Viral Meningitis and Encephalitis

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    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.


    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



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


    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,


    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;12:125.


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  • 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.


    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



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

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  • (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 return