (1949), and Beheim-Schwarzbach (1952), as well as Dr. Bosanquetand myself (Greenfield and Bosanquet, 1953),have found this change very constantly inpost-encephalitic Parkinsonism. It may occur inquite young subjects. One of Hallervorden's caseswas in a girl of 11 years. Divry (1934) showedthat this change is associated with the stainingreactions and optical properties of amyloid, butthere is no generalized amyloidosis (Fig. 4a and b).Malamud, Haymaker, and Pinkerton (1950) andCorsellis (1951) have found a similar change incortical nerve cells in children who have survivedsubacute inclusion encephalitis for some years.

It is still doubtful whether the delay, often ofmany years, between the attack of encephalitislethargica and the appearance of Parkinsonism isdue to the survival of the presumed virus in thetissues of the brain or to a progressive degenera-tion and eventual death of nerve cells which weredamaged during the acute stages of the disease.The latter suggestion is supported by some obser-

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lb,FIG. 4.-Post-encephalitic Parkinsonism: nerve cells from the locus coeruleus

stained by congo red. The upper nerve cell has undergone fibrillary change(a), which gives birefringence under crossed Nicol prisms (b).

vations on cerebral trauma as well as by theneurofibrillary changes which I have already men-tioned. This appears to be a very slow form ofdegeneration, as it has not yet been observed inany of the earlier stages of encephalitis, even inpatients with subacute inclusion encephalitis whosurvive for about a year. The cases of progressiveamyotrophy, which occasionally follow encepha-litis of the lethargica type as well as poliomyelitis,may be interpreted in either fashion. These arecertainly rare, but some cases were reported inthe early years from France and Denmark, andMatthews and I (Greenfield and Matthews, 1954)reported two cases recently. In these there wasthe association of adverse eye movements oroculogyric crises, and Parkinsonism-a syndromeconsidered to be pathognomonic of encephalitislethargica-with wasting of the musculature ofthe upper limbs. Our post-mortem case showednone of the -tract degenerations in the cord thatoccur in amyotrophic lateral sclerosis.At present we know very little about the meta-

bolism of nerve cells, but it seems possible thatviruses may sometimes damage them in such away that, although they are not immediatelydestroyed, their normal span of life is greatlyreduced. Unfortunately no satisfactory transmis-sion of the virus of encephalitis lethargica toanimals was ever achieved, nor has any virusdefinitely been shown to be the cause of subacuteinclusion encephalitis, but this change in nerve cellsis similar to that produced by Achucarro (1910)with rabies virus in rabbits.

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J. G. GREENFIELD

Post-infectious EncephalitisEncephalitis lethargica had scarcely disappeared

when post-vaccinial encephalomyelitis began tocause great anxiety to Ministries of Health,especially in England and Holland. Why itappeared then, almost for the first time, is still in

doubt, but the type and strength of vaccine in use

at that time may have been to blame. As JamesMcIntosh pointed out, the original Jennerianvaccine, derived from milkmaids who had becomeinfected from cows in the natural course of theirwork, disappeared very early, and until the presentcentury variola virus, modified by passage throughcalves, was always used. Sometime in the 1920sthe vaccine was again modified by being passedthrough the brains of rabbits, and this may havealtered its virulence. My own experience showedthat at the time of the outbreak of post-vaccinialencephalomyelitis the vaccine was so potent thatgeneralized vaccinia or widespread skin eruptionsmight follow its use in the accepted manner. Infact the epidemic ceased when the strength of thevaccine was reduced and the skin more lightlyscarified. Soon after the post-vaccinial cases a

similar disease, with lesions of identical type in thebrain and spinal cord, came to be recognized as

following measles, chickenpox, mumps, and influ-enza, as well as after mild smallpox. This was byno means the first appearance of post-infectiousencephalomyelitis-for example, a very typical

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FIG. 5.-Encephalopathy following mumps. (Case of Collins andArmour.)

case following mumps had been described byCollins and Armour in 1912 (Fig. 5)-but itscharacteristic lesions were recognized then owingto their similarity to those seen in post-vaccinialcases. The theory that this was an allergic reac-tion was first put forward by Glanzmann (1927),and has received recent confirmation from theexperimental work which has been carried out,especially in the U.S.A., during the last 15 years.Occasional cases following vaccination appearedagain during the last war when thousands ofrecruits received their first vaccination againstsmallpox. In some of these cases, as in some ofthe cases in the earlier epidemic, the spinal cordbore the chief brunt of the attack and the lesionsin it were sometimes severe enough to result inpermanent paraplegia. In other cases the attackwas milder and cleared up more or less completely,but often leaving sphincter trouble as a sequel(Figs. 6 and 7).During the last war I had the help of Professor

James McIntosh and Dr. Selbie of the MiddlesexHospital in an investigation for the Ministry ofHealth of cases of encephalomyelitis occurring inEngland and Wales. The Ministry was concernedabout the possible transmission to this country ofsome of the forms of encephalomyelitis, especiallyequine encephalomyelitis, which had recently beencausing epidemics in the United States. Our resultshave been summarized in the History of the SecondWorld War (McIntosh, Greenfield, and Selbie,1952), and it is only necessary to say that, apartfrom poliomyelitis, the majority of our cases wereof the post-infectious type following vaccination,measles, and coryza. We had, however, eightother cases of encephalitis of varying acutenessand severity. In none of these cases was the cere-bellum involved, nor was there the special inci-dence on the substantia nigra which characterizedencephalitis lethargica. The workers at theMiddlesex Hospital were unable to transmit virusfrom any of these cases. Since the end of thewar I have examined several cases of encephalitisin material sent to me by members of this Associa-tion. These indicate that a form of encephalitisnot very different from encephalitis lethargica stilloccurs occasionally in Britain.

Acute Haemorrhagic LeucoencephalitisCrawford's recent description (1954) of this

interesting disease is so complete that little needsto be added. With his summary of the evidencefor its allergic nature I am in entire agreement.The vascular lesion and the intense oedemacertainly suggest allergy, though there are usually

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FIG. 6FIG. 6.-Post-vaccinial myelopathy: spinal cord showing gross

lesions in the antero-lateral columns and anterior horns.FIG. 7.-The same condition as in Fig. 6: higher power view of

anterior horn of lumbar enlargement, showing perivenular cellincrease without damage to the nerve cells included in this area.

few eosinophils in the exudate. A very interestingquestion arises here, that of the relationship ofacute haemorrhagic leucoencephalitis to post-infectious encephalitis. If both are aller'gic diseases,and if both may follow influenza, why does theirhistological picture differ ? Or are the differencesquantitative rather than qualitative ? If so weshould expect to find cases with some of thecharacteristics of either, but so far I have nodefinite evidence of such transition cases.* Itshould be noted also that in the experimental pro-duction of encephalitis in monkeys, by injectionof emulsions of brain with so-called " adjuvants,"Wolf, Kabat, and Bezer (1947) found that duringthe first few days

"14 polymorphonuclear neutrophiles, occasional eosin-ophiles and sometimes fibrin were present in thewalls of the vessels, their perivascular spaces andin the perivascular parenchyma. This infiltrationwas associated with congestion, oedema. andoccasional fresh perivascular haemorrhages."These authors comment on the similarity of

these appearancesio those seen in acute haemor-rhagic leucoencephalitis and suggest "that acutehaemorrhagic leucoencephalitis may be an acute

* Cases of this kondhave recentlr been reported by Russell(19a).

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and violent form of disseminated encephalomye-litis." This similarity has been lost sight of bymany who have experimented only with guinea-pigs, in which the lesions are less acute.As Crawford has pointed out, these cases are

considerably less rare than the number publishedwould suggest, but fortunately they are not com-mon. To the clinical pathologist they present aspecial problem, as the high polymorphonuclearcount both in the blood and in cerebrospinal fluidmay well suggest the diagnosis of cerebral abscess.In fact I do not see any escape from this diagnosisin cases with a hemiplegic onset, except perhapsthat so acute a clinical course is unusual in casesof abscess.

Subacute Indlusion Body EncephalitisAt the end of the war I became specially inter-

ested in a form of encephalomyelitis which wasfirst, and very well, described by Dawson in theUnited States in 1933 under the name of "a sub-acute form of lethargic encephalitis." He describeda second case in the following year. He tried topiass the disease to several different kinds ofanimals but without success; and many similar

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FIG. 8.-Subacute inclusionencephalitis in a girl of 9years (duration of illnesseight months): coronalsections through theoccipital lobe, stained (a)scharlach R-haemalum,(b) Victoria blue forneuroglialfibres. The areaof slight demyelination inthe external and inferiorparts of the section in (a)is seen as an area of fibrousgliosis in (b).

attempts have been made since then in Britainwith equally negative results. From one case Dr.Weston Hurst did finally succeed in passing herpessimplex virus, but in most of the other cases sero-

logical tests for herpes simplex infection have beennegative. In Switzerland also a doubtful resultof virus passage was obtained. We consider itvery questionable, although perhaps still possible,that this disease is due to the herpes virus.

In 1945 van Bogaert in Belgium described thesame disease under the name " subacute sclerosingleucoencephalitis." As the name shows, he was

more impressed by the tendency of the disease toproduce demyelination and neuroglial reaction inthe white matter than by its effects on the cortex.There is now no doubt that the disease does pro-

duce a slow, rather localized demyelination, mostoften in the occipital lobes (Figs. 8a and b). Thisis most obvious in long-standing cases, that is, inthose which last for a year or more. In a case

published by Foley and Williams (1953), which Iexamined, the appearances might well have beenconfused with those of Schilder's disease. Thisform of encephalitis has a special interest to theclinician, because of the tendency for sudden jerksor sudden losses of tone in the limbs and trunkduring the middle stage of the disease. Theytend to occur with a regular rhythm, every five to10 seconds. Sometimes the interval varies; forexample, there may be an alternation of seven- andnine-second intervals or there may be apparentlylonger gaps. The E.E.G. is specially interesting, as

complexes of large waves tend to appear with the

greatest regularity, usually synchronous with themovements, and the record may continue in thesame pattern for hours or days at a time, so longas the patient is awake. These jerks may go onwithout change for weeks at quite regular intervalsin an unconscious patient.Another interesting point in this disease is the

cerebrospinal fluid, which is usually normal, oralmost so, with the exception of the gold-solreaction, which is almost always of fairly strongparetic type; The protein chemistry of this reac-tion has not, so far as I know, been studied in thisdisease, and it would be interesting to knowwhether the blood showed an excess of a or /3globulin, or whether this is only present in thecerebrospinal fluid.The most characteristic histological feature of

these cases is the inclusion bodies in nerve cellsand oligodendroglia. These were first pointed outto me by Professor Dorothy Russell in a casewhich she examined at Oxford. Soon after thatI examined another very typical case which, unfor-tunately, I did not see during life. Since then Ihave examined the brains of about 16 cases, manyof which I saw during life, and from this experi-ence I can say that inclusion bodies, and in factall evidences of encephalitis, may be very difficultto find. In one case I examined many sections ofthe brain three times, at intervals of weeks, beforeI found inclusions. In other cases they have onlybeen present in certain areas of the brain; forexample, the nuclei pontis in one case containedmore than any area of cerebral cortex, though it

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FIG. 9a and b.-Subacute inclusion encephalitis: nerve e*-Scells in cerebral cortex showing intranuclear andcrescentic cytoplasmic inclusions. The nucleolus is ;displaced to the nuclear membrane. (Lendrum'sphloxin-tartrazin method.) ^"

is fair to say that, in this case, the occipital cortexwas severely scarred. Similarly many areas ofcortex may show very little evidence of encepha-litis, and others show only loss of nerve cells andgliosis without inflammatory exudate.The inclusions in this disease are both intra-

nuclear and intracytoplasmic and, as I have said,the intranuclear inclusions occur both in nerve

cells and oligodendroglia. The typical intranuclearinclusion almost fills the nucleus of the cell, andis surrounded by an unstained zone, outside whichone can see rather coarse granules of chromatinlying against the nuclear membrane. Thenucleolus is pushed to the periphery by theinclusion. The cytoplasm of these cells usuallyshows a greater or less amount of chromatolysisor it may itself contain acidophilic granular or

floccular inclusions. Later the whole nucleusbecomes filled by the inclusion, and only a fineline of chromatin granules outlines the nuclearmembrane. At this stage the cytoplasm is usuallyshrunken, but sometimes forms a mass of hyalineacidophilic material which seems to lie besiderather than around the nucleus. These inclusionsresemble those of herpes simplex and even more

closely those of certain forms of canine distemper(Fig. 9a and b).On examining the histology of one of these

cases in which intranuclear inclusions are difficultto find, there may be little to distinguish it fromother forms of encephalitis or from a mild case ofgeneral paralysis. But, when the histology is takenalong with the clinical symptoms and signs and theelectro-encephalogram, the disease becomes separ-

able as an entity, and it appears remarkable thatit was not described until 1933. The incidenceof the cerebral lesions is also important. In my

experience the main areas of incidence are theoccipital cortex and white matter, the posteriorparts of the thalamus, the nuclei pontis, and the

inferior olives. In the two latter areas the onlylesions may be clumps of microglial nuclei, so-called "glial stars," but these are rarely absent.There is, at the present time, a tendency on the

continent to distinguish cases, in which the lesionsin the white matter are prominent and intranuclearinclusions in nerve cells difficult to find, fromthose with more evident cortical lesions. In myview this distinction is not justified, since theclinical symptoms are the same in both types ofcase. As a general rule the cortical lesions aremore evident in cases with a short history, and thelesions in the white matter in cases with a longerhistory, so that the acuteness of the process andthe stage of the disease at which the patient diesmay be the most important factors in deciding thehistological picture.One of the many interesting features of this

disease is its world-wide distribution. It wasdescribed first in the United States, then in Englandand on the continent of Europe, but since thencases have occurred in English children in India.This indicates either a common and very wide-spread virus such as herpes febrilis (for which asa cause the evidence is still far from clear), orwidespread carriage by human migration which isnowadays equally likely. Many of our Englishcases occurred in or near sea-ports such asLondon, Bristol, and Southampton, but othershave occurred in rural communities. It certainlyis a disease which, although rare, merits fullerinvestigation, especially from the point of view ofaetiology.During the last 15 years a number of cases of

acute encephalitis due to herpes simplex virushave been studied. These have occurred both inchildren and young adults, and in both age groupsthe disease has run an acute course, fatal in sevento 11 days. The cerebrospinal fluid has showna very high cell count in which lymphocytes pre-

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dominate or may be the only type of cell. In thesecases there is widespread leptomeningitis, andinflammation and necrosis spreads from the cere-bral cortex, where it is most severe, to the under-lying white matter. It may extend as far down asthe pons and medulla, but tends to spare the cere-bellum and the spinal cord. Haymaker (1949)describes the areas of inflammatory necrosis as"mushy" to the touch in the fresh state, andmicroscopically he found many areas in which thenecrosis was as complete as in ischaemic foci, butvascular thrombosis was not seen. Intranuclearinclusions were present in these cases both in thenerve cells and in oligodendroglia.Here I should like to interpose a few remarks

about the relation of viruses and intranuclear in-clusions to the normal constituents of the nucleus.The nucleus of nerve cells, like all nuclei, plantor animal, contains chromatin or deoxyribonucleicacid and a nucleolus which consists partly ofribonucleic acid and partly of acidophilic proteinand is therefore amphophilic. In the larger nervecells there is a large rounded nucleolus, containinga relatively large amount of ribonucleic acid which,along with the ribonucleic acid in the Nissl granules,is considered by Hyden to be essential for thenutrition of the large cell body and still largeraxon. But, as is well known, the nucleolus is stillamphophilic, staining with eosin by Mann's eosin-methyl blue method (Levi, 1897). The amount ofchromatin or deoxyribonucleic acid in the nucleusis relatively small; in fact in the larger nerve cellsthere are only very fine granules along the nuclearmembrane and a small rounded paranucleolar mass,which Barr and Bertram (1949) have shown to belarger and more definite in the female in cortical

FIG. 10.-Same as in Fig. 9: cortical nerve cell with intranuclearinclusion, showing the nuclear chromatin to be unaffected.(Feulgen-light green.)

nerve cells. It is possible to stain either theribonucleic acid or the acidophilic protein in thenucleolus specifically by different methods, andthe Feulgen stain for deoxyribonucleic acid canalso be used. Hyden (1947) has studied thenucleoproteins chiefly by the microspectrographicmethod of Caspersson using ultra-violet lightwith a wavelength of about 2,570 A on un-stained cells, and by this method he has studiedthe effects of various kinds of virus on the con-stituents of the nerve cell. He and Casperssonfound that viruses act as parasites on the nucleo-protein of the cell, and multiply chiefly in thenucleus. Rabies virus, like other relatively largeviruses such as molluscum contagiosum andverruca simplex, produces an excess of deoxyribo-nucleic acid in the nucleus. At the same time rabiesvirus depletes the cytoplasm of the ribonucleic acid,i.e., it produces loss of Nissl granules. Sourander(1953) found that the first effect of rabies virus onnerve cells in the spinal cord of the chick embryowas disappearance of Nissl granules, but later therewas also shrinkage of the cytoplasm. He foundrelatively little change in the nucleus, but Hydenhad found in Purkinje cells in rabies a progressiveincrease of deoxyribonucleic acid in the nucleus.On the other hand, poliomyelitis and louping-ill,which are small viruses, cause an increase of ribo-nucleic acid which may be shown in the early stagesby a swelling of the nucleolus. This seems to applyalso to many human cases of encephalitis in whichswelling of the nucleolus may be an early change.Disappearance of ribonucleic acid from the cyto-plasm also occurs in these forms of encephalitis,leading to the chromatolysis or eosinophilia whichhas already been described.The acidophilic intranuclear inclusions of herpes

simplex and subacute inclusion encephalitis appearto arise independently of both chromatin andnucleolus. They push both of these structures tothe side of the cell, where they may survive un-altered for some time (Fig. 10). Francis andKurtz (1950) by a differential centrifugalizationmethod showed that nuclei containing intra-nuclear inclusions of herpes simplex might con-tain less virus than other constituents of the cell.If, as Hyden has shown, viruses always containnucleoprotein, it seems probable that these inclu-sion bodies do not contain virus, but rather con-sist of waste products formed during the growthof the virus.

It is tempting to correlate the degeneration ofthe white matter seen in these two diseases withthe presence of inclusions in oligodendroglial

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nuclei, since it is probable that the oligodendrogliaplays an important part in preserving the nutritionof myelin. But these are by no means the onlyforms of encephalitis in which the white matter isdamaged. In fact it would appear that the morea virus becomes pantropic, that is, the more ittends to damage tissues other than nerve cells, themore tendency there is for involvement of thewhite matter. In Russian spring-summer or tick-borne encephalitis and in equine encephalomyelitisa varying degree of inflammation and damage tothe white matter is not uncommon, and in casessurviving western equine encephalomyelitis cysticareas have been seen in the cerebral hemispheres(Noran and Baker, 1943, 1945). These softeningsmay of course be due to lesions in the vessel walls,since these are common both in western equineand in Russian tick-borne encephalitis. In milderforms they consist of oedema of the vessel wallsand swelling of endothelial cells, sometimes asso-ciated with thrombosis. When more severe thevessel walls may be invaded by polymorpho-nuclear leucocytes and become necrotic. How-ever, Weil and Breslich (1942) in western equineencephalomyelitis did not find vascular lesions insoftened areas, which they considered were dueto more direct effects of the virus.

Viruses also have special tastes in the nervecells which they attack. This is well known inpoliomyelitis, and is well shown in cases of bulbarpoliomyelitis, in which the sensory nuclei of thecranial nerves may be surrounded by exudate buttheir nerve cells r.emain entirely intact. In facteven the motor nuclei of the cranial nervesusually recover almost completely in such cases,and one rarely sees facial paralysis or atrophy ofthe tongue as a result of poliomyelitis.

In the cases of encephalitis seen by us duringthe last war the cerebellum was never involved,but both in Russian spring-summer and theJapanese B. form the Purkinje cells may beselectively damaged, as shown by the glial shrubformations in the molecular layer to which I havealready referred. In the literature of the earlyyears of the century also a number of cases ofencephalitis with transitory cerebellar symptomswere recorded in Britain, but these now seem tobe rare.

Encephalomyelitis is not always fatal and maycause only a transient illness with headache, neckstiffness, and sometimes coma. In these casesincrease of cells in the cerebrospinal fluid may bethe only definite evidence that the nervous systemis attacked. These cases are usually classified asbenign lymphocytic meningitis, or during an

epidemic of poliomyelitis as " non-paralytic polio."They may be due to a great variety of viruses,among which the Armstrong-Lillie virus of lym-phocytic choriomeningitis is one of the rarercauses. Some appear to be due to psittacosisand some are associated with atypical pneumonia.Hammon (1949) in the U.S.A. found mumps to bethe most common cause. Armstrong (1943), Smadeland Warren (1947) in Washington, and Alm inGothenburg (1951) have found evidence that thevirus of herpes simplex may cause a mild transientform of meningo-encephalitis as well as acute fatalcases. This appears probable enough. Von Magnus(1949) has also brought forward evidence thatviruses of the Coxsackie group may be responsiblefor some such cases and this has been confirmedby Rhodes in Toronto.

Recovery from these forms of encephalitis isusually rapid and complete in older children andadults, and fatal cases are rare, but occasionalcases in young children leave mental disability ofvarying severity as sequelae.The most urgent problem that cases of benign

lymphocytic meningitis present is their differentia-tion from tuberculous meningitis. For this theintravenous bromide test, recently elaborated byHunter, Smith, and Taylor (1954), has, in theirhands, proved of considerable value.A question which is exciting some interest on

the continent of Europe and in the United Statesconcerns the group of viruses to which the generalname encephalomyocarditis or E.M.C. has beengiven. The distribution of these viruses appears to bealmost world-wide. They were first isolated by Sma-del and Warren in the Philippines (1947) and in-dependently by Dick and others on the east coast ofAfrica (Dick, 1949). They have also been found incaptive monkeys in Florida. They appear to havebeen the cause of a mild three-day fever in troopsin Manila, and they produced in laboratoryworkers in Uganda a high fever lasting for fouirdays with complete recovery. Dick and othershave shown that a large proportion of the nativeson the east coast of Africa have antibodies toviruses of this kind. Saphir (1952) collected threefatal cases in which encephalitis was combinedwith acute myocarditis, but did not succeed intransmitting the disease to animals. On thecontinent of Europe also small epidemics in youngchildren have been traced to viruses of the E.M.C.group. Some of these had the symptoms of virusmeningitis. In one fatal case death was due toacute myocarditis (Koch, 1950). Certainly in themonkey E.M.C. virus may cause death in this

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J. G. GREENFIELD

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FIG. 1.-Encephalomyocarditis: lumbar cord of a monkey injectedwith material containing E.M.C. virus. Three anterior horn

cells are seen, one undergoing neuronophagy, a second normal

and the third appearing as a "ghost cell." (Nissl's stain.)

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FIG. 12.-Encephalomyocarditis: heart muscle of another monkeywhich was injected with the same infected material as themonkey from which Fig. 11 was taken, and which died frominterstitial myocarditis. (Haematoxylin and eosin.)

manner or may produce lesions remarkably likethose of poliomyelitis (Figs. 11 and 12).Another disease which is clinically like mild

poliomyelitis has occurred as an epidemic in Ice-land, and a number of similar cases have been seenin the north-eastern states of America, especiallynorthern New York State and the neighbouringparts of Canada (White and Burtch, 1954). Thevirus of this Iceland disease has not yet, so far asI know, been isolated.The continent of Australia has also been visited

by epidemics of encephalitis of recent years, especi-ally during and since the war. In the Murray valleythere were a number of cases of a disease indis-tinguishable from Japanese B. encephalitis. Theavailable evidence favours the idea that the virusmay have been brought to Australia by migratingbirds from neighbouring islands occupied, duringthe war, by Japanese troops, and that it wasspread from birds to other animals and eventuallyto human beings by mosquitoes or other insectvectors. Many of the forms of mosquito whichhave been incriminated for the spread of thedisease in Japan are found also in Australia.It is to be hoped that this disease, which has inthe past produced severe epidemics in Japan withthousands of deaths, has not found a reservoir inthe fauna of Australia.To the morbid anatomist this form of encepha-

litis is specially interesting, as in some of the morechronic cases the deposition of calcium salts in thebrain has been so heavy that it is impossible to cutthe brains with a knife. This tendency to calcifi-cation of brain tissue in encephalitis, which isseen also in western equine encephalomyelitis andin cytomegalic inclusion encephalitis and toxo-plasmosis in infants, provides a nice problemfor the biochemist.

In South Africa also encephalitis seems to havebeen more common of recent years. Geerling(1950) has collected about 100 cases most of whichoccurred in early summer, that is, November andDecember, with a death rate of about 15%. Theyhad a somewhat prolonged course with recovery,when it occurred, in one to three months. Parkin-sonism was a rather frequent late manifestationand other cases were followed by epilepsy, some-times combined with Parkinsonism. These casesgive a further suggestion that the virus of encepha-litis lethargica has not entirely disappeared.

In looking towards the future we may ask our-selves whether we are doing as much as we couldor should to study the aetiology of virus infectionsof the nervous system. Virus laboratories are fewand most are understaffed; virologists are not

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therefore likely to be interested in every case ofthree- or four-day fever in which the cerebro-spinal fluid shows a high cell count. We maytherefore reserve virus studies for fatal cases. Onthe other hand, the development of egg-culture andtissue-culture techniques and of complement devia-tion reactions with viral antigens has brought viro-logy much nearer to the clinical pathologist. Viro-logy is beginning to be considered as a necessarypart of laboratory work, not only in public healthlaboratories but in some of the larger hospitals,especially large children's hospitals. To virologistsworking in such positions problems are presentedin a more intimate, if not so urgent, fashion;they are able to study cases which recover and soto learn something of the commoner and lessvirulent viruses.For the clinical pathologist who is not a viro-

logist, it is also scientifically more satisfactory towork alongside a virologist learning his languageand getting to understand his technique, than tohave him immured in a separate institution. Closeassociation of virologists with clinical pathologistswill thus be of value to both, not least in the posingand solution of new problems.

REFERENCESAchucarro, N. (1910). Nissi Aizheimer Arbeiten, 3, 143.Alm, L. Afzelius (1951). Acta med. scand., 140, Suppl. 263.Armstrong, C. (1943). Publ. Hlth Rep. (Wash.), 58, 16.Barr, M. L., and Bertram, E. G. (1949). Nature (Lond.), 163, 676.Beheim-Schwarzbach, D. (1952). J. nerv. ment. Dis., 116, 619.Bogaert, L. van (1945). J. Neurol. Neurosurg. Psychiat., 8, 101.BraunmfLhl, A. von (1949). Arch. Psychiat. Nervenkr., 181, 543.

Collins, J., and Armour, R. G. (1912). Rev. Neurol. Psychiat., 10,361.

Corsellis, J. A. N. (1951). J. ment. sci., 97, 570.Crawford, T. (1954). Journal of Clinical Pathology, 7, 1.Dawson, J. R. (1933). Amer. J. Path., 9, 7.- (1934). Arch. Neurol. Psychiat. (Chicago), 31, 685.Dick, G. W. A. (1949). J. Immunol., 62, 375.Divry, P. (1934). J. belge Neurol. Psychiat., 34, 197.Economo, C. von (1931). Encephalitis Lethargica. Its Sequelae and

Treatment, trans. K. 0. Newman. Oxford University Press,London.

Einarson, L. (1949). Acta orthop. scand., 19, 27.Foley, J., and Williams, D. (1953). Quart. J. Med., 22, 157.Francis, T., and Kurtz, H. B. (1950). Yale J. Biol. Med., 22, 579.Geerling, R. (1950). S. Afr. med. J., 24, 339.Glanznann, E. (1927). Schweiz. med. Wschr., 8, 145.Greenfield, J. G., and Bosanquet, F. D. (1953). J. Neurol. Neurosurg.

Psychiat., 16, 213.- and Matthews, W. B. (1954). Ibid., 17, 50.Hallervorden, J. (1933). Klin. Wschr., 12, 692.- (1935). Dtsch. Z. Nervenheilk., 136, 68.Hammon, W. McD. (1949). IVe Congris Neurologique International,

Paris, 1949. Vol. 1. Rapports, p. 94.Haymaker, W. (1949). J. Neuropath., 8, 132.Hunter, G., Smith, H. V., and Taylor, L. M. (1954). Biochem. J.,

56, 588.Hyd6n, H. (1947). Cold Spr. Harb. Symp. quant. Biol., 12, 104.Koch, F. (1950). Z. Kinderheilk, 68, 328.Levi, G. (1897). Riv. Patol. nerv. ment., 2, 193, 244.McIntosh, J., Greenfield, J. G., and Selbie, F. R. (1952). In History

of the Second World War, ed. A. S. MacNalty. Medicine andPathology, p. 533. H.M.S.O., London.

Magnus, H. von (1949). Ugeskr. Lag., 111. 1451.Malamud, N., Haymaker, W., and Pinkerton, H. (1950). Amer. J.

Path., 26, 133.Mestrezat, W. (1912). Le liquide cephalo-rachidien. Maloine, Paris.Noran, H. H., and Baker, A. B. (1943). Arch. Neurol. Psychiat.,

(Chicago), 49, 398.- (1945). J. Neuropath., 4, 269.

Russell, D. S. (1955). Brain, 78, 369.Saphir. 0. (1952). Circulation, 6, 843.Smadel, J. E., and Warren, J. (1947). J. clin. Invest., 26, 119'i.Sourander, P. (1953). Acta path. microbiol. scand., Suppl. 95.Weil, A., and Breslich, P. J. (1942). J. Neuropath., 1, 49.White, D. N., and Burtch, R. B. (1954). Neurology, 4, 506.Wolf, A., Kabat, E. A., and Bezer, A. E. (1947). J.'Neuropath., 6,333.

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