Jpn. J. Infect. Dis., 55, 6‑13, 2002

Review

Herpesvirus Infections of the Central Nervous System
Hiroshi Shqji*, Kyoko Wakasugi, Yumiko Miura, Tbshihiro lmaizumi
and Yukumasa Kazuyamal

First Department (Neurology) of Internal Medicine, Kurume University School of Medicine,
AsahimachL'67, Kurume 830‑0011 and/Kitasat0‑0tsuka Virus Laboratory, Tokyo 10818642, Japan(Received October 1 , 2001. Accepted Febnlary 4, 2002)

CONTENTS:
1. Introduction

2. Herpes simplex vims type 1 (HSV‑I) encephalitis
2‑1. 1mcidence and pathogenesis
212. Pathology

2‑3. Clinical features

2‑4. Diagnosis
215. Differential diagnosis
2‑6. Prognosis

3. HSV‑2 and other herpes group viruses infections of the central nervous system (CNS)
3‑1. HSV‑2 acute encephalitis
3‑2. HSV myelitis
3‑3. Varicella‑zoster virus infections of the CNS

3‑4. Epstein‑Barr virus infections of the CNS
3‑5. Cytomegalovirus infections of the CNS
3‑6. Human herpesviruses 6, 7 infections of the CNS
4. Conclusion

SUMMARY: In recent years, advances in the diagnosis and treatment of he叩eS Simplex encephalitis (HSE)have been achieved due to the prevalence of antiviral dmgs and the introduction orthe polymerase chain reaction(PCR) to test the cerebrospinalfluid. The several clinical forms of herpes simplex viruStype I (HSV‑1) infec‑
tions of the central nervous system (CNS), including acute disseminated encephalomyelitis and brainstem
encephalitis, have been clarified. However, fatal, prolonged, or relapsed cases are still observed, and early detection
and approprlate treatment is necessary to lead to a good prognosis f♭r these intractable HSE cases. ln adult HSV‑

2 infections, menlngltlS and myelitis associated with genital herpes are common. In the past, HSV12 myelitis has

been reported as a formof fatal necrotizlng myelopathy; however, uslng PCR and magnetic resonance imaglng
studies, mild survivlng Cases are increaslngly likely to be identified. Meanwhile, various CNS syndromes resulting
from the herpes group viruses, including varicella‑zoster virus and Epstein‑Barr virus have also been reported.
These he叩eSViruses have several characteristics in common, e･g･, they exist in the latent state and they occur inboth mucocutaneous and CNS infections. Adult HSVl 1 and ‑2 infections of the CNS are discussed together withother herpes group virus infections of the CNS.

(3‑9)A In contrast, central nervous syste.ll (CNS) infections

1. Introduction

resulting from other herpes group viruses Such as varicella‑

Herpes simplex encephalitis (HSE) is the甲oSt importantzPsterviruS (VZV), Epstein‑Barr virus (EBV), cytomegalo‑cause ofsporadicヲnCePhalitis in Japan･ Two antlgenictypes of

vlruS (CMV), and human herpesvlruSeS 6, 7 (HHV‑6, ‑7),

he叩eS Simplex vlruS (HSV) are distinguished by neutraliz‑

have tended to increase in both healthy population and ining testing. HSV‑1 (oral type) usually causes adult acuteencephalitis and brainstem encephalitis, whereas HSV‑2

immunocompromised patients such as those with acquired2)･ For more than 10 years, anti‑herpesvlrPS drugs have been

immunodeficiency syndrome (AIDS) (10‑1 7). 1n this paper,
we discuss adult HSV‑I encephalitis and HSV‑2 infectionsof the CNS along with other CNS infections resulting fromused to treat these diseases, and diagnostlC tools such as theherpes group viruses.

(genital type) produces meningitis or甲yelitis (Table 1) (I,enzyme‑linked immunosorbent assay (ELISA, or EIA) andthe polymer?se chain reaction (PCR) have been widely ap‑

2. HSV‑1 encephalitis

plied fわr clinlCal use. HSE has come to be widely recognized

as diagnosable and treatable at an early stage of the disease

2‑1･ Incidence and pathogencsis

HSE, which is prlmarily caused by HSVll, is estimated to*Corresponding author: Tel: +81‑942135‑33 1 I, Fax: +81‑942‑31‑

occur in 1 in 5 × 105 people per year in NorthAmericans

7703, E‑mail: hshqji@med.kunlme‑u.aC.jp(18). A nationwide suⅣey in Japan (19) showed an incidence

6Table 1. Herpesvirus group and CNS infections
He叩eSViridae

CNS

infections

herpessimplexvimstype 1 HSV‑1
type2

HSV‑2

varicella‑zoster viru s VZV

Epstein‑Ba汀Vims

EBV

cytomegalovinlS CMV

Other

importantdiseases

acute encephalitis

mucocutaneous infection s

brainstem encepalitis

keratoconJunCtiviti s

myelitisgenital h印es

menlngltis

disseminated infection of baby

encephalopathy, cerebellar ataxia

varicellamenlngltlS

he叩eS ZOSter, Hunt syndrome

encephalitis, cerebellar ataxia

infectious mononucleosis

chronic CNS infections

chronic active EBV infection

congenital CID

opportunistic infections

ventriculoencephalitis
human he叩eSVirus 6, 7

HHV‑6, ‑7

exanthema subitum

encephalopathy

CNS, central neⅣous system; CID, cytomegalic inclusion body disease･and Dinn (27) has reported HSV particles in the necroticof3･5 cases diagnosed per year among 106 people, while ourdata on the Kyushu and Okinawa reglOnS Or Japan showed

olfactory bulb in an autopsy case ofHSE. Presumably, thean incidence of0.31 in 5 X 105 (20). In our study, the number

vims can reach the brain through branches or the trlgeminalof cases diagnosed within 3 years, 27, was low; this low rate

neⅣe to the basal menlngeS, resulting in localization of theis probably due to the fact that we limited this survey toencephalitis to the temporal and orbital frontal lobes･

hospital, and because we did not include the intemal medicine

2‑3. Clinical features
The most common symptoms and signs ofHSE are fever

and psychiatry departments. Our 27 patients ranged in age

and signs ormenlngeal i汀itation such as headache, alteredpatients in the neurology and pediatric units of the partlCIPatingfrom one year old to 70 years old, with peaks seen in the 20s

consciousness, and seizures. Nuchal rigidity or other slgnS Of

and 50S. The incidence of infection among patients in theirmenlngeal irritation are often found. Mental deficits include

50s in our population group was slightly higher than in those

confusion and personalitychanges, varying fronナWithdrawal

in their 20S. As compared with the results ofa suⅣey ofHSV

to agltation with hallucinations. HelPetic skin les10nS are Seen

encephalitis conducted in Japan in 1982, the peak incidence

in only a few cases.

Cerebrospinal flujd (CSF) pressure may be moderately orof HSV infections of the CNS appears to have shifted frompeople in their 20s to those in their 50S.

greatly lnCreaSed･ The pleocytosis in the CSF varies from less

HSE can occur at any age, but is commonly found in thoseover age 20. In 53 or76 patients with HSE, Nahmias et al.

than 10 to 1 ,000 cells/mm3; lymphocytes may be predominant.

(2 1 ) identified seropositivityby a neutralizing test or immun0‑(EEC) is usually abnormal with dif乱ISe Slowing or fわcal

m10reSCent indirect lgG assay at onset. Mizutani et al. (22)reported a predominant lgG response at 70% in the adult HSEchanges over temporal areas; periodic lateralized epileptifbm

patients. These findings suggest that HSE most often occurs

computed tomography (CT) and magnetic resonance ima写ing

as a result orthe endogenous reactjvation of a vims, rather(MRI) demonstrate approximately 70 ‑ 80% abnormal leslOnS

than from prlmary infection. During the prlmary infection,
the vims becomes latent in the trlgeminal ganglia. Years later,

more sensitive.

Red blood cells arefrequently seen. The electroencephalogram

discharges agalnSt a Slow‑wave background may be seen. Brainin the frontal and temporal lobes; FLAIR or di仇ISion MRl ispatients and different strains in three, suggestlng an etiology

HSV brainstem encephalitis t28), caused by HSV‑1, ischaracterized by brainstem bulbar symptoms and abnomal
lesions in the brainstem visualized by MRl. HSV‑ related acutedisseminated encephalomyelitis (ADEM) can be diagnosed
by CSF PCR, by the presence ofmultifbcal neurologlCal
symptoms, and by multiple brain lesions by means ofMRI

of endogenous reactivation, with a few cases of reinfection.

(20).

nonspecific stimuli can cause a reaction, which is usually

manifested as herp.es labialis･ Whitely et al･ (23) analyzed
both HSV strains using endonucleous restriction enzyme fromherpes labialis and brain materials in eight patientswith HSV
encephalitis; they reported finding the same strain in five

214･ Diagnosis
HSE is diagnosed by clinical symptoms, and also by CSF,
EEC, CT, MRI, and virologlC tests Such as PCR and ELISA

2‑2. Pathology
The fiontal and temporal lesions tend to be necrotic, inflam‑

matolY, Or hemorrhagic. Eosinophilic intranuclear inclusion
bodies are present in the neurons and glial cells. Such inclusions(318) (Table 2, Fig･l)･ Rapid diagnosis is es.sential for early

containlng Viral antlgen and herpesvirus pallicles have beentreatment. The optlmal time to begin adminlStration of anti‑

recognized on immunohistochemisby and electronmicroscopj cherpesvirus drugs remains a controversial issue. Generally,

examination, respectively. Nicoll et al. (24) have reported

anti‑herpesvirus drugs are started when HSE js suspected

pathologlCal changes largely confined to the temporal andbased on CSF findings (increqsed cell count, elevated protein,
and normal sugar concentratlOn), Or When the blood or CSF

frontal lobes in long‑term survivors of HSV‑I encephalitis, and
HSV‑DNA persistlng Over Several years in both the cerebmm

samples are sent for PCR or ELISA testlng Within a few hours

and brainstem. Further, Baringer and Pisani (25) have fわund

a洗er admission. In Japan, medical lawsuits fわr delaylng thelatent states ofHSV by PCR analysts in parts of the limbic

initiation of antiviral drug (acyclovir) therapy or misdiagnosis

system such as in the cerebellar amygdala and hippocampus

have increased in number.

in normal brain.

Tw?mey et al･ (26) described the presen?e of intranuclear

To measure HSV antibody levels, complement fixation
antibody (CF), neutralizing antibody (NT), and ELISA are

incluslOn bodies in the olfactory mucosa ln Cases Of HSE,

available; in addition, CSF ELISA is sensitive and use丘ll fわr7Table 2. Laboratory diagnosis ofHSV‑1 encephalitis

1, 4‑fold elevation ofHSV antibody+ enzyme‑linked immunosorbent assay for lgG & tgM● neutralizing test

● complement fixation test

2. Serum/CSF antibody ratio <20antibody index ≧ 1.91

3. HSV DNA detection by PCR in CSF
HSV isolation from CSF
chemiluminescence assay

CSF, cerebrosplnal nuid; PCR, polymerase chain reaction.

Fig. 1. Diagnostic and therapeutic algorithm for suspected herpes shnplex

encephalitis (HSE). CT, computed tomography; MRI, magnetic
resonance imaglng; EEC, electroencephalogram; CSF, cerebrosplnal
fluid; PCR, polymerase chain reaction.

Fig. 2. MRI orHSV‑1 encepllalitis

early diagnosis. However, normal adults and the elderly haveserum HSV antibodies, and simple antibody leaks from the

A: T2‑welgl1ted axial MRI showlllg abnomlal slgnal lesions in the left
temporal 10bel including in the left hippocチmPi alld alnygdala (arrow)I

serum to the CSF are often seen. Accordingly, 1ntrathecal

B: T2‑weighted coronal MRl dcmonstratlng the sanle distribution as

antibody production should be deter1‑一ined as follows: i) athat described in A.

semm/CSF antibody level below 20, and ii) an antibody index
of over 1.91 (29).

30 0n the Japan Coma Scale (JCS). The serum HSV CF liter

Since 1990, CSF PCR is used fわr early diagnosis, and thedetection rate has been reported to be 60 ‑ 80%within thewas 8X, and the ELISA was 72.5 (positive 4≦). HSV ELISA

seventh day of illness (4‑8). A一though PCR is a noninvasive

IgG in the CSF was O･45. Both the serum and CSF were tested

method,there remains the need for standardization, including

by real‑time PCR uslng the HSV UL 19 reglOn and the Taqthat of the prlmer Or in expression of the detection rate･ ln

Man Probe (Kazuyama Y, personal commtlnication, 2000);

North American and European studies, PCR has been thethese tests revealed HSV genomes at a rate of300,000 copies/

prlmary method fわr early diagnosis and monitorlng Orthe

ml in the CSF. HSV‑1 was detected in the CSF bynested

therapy (7,8).

PCR; i.e･, the PCR product was not digested by the restric‑tion enzynle Bam HI and was identifled as HSV‑I. Prompt

We present herein a case orHSE fわllowed by a recently

treatment with acyclovir l.5 g/day was initiated. At both 2developed method of quantitative reaトtime PCR.

A 65‑year‑old woman presentedwith a history of repeatedbeginnlng in October 2000. Three days later, generalized tonic

and 4 weeks, HSV genomes were under 50 copies/ml, andthe nested PCR analysts Was negative. HSV CSF ELISA IgG
had increased significantly by 4 weeks. One month later, theseizures appeared togethr with a fever of37.8oC. A brain MRI

patient began to recover gradually, and she was discharged.

oral herpes and was disoriented with regard to date and place

revealed a lesion of abnormal intenslty ln the left temporal

1t is of note that the patient's HSV genomes rapidly disap‑

lobe and limbic system (Fig･ 2)･ The patient's CSF contained

peared after treatment with acyclovir. Several other cases have

patient was transferred to our Universlty Hospital. Uponshowed similar results. On the other hand, in one case thatwas resistant to therapy, the HSV genome persisted at highadmission, a neurologlCal examination revealed a score oflevel for over 2 weeks. Real‑time PCR is quantitative; in

22 ceus/mm3; protein, 30 mg/dl; glucose, 73 mg/dl. The

8contrast fo single and nested PCR; real‑time PCR is moreover

the application of corticosteroids･ Further virologlC andadvantageous due to its relative rapidity. Therefore, real‑timeimmunologlC Studies will be necessaⅣ to investigate real‑time

PCR is a useful method of measuring the effectiveness of

PCR, speci丘c PCR fわr acycloviトreSistant HSV myelin basic

acyclovir ther叩y･protein, and the various cytokines involved in HSV infection･

2‑5. Differential diagnosis

The differential diagnosis ofHSV‑1 ep･cephalitis includes the

3. HSV12 and other herpes group viruses infections of
the CNS

following: Other viraland postinfectioustypes of encephalitis
and bacterial menlngitis, including fungal and tuberculous

311. HSV‑2 acute encephalitis

menlngltlS, are excluded on the basis of a decrease of glucose
concentrations in the CSF. In cases ofpostinfectious encepha‑HSV‑2 (genitaltype) infections occur primarily via the birth

litis, preceding viral infections such as measles andrubella

canal in newborn baby and by sexual contact in adults･

should be excluded.

Although HSV‑2 infection in the newborn baby is divided

into the disserpinatedtype and the localizedtype, encephalitis

Mitochondrial encephalopathy, lactic acidosis, and stroke‑

like episodes (MELAS) are sometimes manifested and areof either type lS associated with high mortality･ In the adult,

prone to relapse in later life in cases Involving the clinicalmenlngltlS and myelitis associated with genital herpes are

picture ofHSV‑1 encephalitis (30)･ When encephalitic symp‑

common. The treatment is similar to血at f♭r HSV 1 encephalitis.

Only a few adult HSV‑2 encephalitis have been reported

toms are repeated, mitochondrial cytopathy should also be(34); Baker et al. (35) have described adult HSV2 encepha‑considered.

During an intensive survey and study of HSE, acutelitis, and Perry et al. (36) have reported a 64‑year‑old woma.n

nonherpetic limbic encephalitis was identified as a newwith HSV‑2 encephalitis and bilateral acute retlnal necrosIS

subgroup (3 1 ). This subgroup is differentiated舟om those withsyndrome a洗er craniotomy･

HSE, as it lacks evidence of the HSV genome or ELISA anti‑
body･ 1n addition, the MRI findings tend to be localized in theopportunistic infection accompanylng AIDS, causes acutebilateral hippocampl and the cerebellar amygdala, althoughencephalitis and acute necrotizlng myelopathy･ With regard

MRIs of HSE prlmarily show unilateral involvement of theto cases ofHSV‑2 encephalitis associated with AIDS, Levy

On the other hand, it has been reported that HSV2, as antemporal lobe. To date, approximately 30 cases have been

et al. (37) have reported a case of acute encephalitis with

reported in Japan. This new subtype is thought to occur along

periodic synchronous discharges on EEC, a鮎r which HSV‑

the spectrum withHSE and paraneoplastic limbic encephalitis･

2 was isolated and identified. They have also reported a case

2‑6. Prognosis

complicated by CMV an atypical encephalitis predominantly

The recommended antiviral treatment fわr HSE is a 14‑day

involving white matter･

HSV2 causes menlngltlS With or without genital herpes
than does HSV･ 1. In addition, Mollaret's menlngltlS, a benign

course ofacyclovlr glVen intravenously at a dosage of 10 mg/
kg every 8 hours. The disease has been fatal in approximately

30% of the reported cases in Japan･ Since induction of theacyclovir treatment, the mortality rate has decreased to 8･2%
in Japan; 30% of the cases have remainlng Sequelae such astype of recurrent aseptlC menlngitis, has been associated withamnestic syndrome, while others are able to retum home orHSV‑2 recurrent meningitis (Mollaret's meni.ngitis), for which

HSVinfections (38); HSV‑2 has been identified as responsible
for the majorityofthese cases. Kojima et all (39) have reported

to work within 6 months. Tb date, HSE has been regarded asa treatable disease. However, HSE cases that develop to anoral valaciclovir is administered with the alm Of preventlng

apallic state and even to death continue to occur, desplte early

HSVrecurrent menlngltlS･
Regarding HSVtype differentiation, recent cases have beentreatment. It is conceivable that in the RIture, early detection

analyzed by CSF PCR uslng restriction endonuclease analysis.

CSF PCR is applied prlmarily for acute‑stage HSV infec‑

and approprlate treatment Will lead to a better prognosis f♭rtions of the CNS, whereas an EuSA kit uslng type‑specificpatients with intractable HSE･
A tentative definition of the subtypes of intractable cases

glycoprotein G can differentiate between HSV‑1 and ‑2 inserum from patients in the convalescent stage. In our recent

ofHSE are as fわllows:

study (40), of 17 patients withHSV infections of the CNS,

( i ) Cases ofHSE that develop to an apallic state and then tofatality.

HSV‑1 and HSV‑2 antibodies were fわund to be present in 13

patients. Furthermore, ll patients with HSV‑1 and twopatients with HSV‑2 were identified; the data were qulte( ii ) Prolonged cases that require more than 6 months'hospi‑
talization.

compatible with the results of studies involving the PCRtype(iii) Recu汀ent Cases.

of differentiation. These findings suggest that HSV‑type

It seems likely that the main reasons fわr the development

specific ELISA is a useful test for identifying HSV types,of intractable HSE are a profわund consciousness disturbance3‑2. HSV myelitis
HSV myelitis occurs primarily in response to HSV‑2. 1t

and a delay in the initiation ofantiviral dmg therapy. Conven‑tionally, in the US, a profわund disturbance of consciousness

in patients with HSE who are over 40 years of age has been
regarded as a factor in a fatal prognosis (32). Dennett et al.

reveals acute ascending myelopathic symptoms such as backpalm Or urinary disturbance. Fewer than halfofall cases show
mucocutaneous symptoms. In the past, autopsy cases have(33) have reported PCR results were negative, and increased
myelin basic protein was detected in the CSF at the time ofbeen reported as necrotizmg myelopathy; however, With therelapse in cases ofrecu汀ent HSE, although PCR positive isintroduction ordiagnostic tools such as MRI and CSF PCR,

found in infantile recurrent HSE. Intractable cases are often

mild suTivi.ng cases are likely to be identified (41 )A Althoughattributed to prolonged viral infection or to secondary

contamlnat10n Of the HSV‑1 infection is rarely seen in

encephalitis (postinfectious/autoimmune encephalitis)･ The
former indicates that the use of higher doses of acyclovir

patients with HSV myelitis, We have encountered a case of
HSV‑ I myelitis with a favorable outcome (42). Lesions (Fig.

therapy may be necessary, Or suggests the possibility of an3) can be found relatively frequently on MRI of the posterior

acyclovir‑resistant HSV; the latter indicates the usefulness offuniculus of the splnal cord. Such findings may reflect the9system infections associated with VZV menlngitis have arelatively high incidence,followed by those associated withencephalitis, myelitis,and neuropathy (I 1).Asin other forms,
a delayed contralateral hemiplegia followed by trlgeminal

herpes zoster has been reported (44). The hemiplegia developed
as a result ofvasculitis along the internal artery from thetrlgeminal ganglionitis. In such cases, anti‑viral dmgs, similar
to those used fわr HSE patients, are applied; in addition,

corticosteroids are also used. Recently, Opportunistic CNS

infections concomitant with AIDS have been increaslng ln
frequency (13, 45)･ These CNS syndropleS are noteworthy
for their lack of skin eruptions (Zoster slne herpete).

Meanwhile, encephalitis, Reye's syndrome, and acutecerebellar ataxia are more familiar in CNS infTections associatedwith varicella. Infantile acute encephalopathy, Reye 's syndrome,is characterized by acute brain edema, convulsive seizure,

impalment Of consciousness, and hyperamoniazemia. Since
1985, when the Japanese Ministry of Health and Welfare
recommended the prohibition of asplrln use for infantile
innuenza, the incidence of the syndrome has decreasedl

3‑4. EBV infectioTIS Ofthe CNS
EBV targets a‑1ymphocytes, and is known to have bothinflammatory and oncogenic characteristics. Infectious mono‑

nucleosis (IM) by EBV is characterized by fever, eruption,
atyplCal lymphocytes in the peripheral blood, tonsilar andlymph node swelling, and liver dysfunction. EBV infectionsof the CNS appear to be associated with an IM or an IM‑like
syndrome. EBV infTectionsofthe CNS are very broad comparedwith HSV infections of the CNS. CNS syndromes such as

encephalitis, ADEM, encephalopathy, acute cerebellar ataxia,
myelitis, and Guillain‑Barre syndrome have been reported･Among these, encephalitis or acute cerebellar ataxia has thehighest incidence (10,12,46).
We have previously reported rel叩Slng ADEM‑associatedchronic EBV infections. An ADEM case associated withchronic EBV infection was found to relapse alter a year (47).
At the time of relapse, the EBV genome was found by PCR

to be negative in the CSF, and MRI abnormalities appeared

Fig. 3. MRl ofHSV‑1 myelitis
A: T2‑Weighted saglttal MRl presentlng a lesion with high signal

in the opposite basal ganglia and in the right white matter,

intenslty extending from the 3rd to 7th thoracic level. A: T2‑Weighted
instead of at the locations noted in a丘rst attack (Fig. 4). ln

axial MRl revealing an intra‑axial longitudinaHesion in the thoracic

the presence of white matter lesions and a favorable cortico‑spinal cord, predominantly on the left side (arrow)･

steroid response, the pathogenesis was presumed to be an

autoimmune mechanism trlggered by chronic EBV infection･
Several EBV CNS syndromes associated with chronic active
EBV infection have been reported. Cases of chronic encephallitis or recurrent menlngitis have also been described. CNS
infections associated with chronic active EBV infection may

neural spread ofHSV from the infected dorsal root into the

splnal cord. In an experiment uslng mice, Nakajima et al･(43) showed a worsening of myelitis in response to Th 2

cytokine‑lL‑4 and ‑IL 1 0, induced by monocyte chemotactic
protein‑ 1. This result may suggest the useRllness of immuno‑

characteristically produce舟equently chronic or recurrent CNS

suppressant and cytokine therapy. Administration of acyclovir

syndromes.

and corticosteroids is usually recommended for patientswith

Recently, Morita et al. (48) have reported three infantile
cases of chronic active EBV infection with symmetrical

HSV myelitis.
313. VZV infections of the CNS

calcification in the basal ganglia as well as hypersensitivlty

The virus causlng herpes zoster lesions is identical to VZV
the causative agent of chickenpox. lt is thought that herpes

to mosquitoes and an increased number ofnatural killer (NK)cells. However, these cases did not reveal any innammatory

zoster is the lesion by reactivation oflatent VZV orlglnallyfhdings such as CSF pleocytosis. As such, further cases

acquired in a childhood attack or chickenpox･ Common

should be investlgated regarding whether or not such cases

symptoms are impalrment Of cutaneous sensation andbelong to the same group associated withchronic EBV infec‑

muscular weakness in the distribution of the affected root,tion.

headache, neck stiffness, and confusion. The presence ofpercentage of cases. The CNS syndromes appear to be more

EBV‑related CNS lymphoma in AIDS is increaslng, andCSF PCR is useful for this diagnosis (49).
3‑5. CMV infections of the CNS
CMV is an important member of the herpesvirus family
that is among the common pathogens in humans. CMV

closely related to reactivation in the ganglia. Thus, neⅣous

infection in cells results in the appearance of large, swollen

characteristic skin eruptlOnS Or scars are helpful for the

diagnosis of VZV infections of the CNS, though HSV‑1
encephalitis accompanies skin lesions in only a small

10Meanwhile, in adult and elderly patients, HHV‑6 may berelated to myelopathy and to multiple sclerosis without skinlesions. Mackenzie et al. (16) have reported detecting the
HHV‑6 genome in the splnal cord in a 75‑year‑old patientwith myelopathy, and Carrigan et al. (17) have described the

HHV‑6 genome in a 72‑year‑Old patient with subacute white
platter enCePhalopathy; Akhyani et al･ (5 1) have reported thelnCreaSed prevalence of HHV‑6A in patients with multiple
sclerosis.

HHVl7 also causes infantile hemiplegla together with skinrash. Kaposi 's sarcoma‑associated herpesviruS仙uman herpes‑

vims type 8 might be related to encephalitis in immuno‑
suppressed individuals, and should be considered in the
differential diagnosis ofunexplained viral encephalitis (52).

4. Conclusion

With the recent progress of PCR and other diagnostic tools,
several clinical forms of HSV‑1 infections of the CNS,

including ADEM and brainstem encephalitis, have beenreported. Although fatal, prolonged, or relapsed patient cases
are still found,further virologlC and immunologlC Studies are
expected to help iden的these intractable HSE Gas?S･ In a血山

HSVl2 infections, menlngltlS and myelitis assoclatedwith
genital herpes are common. Previously, HSV‑2 myelitis has
been reported as fatal necrotlZlng myelopathy; however, With
the introduction ofPCR or MRI studies, mild suⅣivlng Cases
are 一ikely to be ident捕ed.

The VZV CNS syndromes appear to be more closely related
to reactivation of the latent vims in the ganglia. The nervous

systenl infections associated with VZV menlngitis have arelatively high incidence, followed by those associated withencephalitis, myelitis, and neuropathy.

EBV infections of the CNS appear to be associated withan lM or an IM‑like syndrome. EBV infections of the CNS
are very broad compared with HSV infections of the CNS.
Several cases of chronic encepha】itis or recu汀ent menlngltlS‑

associated chronic active EBV infection have been described.

CNS infections associated with chronic active EBV infections
may斤equently produce chronic or recu汀ent CN S syndromes.

Fig. 4. MRI ofADEM associated with chronic active EBV infection
A, B: At the time of recurrence, T2‑Weighted axial MRTs revealed

CMV ventriculoencephalitis or encephalopathy has increased
in immunocompromjsed hosts such as AIDS patients.
Recently, CMV lumbo‑sacral radiculoneuritjs has also been

new lesions in the opposite basal ganglia (arrow) and right temporaland parletal white matter (a汀OW).

reported.

Finally, 1n adult and elderly patients, HHV16 may be related
cells that often contain large eosinophilic intranuclear andto myelopathy and to multiple sclerosis without skin lesions.

basophilic cytoplasmic inclusions. CMV infections may
occur in adults, producing a mononucleosis‑like syndrome;

ACKNOWLEDGMENTS

however, involvement ofa CNS syndrome is unusual in adults.
Ventriculoencephalitis or encephalopathy has increased in
immunocompromised hosts such as AIDS patients (14), andThis study was supported by a Grant‑in‑Aid for Scientific
Research (C) 1 , (1267063 1) from the Ministry of Education,

recently, CMV lumbo‑sacral radiculoneuritis has also been

Culture, Sports, Science and Technology, Japan.

reported (15); its symptoms include prQgresPiveflaccid
paralysIS Of limbs, areflexia, recto‑urinary lmpalrment, CSF

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