Postgrad. med. J. (June 1969) 45, 386-391.

Herpes encephalitis

II. Pathology of herpes encephalitis

J. A. DUDGEONThe Hospital for Sick Children, Great Ormond Street, London, W.C.1

SummaryHerpes simplex infection of the CNS may occur aspart of a generalized infection with visceral involve-ment or with the CNS alone involved. Asepticmeningitis due to herpes simplex is rare, but necro-tizing encephalitis is being recognized with increasingfrequency.The distribution of lesions within the CNS and

the mode of spread to and within the CNS are dis-cussed.

Serological tests indicate that some cases are dueto primary infection and others due to re-activation.The importance of early diagnosis by electron and

fluorescence microscopy and virus culture arediscussed.The natural history and pathogenesis of herpes

simplex and B virus are discussed.

IntroductionThe herpes viruses comprise a composite group of

infectious agents which are widely distributed innature amongst different animal species. Some of themore important members of the group are shown inTable 1.The herpes viruses are all DNA viruses and those

that have been studied by electron-microscopy havea cubic symmetry with 162 capsomeres (Andrewes,1964). their size is about 100-150 mtL. There areserological cross-reactions between several membersof the group but individual strains are closely relatedantigenically. Under natural conditions these virusesexhibit a marked species specificity, but in the

laboratory they can be made to infect a wide rangeof experimental animals and cell cultures. Severalherpes viruses may produce neurological disease.This includes disease contracted as part of a naturalinfection, as for example in herpes simplex, varicella-zoster and pseudo-rabies, or from disease followingan accidental infection, as for example B virusinfections in man.

In human medicine, the two most importantviruses which are capable of causing severe CNSdisease in man are herpes simplex and B virus, itssimian counterpart.

Herpes simplex encephalomyelitis (Herpesvirushominis)Natural history and epidemiology

This virus is one of the most common of all viralagents infecting the human race. This is revealedfrom serological studies which show that herpesantibody is widely distributed throughout thepopulations of the world. Herpetic infections are oftwo main types, primary and recurrent. Both types ofinfection are distinct and both may be important inthe pathogenesis of infections of the central nervoussystem.

(a) Primary infections occur in individuals withoutprevious immunity and as a result specific neutraliz-ing antibody develops. Primary infection, which isfrequently inapparent, commonly occurs in child-hood after maternal antibody has disappeared, butit may be, and frequently is, delayed until adult lifeowing to the changing environmental conditions in

TABLE 1. Herpes group of viruses

Proper name Synonym Common name Natural host

Herpesvirus hominis Herpes febrilis, labialis Herpes simplex ManHerpesvirus varicellae Varicella-zoster Chickenpox and shingles ManHerpesvirus simiae B virus - MonkeysHerpesvirus suis Aujesky's disease Pseudo-rabies, mad itch, Cattle, sheep, pigs

infectious bulbar paralysisHerpesvirus ciniculi Virus III - Rabbits

copyright. on M

arch 28, 2021 by guest. Protected by

http://pmj.bm

j.com/

Postgrad M

ed J: first published as 10.1136/pgmj.45.524.386 on 1 June 1969. D

ownloaded from

Herpes encephalitis. II

many countries. Following primary infection thevirus is not completely eliminated but a state of latentinfection ensues.

(b) Recurrent infections occur in individuals whohave previously been infected and who possesscirculating antibody. They are seen more commonlyin adults and result from reactivation of latent virus.It is unlikely that re-infection is ofmuch consequencein recurrent herpes. Lesions are commonly found onthe skin or muco-cutaneous borders on the face,particularly in the area supplied by the second andthird divisions of the fifth nerve, on the skin andmucous surfaces around the external genitalia andon other areas of skin at the site of primary infec-tion. Individuals subject to recurrent herpes oftendevelop herpes at precisely the same site on the skin.This is also commonly seen in recurrent cornealherpes. The factors responsible for the recurrence ofherpetic eruptions are not known. In many indivi-duals there appears to be some trigger mechanismsuch as fever, a cold or some other respiratory infec-tion, sunlight or menstruation, but in many indivi-duals no such inciting cause can be elicited. At thetime of a recurrence, infectious virus can be recoveredfrom the cutaneous lesions, but in between attacksvirus apparently disappears from these areas andpresumably remains in a latent and non-infectiousform. The site of this is not known; it may be inectodermal cells in the skin or in the mouth or innerve endings. The relationship between recurrentherpes and trigeminal neuralgia is of special interestin this connection. Patients with trigeminal neuralgiasometimes suffer from recurrent herpes, and morefrequently crops of vesicles may develop 2-3 daysfollowing operation for relief of pain along thecourse of the divided nerve. This could be explainedon the basis that virus was latent in the Gasserianganglion or nerve and was re-activated by trauma.

Herpes simplex is transmitted from one person toanother by direct contact with the skin or mucoussurfaces. Sources of infection are secretions of themouth, eye and genitalia from individuals withactive herpes, particularly recurrent labial herpes,and from asymptomatic carriers. Approximately 5 %of apparently healthy individuals carry herpesvirusin their saliva. Herpes antibody is widespread in mostadult populations and as a result most women haveacquired infection by the age of child-bearing.Antibody of the IgG type passes across the placentafrom the mother and confers passive protection onthe child in the early weeks of life. After this hasdisappeared by about 6-9 months of age the childbecomes fully susceptible, but primary infectionseldom occurs until about 18 months to 2 years ofage except for those at special risk, for examplepremature infants and infants with eczema. By theage of 5 years 10% of children are found to possess

antibody and by 15 years 75 '. Infection is acquiredearlier in the lower socio-economic groups orwherever overcrowding occurs. Once acquiredantibody is maintained throughout life. Littledifference can be detected in antibody levels ofpatients who have experienced clinical as opposed tosubclinical infections or in patients who suffer fromrecurrent attacks of herpes.

Pathology and pathogenesisThe characteristic lesion of herpes simplex

whether it is in the skin, liver, adrenals or brain isone of cell necrosis associated with intranuclearchanges consisting of margination of the nuclearchromatin and development of intranuclear inclu-sions. Cell necrosis may be focal or massive. In theskin, cell necrosis leads to vesicle formation; in thebrain to destruction of nerve cells and supportingstructures.

Herpesvirus probably enters the body throughsmall abrasions in the skin or mucosae, or by directinoculation caused by trauma. After initial localmultiplication, virus passes to the regional groupnodes and may then pass to the blood stream fromwhich it may spread to other organs. Virus multi-plication may be halted at any stage by the body'sdefence mechanisms. In recurrent herpes, infection ismore restricted; often the same area of skin ormucosa is repeatedly involved. It is probable thatvirus passes from one infected cell to another, beingrestricted from more general spread by the presenceof circulating antibody. Under certain conditionsvirus may spread to cause more extensive disease.

CNS infectionsInvolvement of the CNS may occur as a result of

either primary or recurrent infection, but a precisedelineation between the two forms is not possiblewithout appropriate laboratory tests. In cases whereencephalitis is associated with cutaneous lesions anda disseminated visceral infection, it can be presumedthat these have resulted from primary infection, butin older patients and children with CNS symptomsonly it is difficult to determine whether infection isprimary or results from reactivation. The followingtypes of herpetic infection of the CNS have beenrecognized:

(i) Aseptic meningitis(ii) Acute encephalomyelitis with or without

visceral necrosis(iii) Acute necrotizing encephalomyelitis.

Aseptic meningitisReports in the 1940s suggested that herpetic

meningitis was by no means uncommon. This viewis not held today. Some appeared to be recurrent

387

copyright. on M

arch 28, 2021 by guest. Protected by

http://pmj.bm

j.com/

Postgrad M

ed J: first published as 10.1136/pgmj.45.524.386 on 1 June 1969. D

ownloaded from

J. A. Dudgeon

and some followed lumbar puncture (Janbon,Chaptal & Labraque-Bordenave, 1942). As herpes-virus is such a common infectious agent and can berecovered quite readily from the saliva of apparentlyhealthy individuals, great care must be taken in theinterpretation of reports of isolation of the virusfrom spinal fluid particularly when the CSF showsno abnormality. Armstrong (1943) reported theisolation of herpes simplex virus from the spinalfluid of a case of aseptic meningitis and suggestedthat herpes was one of the causal agents of theaseptic meningitis syndrome. Laboratory studiesreported by Macrae (1961) in this country indicatethat herpes is a rare cause of aseptic meningitis. In arecent survey of fifty-two cases of herpetic involve-ment of the CNS Leider and his colleagues (1965)encountered three cases of meningitis, one in a girl of15 and two in adults. A recent review by Olson andhis colleagues (1967) records ten cases of asepticmeningitis in a retrospective study of forty-ninecases of CNS disease associated with herpes simplexinfection. Clinically these ten cases were indistin-guishable from aseptic meningitis due to otherviruses.

Acute encephalitis with or without visceral necrosisThis severe type of fulminating infection is in the

main confined to infants under 1 year of age and is ofspecial consequence in premature infants in thenewborn period. Other predisposing causes areinfantile eczema and severe protein malnutrition.Hass (1935) first described a case of hepato-adrenalnecrosis in a premature infant and because of theintranuclear inclusions this was ascribed to herpessimplex. In 1941, Smith, Lennette & Reames (1941)reported the isolation of herpesvirus from the brainof a 4-week-old infant who died of an acute encepha-litis. Zuelzer & Stulberg (1952) reported five cases offulminating herpes simplex infection in the newborn.All were premature by weight and had extensivevisceral necrosis. Herpesvirus was recovered fromthe brain of three of these patients, but encephaliticsymptoms were not a marked feature in these ful-minating cases. Haymaker and his colleagues (1958)summarized the findings of nine cases of acuteencephalitis in infants under 1 year; in two therewere accompanying visceral lesions and in severalthe lesions were confined to the central nervoussystem.

Acute necrotizing encephalornyelitisThe first report of this type of case, presenting

usually in adults, but occasionally in children andadolescents, without clinical manifestation of in-volvement of other systems, was made by VanBogaert, Radermecker & Devos (1955). Later furthercases were reported by Haymaker and colleagues

(1958) and in the past 5 years further reports haveappeared (Leider et al., 1965; Adams & Jennett,1967; Harland, Adams & McSeveny, 1967). Alto-gether over 100 cases have now been recorded.

Thte pathology of herpetic infection of the CNSThe pathological changes in cases of aseptic

meningitis are not known as few cases, if any, havecome to autopsy. The morbid-anatomical changes incases of acute encephalitis in both infants and adultsare similar but differ in the severity of the necrosis.In the infantile group there is usually such grosssoftening that the brain is semi-liquid at autopsy.Haemorrhages are found throughout the brain beingmarked in cortical areas, basal ganglia and brain-stem. In adults there is usually softening which isgenerally asymmetrical, with numerous smallhaemorrhages on the surface of softened tissue.Histologically the characteristic lesion is one ofacute haemorrhagic necrotizing encephalitis. Thelesions are widespread, bilateral and asymmetrical.Areas most commonly affected are the temporal andorbital gyri, the insulae and the cingulate gyri. Thenecrotic areas in the cortical grey matter tend to bewell demarcated with some spread into the adjacentwhite matter. Meningeal cellular exudate and peri-vascular cuffing with neuronophagia is found innecrotic areas. Intranuclear inclusions are found inneurones and microglia but their presence is extre-mely variable.The appearances of a fairly typical case of herpes

necrotizing encephalitis in a 13-year-old girl fromwhich the virus was recovered at autopsy (Blackwoodet al., 1966) is shown in Fig. 1.

FIG. 1. Hemi-section of brain of a 13-year-old girlshowing distribution of lesions in cases of herpes necro-tizing encephalitis diagnosed virologically. (Reprintedfrom the British Medical Journal, 1966, i, 1519, bypermission of the Authors and Editor.)

388

copyright. on M

arch 28, 2021 by guest. Protected by

http://pmj.bm

j.com/

Postgrad M

ed J: first published as 10.1136/pgmj.45.524.386 on 1 June 1969. D

ownloaded from

Herpes encephalitis. II

Infection may be acquired at birth from virus inthe motlher's genital tract, or after birth from themother or attendant with active recurrent herpes.Such cases may be found to have vesicular lesionson the skin or a conjunctivitis pointing to skin or eyeas the portal of entry (Zuelzer & Stulberg, 1952).Virus probably reaches the CNS via the blood-stream. In a few cases of the fulminating dissemin-ated type of herpes simplex in premature infants ahistory has been obtained of recurrent herpes in themother (MacCallum, 1959). In such cases onewould expect the mother to have maternal antibodyand that this would cross the placenta and be presentin the child's serum at birth. This antibody would bemainly IgG or 7S globulin; it is possible in order tolimit infection acquired through a mucous surface,particularly if it is overwhelming, that specific anti-body would be required in the secretory IgA fraction.IgA is a macroglobulin and does not normallycross the placenta.

It would appear from serological results that someof the cases of acute encephalitis in older childrenand adults have resulted from primary infection. Ofeleven cases in adults five showed a marked increasein herpes CF antibody from undetectable levelswithin the first 7-10 days of the illness to titresusually encountered in primary herpetic infections.Three other cases without a history of recurrentherpes showed a rise in antibody of four-fold orgreater, and three patients with a history of havingrecurrent herpes but not associated with the encepha-litic illness also showed a rise in antibody of at leastfour-fold. It would seem, therefore, that the CNSmay be involved as a result of either primary orrecurrent infections. The routes by which virusspreads to the central nervous system are not knownbut presumably it can spread by haematogenousroutes or nerve pathways such as along the olfactorynerves, or by both routes. Blood stream spreadwould appear unlikely in the presence of antibodyin which case one must postulate spread via nervepathways or by some other route. Whatever themode of spread may be one cannot escape the con-clusion that the extraordinary localization of lesionsin herpes necrotizing encephalitis is to some extentthe result of a predilection of herpesvirus for cells inthe areas of the brain involved.

Diagnosis of herpetic encephalomyelitisAseptic meningitis caused by herpes simplex can

only be distinguished from other viral causes such asmumps and Coxsackie viruses by appropriatevirological procedures employing virus culture andantibody determinations. The recent development ofanti-viral drugs, such as idoxuridine against herpessimplex and other DNA viruses makes the earlydiagnosis of herpetic necrotizing encephalitis of

special importance, as to be effective the drug must beused before neuronal necrosis is too far advanced.The problem of differential diagnosis of herpeticencephalitis from other space-occupying lesions hasalready been discussed in Part I (Campbell, 1969).Laboratory tests are now available which can assistin the early diagnosis of herpes encephalitis. Theseare aimed at rapid identification of viral antigen andvirus isolation from cortical biopsies.

Examination ofspinal fluid. In most cases reportedthe spinal fluid has been abnormal but it is importantto remember that it may be normal. Pleocytosis of50-300 cells/mm3 with predominantly mononuclearcells is not uncommon. The sugar level is usuallynormal and the protein may be raised to 70-150mg/100 ml. These findings and absence of micro-organisms are useful in distinguishing viral frombacterial infection of the CNS. If the sugar level ofthe CSF is low or marginal a further specimenshould be examined together with a blood sugarbecause of the importance of tuberculous meningitisin the differential diagnosis. The sugar level in herpesencephalitis is never consistently low and does notcontinue to fall as in untreated cases of tuberculousmeningitis.

Demonstrating viral antigen. The presence ofherpesvirus particles or antigen can be demonstratedby electron-microscopy and by fluorescence micro-scopy on cortical biopsy specimens. Both are of thegreatest value and, provided the virologist is warnedbefore the operation takes place so that the appro-priate material can be collected, a precise diagnosismay be possible within a few hours of collecting thespecimen. Harland et al. (1967) have reported sixfatal cases in which virus particles were demonstratedin brain material and one further case treated withIDU.

Virus culture. Spinal fluid or biopsy material orboth should be inoculated into susceptible cellcultures, for example human amnion, rabbit kidneyor human fibroblasts. Specific cytopathic changeshave been reported in a number of cases within 24hr of inoculation (MacCallum, Potter & Edwards,1964). The early appearance of lesions from thesecases is probably a reflection of the amount of virusantigen present. This is borne out by the finding ofvirus particles in the biopsies because as a generalrule the ease with which virus particles are found byelectron-microscopy is related to the numberpresent.

Serological tests for herpes antibody. These shouldbe carried out whenever possible in order to obtain

389

copyright. on M

arch 28, 2021 by guest. Protected by

http://pmj.bm

j.com/

Postgrad M

ed J: first published as 10.1136/pgmj.45.524.386 on 1 June 1969. D

ownloaded from

390 J. A. Dudgeon

more information about the pathogenesis of thistype of infection. They are of limited diagnosticvalue. Sera should be collected as early as possibleafter the onset of neurological disease and again10-14 days later and tested both by neutralizationand complement-fixation because of some cross-antigenic relationship between the viruses of herpessimplex and varicella-zoster.

Herpesvirus simiae (B virus encephalomyelitis)Herpesvirus simiae (B virus) is the simian variant

of herpes simplex. The two viruses are closely relatedantigenically, but differ markedly in virulence.

Natural historyThe natural history is very similar to that of herpes

in man. Monkeys provide the reservoir. Primaryinfections occur mainly in young monkeys and areusually sub-clinical. Ten to 15% of newly-caughtmonkeys may have antibodies to B virus and thepercentage may rise to 60% when animals are housedin communal cages (Hull & Nash, 1960). Clinicaldisease usually presents as a stomatitis with vesiclesand ulcers on the tongue, lips and gum margins.The similarity of this condition to herpetic gingivo-stomatitis is striking.

Pathogenesis and epidemiologyKeeble, Christofinis & Wood (1958) found that

2-3 % of monkeys had mouth lesions when examinedon arrival in this country. The incidence of antibodyto B virus was found to be 17% in normal monkeysused for poliovaccine production. The incidence ishigher in rhesus monkeys but any species of monkeyshould be regarded as a potential carrier of the virus.The virus is present in large amounts in monkeysaliva. In infected monkeys focal lesions withperivascular cuffing and glial infiltration in the rootsof the fifth and seventh nerves can be found and alsoin the tractus solitarius.

Human infectionsIn the past 30 years fifteen cases of B virus infec-

tion have occurred and thirteen have been fatal(Perkins & Hartley, 1966). The majority haveoccurred in the past 10 years since the large-scaleproduction of polio vaccine which entails the use oflarge numbers of experimental animals. Nearly allsuch infections have been associated with trauma,either a bite from a monkey or direct inoculation ofinfected material, saliva or tissue culture fluid intothe skin. Infection can also be acquired via therespiratory tract. A local vesicular lesion may developat the site of entry of the virus. In contrast to herpessimplex virus introduced by trauma, B virus spreadsrapidly v[a lymphatics to regional lymph nodes and

then by the bloodstream to the CNS and otherorgans. In the CNS lesions may be found pre-dominantly in the cord with intense necrosis ofnerve cells. Extensive lesions may also be found ashigh as the medulla and brain-stem. Intranuclearinclusion may be difficult to find.

Prevention and treatmentB virus is a lethal disease in man. There is no

specific treatment and there are limitations to the useof specific prophylactic procedures. The mainemphasis should be placed on preventive measuresand ensure that animal handlers and all scientificstaff are aware of the risk and take precautions tosee that the risk of infection is minimized. Instruc-tions regarding this have been prepared by Perkinset al. (1966). If these are adhered to the risk of fur-ther cases should be materially reduced. In the eventof a monkey bite immediate steps should be taken totreat the wound locally. The monkey should becarefully examined by trained staff for evidence ofB virus infection.

ReferencesADAMS, J.H. & JENNETT, W.B. (1967) Acute necrotizing

encephalitis: a problem in diagnosis. J. Neurol. Neurosurg.Psychiat. 30, 248.

ANDREWES, C.H. (1964) Viruses of Vertebrates, Bailliere,Tindall & Cassell, London.

ARMSTRONG, C. (1943) Herpes simplex virus recovered fromthe spinal fluid of a suspected case of lymphocytic chorio-meningitis. Publ. Hlth Rep. (Wash.), 58, 16.

BLACKWOOD, W., DUDGEON, J.A., NEWNS, G.H. & PHILLIPS,B.M. (1966) Case of encephalitis due to herpes simplex.Brit. med. J. 1, 1519.

CAMPBELL, A.M.G. (1969) Herpes encephalitis. I. The clinicalpicture. Postgrad. med. J. 45, 382.

HARLAND, W.A., ADAMS, J.H. & MCSEVENEY, D. (1967)Herpes-simplex particles in acute necrotizing encephalitis.Lancet, ii, 581.

HASS, G.M. (1935) Hepatoadrenal necrosis with intranuclearinclusion bodies. Amer. J. Path. 11, 127.

HAYMAKER, W., SMITH, M.G., VAN BOGAERT, L. & DECHENAR, C. (1958) Symposium on Viral Encephalitis (Ed. byW. S. Fields and R. J. Blattner), p. 95. Thomas, Spring-field, Illinois.

HULL, R.N. & NASH, J.C. (1960) Immunization againstB virus infection. I. Preparation of an experimentalvaccine. Amer. J. Hyg. 71, 15.

JANBON, M., CHAPTAL, J. & LABRAQUE-BORDENAVE, M.(1942) Le probleme de la meningite herpetique: contribu-tion a son etude clinique et experimentale. Presse Med.50, 145.

KEEBLE, S.A., CHRISTOFINIS, G.J. & WOOD, W. (1958)Natural virus-B infection in rhesus monkeys. J. Path.Bact. 76, 189.

LEIDER, W., MAGOFFIN, R.L., LENNETTE, E.H. & LEONARDS,L.N.R. (1965) Herpes-simplex-virus encephalitis: itspossible association with reactivated latent infection. NewEngl. J. Med. 273, 341.

MACCALLUM, F.O. (1959) Generalized herpes simplex in theneonatal period. Acta. virol. 3, 17.

copyright. on M

arch 28, 2021 by guest. Protected by

http://pmj.bm

j.com/

Postgrad M

ed J: first published as 10.1136/pgmj.45.524.386 on 1 June 1969. D

ownloaded from

Herpes encephalitis. II 391

MACCALLUM, F.O., POTTER, J.M. & EDWARDS, D.H. (1964)Early diagnosis of herpes-simplex encephalitis by brainbiopsy. Lancet, ii, 332.

MACRAE, A.D. (1961) Viruses as a cause of meningo-encepha-litis. Virus Meningo-Encephalomyelitis (Ed. by G. E. W.Wolstenholme and M. P. Cameron) Ciba FoundationStudy Group No. 7, p. 6. Churchill, London.

OLSON, C., BUESCHER, E.L., ARTENSTEIN, M.S. & PARKMAN,P.D. (1967) Herpesvirus infections of the human centralnervous system. New Engl. J. Med. 277, 1271.

PERKINS, F.T. & HARTLEY, E.G. (1966) Precautions againstB virus infection. Brit. med. J. 1, 899.

SMITH, M.G., LENNETTE, E.H. & REAMES, H.R. (1941)Isolation of the virus of herpes simplex and the demonstra-tion of intranuclear inclusions in a case of acute encepha-litis. Amer. J. Path. 17, 55.

VAN BOGAERT, L., RADERMECKER, J. & DEVOS, J. (1955) Surune observation mortelle d'encephalite aigue necrosante(sa situation vis-a-vis du groupe des encephalites transmisespar arthropodes et 1'encephalite herpetique). Rev. neurol.92, 329.

ZUELZER, W.W. & STULBERG, C.S. (1952) Herpes simplexvirus as the cause of fulminating visceral disease andhepatitis in infancy: report of eight cases and isolation ofthe virus in one case. Amer. J. Dis. Child. 83, 421.

copyright. on M

arch 28, 2021 by guest. Protected by

http://pmj.bm

j.com/

Postgrad M

ed J: first published as 10.1136/pgmj.45.524.386 on 1 June 1969. D

ownloaded from