viral meningitis and encephalitis

VIRAL MENINGITIS ANDENCEPHALITISRoberta L. DeBiasi, Kenneth L. Tyler

ABSTRACT

Hundreds of human viral pathogens exhibit a tropism for the central nervoussystem (CNS). In the case of some viruses, involvement of the CNS is thepredominant feature of the resulting illness whereas in others involvement of theCNS is a rare complication of a more generalized illness (Corboy and Tyler, 2000).Infection with these viruses may result in several recognizable neurologicalsyndromes, depending upon the specific elements of the CNS that are pref-erentially attacked. The most common syndrome resulting from viral CNS infectionis meningitis, which can be defined as inflammation of the subarachnoid space andmeninges without direct involvement of brain parenchyma (Hammer and Connolly,1992). In contrast, the syndrome of encephalitis is characterized by viral infection ofbrain tissue itself. Although the same viruses are responsible for inducing bothmeningitis and encephalitis, individual viruses may more commonly produce one orthe other syndrome (Johnson, 1998; Johnson, 1996). Viruses often simultaneouslyaffect both meninges and brain parenchyma as so-called meningoencephalitis.According to data from the US Centers for Disease Control and Prevention (CDC),over 100,000 cases of aseptic meningitis occur annually in the United States, themajority of which are of viral etiology. Approximately 20,000 cases of encephalitisoccur in the United States each year, most of which are mild. In this chapter, viralagents that cause meningitis and encephalitis will be addressed, as well as thedifferential diagnosis of these viral diseases in normal and abnormal hosts. Thischapter concentrates, for the most part, on the most common causes of thesediseases in North America.

VIRUS ENTRY AND SPREAD TOTHE CENTRAL NERVOUS SYSTEM

Viruses initially gain entrance into thehost by penetration of mucosal, skin,gastrointestinal, or urogenital barriers.Once within the host, access to theCNS is via one of two routes: hema-togenous or neuronal spread. Hema-togenous dissemination, the morecommon of the two, generally resultsfrom primary viral replication near thesite of entry, followed by secondaryviremia and seeding of distant sites,such as endothelial cells of meningealcapillaries with secondary passage tothe subarachnoid space, or directseeding of choroid plexus. Viruses can

subsequently spread from the choroidplexus to cerebrospinal fluid (CSF), toependymal cells lining the ventricles,and into brain tissue, depending onthe specific tropism of the particularvirus and the host immune response.Many enteroviruses (EVs) cause CNSdisease by this route after primaryreplication within the gastrointestinaltract. Alternatively, viruses spread tothe CNS via peripheral nerve endingsby means of retrograde axonal trans-mission; such transmission is charac-teristic of rabies, for example, but mayalso occur with herpes simplex virus(HSV), varicella-zoster virus (VZV), andpoliovirus (Figure 3-1). Neurotropic

58

KEY POINTS:

A The most

common

syndrome

resulting from

viral CNS

infection is

meningitis,

which can be

defined as

inflammation

of the

subarachnoid

space and

meninges

without direct

involvement of

brain

parenchyma.

A Neurotropic

viruses usually

spread to the

CNS by the

hematogenous

route but may

also spread

along nerves via

retrograde

axonal

transmission.

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

viruses usually spread to the CNS bythe hematogenous route but may alsospread along nerves via retrogradeaxonal transmission (Tyler, 2001).

ENCEPHALITIS, ACUTEDISSEMINATEDENCEPHALOMYELITIS, ANDENCEPHALOPATHY

When evaluating patients with alteredmental status, the clinician must dis-

tinguish infectious encephalitis fromencephalopathy as well as postinfec-tious or parainfectious immune-medi-ated neurological syndromes such asacute disseminated encephalomyelitis(ADEM) (Kennedy, 2004; Whitley andGnann, 2002).

Although viruses more commonlycause disease at the time of host entryand invasion, postinfectious or para-infectious neurological conditions,

59

FIGURE 3-1 Pathogenesis of viral infection of the central nervous system.

HIV = human immunodeficiency virus; HSV = herpes simplex virus.

Modified from Hammer SM, Connolly KJ. Viral aseptic meningitis in the United States: clinicalfeatures, viral etiologies, and differential diagnosis. Cur Clin Top Infect Dis 1992;12:1–25.

KEY POINT:

A Acute

disseminated

encephalo-

myelitis is a

condition

in which

widespread

demyelination

occurs in a

monophasic

pattern, often

following a

definite or

suspected viral

infection or

immunization.

It is presumably

the result of

an immune-

mediated

reaction against

a component of

normal brain

such as myelin.


presumably immune mediated, appearafter many viral infections. These willbe discussed in detail later. In brief,ADEM is a condition in which wide-spread demyelination occurs in amonophasic pattern, often followinga definite or suspected viral infec-tion or immunization. It is presumablythe result of an immune-mediatedreaction against a component of nor-mal brain, such as myelin (Davis,2000). Multiple sclerosis (MS) is alsoin the differential diagnosis of ADEM,although MS affects an older agegroup, and the pattern of demyelin-ation in MS is not typically mono-phasic. The following features mayhelp distinguish ADEM from acuteencephalitis.

ADEM tends to occur preferentiallyin children and often occurs within amonth of a vaccination or an uncom-plicated prodromal illness such as achildhood exanthem, upper respiratoryinfection, or gastroenteritis. Impor-tantly, neurological illnesses typicallybegin at the end of a prodromal illnessrather than preceding or occurringconcomitantly with it. Symptoms aremonophasic and develop over a fewdays. Multiple focal signs develop, withoptic nerve, spinal cord, and cerebellarinvolvement noted more frequentlythan in viral encephalitis. Rapid pro-gression to coma is more commonin ADEM than in most viral encepha-litides. Magnetic resonance imaging(MRI) findings distinguish ADEM fromencephalitis and include the presenceof disseminated white matter lesions,with a high T2 and low T1 signal,which enhance following gadolinium.The presence of coincident enhance-ment of the lesions suggests thatthey are of recent and similar age, asenhancement resulting from inflam-matory blood-brain barrier disruptionusually resolves within 6 weeks of anacute lesion. The presence of myelinbasic protein and oligoclonal bands in

the CSF all favor the diagnosis ofADEM, although these may also bepresent in patients with some types ofencephalitis.

Conversely, patients with ADEM donot have detectable viral infection inthe CNS, and as a result, viral culturesof the CSF or brain tissue and CSF-polymerase chain reaction (PCR) stud-ies are usually negative.

An additional condition that must bedistinguished from infectious encepha-litis is encephalopathy, whether of met-abolic, toxin-mediated, or other origin.Although mental status is also alteredin encephalopathy, as it is in infectiousencephalitis, patients generally do notexhibit fever or headache, and the CSFis usually normal. Seizures and focalneurological signs are uncommon, andpatients exhibit steady deterioration ofmental status rather than the morecommonly seen fluctuating mental sta-tus of encephalitis.

DIAGNOSIS

Although this review addresses theprimary agents of viral meningitis andencephalitis, many infectious (eg, bac-terial, viral, fungal, parasitic, rickettsial,myoplasmal), and noninfectious etiol-ogies must be considered in anypatient who presents with findingssuggestive of CNS disease. Severalgroups have recently attempted toidentify the relative frequencies withwhich these occur, using a battery ofserological and molecular diagnostictechniques. In the California Encepha-litis Project, one of the largest studiesto date, a viral etiology was confirmedor probable in 9% of 334 cases, withfewer cases due to bacterial (3%) andparasitic (1%) etiologies. Noninfectiousetiologies were identified in 10% andnonencephalitic infections in 3%. Apossible etiology was found in 12%.Despite extensive testing, the etiologyremained unexplained in 62% of cases

60

" VIRAL MENINGITIS AND ENCEPHALITIS


61

FIGURE 3-2 Algorithm for management of patient with suspected viral central nervoussystem infection.

Continued on next page


(Glaser et al, 2003). A larger study thatutilized an extensive panel of CSF PCRassays for detection of 11 virusesdetected an etiological agent in 14%of 3485 specimens tested (Huang et al,2004). Although these disparate etiol-ogies produce symptoms that mayappear similar, each disease hasunique features that suggest it ascausative in a given patient. The mostcommon viruses identified in NorthAmerica causing meningitis and en-cephalitis are noted in Table 3-1. Theyare listed in the relative order offrequency with which they occur, andtheir relative propensity to causemeningitis, encephalitis, and/or post-infectious encephalomyelitis is indicat-ed. Additional causes of viral enceph-alitis that should be considered inpatients who have returned from

abroad are noted separately in Table3-2. The nonviral etiologies of CNSdisease are summarized in Table 3-3,which includes distinguishing featuresof each agent or disease (Rubeiz andRoos, 1992; Tyler, 2001).

In any given patient, the most ur-gent distinctions to be drawn center onidentification of bacterial meningitisand/or HSV encephalitis. Effectiveantimicrobial therapy is available forboth with the capability of drasticallyreducing associatedmorbidity andmor-tality when administered in a timelyfashion. It is imperative to instituteimmediately appropriate empirical an-tibacterial and antiviral therapies whileinitiating a detailed diagnostic evalua-tion. Once these diagnoses have beenexcluded by Gram’s stain and culturedata of CSF and HSV-PCR studies (see

62

FIGURE 3-2 Continued.

ADEM = acute disseminated encephalomyelitis; CT = computed tomography;MRI = magnetic resonance imaging; CSF = cerebrospinal fluid; PCR = polymerasechain reaction; HSV = herpes simplex virus; IgM = immunoglobulin M; WNV =West Nile virus; DFA = direct fluorescent antibody (test); VZV = varicella-zostervirus; VDRL = Venereal Disease Research Laboratory (test); AFB = acid-fastbacilli; EBV = Epstein-Barr virus; IVDA = intravenous drug abuse; CTFV =Colorado tick fever virus; LCMV = lymphocytic choriomeningitis virus; HIV =human immunodeficiency virus.

KEY POINTS:

A In acute

disseminated

encephalo-

myelitis, optic

nerve, spinal

cord, and

cerebellar

involvement are

noted more

frequently than

in viral

encephalitis.

A The presence of

myelin basic

protein and

oligoclonal

bands in the

cerebrospinal

fluid all favor

the diagnosis

of acute

disseminated

encephalo-

myelitis,

although these

may also

be present in

patients with

some types of

encephalitis.



63

TABLE 3-1 Primary Causes of Viral Meningitis and Encephalitis in North America

Agent Meningitis Encephalitis

PostinfectiousAcuteDisseminatedEncephalomyelitis

Nonpolioenteroviruses

Echovirus *** *

Coxsackievirus *** *

Arboviruses(United Statesand Canada)Togaviruses St Louis encephalitis

virus (SLE)* **

FlavivirusWest Nile virus * **

Powassan **

Alphavirus Easternequine (EEE)

* ***

Western equine(WEE)

* **

Venezuelan equine(VEE)

** *

Reoviridae:orbivirus

Colorado tick fever ** *

Bunyavirus California(La Crosse)

* **

Jamestown Canyon * *

Snowshoe hare * *

Herpes viruses HSV-1 * **

HSV-2 ** *

VZV * ** *

CMV * **

EBV * * *

HHV-6 * **

Herpes B virus ***

Lymphocyticchoriomeningitisvirus (LCMV)

** *

Mumps virus ** * *

Humanimmunodeficiencyvirus (HIV)

** *

Rabies virus *** *

Measles virus * ***



below), a staged approach to identifyother nonbacterial causes of meningitisor encephalitis can be initiated. A tieredalgorithmic approach to this process issummarized in Figure 3-2, suggestingimmediate evaluation for treatable life-threatening etiologies, followed by sec-ond-tier evaluation for other commonagents for which identification is lessurgent. Finally, third-tier evaluation formore rare etiologies is indicated forpatients in whomno diagnosis has beenmade. A history of unusual exposures,travel, or specific symptoms may clearlyalter the diagnostic approach to certainpatients in whom atypical etiologies aremore likely.

GENERAL FEATURES OF VIRALMENINGITIS AND ENCEPHALITIS

The hallmark of both viral meningi-tis and encephalitis is the acute onsetof a febrile illness accompanied by

headache and, often, nuchal rigidity.With many forms of encephalitis, al-tered mental status, disorientation,behavioral and speech disturbances,and focal or diffuse neurological signssuch as hemiparesis or seizures mayoccur, and these symptoms help dis-tinguish it from meningitis, in whichthey are generally absent (Table 3-4)(Tyler, 2001).

Historical points that may helppinpoint a specific viral infection in-clude the season of year (eg, fall for EVs,summer/fall for arboviruses); travelhistory (eg, regional arboviruses, viruseswith foreign distributions); knowl-edge of diseases prevalent withinthe community (eg, enteroviral orarboviral outbreaks); history of ani-mal exposure (eg, rabies, lymphocyticchoriomeningitis virus [LCMV]) ormosquito or tick (arboviruses) expo-sure. It is helpful to review preceding

64

TABLE 3-1 Continued

Agent Meningitis Encephalitis

PostinfectiousAcuteDisseminatedEncephalomyelitis

Rubella virus *

Poliovirus(now eradicatedfrom Westernhemisphere)

* ** *

Adenovirus * **

Vaccinia *

Influenza ? ? *

Parainfluenza * * *

Rotavirus *

Parvovirus B-19 *

HSV-1 = herpes simplex virus l; HSV-2 = herpes simplex virus 2; VZV = varicella-zoster virus; CMV = Cytomegalovirus; EBV =Epstein-Barr virus; HHV-6 = human herpesvirus 6.* Occasional** Common*** Very common? Unknown



or concurrent illnesses or symptomsthat have occurred in the days toweeks leading up to the presentingdisorder (eg, ADEM, VZV, Epstein-Barrvirus [EBV], HSV, mumps). Sexualactivity and intravenous (IV) drug usecomprise other potentially importanthistorical points (ie, patients with the

possibility of human immunodeficien-cy virus [HIV]). All patients should, ofcourse, undergo a complete generalmedical and neurological examinationwith special attention to alterationof mental state, papilledema, cranialnerve deficits, abnormal reflexes, orfocal weakness. Althoughmany viruses

65

TABLE 3-2 Additional Causes of Viral Encephalitis Resulting From Foreign Exposures

Agent Geographical Distribution

Nipah virus Indonesia

Filovirus Ebola Africa

Marburg

Arbovirus

Togavirus

Mosquito-borne Eastern equine Caribbean, South America (plusUnited States)

Venezuelan equine Central and northern South America(plus United States)

St Louis Caribbean, Central and northernSouth America (plus United States)

Japanese B Japan, China, Southeast Asia, India

Murray Valley Australia, New Guinea

West Nile Africa, Mideast, parts of Europe(plus United States)

Ilheus South and Central America

Rocio Brazil

Tick-borne complex Far Eastern Eastern Russia

Central European Eastern and Central Europe, Scandinavia

Kyansur Forest India

Louping Ill England, Scotland, Northern Ireland

Negishi Japan

Russian spring-summer Eastern Europe, Asia

Bunyavirus Tahyna Czech Republic, Slovakia,Yugoslavia, Italy,Southern France

Inkoo Finland

Rift Valley East Africa

Rabies Many underdeveloped countries


66

TABLE 3-3 Diseases That Can Masquerade as Viral Meningitis or Encephalitis

Etiology Suggestive Features

Reoviridae:orbivirusInfectious

Bacterial Parameningeal focus(sinusitis, intracranial abscess)

Very mild pleocytosis,focal neurologicalabnormalities

Partially treatedbacterial meningitis

Prior antibiotic treatment,right shifted cerebrospinal fluid

Lyme disease Tick exposure, arthritis,appropriate geography,erythema migrans

Tuberculosis Very high protein, hypoglycorrhachia

Leptospirosis Conjunctival suffusion,jaundice

Syphilis Chronic course

Brucella Farm animal exposure

Whipple’s disease Gastrointestinal complaints

Bartonella (catscratch) Cat exposure, adenopathy

Listeria Brain stem encephalitis

Typhoid fever Exposure history, bradycardia

Fungal Cryptococcus Usually immunocompromisedpatient

Coccidioides SouthwesternUnited States exposure,pulmonary symptoms

Histoplasma Pulmonary nodules

Blastomycosis Midwest, pulmonary symptoms

Candida Immunocompromised patient

Nocardia Immunocompromised patient

Parasitic Toxoplasma Retinitis, cat exposure

Cysticercosis Calcified lesions

Amoebic Fresh water: Naegleria

Malaria(Plasmodium falciparum)

Exposure history

Rickettsial Rocky Mountainspotted fever

Leukopenia, thrombocytopenia,hyponatremia, petechial rash

Ehrlichia See above

Coxiella burnetii (Q fever) Exposure to sheep,pulmonary disease

Mycoplasma Precedent pulmonary symptoms




cause diffuse cerebral involvement,the tropism of viruses for different celltypes within the CNS may lead tocharacteristic neurological findings.For example, the predisposition ofHSV for the temporal lobe may leadto clinical findings of aphasia, anosmia,and temporal lobe seizures. Althoughfocal signs should always suggest HSV,other viruses may present as focalencephalitis and must also be consid-ered (Table 3-5).

Since many of the features of asep-tic meningitis and encephalitis arecommon to the majority of viral etiolo-gies, the presence of unusual physi-cal findings can better help define aspecific viral diagnosis (Gutierrez andProber, 1998). The presence of mu-cous membrane or skin abnormali-ties may be especially helpful in thisrespect since different viruses tend to

cause characteristic enanthems or ex-anthems (Table 3-6). Other unusualfindings such as alopecia, arthritis,lymphadenopathy, myocarditis, orchi-tis, pneumonia, urinary difficulty, orretinitis are also suggestive in specificinstances (Table 3-7) (Roos, 1998;Tyler, 1984).

Evaluation of the CSF and perfor-mance of appropriate imaging studiesare essential features of the labora-tory evaluation. Blood studies may behelpful in certain conditions. For exam-ple, leukopenia and thrombocytopeniaare often seen with rickettsial infec-tions as well as certain arboviral infec-tions such as Colorado tick fever virus.Serum serologies are useful in manyconditions.

The CSF should be obtained andanalyzed as quickly as possible. It ishelpful to send routine studies on a

67

TABLE 3-3 Continued

Etiology Suggestive Features

Parainfectious Acute disseminatedencephalomyelitis(ADEM)

Characteristic magneticresonanceimaging findings

Noninfectious Connective-tissuedisorders

Systemic lupuserythematosus (SLE)

Malar rash, multisystemorgan involvement

Sarcoidosis Hilar adenopathy,erythema nodosum

Uveomeningiticsyndromes

Behcet’s Genital/oral ulcers, uveitis

Intracranialtumors and cysts

Recurrent episodes,dermal sinus tract

Drugs Nonsteroidalanti-inflammatorydrugs (NSAIDs),antibiotics,immunomodulators,anticonvulsants

Exposure history

Intracranialhemorrhage

Characteristicneuroimaging findings

Encephalopathy Toxic or metabolic


portion of the CSF, reserving onetube for specific studies such as virus-specific serologies and PCR, as sug-gested by the pattern of results fromroutine studies (discussed individuallybelow) (DeBiasi and Tyler, 1999). Inmost forms of viral CNS disease, theCSF contains a mild to moderatepleocytosis, from a few to up to 1000

white blood cells (WBCs)/mm3; a slight-ly lower range is usual in viral enceph-alitis (up to hundreds of cells). Alymphocytic or mononuclear WBCpredominance is common, distinguish-ing this syndrome from bacterial etiol-ogies in which predominance of poly-morphonuclear cells is characteristic. Ifthe CSF is examined early in the clinical

68

TABLE 3-4 Characteristic Findings in Viral Meningitis and Encephalitis

Category Meningitis Encephalitis

Physicalexamination

Mental status Usually normal Altered: confusion, delirium,lethargy, stupor, coma

Seizures Uncommon Often present: focal orgeneralized

Neurologicalexamination

Usually normal; cranialnerve deficits possible

Focal findings common

Fever Usually less than 408C Often high

Laboratory

Cerebrospinalfluid

White blood cell(WBC) count

10 mm3 to 1000/mm3,usually less than 300/mm3

Up to several hundredWBCs/mm3. Occasionallyacellular

WBC shift Early polymorphonuclear(PMN) predominance,followed by mononuclearshift in 24 to 48 hours(in West Nile virus, PMNsmay persist)

Same

Glucose Usually normal (exceptmumps, or lymphocyticchoriomeningitis virus—low)

Same

Protein Normal or mildly elevated50 mg/100mL to100 mg/100mL

Same

Imaging Magnetic resonanceimaging/computedtomography

Usually normal—may seemeningeal enhancement

Usually abnormal

Electroencephalogram Normal Usually abnormal with diffusebilateral background slowingand/or epileptiform activity

Brainpathology

Normal Perivascular inflammation,neuronal and glial necrosis,edema, inclusion bodies



disease, however, polymorphonuclearcells may also be present in nonbacte-rial (including viral) infections of theCNS. In viral CNS infection, however,this pattern shifts within 8 to 24 hourstoward the more usual mononuclearpredominance. Infection with EV andHSV may be more likely to produce thispattern than other viruses. A polymor-phonuclear predominance that persists

is typical of HIV-associated Cytomegalo-virus polyradiculomyelitis, as well asWest Nile virus meningoencephalitis;with these exceptions, a persistentlypolymorphonuclear pleocytosis is in-consistent with viral etiologies andrequires careful exclusion of bac-terial and nonviral processes. TheCSF glucose is usually normal in viralmeningitis and encephalitis, although

69

TABLE 3-5 Differential Diagnosis of Viral Encephalitis With FocalCerebral Involvement

Agent Characteristic Pattern

Herpes simplex virus Magnetic resonance imaging with increased signal intensity inorbitofrontal and temporal lobe areas on T2-weighted images

Electroencephalogram with pseudoperiodic, focal or unilateral,high-amplitude complexes in one or both temporal lobes(periodic lateralizing epileptiform discharges)

Human herpesvirus 6 May mimic herpes simplex virus (temporal lobe involvement)

Focal seizures, hemiparesis, or focal cranial nerve deficits)

Varicella-zoster virus May follow zoster eruption (days to months) or occur withoutany skin eruption

May occur with disseminated zoster

May occur in setting of primary varicella-zoster virus infection(1 week after onset of rash)

Enterovirus Primarily in infants and hypogammaglobulinemic patients

Arboviruses:

LaCrosse Focal neurological signs in 20% of cases

St Louis May mimic herpes simplex virus

Powassan

Measles virus—postmeaslesencephalomyelitis

Multifocal neurological signs during convalescence frommeasles (within 2 weeks of eruption of rash)

Magnetic resonance imaging with multiple hyperintense areason T2-weighted images in subcortical white matter

Subacute measles encephalitis Occurs in immunocompromised patients with latent periodof 1 to 20 months between the measles illness and encephalitis

Lymphocytic choriomeningitis virus Mild encephalitis with only rare fatalities

JC virus Progressive multifocal leukoencephalopathy in patients withdepressed cell-mediated immunity—usually insidious onset

From Roos KL. Pearls and pitfalls in the diagnosis and management of central nervous system infectious diseases. Semin Neurol 1998;18:185–196.Modified with permission from Thieme Medical Publishers.


hypoglycorrhachia is well recognized inLCMV and mumps meningitis. Even inthese conditions, the glucose is usuallygreater than 25 mg/dL. Values below25 mg/dL should suggest the possi-bility of bacterial or fungal infectionand sarcoid or carcinomatous menin-gitis. CSF protein is generally normal

or slightly elevated in viral meningitis;viruses that tend to present with ele-vated CSF protein include HSV (late)and EV (early). Table 3-4 summarizesthese common CSF findings (Davis,2000).

Table 3-8 outlines the utility of CSFand serum PCR, serology, and culture

70

TABLE 3-6 Skin/Mucous Membrane Findings Suggesting Specific Viral CentralNervous System Diseases

Exanthem or MucousMembrane Change Viral Agent Specific Changes

Vesicular eruption Enterovirus Hand-foot-and-mouth disease—macules/papules/vesicles on palms, soles, buttocks

Herpes simplex Grouped small (3 mm) vesicles on anerythematous base

Varicella-zostervirus (VZV)

Zoster: vesicles in dermatomal distributionPrimary VZV: multiple vesicles, papules, pustules invarious stages of eruption

Maculopapulareruption

Epstein-Barr virus Diffuse maculopapular eruption followingampicillin treatment

Measles Diffuse maculopapular erythematous eruptionbeginning on face/chest and extending downward

Human herpesvirus 6 Roseola: Diffuse maculopapular eruption following4 days of high fever

Colorado tick fever Maculopapular rash in 50%

Lymphocyticchoriomeningitisvirus

Occasionally occurs with lymphadenopathy

West Nile virus Diffuse truncal eruption—may spread to limbsand face

Erythemamultiforme

Herpes simplexMycoplasma*

Many types of rash

Confluentmacular rash

Parvovirus Confluent erythema over cheeks (‘‘slapped cheek’’)followed by lacy, reticular rash over extremities (late)

Purpura Parvovirus Rare stocking-glove syndrome—purpuric lesionson distal extremities

Pharyngitis Enterovirus Herpangina—vesicles on soft palate

Adenovirus Pharyngoconjunctival fever

Conjunctivitis St Louis encephalitis Conjunctivitis

Adenovirus Conjunctivitis with pharyngitis (see above)

* Mycoplasma is not a virus.



for the most common forms of viralmeningitis and encephalitis. In someviral infections such as nonpolio EV,LCMV, mumps, and rabies it is possibleto culture virus directly from CSF.However, this is time-consuming, andsensitivity of culture methods variesgreatly with virus strain and laboratorytechnique. Some viruses, on the otherhand (eg, EBV and HSV), can onlyrarely be cultivated from CSF, evenunder the best conditions. Culture ofother specimens such as throat/respi-ratory washings, rectal swabs, skinvesicles, urine, saliva, or blood maybe helpful in some cases but may notalways prove CNS involvement, as

unrelated shedding from prior infec-tion is always possible.

Acute and convalescent serologicaldiagnosis is also potentially useful insome viral infections, but the utility ofthis method is limited by the length oftime required to firmly establish acuteinfection (weeks in many cases), aswell as the limited specificity of manyserologies. One exception is in thecase of acute EBV infection, in which thepresence of immunoglobulin M (IgM)to viral capsid antigen is extremely sug-gestive of acute infection. Serologyremains the most generally availablemeans of diagnosing arboviral infection.The presence of specific intrathecal

71

TABLE 3-7 Other Specific Findings Associated With VirusesCausing Central Nervous System Disease

Finding Viruses

Alopecia LCMV

Arthritis LCMV, Parvovirus

Biphasic illness LCMV, Colorado tick fever

Lymphadenopathy LCMV, mumps

Mastitis Mumps

Mononucleosis Cytomegalovirus, Epstein-Barr virus

Myelitis West Nile virus, St Louis encephalitis virus,varicella-zoster virus, herpes B virus, LCMV,human T-lymphotropic virus, rabies

Myocarditis/pericarditis Enterovirus (mumps, LCMV)

Orchitis/oophoritis Mumps (LCMV, Epstein-Barr virus)

Paraesthesias Colorado tick fever, LCMV, rabies

Parotitis Mumps (LCMV)

Pneumonia Influenza, parainfluenza

Retinitis Cytomegalovirus

Tremors Arboviruses (West Nile virus and others)

Urinary problems St Louis encephalitis virus, varicella-zostervirus, herpes B virus, LCMV

Weakness West Nile virus, rabies

LCMV = Lymphocytic choriomeningitis virus.

KEY POINTS:

A When evaluating

patients with

altered mental

status, the

clinician must

distinguish

infectious

encephalitis

from

encephalopathy

as well as

postinfectious

or parainfec-

tious immune-

mediated

neurological

syndromes

such as acute

disseminated

encephalo-

myelitis.

A In any given

patient, the

most urgent

distinctions to

be drawn

center on

identification of

bacterial

meningitis and/

or herpes

simplex virus

encephalitis.

A The hallmark of

both viral

meningitis and

encephalitis is

the acute onset

of a febrile

illness

accompanied

by headache

and, often,

nuchal rigidity.


72

TABLE 3-8 Laboratory Evaluation for Identification of Specific Viral Agents CausingAcute Meningitis and Encephalitis

VirusPolymeraseChain Reaction Serology* Culture Specimens

Serum CSF Serum CSF Throat Rectal Blood CSF Other

Enterovirus + ++ + � + ++ +/� ++

Poliovirus + ++ +y � + ++ � � Urine

Arboviruses +z +z ++ ++ � � ++ +/�

Herpes simplex virus 1and herpes simplex virus 2

� ++ +/� + � � � � Skin vesicle,brain tissuex

Varicella-zoster virus ++ + +y

++ � � � + Skin vesiclex

Cytomegalovirus + ++ + ++ + � + Rare Urine

Epstein-Barr virus + + ++ ++ +/� � +/� +/�

Human herpesvirus 6 +/� +/� +/� � � � +z +z

Lymphocyticchoriomeningitisvirus

� + ++ ++ +/� � + ++ Urine

Adenovirus � + +/� +/� ++ + � + Conjunctivalswab, stool,electronmicroscopy

Mumps � � +y

+ ++ � +/� ++ Urine, saliva

Measles � +z +y

+ + � + � Urine

Humanimmunodeficiencyvirus

++ + + � � � +/� �

Rabies � + ++ ++ � � � + Saliva, braintissue, nuchalskin biopsy,cornealimpressionx

Influenza � � +/� � ++x � � �

Parainfluenza � � +/� � ++ � � �

Parvovirus ++ � + � � � � �

West Nile � +/�k ++ ++ � � � �

++ Extremely effective for diagnosis.+ Effective test for diagnosis.+/� Variable effectiveness.� Not useful.CSF = cerebrospinal fluid.

*Serological indexing, which compares CSF to serum-specific antibody levels in reference to total CSF, and serum albuminor total immunoglobulin may be required for definitive diagnosis. Fourfold rise in immunoglobulin G (IgG) from acute toconvalescent specimens or single positive immunoglobulin M (IgM) may also be diagnostic.ySerology may be difficult to interpret in vaccinated patients or postviral setting. In these patients, presence of IgM indicatesactive or reactivated viral disease rather than past immunity.zNot widely available but can be sent to research laboratories.xDirect fluorescent antibody test (DFA) on tissues or secretions is more rapid and may be more sensitive than culturemethods. DFA has replaced Tzanck prep, which is less sensitive and specific.kMost helpful in immunocompromised patients in whom viremia is prolonged/persistent.



synthesis of antibody, directed againsta particular viral pathogen, is highlysuggestive of its role in CNS disease;these tests are, however, time-consum-ing and not highly sensitive.

The most promising developmentfor diagnosis of CNS infection is thePCR technique, which has the capa-bility of detecting minute amounts ofviral DNA or RNA in CSF or other bodyfluids (DeBiasi and Tyler, 2004; DeBiasiand Tyler, 2000). PCR has improvedthe rapidity and accuracy of diagnosisof viral CNS infections, enhanced theunderstanding of pathogenesis, andhelped identify additional, previouslyunknown infectious causes of CNSdisease. By making quick and precisediagnoses, appropriate treatments canbe instituted and unnecessary or inva-sive investigations can be avoided. PCRfor HSV and EV has had the most dra-matic impact onmanagement of patientswith viral meningitis and encephalitisto date (see below).

MRI and computed tomography (CT)scan can also provideuseful informationin the evaluation of CNS infection.Although CT scans may demonstrateabnormalities in the setting of enceph-alitis, with hypodensity of involvedbrain parenchyma and irregular zonesof contrast enhancement, such changesare often slow to develop and arefrequently nonspecific. MRI with gado-linium contrast is by far more sensitiveand is the neuroimaging procedure ofchoice in most cases. Changes in acuteencephalitis may include edema andabnormalities of the basal ganglia,cortex, and gray-white matter junction.Focal abnormalities on MRI may sug-gest particular diagnoses, such as T1-hypointense and T2-hyperintense sig-nal in orbitofrontal and temporal lobeareas in HSV encephalitis. MRI may alsobe helpful in distinguishing encephalitisfrom ADEM, in which prominent areasof demyelination (often symmetrical) ofspinal cord, white matter, and basal

ganglia are common, as has alreadybeen discussed. Positron emission to-mography and single-photon emissionCT imaging are newer modalities thatmay provide even more sensitive func-tional and metabolic data in the settingof viral encephalitis. However, thesestudies are costly, complex, and notreadily available in many areas (Steineret al, 2005).

The three most common causes ofviral meningitis and encephalitis inNorth America are EVs, arboviruses(particularly West Nile virus), andHSV. In adolescents and adults herpessimplex virus 1 (HSV-1) more com-monly causes encephalitis, whereasHSV-2 commonly causes meningitis.Less common, but not rare, etiologiesof viral meningitis and/or encephalitisinclude LCMV, HIV, other herpes viruses(eg, humanherpesvirus 6 [HHV-6], EBV,Cytomegalovirus, VZV), and rabies.

Enteroviruses

Since the eradication of poliovirusfrom the Western Hemisphere, non-polio EVs are the most commonly im-plicated group of viruses in patientswith viral meningitis (Rotbart, 1997).The EV family comprises nearly 70different serotypes within the Picorna-virus family. They can be subgroupedinto the polioviruses, coxsackie virusesA and B, echoviruses, and the newersequentiallynumberedEVs.Thestrainsmost commonly isolated in asepticmeningitis are coxsackie A9, B3, B4,B5, and echovirus 4, 6, 7, 9, 11, 18, and30. Typically, EV infections are eitherasymptomatic or result inmild disease,and fewer than one in 500 infectionsresults in aseptic meningitis. Morethan 75,000 cases of EV meningitisoccur in the United States each year.Spread of infection is by the fecal-oraland, occasionally, respiratory routes.

Outbreaks tend to cluster in thelate summer and early fall and maybe associated with pharyngitis and

73

KEY POINTS:

A Historical points

that may help

pinpoint a

specific viral

infection

include the

season of

year (fall for

enteroviruses,

summer/fall for

arboviruses),

travel history

(regional

arboviruses,

viruses with

foreign

distributions),

knowledge of

diseases

prevalent

within the

community

(enteroviral or

arboviral

outbreaks),

history of

animal

exposure

(rabies,

lymphocytic

choriomeningi-

tis virus), or

mosquito/tick

(arboviruses)

exposure.

A The tropism of

viruses for

different cell

types within the

CNS may lead

to characteristic

neurological

findings.

A The presence of

unusual

physical

findings can

better help

define a specific

viral diagnosis.


gastrointestinal symptoms such asanorexia, vomiting, or diarrhea. Otherfindings suggestive of enteroviral in-fection include the enanthem ofherpangina or the exanthem of hand-foot-mouth syndrome. Onset of symp-toms is usually sudden with feverusually under 40oC as a consistentfinding. Although EV is the most com-mon cause of aseptic meningitis inadults as well as in the pediatric popu-lation, children are epidemiologicallyoverrepresented as victims of entero-viral infection (Case 3-1). Fortunately,enteroviral meningitis occurring be-yond the neonatal period in normalhosts is only rarely associated withsevere disease or subsequent neuro-logical deficits (Sawyer, 1999).

Although more commonly the etio-logical agent in aseptic meningitis, EVsmay also cause encephalitis, particu-larly in immunodeficient patients withagammaglobulinemia and in neonates.EV strain 70 has been implicated mostfrequently in instances of encephalitis.

In addition to being one of the majorcausative agents of hand-foot-and-mouth disease, EV strain 71 has alsobeen reported in association with moresevere neurological illness, includingpoliomyelitislike paralysis and fulmi-nant brain stem encephalitis. Epide-mics of severe EV71 disease have re-cently occurred in children in Taiwan(50 deaths in 1998) and Malaysia(30 deaths in 1997). In neonates, EVmeningoencephalitis is generally partof an overwhelming sepsislike illness,with up to 10% mortality. Infection ofhypogammaglobulinemic patients com-monly leads to a chronic and pro-gressive meningoencephalitis; thesepatients are treated with IV immuno-globulin therapy and, more recently,antivirals active against EVs (see below).Until recently, recovery of EVs fromthe CSF was the primary means of es-tablishing the diagnosis of CNS entero-viral disease. Recovery of nonpolio EVfrom throat or rectal swabs is alsosuggestive but not diagnostic in a

74

Case 3-1A 4-year-old girl presents during the autumn with headache, nuchalrigidity, and vomiting. She is noted to have skin lesions on her palms andsoles consisting of tender papules and clear vesicles, with surroundingerythema, and is found to have scattered mildly erythematous oralulcerations on her soft palate, gingiva, tip of her tongue, and inner lip.CSF contains 200 WBCs/mm3, with 50% polymorphonuclear cells and50% mononuclear cells, a protein content of 60 mg/dL, and glucose of60 mg/dL. The CSF-PCR study is positive for EV.

Comment. EVs are responsible for approximately 80% of asepticmeningitis cases, especially those occurring in the autumn. The pediatricpopulation is overrepresented. Patients may have other physical findingssuggesting enteroviral disease, such as the exanthem/enanthem ofhand-foot-mouth syndrome. CSF may demonstrate a pleocytosis withpolymorphonuclear predominance in the first 48 hours of illness, whichsubsequently shifts to mononuclear cells. CSF reverse transcriptase (RT)-PCRis more sensitive than culture for detection of EVs. Serious morbidity fromthis illness is rare, except in neonates and hypogammaglobulinemicpatients who may develop overwhelming sepsislike illness or evolve into achronic meningoencephalitis. Recently, enterovirus 71 outbreaksassociated with more severe illness, including brain stem encephalitisand paralytic poliomyelitislike presentations.

KEY POINTS:

A In most forms

of viral CNS

disease, the

cerebrospinal

fluid contains

a mild to

moderate

pleocytosis,

from a few to

up to 1000

WBCs/mm3; a

slightly lower

range is

usual in viral

encephalitis

(up to hundreds

of cells).

A A polymorpho-

nuclear

predominance

that persists is

typical of

HIV-associated

Cytomegalo-

virus polyradi-

culomyelitis,

as well as

West Nile

virus meningo-

encephalitis;

with these

exceptions, a

persistently

polymorpho-

nuclear

pleocytosis

is inconsistent

with viral

etiologies and

requires careful

exclusion of

bacterial and

nonviral

processes.



patient with aseptic meningitis, sinceshedding from a previous, unrelatedEV infection may occur in the upperrespiratory tract for 1 to 3 weeks and inthe feces for up to 8 weeks followinginfection. The clinical utility of obtain-ing a viral culture is further limited bythe amount of time required for theseagents to grow (days to weeks), rel-atively low sensitivity (65% to 75%), aswell as the poor cultivability of someEV serotypes. The development of areliable PCR for the detection of EV hasbeen extremely useful in this regard(Ramers et al, 2000). The PCR primersand probes are directed against the 50

noncoding region of the viral genome,which is highly conserved amongalmost all enteroviral strains. Theseprimers and probes are designed forreverse transcription of the viral RNAgenome combined with PCR (RT-PCR).The newest generation of the entero-viral PCR on CSF has 95% to 96%sensitivity and 100% specificity for the67 known strains of EV. For reasonsthat are not clear, CSF PCR is oftennegative in the setting of EV71 disease,but enteroviral genome is readilydetectable from throat, rectal, andserum specimens. Conventional RT-PCR methods can produce resultswithin 24 hours, and a more recentlydeveloped colorimetric assay can beperformed in approximately 5 hours.The availability of EV RT-PCR shouldallow for the more rapid diagnosis ofthis common illness and limit unnec-essary hospitalizations and empiricantibacterial therapy.

Although treatment has been sup-portive to date, resolution of theatomic structure of EVs by x-raycrystallographic studies has led to thedesign of new antiviral therapy. Thesestudies demonstrate a deep cleft orcanyon in the center of each proto-meric unit of the viral capsid intowhich the susceptible host cell’s spe-cific cellular receptor for the EV fits.

The drug pleconaril was specificallydesigned to fit into this cleft, and ittherefore can block the cell/receptorinteraction required for viral entry intothe host. A double-blind, placebo-controlled multicenter trial study of130 patients aged 14 to 65 years withenteroviral meningitis demonstratedresolution of headache and othermeningitis symptoms 2 days earlier(P=.04) in pleconaril-treated (200 mg3 times a day for 7 days) as comparedwith placebo-treated patients. Pre-liminary outcomes of potentially life-threatening enteroviral infections trea-ted with compassionate-use pleconaril(including chronic enteroviral menin-goencephalitis in agammaglobulinemicpatients, enteroviral encephalitis, andneonatal EV sepsis) have been repor-ted and demonstrate beneficial effecton clinical, virologic, laboratory, andradiologic parameters. Unfortunately,pleconaril is not currently in activeproduction nor easily obtained. Al-though pleconaril was not submittedto the US Food and Drug Admin-istration for approval for treatmentof enteroviral meningitis or other life-threatening enteroviral infections, thisdrug should be considered in the caseof more severe or overwhelming dis-ease, as in neonates and agammaglob-ulinemic patients, in the case that acompassionate-release program is re-instated in the future.

Herpes Simplex VirusTypes 1 and 2

Herpes viruses are double-strandedDNA viruses that share the ability toremain latent within the human host.They are commonly implicated in in-fections of the CNS. In adults, HSV-2 isclassically associated with aseptic men-ingitis, including recurrent episodes,and it also accounts for about 10%of cases of HSV-related encephalitis.Conversely, HSV-1 is more commonly

75

KEY POINTS:

A In some viral

infections such

as nonpolio

enterovirus,

lymphocytic

choriomeningitis

virus, mumps,

and rabies it

is possible to

culture virus

directly from

cerebrospinal

fluid.

A Acute and

convalescent

serological

diagnosis is

potentially

useful in some

viral infections,

but the utility of

this method is

limited by the

length of time

required to

firmly establish

acute infection

(weeks in many

cases), as well

as the limited

specificity

of many

serologies.

A The most

promising

development

for diagnosis of

CNS infection is

the polymerase

chain reaction

technique,

which has the

capability of

detecting

minute

amounts of

viral DNA or

RNA in

cerebrospinal

fluid or other

body fluids.


associated with encephalitis in adultsand less frequently with aseptic men-ingitis. This distinction is, however,not invariable, since neonates aremore likely to develop meningoen-cephalitis with either HSV-1 or HSV-2.

Aseptic meningitis. At the time oftheir first episode of genital herpes(generally HSV-2), approximately 36%of women and 11% of men have symp-toms of meningitis, including fever,headache, and nuchal rigidity. Ofthese patients, 20% will go on to haverecurrent episodes of meningitis. Themeningitis may result from viremicspread to the CNS or, alternatively,by direct invasion of the CNS viaascent from sacral nerve roots. Whenaseptic meningitis occurs in this set-ting, genital lesions are present anaverage of 1 week before CNS symp-toms. Other neurological symptomssuch as paraesthesias, urinary reten-tion, and transverse myelitis have been

described. Recovery is usually com-plete, although persistent or recurrentradiculopathy may occur. Treatmentwith acyclovir in the setting of primaryinfection is reasonable as it mayshorten the overall course of this formof HSV-2 infection, but it has noimpact on latency or genital recurren-ces. CSF viral cultures are invariablynegative during recurrent episodes ofmeningitis in these patients, althoughthe virus may be isolated during thefirst (primary) episode of meningitis.As in Case 3-2, diagnosis depends onPCR of the CSF, which currently hasa sensitivity of 95% and specificity of100% in experienced laboratories, witha turnaround time generally within48 hours.

A large subset of patients with thesyndrome of benign recurrent asepticmeningitis has been found to haveHSV-specific DNA detectable in theirCSF (DeBiasi and Tyler, 2000). In one

76

Case 3-2A 30-year-old man presents with fever, headache, and nuchal rigidity butotherwise appears well. There is no history of travel, rash, or precedentillness, although he has had a new sexual partner for the last 2 months, andhe has noticed itching and painful urination starting 1 week ago. Theneurological examination is normal. The CSF evaluation demonstrates150 predominantly mononuclear cells, with a protein of 45 mg/dL andglucose of 60 mg/dL. Penile examination shows multiple crusted erosionson an erythematous base with a few intact vesicular lesions also present.Culture of the lesions, as well as CSF-PCR, is positive for HSV.

Comment. Aseptic meningitis occurs in 11% to 36% of patients withprimary genital herpes (usually HSV-2), more commonly in women thanmen. Most patients with their primary episode of genital herpes areclinically asymptomatic; fewer than 10% of those with HIV-associatedaseptic meningitis report a history of genital lesions. Systemic symptoms(eg, fever, malaise, and headache) are more common in women than inmen. Localized itching, pain, and dysuria can occur. Genital lesions includemultiple vesicles with red bases that form pustules, rupture, and crust over.Treatment with acyclovir may shorten the duration of symptoms but has noimpact on latency or frequency of subsequent episodes. Neurologicalsequelae are unusual, but up to 20% of patients experience recurrentepisodes of meningitis, which likely reflects a subset of patients withbenign recurrent lymphocytic meningitis (Mollaret’s meningitis).

KEY POINTS:

A MRI with

gadolinium

contrast is

by far more

sensitive than

CT and is the

neuroimaging

procedure of

choice in most

cases in the

evaluation of

CNS infection.

A Focal

abnormalities

on MRI may

suggest

particular

diagnoses

such as T1-

hypointense

and T2-

hyperintense

signal in

orbitofrontal

and temporal

lobe areas

in herpes

simplex virus

encephalitis.

A The three most

common

causes of viral

meningitis and

encephalitis

in North

America are

enteroviruses,

arboviruses

(particularly

West Nile

virus), and

herpes simplex

virus.



of the largest series to date, 85% ofpatients had HSV detectable by PCR,of which 91% were HSV-2. These pa-tients are predominantly female andexperienced three to nine attacks ofmeningitis over a period of 2 to23 years. Of these patients, only 23%have a history of genital herpes, nonewith lesions concurrent with theirmost recent episodes of meningitis.

Encephalitis. As exemplified byCase 3-3, HSV-1 (and rarely HSV-2)is typically associated with focal en-cephalitis in adolescents and adults,and it carries a 70% mortality if un-treated; over 97% of survivors are leftwith permanent neurological deficits(Baringer, 2000). It is the most com-mon cause of sporadic, acute, focalencephalitis in the United States andaccounts for approximately 10% of allcases of encephalitis in the UnitedStates annually. Early recognition isessential because of the availability ofeffective antiviral therapy. HSV-1 en-cephalitis occurs throughout the yearwithout seasonal preference and inall age groups, although one third ofthe cases develop in patients youngerthan 20 years and 50% in those olderthan 50 years. It is possible that thisbimodal age distribution reflects pri-

mary infection in younger patients andreactivation of latent virus in olderindividuals. The majority of cases ofHSV encephalitis occurs in previouslyhealthy individuals. About 30% to60% of patients report a brief prodro-mal illness prior to the onset of en-cephalitis, the most common beingupper respiratory and gastrointestinalillnesses. Fever, headache, and alteredmental status are invariably presentand the patient may exhibit confusedor bizarre behavior. Vivid auditory,olfactory, or visual hallucinations areexperienced by 20% of patients. Sei-zures, focal, generalized, or both, occurin 75% of patients.

A variety of focal signs and symp-toms appear in 75% of patients thatmay help localize the disease to theinferior frontal and medial temporallobes. The most common finding ishemiparesis or motor weakness, whichoccurs in 45% of patients. Aphasia ofany degree of severity is particularlycommon (75%). Impaired memory,especially for events of the recentpast, may suggest medial temporallobe involvement. Other findings oc-casionally encountered include cra-nial nerve abnormalities, movementdisorders, eye movement abnormalities,

77

Case 3-3A 60-year-old man is brought to the hospital with aphasia, right-sidedweakness, fever, and confusion. A lumbar puncture demonstrates CSFwith 400 red blood cells (RBCs)/mm3, 30 WBCs/mm3 (predominantlymononuclear cells), glucose of 70 mg/dL, and protein of 60 mg/dL. Theelectroencephalogram (EEG) shows periodic high-voltage spike-waveactivity from the left temporal region, and an MRI documentsT1-hypointense and T2-hyperintense signal in cortex and gray-whitematter junction in the left temporal lobe. PCR of CSF for HSV is positive.

Comment. The main clue to a diagnosis of HSV in adults and adolescentsis evidence of focal disease, especially referable to the temporal lobe. Thepresence of RBCs in the CSF and mildly elevated protein are characteristicof HSV encephalitis but are not specific. Rapid institution of IV acyclovirtherapy is essential; treatment reduces mortality from 70% in untreatedpatients to 19%. Many patients have significant sequelae, despiteappropriate therapy.

KEY POINTS:

A Enteroviruses are

responsible for

approximately

80% of aseptic

meningitis

cases, especially

those occuring

in the autumn.

A Outbreaks of

enterovirus

meningitis tend

to cluster in the

late summer

and early fall

and may be

associated with

pharyngitis and

gastrointestinal

symptoms such

as anorexia,

vomiting, or

diarrhea.

A Enteroviral

meningitis

occuring

beyond the

neonatal period

in normal hosts

is only rarely

associated with

severe disease

or subsequent

neurological

deficits.

A Enteroviruses

may also cause

encephalitis,

particularly in

immuno-

deficient patients

with agamma-

globulinemia

and in

neonates.


frontal release signs, and autonomicinstability.

CSF abnormalities are generallysimilar to those found in other formsof viral encephalitis. Protein elevationsoccur in 90% but rarely exceed 200mg/dL. Hypoglycorrhachia is decidedlyunusual in HSV disease (less than 5%).RBCs are found in the CSF in 50%to 75% of cases but rarely exceed500 cells/mm3. The presence of CSFprotein elevation or of RBCs is sug-gestive of the diagnosis but is notunique to HSV encephalitis. Rarely,patients with HSV encephalitis failto have a CSF pleocytosis. A normalCSF cell count occurs in less than 5%of patients but may occur with greaterfrequency in immunocompromisedpatients, including those infected withHIV. EEG abnormalities may also pro-vide clues to diagnosis since 90% ofpatients have focal or generalizedslowing. The presence of periodicsharp-wave complexes in temporalleads superimposed on a slow-ampli-tude background is highly suggestiveof HSV. The sharp waves may bemonophasic or polyphasic; they lastfrom 100/ms to 1500/ms and occur at1-second to 5-second intervals. Thispattern is only rarely seen after the first2 weeks of illness. MRI (Figure 3-2)may be normal early in the course ofHSV encephalitis, but within days focaledema and hemorrhage are usuallyevident. MRI is much more sensitivethan CT scan, but eventually 60% to100% of patients will show someabnormality on CT scan as well.

In the past, cerebral biopsy withvirus isolation had been the goldstandard for diagnosis of HSV enceph-alitis. However, this has been replacedby detection of HSV DNA by PCR inthe CSF (Lakeman and Whitley, 1995).If done with optimal techniques in anexperienced laboratory, the specificityis 100% and the sensitivity 95% inmost recent studies. However, multi-

ple groups have reported the occur-rence of false-negative (initially nega-tive, subsequently positive) CSF PCRfor HSV, leading to the realization thattesting performed within the first72 hours of symptoms may not besensitive. A negative PCR result in apatient with clinically compatible dis-ease and no alternative identifiedetiology should not deter treatmentfor this treatable cause of encephalitis.The CSF PCR remains positive for ap-proximately 2 weeks following onsetof illness, but sensitivity declines rap-idly after that point. Brief (less than72 hours) antiviral therapy does notsignificantly reduce the likelihood of apositive PCR, but the amount of viralDNA declines with prolonged thera-py. Almost all patients have negativePCR tests after the completion of a 14-day course of acyclovir. CSF serologyto detect the presence of intrathecalproduction of antibody may providesupportive evidence of HSV infection.Serological studies are less sensitiveand less specific than CSF PCR but maybe useful in late diagnosis when viralnucleic acid is no longer detectable.More recently developed type-specificHSV serology (immunoglobulin G [IgG]and IgM) may have improved sensiti-vity and specificity and may be a usefuladjunct to diagnosis. Treatment withacyclovir (at a dose of 30 mg/kg/dIV divided every 8 hours for 14 to21 days in adults, and 60 mg/kg/ddivided every 8 hours for 21 daysin neonates, is the management ofchoice (see below).

Neonatal herpes simplex virusdisease. Infants who acquire HSV,(HSV-2 more commonly than HSV-1)during the newborn period developinfection of the CNS in over 50% ofcases. Infection most frequently occursat the time of birth from the maternalgenital tract (85%) but may also occur asa result of transplacental transmission(5%)or in thepostpartumperiod (10%).

78

KEY POINTS:

A Nearly 70

serotypes of

enteroviruses

(predominantly

coxsackievirus

and echovirus)

cause viral

meningitis and,

less commonly,

encephalitis.

A Aseptic

meningitis

occurs in 11%

to 36% of

patients with

primary genital

herpes (usually

HSV-2), more

commonly in

women than

men.

A Diagnosis of

herpes simplex

virus aseptic

meningitis

depends on

polymerase

chain reaction

of the CSF,

which currently

has a sensitivity

of 95% and

specificity of

100% in

experienced

laboratories,

with a

turnaround

time generally

within 48 hours.

A A large subset of

patients with

the syndrome of

benign recurrent

aseptic

meningitis has

been found to

have herpes

simplex virus–

specific DNA

detectable in

their CSF.



CNS disease occurs in primarily twoforms: disseminated disease, with multi-organ involvement such as lung andliver in addition to the CNS, or diseaselocalized to the CNS with or withoutaccompanying characteristic skin vesi-cles (Case 3-4). The route to the brainin infants with multiorgan dissemina-tion is likely hematogenous and associ-ated with a diffuse encephalitic process.Alternatively, nondisseminated neuro-nal transmission may occur with diseaselimited to the CNS only (unitemporalor bitemporal). Importantly, infants(usually aged 2 to 10 weeks) with HSVmeningoencephalitis may present withisolated skin, eye, and mouth vesicles inabsence of fever, and little or nosymptomatology suggesting CNS dis-ease. In this age group, it is impera-tive to evaluate the CSF for evidenceof pleocytosis and HSV DNA despitean otherwise normal-appearing infant.Treatment andoutcomeofneonatalHSVdisease are described below (Kimberlin,2004; Whitley and Kimberlin, 1999).

Arboviruses

The rubric arbovirus is an umbrella termdefining viral agents that are transmit-ted to humans by mosquito and tickvectors. They persist in nature incomplex cycles involving birds andmammals, which serve as reservoirs ofdisease. When transmitted to humans,they can cause fever, headache, menin-gitis, encephalitis, and even death. Thethree primary families into which arbo-viruses are divided are: (1) togaviruses(subdivided in turn into flaviviruses andalphaviruses), (2) reoviruses, and (3)bunyaviruses. All are single-strandedRNA viruses (Table 3-1). The mostcommon arboviruses affecting hu-mans in North America are West Nilevirus, St Louis encephalitis (SLE) virus(flaviviruses), California (La Crosse)encephalitisvirus(bunyavirus),andeast-ern equine encephalomyelitis (alpha-virus). Western equine encephalitis,Venezuelan equine encephalitis, Colo-rado tick fever virus, and Powassanvirus are rare but important arboviruses

79

Case 3-4A 3-week-old infant, born at full term by uncomplicated vaginaldelivery, presents with poor feeding, lethargy, and a temperature of38.38C. Findings from physical examination are unremarkable andwithout focal neurological deficits. Liver enzymes are mildly elevated;leukopenia and thrombocytopenia are evident in the blood count. TheCSF contains 200 WBCs (100% mononuclear) with a protein of 120 mg/dL and glucose of 60 mg/dL. Blood, urine, and CSF cultures are obtained;and ampicillin, cefotaxime, and acyclovir are administered IV. CSF PCRfor HSV is positive.

Comment. HSV disease of the newborn presents as one of three distinctentities: (1) Disseminated disease (20%), which presents as a nonspecificmultiorgan sepsislike syndrome with meningoencephalitis, pneumonitis,hepatitis and coagulopathy; (2) CNS disease (35%), characterized bymeningoencephalitis (with detectable HSV by CSF PCR), with or withoutaccompanying classic vesicular skin lesions; and (3) skin, eye, mouth disease(45%), in which HSV is limited to mucosal and/or skin surfaces only.Although infants with CNS disease may present with relatively mildsymptoms of low-grade fever and lethargy, mortality approaches 50% inuntreated infants. With appropriately instituted acyclovir therapy,mortality has been reduced to 14%, but severe neurological sequelae stilloccur in two thirds of treated, surviving infants.

KEY POINTS:

A Herpes simplex

virus 1 (and

rarely herpes

simplex virus 2)

is typically

associated

with focal

encephalitis in

adolescents

and adults and

carries a 70%

mortality if

untreated; over

97% of

survivors are

left with

permanent

neurological

deficits.

A The most

common

finding inherpes

simplex virus

encephalitis is

hemiparesis

or motor

weakness,

which occurs in

45% of

patients.

A Red blood cells in

herpes simplex

virus are found

in the CSF in

50% to 75% of

cases but rarely

exceed 500

cells/mm3.


causing disease in North America. Thesevirusesexist inwell-definedgeographicalregions, which vary from strain to strain.Theageof targetedvictimsandvirulencealso vary among arboviruses. Most casesoccur in thesummermonthssince trans-mission depends on the bite of mos-quito or tick. Differences among theseare summarized in Table 3-9 (Calisher,1994; Lowry, 1997).

West Nile virus. Although neverobserved in the Western Hemisphereprior to 1999, West Nile virus hasemerged as the most common causeof epidemic meningoencephalitis inNorth America. First isolated in 1937from a febrile patient in Uganda,West Nile virus is widely distributedthroughout the world. The virus hasrecently exhibited a propensity forincreased neurovirulence and hascaused major outbreaks of meningoen-cephalitis in Eastern Europe andthe Middle East throughout the lastdecade. The first cases ofWest Nile virusdisease in North America were reportedin New York state in the summer of1999, with the simultaneous occurrenceof an unusual number of deaths ofexotic birds at the Bronx Zoo as wellas crows in the New York City metro-politan area, soon followed by anunusually high incidence of encephalitisin humans (66 cases and 9 deaths).Analysis of sequences of genome frag-ments isolated from dead birds andmosquitoes (by RT-PCR) revealed WestNile virus, which was 99.8% identical tosequences analyzed from human iso-lates/autopsy specimens, as well as a1998 isolate from the brain of a deadIsraeli goose. As the virus has spreadprolifically within bird reservoirs (great-er than 200 species) and an unprece-dented number of mosquito species insubsequent years, the number andgeographical range of human cases inthe United States have greatly expand-ed: 4156 cases/284 deaths in 2002; 9864cases (2866 neuroinvasive)/264 deaths

in 2003; and 2539 cases (1142 neuro-invasive)/100 deaths in 2004. Currently,West Nile virus has been identified in allparts of the United States with theexception of Washington, Alaska, andHawaii. Transmission to humans occurspredominantly followingmosquito bite,but cases have also resulted fromblood-product transfusion, organ transplanta-tion, percutaneous (occupational), aswell as intrauterine and breastfeedingexposures.

Eighty percent of individuals infectedwith West Nile virus remain completelyasymptomatic. Twenty percent devel-op a self-limited flulike illness follow-ing a 2- to 14-day incubation period,consisting of fever, myalgia, headache,and gastrointestinal disturbance, withnonspecific maculopapular rash in 50%of cases. Neuroinvasive disease occursin less than 1% of cases (1 in 150infected individuals). Neuroinvasivepresentations are varied and includeaseptic meningitis, meningoencephali-tis, and acute flaccid paralysis syn-drome (poliomyelitislike). Brain stemencephalitis, movement disorders, cra-nial neuropathies, polyneuropathy/rad-iculopathy, and optic neuritis are alsorecognized West Nile virus neurologi-cal presentations. The proportion ofneuroinvasive disease manifesting asmeningitis as opposed to encephalitisor myelitis has varied greatly within agiven epidemic season and locale.Persons more than 50 years of ageare at highest risk (20-fold increase)for developing meningoencephalitis(Case 3-5). Despite being equally sus-ceptible to West Nile virus infection,neuroinvasive disease is very uncom-mon in pediatric patients, althoughall three forms of neuroinvasive dis-ease have been reported in this agegroup.

Several clinical features are distinc-tive of West Nile virus neurologicalinfection. Muscle weakness has been aprominent finding in patients with

80

KEY POINTS:

A A normal CSF cell

count occurs in

less than 5%

of patients

with herpes

simplex virus

encephalitis but

may occur

with greater

frequency in

immuno-

compromised

patients,

including those

infected with

human

immuno-

deficiency virus.

A The presence on

EEG of periodic

sharp-wave

complexes in

temporal leads

superimposed

on a slow

amplitude

background

is highly

suggestive of

herpes simplex

virus.

A Cerebral biopsy

with virus

isolation had

been the gold

standard for

diagnosis of

herpes

simplex virus

encephalitis.

However, this

has been

replaced by

detection of

herpes simplex

virus DNA by

polymerase

chain reaction

in the CSF.



either meningitis or meningoenceph-alitis (30% to 50%). Other distinctivefindings have included hyporeflexia(30%) and cranial neuropathies (20%),most commonly facial palsy. Posturalor kinetic tremor has been reportedin up to 80% of cases of meningitisand meningoencephalitis. Myoclonushas also been appreciated in 20% and40%, respectively. Parkinsonian fea-tures, including rigidity, bradykinesia,and postural instability, have beennoted in up to 75% of patients withmeningoencephalitis.

Patients with West Nile virusacute flaccid paralysis syndrome haveacute onset and rapid progression ofasymmetrical flaccid weakness withassociated hyporeflexia or areflexia ininvolved limbs. Acute flaccid paralysismay occur in isolation or in combina-tion with meningitis or meningoen-cephalitis. Weakness may occur in asingle limb or any combination of thefour extremities, and respiratory insuf-ficiency may also occur. Sensation ispreserved. Bowel and bladder dysfunc-tion occurs in one third of patients.Unlike meningoencephalitis, the WestNile virus acute flaccid paralysis syn-drome does not have a predilection forthe elderly and has been reported in allage groups. Electromyography studiesdemonstrate reduced amplitudes ofcompound muscle action potentialswith normal amplitudes of sensorynerve action potentials. Follow-upstudies 3 or more weeks later mayshow denervation changes. Pathologi-cal studies have demonstrated acuteanterior poliomyelitis in some cases.

Typical CSF findings inWest Nile virusneuroinvasive disease include pleocyto-sis (polymorphonuclear or lymphocyticpredominance) with elevated proteinand normal glucose levels. Featuresof the pleocytosis that appear to beunique to West Nile virus include aprolonged (up to 1 week) polymor-phonuclear predominance and a plas-

macytoid appearance to the lympho-cytes. MRI is unremarkable in themajority of cases; however, abnormal-ities of the brain stem and deepnuclei (thalamus, basal ganglia, sub-stantia nigra) as well as leptomenin-geal enhancement have been re-ported in approximately 30% of casesof meningoencephalitis. Patients withacute flaccid paralysis syndrome mayshow signal abnormalities within thecord, but most do not. EEG abnorma-lities occur in the majority of patientswith encephalitis; 60% to 100% demon-strate diffuse irregular slowing, whereasfocal sharp waves or seizure activity areuncommon. Serological and molecularmethods for diagnosis are discussedbelow (in the context of other arboviralinfections).

Treatment of West Nile virus (andall arboviral) disease is generally sup-portive, and person-to-person trans-mission does not occur. Severaltreatment modalities for West Nile virusCNS disease are currently being evalu-ated, including passive immunizationusing IV immunoglobulin with high titerto West Nile virus (multicenter random-ized trial), interferon alpha, and anti-sense oligomer constructs. Ribavirinappears to have limited clinical efficacydespite demonstrated efficacy againstWest Nile virus in vitro. These treat-ments may prove to be most usefulfor affected immunocompromised pa-tients, in whom disease is most severe.An effective formalin-inactivated equinevaccine exists but cannot be used inhumans. Much progress toward thedevelopment of a human West Nilevirus vaccine has been made, andclinical trials of a chimeric vaccine, inwhich West Nile virus genes are in-serted into the genetic background ofanother flavivirus, are underway. Theoverall mortality rate for West Nile virusinfection is 2% to 7%; the mortality at-tributable to encephalitis is estimated at12% to 15% and is higher in the elderly

81

KEY POINTS:

A Multiple groups

have reported

the occurrence

of false-

negative

(initially

negative,

subsequently

positive) CSF

polymerase

chain reaction

for herpes

simplex virus,

leading to the

realization that

testing

performed

within the first

72 hours of

symptoms may

not be

sensitive.

A Treatment with

acyclovir

(at a dose of

30mg/kg/d

intravenously

divided every

8 hours for 14

to 21 days in

adults, and

60 mg/kg/d

divided every

8 hours for

21 days in

neonates, is the

management

of choice for

herpes

simplex virus

encephalitis.

A Infants who

acquire herpes

simplex virus,

(HSV-2 more

commonly than

HSV-1) during

the newborn

period develop

infection of the

CNS in over

50% of cases.


population (35%). Long-term outcomeand sequelae from West Nile virus me-ningoencephalitis are not fully knownat this time, but several reports havedocumented prolonged fatigue,myalgia,residual tremor, and parkinsonism. Pa-tients with acute flaccid paralysis havethe worst overall prognosis and oftenhave permanent disability (Petersen andMarfin, 2002; Tyler, 2004).

St Louis encephalitis virus.SLE virus remains one of the mostimportant (although only third mostcommon) causes of epidemic enceph-alitis in North America since it carries ahigh rate of neurological sequelae(25%) and mortality (up to 20%).Since 1964, 4478 reported humancases of SLE have been reported, withan average of 128 cases reportedannually. Cases of SLE are widespreadthroughout the United States, occur-

ring periodically in focal outbreaks (upto 3000 cases per year in large out-breaks, such as 1975). The most recentoutbreak of SLE occurred in NewOrleans, Louisiana, in 1999 with 20reported cases. The risk of encephali-tis following infection with SLE virusincreases with age, with almost 90% ofelderly patients developing encephali-tis (Case 3-6). Humans infected withSLE may exhibit a wide array of clinicalmanifestations, but most are asymp-tomatic. If symptomatic, fully 40% mayhave only fever and headache as theircomplaint. Urinary complaints occurin up to 25% of patients with SLE andcranial nerve palsies in 20%.

California (La Crosse) virus en-cephalitis. California (La Crosse) vi-rus encephalitis is a much milderdisease, with only rare incidence ofneurological sequelae and less than

82

TABLE 3-9 Details of North American Arboviruses

Agent Geographical Distribution Reservoir Vector

West Nile Throughout United States Birds Mosquito

St Louis Throughout United States butgreatest prevalence in Texas,Florida, and Ohio-MississippiRiver Valley

Birds Mosquito

California (La Crosse) Midwest and Northeast UnitedStates, southern Canada

Chipmunk, squirrel, smallmammals

Mosquito

Eastern equine Atlantic and Gulf coasts, GreatLakes region

Birds Mosquito

Western equine Western United States andCanada

Birds and small mammals Mosquito

Venezuelan equine Texas and Florida Horses, small animals Mosquito

Powassan North central United States,Eastern Canada

Squirrel, porcupine, groundhog Tick

Colorado tick fever United States and CanadianRocky Mountains

Chipmunk, squirrel, rodent Tick



1% mortality. An average of 70 casesper year have been reported in theUnited States since 1964. Ninety per-cent of cases occur in children lessthan 15 years of age. In areas endemicfor California (La Crosse) virus en-cephalitis (ie, the Midwest and north-east United States, southern Canada),a high proportion of the populationappears to have been infected. Sero-positivity rates as high as 12% to 18%have been reported in some studies,and many experts believe that thesenumbers underestimate the true prev-alence in endemic populations. Mostinfections are asymptomatic. Whenillness does occur, onset is abrupt.Patients present with fever, chills, andheadache and may also have photo-phobia, abdominal pain, or upperrespiratory illness symptoms. Fortypercent have seizures.

Eastern equine encephalitis.Eastern equine encephalitis virus pro-duces the most severe illness amongarboviruses, with 50% to 70% mortalityand neurological sequelae among80% of survivors. Fortunately, thisvirus infection occurs only infrequent-ly in the United States. Only four casesfrom four states were reported to theCDC in 1998 (median of four cases peryear from 1964 to 1998). The diseaseoccurs almost exclusively along theAtlantic and Gulf coasts, as well asin the Great Lakes region. Onset istypically abrupt. Patients present withhigh fever, convulsions, and rapidmental deterioration, with progressionto coma. Young children are particu-larly susceptible and have a high rate ofneurological sequelae if they survive.

Western equine encephalitis. Nocases of Western equine encephalitis

83

TABLE 3-9 Continued

Season Group Affected Mortality Neurological Sequelae

Peak in Juneto September(Cases reportedyear-round)

Severe disease inadults over 50 years

12% to 15% of patientswith severe disease(but less than 1% havesevere disease)

Common (varies withpresentation)

June to August Adults over 50 years 2% to 20% 25% to 50% mildLess than 10% severe

June to September Children Less than 1% Rare

June to August Children 50% to 80% 80% (especially young)

June to September Infants, adults over Adults: 3% to 5% Adults: 5%

50 years Infants: 10% to 20% Infants: 50%

Rainy season Adults Less than 1% Rare

May to December

Spring/summer Rare 50%

March to September Children and adults Less than 1% Rare


have been reported in the UnitedStates since 1994, with the last epidem-ic occurring in 1987 in Colorado. Thesingle largest outbreak occurred in1941, with over 3000 human cases rec-ognized. Equine surveillance continuesin many western states and Canada,since equine cases precede human

cases by 2 to 3 weeks. Infants appearto be particularly susceptible to CNSdisease; 20% of patients are less than 1year of age.

Venezuelan equine encephalitis.The strain of Venezuelan equine en-cephalitis virus endemic in the south-ern United States only rarely causes

84 Case 3-6A 70-year-old man presents in July with low-grade fever, headache, andurinary incontinence followed by generalized seizures. He had spent theprior week fishing with his grandchildren at a wooded lake. The CSF viralculture is negative, but CSF PCR is positive for SLE virus, and acute/convalescent titers show a fourfold rise in IgG for SLE virus. In the nextseveral weeks, a notable increased incidence of aseptic meningitis andfebrile seizures occurs in local emergency departments.

Comment. SLE virus is transmitted by mosquito vector, most commonlyduring the summer months. More severe disease is noted in elderlypatients, with up to 90% developing frank encephalitis. Although lesscommon than California (La Crosse) virus, the geographical distribution isless restricted, and widespread outbreaks have occurred throughout mostof the United States. Neurological sequelae result in 25% of infectedpatients.

KEY POINTS:

A The rubric

arbovirus is an

umbrella term

defining viral

agents that are

transmitted to

humans by

mosquito and

tick vectors.

A Most cases of

arbovirus occur

in the summer

months since

transmission

depends on

the bite of

mosquito

or tick.

A St Louis

encephalitis

virus remains

one of the most

important

(although only

third most

common)

causes of

epidemic

encephalitis in

North America

since it carries a

high rate of

neurological

sequelae (25%)

and mortality

(up to 20%).

A Cases of St Louis

encephalitis are

widespread

throughout the

United States,

occurring

periodically in

focal

outbreaks.

Case 3-5A 70-year-old man presents in midsummer with headache, confusion, leftleg weakness, and diplopia, following a 3-day history of high fever (398C),nausea, and nonspecific rash. His history is otherwise unremarkable, otherthan multiple mosquito bites during the previous 3 weeks. Findings fromthe physical examination are remarkable for altered mental status,hyporeflexia of the left lower extremity, and a kinetic tremor. An MRI scanof the brain is normal. Analysis of CSF reveals 100 WBCs/mm3 withpolymorphonuclear predominance, glucose 60 units, and protein90 mg/dL. CSF for West Nile virus IgM is positive.

Comment. West Nile virus has emerged as the most common causeof epidemic meningoencephalitis in North America and the mostcommon of the arboviral encephalitides in the United States. Elderly andimmunocompromised persons are at disproportionate risk for severeneuroinvasive disease. Neuroinvasive presentations include asepticmeningitis, meningoencephalitis, and poliomyelitislike paralysis. Motorweakness is a prominent associated finding in 50% of cases of West Nilevirus meningoencephalitis. Cranial neuropathies, movement disorders,gastrointestinal complaints, and rash are also seen in a significantproportion of cases (see discussion above). Treatment is supportive,although IV immune globulin with high titer to West Nile virus and othermodalities are being investigated as potential therapeutic interventions.



encephalitis. The majority of cases arepresumed to be asymptomatic; a flulikesyndrome of fever, malaise, headache,myalgia/arthralgia, and gastrointestinalsymptomsmay be noted. Encephalitis isfound in about 6% of these patients andhas less than 1% mortality with rareneurological sequelae.

Colorado tick fever. Colorado tickfever virus is likely under-recognized asa cause of aseptic meningitis and en-cephalitis during the summer monthsamong residents of the United Statesand Canadian Rocky Mountain regions(average 200 reported cases per year).After an incubation period of 3 to 6 days,symptoms appear abruptly and include5 to 8 days of high fever, chills, joint/muscle pain, severe headache, ocularpain, conjunctival injection, and nausea.A transitory petechial or maculopapularrash is present occasionally. Coloradotick fever virus classically causes abiphasic illness with remission of initialsymptoms for 2 to 3 days, followed by arelapse of 2 to 3 days in 50% of patients.Leukopenia and thrombocytopenia arecommon. The vast majority of cases aremild and uncomplicated with an excel-lent prognosis. Antibody to Coloradotick fever virus is not detected until 1 to2 weeks after the illness; viremia ispresent for months. Virus may beisolated from blood and CSF. A PCRhas been developed for diagnostic usein endemic regions.

Powassan virus. Powassan virus isan extremely rare and severe cause ofencephalitis, distributed in the northcentral United States and eastern Can-ada. In reported cases, the onset issudden with headache, high fever, andseizures common. Prodromal symptomsinclude sore throat, sleepiness, disorien-tation, and headache 1 week following atick bite. Most patients have focal le-sions, and sequelae such as hemiplegia,recurrent severe headache, and dam-age to upper cervical cord have beenreported in nearly 50% of survivors.

Additionally, many other arbovi-ruses exist that are endemic in foreigncountries and must be considered inthe returning traveler with infectiousCNS disease (Table 3-2).

Diagnosis of arboviral disease isdependent upon specific serologicalstudies in the setting of mosquito ortick exposure in an appropriate geo-graphical region. The presence of arbo-virus-specific IgM in CSF is diagnostic ofneuroinvasive disease (since IgM anti-bodies do not cross the blood-brainbarrier), indicating intrathecal synthesisof antibody from local antigen expo-sure. IgM antibody capture enzyme-linked immunoassay (ELISA) from acuteCSF is the most sensitive and specificmeans of making the diagnosis and hasbeen developed for each of the arbo-viral encephalitides described here. Afourfold change in specific IgG antibody(2 to 3 weeks after presentation) is alsodiagnostic. Viral culture of CSF or serumhas low yield. CSF PCR tests for specificarboviral diseases are not yet widelyavailable except in specialized researchlaboratories; serology thus remains themainstay of diagnosis.

As in other arboviral diseases, CSFserology for West Nile virus is thediagnostic test of choice. West Nile virusIgM is detectable in CSF and serum inthe majority (greater than 90%) ofinfected individuals by day 8 of illness.It should be noted that West Nile virusIgM antibody responses may persist formore than 500 days in some individuals;thus serum IgM cannot definitivelydistinguish between patients who hadremote asymptomatic or non-neuro-invasive infection and those with activeCNS disease. West Nile virus IgG peaksat 4 weeks postinfection and persistslifelong. CSF PCR is negative in 30% ofimmunocompetent individuals withneuroinvasive disease, likely reflectiveof a short-lived viremia which precedessymptom onset. In immunocompro-mised individuals who may not mount

85

KEY POINTS:

A In areas endemic

for California

(La Crosse) virus

encephalitis

(ie, the Midwest

and northeast

United States,

southern

Canada), a high

proportion of

the population

appears to have

been infected.

A Eastern equine

encephalitis

virus produces

the most severe

illness among

arboviruses,

with 50% to

70% mortality

and

neurological

sequelae

among 80%

of survivors.

A No cases of

Western equine

encephalitis

have been

reported in the

United States

since 1994,

with the last

epidemic

occurring in

1987 in

Colorado.

A The strain of

Venezuelan

equine

encephalitis

virus endemic

in the southern

United States

only rarely

causes

encephalitis.


an appropriate neutralizing antibodyresponse, CSF PCR may be a usefuldiagnostic modality. Nucleic acid ampli-fication tests are also highly effectivefor the purpose of screening bloodproducts and organ tissues donated byasymptomatic infected individuals. In2004, with the employment of universalWest Nile virus screening measuresmore than 500 infected specimens wereintercepted and prevented from enter-ing the donor supply.

Since the advent of West Nile virusdisease, surveillance programs in theUnited States have been greatly expand-ed to detect enzootic arboviral activity inmosquito, sentinel (ie, equine, chick-ens), or wild bird populations. Wide-spread, coordinated local and nationalsurveillance andpublic healthmeasures,including public education, mosquitoabatement programs, and screening ofblood products have been importantcontrolmeasures to limit disease duringperiods of epidemic activity. Humanrisk has been reduced through vectorcontrol and modification of humanactivitypatterns(eg,minimizationofout-door activity during evening and night-time hours, ensuring proper screeningof doors and windows, and appro-priate use of insect repellents andprotective clothing). Irrigation manage-ment has also had an impact on theincidence of arboviral diseases.

LESS COMMON CAUSES OFVIRAL MENINGITIS ANDENCEPHALITIS

LymphocyticChoriomeningitis Virus

LCMV should be considered in patientswith aseptic meningitis who have hadexposure to hamsters or rodents, es-pecially if the illness occurs in the fall orwinter and is associated with moderateCSF pleocytosis (up to 1000 WBCs/mm3) and hypoglycorrhachia.

Predominant symptoms include fe-ver, headache, and myalgia, describedas severe and involving large musclegroups as well as ocular muscles. Somepatients have an associated rash (ery-thematous eruptions on face andtrunk, sometimes with desquamation)in conjunction with lymphadenopa-thy. Following 3 to 5 days of non-specific illness, fever subsides for 2 to4 days and then returns with severaldays of even more severe headacheand often frank meningitis. Myoperi-carditis may occur during this secondfebrile period. Rare findings duringthe convalescent phase (1 to 3 weeksinto illness) include alopecia, orchitis,or arthritis. Laboratory findings mayinclude leukopenia, thrombocytope-nia, abnormal liver function tests, orpulmonary infiltrates. Compared withother viral meningitides, LCMV is morelikely to produce a marked (greaterthan 1000 cells) pleocytosis and hypo-glycorrhachia in the CSF. Diagnosis isbased on serological evaluation ofserum and CSF as well as culture ofCSF (and sometimes blood or urine)for LCMV.

Mumps

Mumps should be considered in un-vaccinated children or adolescentswith aseptic meningitis, especially ifoccurring in late winter or early spring,in association with parotitis or orchitis/oophoritis. Vaccination has greatly de-creased the incidence of mumps andmumps-related meningitis in NorthAmerica, but mumps remains a com-mon cause of meningitis in the latewinter or early spring in other partsof the world where the vaccine isnot routinely administered. Followingvaccine licensing in the United Statesin December 1967, the incidence ofmumps has steadily declined—from212,000 cases in 1964 to a record lowof 231 cases reported to the CDC in

86

KEY POINTS:

A Colorado tick

fever virus is

likely under-

recognized as a

cause of aseptic

meningitis and

encephalitis

during the

summer

months among

residents of the

United States

and Canadian

Rocky

Mountain

regions

(average 200

reported cases

per year).

A Lymphocytic

choriomeningitis

virus should be

considered in

patients

with aseptic

meningitis who

have had

exposure to

hamsters or

rodents,

especially if the

illness occurs in

the fall or winter,

and is associated

with moderate

CSF pleocytosis

(up to 1000

WBCs/mm3) and

hypoglycorrhachia.



2001. Rare cases of mumps vaccine-associated meningitis have been re-ported but are very uncommon. Thepresence of orchitis, oophoritis, paro-titis, or pancreatitis in an unimmunizedpatient with aseptic meningitis is sug-gestive of the diagnosis. Ninety per-cent of reported cases occur inchildren less than 14 years of age. Ofall patients with mumps parotitis, atmost 10% develop clinical meningitis.However, nearly 50% of the cases ofmumps meningitis have occurred inthe absence of parotitis. A documentedhistory of previous infection or immu-nization excludes this diagnosis. Hypo-glycorrhachia, as well as a left-shiftedCSF pleocytosis, may be more com-mon with mumps meningitis thanother viral meningitides. Much lessfrequently, mumps may be compli-cated by acute encephalitis, which isgenerally mild, without focal signs,and with low mortality and few se-quelae. A still rarer but more severeencephalitic syndrome presenting asa form of immune-mediated post-infectious encephalomyelitis may oc-cur 7 to 10 days after mumps parotitis.A high percentage of these patientsexhibit seizures, hemiparesis, andsevere obtundation, and the illnesshas a mortality of 10%. Diagnosis isbased on serological analysis of se-rum and spinal fluid in conjunctionwith a culture of nasopharyngeal, CSF,urine, and saliva specimens for mumpsvirus.

Other Herpes-Group Viruses

Human herpesvirus 6. HHV-6 hasrecently been identified as anotherpotential cause of aseptic meningitisand focal encephalitis. The frequencyof neurological sequelae is unknownat this time. HHV-6 has been associat-ed with cases of meningitis andencephalitis in both children andadults. In children, it is the cause ofroseola infantum, or exanthem sub-

itum, and is frequently associated withfebrile seizures. Encephalitis can befocal and thus mimic HSV-1 encepha-litis. The importance of HHV-6 as acause of acute encephalitis is still notclear, but recent retrospective studieshave indicated approximately 6% of aseries of children and adults withencephalitis had HHV-6 genome de-monstrable in CSF by PCR analysis. Noclinical features characterized thosewith HHV-6 as different from otherviral encephalitides. Diagnostic testsare generally only available in researchlaboratories and may include PCR ofCSF and serum, serum serology, andblood and CSF culture for HHV-6.HHV-6 has also recently been associ-ated with a variant of MS termedBalo’s concentric sclerosis.

Epstein-Barr virus. Focal encepha-litis complicates EBV infection in lessthan 1% of cases of acute infectiousmononucleosis. Although focal involve-ment of brain parenchyma is itselfcommon, no particular characteristiclocalization is seen. Recovery is usu-ally complete. Other clinical syndromescaused byEBV includemeningitis, trans-verse myelopathy, and Guillain-Barresyndrome. Serum IgM antibody to EBVviral capsid antigen in a patient withmeningitis or encephalitis is stronglysuggestive of EBV infection. A DNAPCR assay for EBV on CSF is available,but sensitivity and specificity of theassay in patients with CNS disease isunclear. Treatment is symptomaticsince acyclovir has only limited activityagainst EBV.

Varicella-zoster virus. Cerebellarataxia is a common complication asso-ciated with primary chickenpox, occur-ring 1 week after the onset of rash,and is usually benign. It occurs in immu-nocompetent individuals. Zoster en-cephalitis, however, tends to occurin immunocompromised patients, mayfollow skin eruption by days to monthsor even occur without recognizable

87

KEY POINTS:

A Compared with

other viral

meningitides,

lymphocytic

chorio-

meningitis virus

is more likely

to produce a

marked (greater

than 1000 cells)

pleocytosis and

hypoglycorrha-

chia in the CSF.

A Mumps should

be considered

in unvaccinated

children or

adolescents

with aseptic

meningitis,

especially if

occurring in

late winter or

early spring, in

association

with parotitis or

orchitis/

oophoritis.

A Of all patients

with mumps

parotitis, at

most 10%

develop clinical

meningitis.

A Hypogly-

corrhachia,

as well as a

left-shifted CSF

pleocytosis,

may be more

common with

mumps

meningitis

than other viral

meningitides.


skin lesion, and is more severe. VZVencephalitis is for the most part avasculopathy affecting small or largevessels of the CNS or both. Small vesseldisease is more common, presenting asheadache, fever, vomiting, mental sta-tus change, seizure, and focal deficits.An MRI shows ischemic or hemorrhagicinfarcts in cortex and subcortical gray-white matter. Large vessel disease(granulomatous arteritis) presents withacute focal deficit developing weeks tomonths after contralateral trigeminaldistribution zoster. Diagnosis can bemade by PCR of CSF for VZV DNA andby detection of intrathecal synthesis ofVZV antibody, especially of the IgMclass. Patients with VZV encephalitisshould be treated with IV acyclovir at asuggested dose of 1500 mg/m2/d(equivalent to 30 mg/kg/d in adults,but often up to 60 mg/kg/d in children)divided into 3 doses for 14 days.

Cytomegalovirus. Cytomegaloviruscan cause an acute necrotizing anddemyelinating encephalitic process. Itis unusual in an immunocompetenthost but should always be consideredin patients with acquired immune defi-ciency syndrome or patients undergoingimmunosuppressive therapy. Encepha-litis may be accompanied by an acuteviral retinopathy, which is diagnostic. Inimmunocompromised hosts, the distri-bution of lesions may be diffuse withinthe cerebral hemispheres. Diagnosis ismade by serological analysis of CSF andserum (with IgM class antibody moresuggestive of acute infection), as wellas PCR of CSF and serum. Recovery ofvirus from throat, blood, or urinespecimens may be supportive but isnot diagnostic because of the highrate of asymptomatic intermittent shed-ding of virus in seropositive patients.Ganciclovir or foscarnet may be usedtherapeutically.

Herpes B virus. This condition istransmitted by monkey bite and re-sults in severe and fatal encephalitis.

Rabies

Although cases of rabies encephalitisare very uncommon in North Amer-ica, rabies should be consideredin the differential diagnosis of anyperson presenting with unexplainedrapidly progressive encephalitis. Thedisease, once instituted, is invariablyfatal (with the exception of one caseof survival reported in 2004), butappropriate postexposure prophylaxisis highly effective in preventingdisease.

Approximately 8000 cases of ra-bies per year are reported in wild anddomestic animals in the continentalUnited States and Puerto Rico, withonly rare transmission to humans. Only36 cases of rabies were diagnosed inhumans in the United States between1990 and 2001. Bats and, to a lesserextent, raccoons, foxes, coyotes, andskunks are the primary carriers ofrabies in the United States. Rodentsand lagomorphs are not carriers. InSouth and Central America, dogs andcattle are the primary carriers. Epizo-otic transmission occurs more often aswildlife population density increases;as populations are decimated, trans-mission declines. Infection in humansoccurs following the bite of a rabidanimal, with an incubation period ofdays to months. It is important to rec-ognize that in the United States, manycases of confirmed rabies have a his-tory of bat exposure but no clear his-tory or evidence of being bitten. Rabieshas also been transmitted by organtransplantation. In some patients, noexposure history can be elicited. Thelack of a known bite or other exposurehistory does not, therefore, completelyexclude the diagnosis of rabies. Wheninfection develops, viral spread occursby retrograde axonal transport, andthe resulting encephalomyelitis is inva-riably fatal. Although evaluation ofbrain biopsy tissue by direct immuno-fluorescent antibody stain against rabies

88

KEY POINTS:

A Human

herpesvirus 6

has recently

been identified

as another

potential cause

of aseptic

meningitis and

focal

encephalitis.

A Focal encephalitis

complicates

Epstein-Barr

virus infection

in less than 1%

of cases of

acute infectious

mononucleosis.

A Cerebellar ataxia

is a common

complication

associated with

primary

chickenpox,

occurring 1

week after the

onset of rash,

and is usually

benign.

A Varicella-zoster

virus

encephalitis is

for the most

part a varicella-

zoster virus

vasculopathy

affecting small

or large vessels

of the CNS

or both.

A Cytomegalovirus

can cause an

acute

necrotizing and

demyelinating

encephalitic

process.



proteins is the diagnostic gold stan-dard, RT-PCR is also available. Diag-nosis can also be attempted byperforming direct immunofluorescentantibody staining and RT-PCR on nu-chal skin biopsy, corneal smears, se-rum, or buccal mucosa specimens. Noeffective treatment is available al-though survival has been reported ina single patient who was treated withinduction of coma in conjunction withribavirin and amantidine; optimalmedical management is preventionby use of postexposure vaccine andimmune globulin.

ANTIVIRAL THERAPY

Acyclovir and pleconaril are the twomost effective specific antiviral agents

available for treatment of viral enceph-alitis for HSV and enteroviral disease,respectively. General supportive care,including close attention to seizurecontrol, antipyretics, monitoring forsyndrome of inappropriate secretion ofantidiuretic hormone (SIADH), andevidence of increased intracranial pres-sure, should be instituted in all patientswith viral encephalitis. The use ofcorticosteroids is controversial (Steineret al, 2005).

Specific antiviral therapies are notavailable at this time for most in-stances of viral meningitis and en-cephalitis. However, several effectiveantiviral agents have become avail-able in the past decade (Table 3-10).The newest of these agents, pleconaril,

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TABLE 3-10 Antiviral Agents Available for Viral Central NervousSystem Diseases

Virus Treatment

Herpes simplexviruses 1 and 2

Acyclovir 10 mg/kg dose IV every 8 hours � 14to 21 days

Higher doses for neonatal encephalitis (20 mg/kgdose IV every 8 hours for 21 days)

Oral acyclovir, famciclovir, valacyclovir formeningitis associated with primary genital herpessimplex virus

Varicella-zoster virus Acyclovir 20 mg/kg dose IV every 8 hours

?Famciclovir, valacyclovir

Cytomegalovirus Ganciclovir

Foscarnet

Epstein-Barr virus Acyclovir (limited effectiveness)

Enterovirus Pleconaril (compassionate release only)

IV immunoglobulin (for hypogammaglobulinemicpatients and neonates with sepsis syndrome)

La Crosse virus ? Ribavirin

Measles virus Ribavirin

West Nile virus Under study: IV immunoglobulin with high titerto West Nile virus, interferon, antisense nucleotides

IV = intravenous.

KEY POINTS:

A Although cases

of rabies

encephalitis

are very

uncommon in

North America,

rabies should

be considered

in the

differential

diagnosis of

any person

presenting with

unexplained

rapidly

A The lack of a

known bite or

other exposure

history does not

exclude the

diagnosis of

rabies.

A Acyclovir and

pleconaril are

the two most

effective

specific antiviral

agents available

for treatment

of viral

encephalitis for

herpes simplex

virus and

enteroviral

disease,

respectively.


has already been noted above in thediscussion of enteroviral disease. Themost important of these is acyclovir,which has greatly improved the survivaland outcome of patients with herpeticencephalitis.

Acyclovir works by inhibition of theviral DNA polymerase, thus interferingwith viral replication. The active formof this drug is a triphosphate. Theinitial phosphorylation step is catalyzedby a virally encoded thymidine kinase,with subsequent phosphorylations byhost cell kinases. Because of its meth-ods of activation and action, acyclovir isonly effective against DNA viruses thatencode a thymidine kinase or relatedenzyme. For all practical purposes, thislimits acyclovir’s efficacy to certainherpesviruses including HSV, VZV,and, to a lesser extent, EBV. Acycloviris not effective therapy for Cytomega-lovirus, which is susceptible only toganciclovir or foscarnet.

In adults with HSV encephalitis,therapy with acyclovir has reducedthe mortality rate to 19% from 70% inpatients treated with placebo and 50%in patients treated with vidarabine. Aspreviously observed, the patient’s ageand level of consciousness at the startof therapy are important prognosticfactors. In a small study, a GlasgowComa Scale score of greater than 6predicted 100% survival, whereaspatients with a Glasgow Coma Scalescore of less than 6 had a 100%incidence of severe sequelae or death.In neonatal HSV disease, mortalityfrom disseminated disease has beenreduced from 85% to 54% with high-dose acyclovir (60 mg/kg/d dividedevery 8 hours for 21 days); however,20% of surviving infants have subse-quent neurological impairment. Theimpact of high-dose acyclovir onmortality from isolated CNS diseasehas been more encouraging, with areduction from 50% to 14% mortalityin treated infants. Unfortunately, two

thirds of treated survivors still havesubsequent neurological impairment.Most experts recommend increasingthe dose of acyclovir in neonates to60 mg/kg/d divided every 8 hours for21 days, based on results of studiesthat showed improved neurologicaloutcome compared with infants trea-ted with lower doses of acyclovir.

The use of CSF PCR for HSV DNA tomonitor the efficacy of acyclovir ther-apy for HSV encephalitis has gene-rated increasing interest. Most patientstreated with a standard 14-day IVcourse of acyclovir will no longerhave detectable HSV DNA in theirCSF. A recent consensus report onthe role of PCR in management ofthis disease (Lakeman and Whitley,1995) suggested that patients whostill have detectable HSV DNA in CSFat the end of 14 days should receivean additional course of therapy. Theavailability of PCR techniques thatallow accurate quantitation of theamount of HSV DNA present in CSFwill undoubtedly facilitate the use ofPCR in therapeutic monitoring.

The use of IV corticosteroids iscontroversial in the setting of enceph-alitis and ADEM. In the context of HSVencephalitis in adults, therapy with IVsteroids is sometimes employed in anattempt to decrease temporal lobeswelling, which can encroach on theperimesencephalic cistern, resulting inlateral shift and compression of thebrain stem. No clear data are availableto definitely support or refute this prac-tice. In the case of ADEM, IV steroidsare widely used and have been anec-dotally reported to be effective. How-ever, in several studies of sequentialpatients with or without such ther-apy, no difference was found in clini-cal course or recovery. A variety ofother immunomodulatory therapies,including immunosuppressive drugs,plasmapheresis, and IV immune glob-ulin, have also been employed, but

90

KEY POINTS:

A Because of its

methods of

activation and

action, acyclovir

is only effective

against DNA

viruses that

encode a

thymidine

kinase or

related enzyme.

A In the context

of herpes

simplex virus

encephalitis in

adults, therapy

with

intravenous

steroids is

sometimes

employed in an

attempt to

decrease

temporal lobe

swelling, which

can encroach

on the

perimesence-

phalic

cistern,

resulting in

lateral

shift and

compression of

the brain stem.



definitive controlled clinical trials arelacking.

Supportive measures are indicatedin all forms of viral encephalitis andinclude seizure control with standardanticonvulsant regimens, monitoringfor signs of increased intracranialpressure, including the use of intra-cranial pressure bolts in appropriate

cases, and treatment of increased intra-cranial pressure with standard thera-pies such as hyperventilation and os-motic diuresis. Monitoring for SIADHis necessary, and the use of hypoto-nic fluids should be avoided. ShouldSIADH occur, fluid restriction measuresshould be instituted. Hyperthermiashould be controlled with antipyretics.

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Extensive review of newer methodologies, including polymerase chain reaction (PCR), forthe diagnosis of viral (and other) etiologies of meningoencephalitis. Includes discussionand clinical applications of multiplex and quantitative real-time PCR.

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Discussion of the PCR technique with practical considerations and sensitivity andspecificity for all available viral CSF PCRs, as well as bacterial, mycobacterial, fungal,rickettsial, and protozoal PCRs, with application to diagnosis of neurologicaldiseases.

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Discussion of history and physical examination clues, as well as cerebrospinal fluid (CSF)analysis, magnetic resonance imaging (MRI), and adjunctive studies (culture and PCR) forthe differential diagnosis of enterovirus, herpes simplex virus (HSV), and arbovirusencephalitis.

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A broad review of viral aseptic meningitis, including epidemiology and pathogenesis withspecific discussion of enteroviral, HSV, mumps, human immunodeficiency virus (HIV),and arbovirus meningitis.

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Detailed description of interpretation of CSF chemistries and cell counts for the diagnosisof viral CNS infection as well as suggested diagnostic evaluation for HSV (including HSVPCR), human herpes virus 6, varicella-zoster virus, enterovirus, and arbovirus CNSinfection.

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Thorough discussion of common causes of aseptic meningitis and their current relativeincidences (enterovirus, arbovirus, mumps, lymphocytic choriomeningitis virus), withdetailed discussion of enteroviral epidemiology, clinical manifestations, typical CSFpatterns, and use of PCR for diagnosis.

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An up-to-date review with consensus-based recommendations encompassing diagnosis,neuroimaging, and medical and surgical management of patients with viral encephalitis.

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A thorough and up-to-date review, including epidemiology, diagnosis, clinical features,treatment, and sequelae.

" Tyler KL. Viral meningitis and encephalitis. In: Braunwald E, Fauci AS,Kasper DL, et al, eds. Harrison’s principles of internal medicine. 15th edition.New York: McGraw-Hill, 2001.

The most current general textbook review of viral etiologies of meningitis andencephalitis.

" Tyler, KL. Diagnosis and management of acute viral encephalitis. SeminNeurol 1984;4:480–489.

A thorough review with tables differentiating epidemiological, historical, clinical, andlaboratory features of various etiologies of viral encephalitis.

" Whitley RJ, Gnann JW. Viral encephalitis: familiar infections and emergingpathogens. Lancet 2002;359:507–513.

Excellent concise review.

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General review including discussion of Cytomegalovirus and HSV CNS infection ofneonates, as well as arbovirus, HSV, HIV, and rabies encephalitis in older patients.

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