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Encephalitis andPostinfectious Encephalitis

John E. Greenlee, MD, FAAN

ABSTRACTPurpose of Review: Encephalitis and postinfectious encephalitis represent twoimportant conditions for the neurologist, both in terms of their presentations asneurologic emergencies and their potential to cause death or serious neurologicimpairment. This article reviews the major infectious and noninfectious causes of en-cephalitis and discusses postinfectious encephalitis as an indirect effect of systemicillness.Recent Findings: Encephalitis caused by herpes simplex virus type 1 and WestNile virus are of major importance. In addition, within the past few years we havegained improved understanding of the neurologic syndromes caused by varicella-zoster virus, the recognition of enterovirus 71 as a significant human pathogen, andthe realization that encephalitis may also occur by autoimmune mechanisms re-quiring immunosuppressive therapy. We have also learned that postinfectious en-cephalitis may be recurrent rather than monophasic, and that children and adultsinitially diagnosed with postinfectious encephalitis may later develop classic mul-tiple sclerosis.Summary: Encephalitis and postinfectious encephalitis present as neurologic emer-gencies requiring prompt diagnosis and initiation of treatment. Important concerns areto identify infectious conditions requiring antibiotic or antiviral therapy and post-infectious or other autoimmune encephalitides requiring immunosuppression.

Continuum Lifelong Learning Neurol 2012;18(6):12711289.

INTRODUCTIONIn approaching patients with suspectedCNS infection, the first task for the neu-rologist, as discussed in the article AcuteBacterial and Viral Meningitis, is todetermine whether the patient has bac-terial meningitis requiring emergent an-tibiotic therapy. When evidence of focalor diffuse parenchymal involvement ispresent, however, an important diag-nostic consideration becomes whetherthe patient has encephalitis or a post-infectious illness in which systemicinfection has caused an immune re-sponse directed against myelin or otherantigens. In recent years, a third possi-bility has been recognized: encephalitismay represent an autoimmune response

directed against neuronal membraneantigens or intraneuronal proteins.The clinical and radiologic features ofthese three entitiesVencephalitis, post-infectious encephalomyelitis, and auto-immune encephalopathyVmay differsignificantly, and recognition of thesedifferences facilitates diagnosis. This ar-ticle reviews the presentation, diagnosis,and treatment of these three importantclinical entities.

ENCEPHALITISAlthough encephalitis is usually consid-ered in termsofviral infections,other agentsmay involve brain parenchyma aswell. Themost urgent question to ask is whether thepatientwill require antiviral or antimicrobial

Address correspondence toDr John E. Greenlee,University of Utah, ClinicalNeuroscience Center, 175North Medical Dr E, Salt LakeCity, UT 84132,john.greenlee@hsc.utah.edu.

Relationship Disclosure:Dr Greenlee has served as anauthor and associate editorfor MedLink and for TheMerck Manual, and hasreviewed records regardinglitigation for Oliver Maner LLP.Dr Greenlee also holds a meritreview from the United StatesDepartment of VeteransAffairs.

Unlabeled Use of Products/Investigational UseDisclosure: Dr Greenleereports no disclosure.

* 2012, American Academyof Neurology.

1271Continuum Lifelong Learning Neurol 2012;18(6):12711289 www.aan.com/continuum

Review Article

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

therapy. Three viral infections are ofprimary concern: herpes simplex virus(HSV) encephalitis, CNS involvement byvaricella-zoster virus, and West Nile virusencephalitis. Other infectious encephalit-ides, although important, are less common.

Herpes SimplexVirus EncephalitisHSV encephalitis (Table 2-1) representsonly 10% to 15% of cases of viral en-cephalitis in the United States. How-ever, it remains the most important ofviral encephalitides, because it is bothlethal if untreated and the only viralencephalitis for which therapy has beenproven effective in clinical trials. HSV isubiquitous in human populations. Twosubtypes of HSV infect humans: HSVtype 1 (HSV1) and HSV type 2 (HSV2).HSV1 is most commonly acquired inearly childhood. HSV2 is more commonlysexually transmitted and thus usuallyacquired during adolescence or adult-hood. Both agents persist in neuronswithin sensory ganglia. Limited evidencesuggests that HSV1 may also persistwithin the CNS.1 HSV1 is responsible for90% of cases of HSV encephalitis inadults; of these cases roughly two-thirdsrepresent reactivated infection.2

The pathogenesis of HSV encephali-tis is not well understood. Encephalitishas been postulated to follow spread ofvirus from trigeminal ganglia throughsensory fibers to the meninges over-lying temporal lobes and orbitofrontalcortex.3 Alternatively, encephalitis couldarise following reactivation of a latentvirus within the brain.1

HSV encephalitis affects men andwomen equally and may occur at any age.There is no seasonal incidence of infec-tion. Impaired host immunity is not arisk factor for HSV encephalitis, but theinfection may progress more graduallyin immunocompromised individuals.4

HSV encephalitis is usually unilateral butmay also be bilateral. The virus has a

predilection for orbitofrontal cortexand temporal lobes, with many cases alsoinvolving the cingulate cortex. The vi-rus is able to infect neurons, glia, andependyma. Vascular congestion and pe-techial hemorrhages may be present.Progression of the infection results in ex-tensive, frequently hemorrhagic, destruc-tion of the brain.5

HSV encephalitis presents with analmost universal triad of headache (inover 90% of cases), fever, and alterationin mental status, at times preceded bysymptoms of nonspecific mild illness.Changes inmental status at presentationmay range from confusion, frank psy-chosis, or somnolence to stupor or coma.Temporal lobe involvement may resultin seizures characterized by olfactory orgustatory hallucinations, or deja vu phe-nomena.6 Examination may reveal subtleor overt corticospinal tract signs or signssuggesting temporal lobe dysfunction.6

These may include upper-quadrant vi-sual field defects; aphasia when the dom-inant hemisphere is involved; and, whenthe infection is bilateral, loss of ability tostore and recall new information. Occa-sional patients will exhibit papilledemaat presentation. Rare patients may pre-sent with evidence of injury to other partsof the CNS, including occipital lobes andbrainstem, without temporal lobe involve-ment.7 Focal or generalized seizures,however, may occur at any point duringacute illness or after recovery.

CSF in HSV encephalitis typically con-tains a lymphocytic pleocytosis of 50 ormore cells/2L (median 130 cells/2L).6 Inoccasional patients, however, cell countmay be normal.6 Although HSV ence-phalitis is frequently hemorrhagic, thepresence or absence of red blood cellsin CSF does not differentiate HSV en-cephalitis from encephalitis due to othercauses.6 Median CSF protein concen-tration is 80 mg/dL but may range fromnormal to over 700 mg/dL; CSF glucoseconcentration is usually normal.6 MRI


h The most urgent questionto ask in the case of apatient with suspectedCNS infection is, Doesthe patient requireimmediate antibiotic orantiviral therapy?

h Viral agents of primaryconcern are herpessimplex virus,varicella-zoster virus,and West Nile virus.

h Herpes simplex virusencephalitis remainsthe major cause ofnonepidemic fatalencephalitis.

h Herpes simplex virusencephalitis presentswith an almost universaltriad of headache,fever, and alterationin mental status.

h Temporal lobeinvolvement in herpessimplex virus encephalitismay result in seizurescharacterized byolfactory or gustatoryhallucinations, or deja vuphenomena.

1272 www.aan.com/continuum December 2012


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

TABLE 2-1 Major Infectious Agents Associated With Encephalitis

Agent (Vector)GeographicDistribution


High-RiskPopulations Acute Diagnosis Treatment

VirusesHerpessimplex virus

Ubiquitous Noseasonalincidence

N/A; course of infectionmay be atypical inindividuals who areimmunosuppressed

CSF PCR Acyclovir


Ubiquitous Noseasonalincidence

Individuals who areimmunocompromised

CSF PCR, IgM andIgG antibodies


Cytomegalovirus Ubiquitous Noseasonalincidence

Individuals who areimmunocompromised,especially thosewith HIV

PCR Ganciclovir;foscarnet

West Nile virus(mosquito)

Entire UnitedStates

Summerand earlyfall

Individuals who areimmunocompromisedand older adults

CSF IgM Supportive

St Louisencephalitisvirus (mosquito)

Entire UnitedStates,especially theMidwest,MississippiRiverregions, andTexas

Summerand earlyfall

Older adults CSF IgM Supportive

Eastern equineencephalitisvirus (mosquito)

Easternseaboard,Gulf coast(includingTexas), andthe upperMidwestregions

Summerand earlyfall

Children and olderadults

CSF IgM Supportive

Enteroviruses Worldwide Summerand earlyfall

Individuals with IgGdeficiency, includingthose treated withrituximab

PCR Supportive(pleconaril)

Nonviral AgentsTreponemapallidum

N/A N/A AIDS Serology (rapidplasma reagenttest, CSF, VenerealDisease ResearchLaboratory test,fluoresceintreponemaantibody test)

Penicillin orceftriaxone

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