CNSINFECTIONSII

ReidHeffner,M.D.DepartmentofPathologyandAnatomicalSciences

December15,2016

CNSINFECTIONSREFERENCES

• Robbins.Kumar.9th edition,2013,Chapter22

• Prusiner SB.Geneticandinfectiouspriondiseases.ArchNeurol 50:1129-1153,1993.

CNSINFECTIONSContents

• Meningitis• Focalparenchymallesions

• Viralencephalitis• Parasiticdisease• Unconventional(slow)agents

CNSInfectionsLearningobjectives

• Knowdefinitionsandterms• Knowessentialsofdiseasesdiscussed• Compareandcontrasteachdisease• Knowkeydiagnosticfeaturesofeachdisease

• Beabletoanswercaserelatedquestions

CNSINFECTIONSLEARNINGOBJECTIVES

• Astudentshouldbefamiliarwiththefollowingterms:– Slowandlatentvirusinfection– XanthochromiaintheCSF– Cowdrytypeinclusions– Negribody– Glialnodule– Neuronophagia– Spongiformchange– Prion,PrPc,PrPsc

CNSINFECTIONSCaseSummary

• Healthy70yearoldmansuddenlybecomesill• Confusion,fever,fatigue,headache• Diffuseweakness,↓DTRs,rash• EMGshowsaxonalneuropathy• Requiresintubation• Diesafter10days

CASEDISCUSSIONQuestionstobeanswered

• Anyadditionalinformationneededtomakethediagnosis?

• Whatisthediagnosis?• Whatisthecause?• Whatistheprognosis?• Whatisthetreatment/prevention?

TYPICALVIRALENCEPHALITISArbovirus Infections

Robbins,pp.826-827

• Representsthe“typical”viralencephalitis– ActuallyCNSviralinfectionismeningoencephalitis

• Mostcommontypeofencephalitis– Mostencephalitisisviral inorigin

• Manyagents• Usuallyinsummer,warmerweather• Suddenonset,fever,headache,drowsiness,stupor,coma

• Coursevariable

“Typical”ViralEncephalitisPrimarilyagreymatterdisease

Brain is diffusely swollen and congested

ViralEncephalitisHistologicFeatures

Lymphocytic perivascular cuffing

ViralEncephalitisHistologicFeatures

Neuronophagia of dead cells

ViralEncephalitisHistologicFeatures

Glial nodule with numerous rod cells

WESTNILEFEVER

WestNileFever

• WasconfinedtoMiddleEastforcenturies• FirstUScaseinsummerof1999– Thatyearwere59cases,7deaths– Thousandsofcrowsalsodied=firstclue– Probablycamefromimportedbird

• NowhasspreadthroughoutUS– Reservoirinbirds,mosquitotransmission

WestNileFever

Culex mosquito

Reservoir in crows and other birds

WestNileFever

• DiagnosisbasedonIgMantibodiesinCSF• Suddenonset,fever,headache– Rash,muscleweakness,myalgia,lymphadenopathy

• Mostcasesaremild– 15-20%mortalitywithdevelopmentofencephalitis

• Riskgreaterafterage50

WestNilemorbilliformrash

Red, maculopapular, pruritic, trunk and extremities

WestNileFeverJNeuropathology68:1053,2009

Brainstem encephalitis Severe axonal neuropathyAnterior horn cell neuronophagia and lossLooks like poliomyelitis

WestNileFever

Lymphocytic cuffing, glial nodules, demyelinationMore prominent in the brainstem but affects other areas

RABIES

Rabies is worldwide

RABIESor([Fr]RAGE)

• Usuallyduetoananimalbite– Rabidanimalisaggressive– Dogs,cats,wildcarnivores

• Contactwithbatslesscommon– Spreadinaerosol

• Findtherabidanimalandtestit• Longincubationperiod

– Shorterwhenbiteisclosertohead• Humandiagnosiscanbemadewithcorneal

smear– Showrabiesantigenwithimmunofluorescence

RABIES-CLINICALFACTS

• Headache,fever,paresthesiasorpainatwoundsite• Patientsthenbecomerestless,developseizures• Havelaryngealmusclespasmwith“hydrophobia”• Nearly100%mortalitywithouttherapy• Vaccineisavailable

– Canbegivenafterabitealongwithhumanrabiesimmuneglobulin

RABIESPATHOLOGY

• Lymphocyticperivascularcuffing– Especiallybrainstem

• Negribodies=cytoplasmicviralinclusions– EspeciallyinhippocampusandPurkinjecells

EM showing rhabdovirus

LATENTVIRUSINFECTIONSHerpesSimplexEncephalitis

• Mostcommonsporadic encephalitisinUS• UsuallyduetoHSV-1– HSV-2causesmeningitis

• 90%adultpopulationhasHSV-1antibodies• Primaryinfectionoccursinchildhood– Oftensubclinical

• Encephalitisrepresentsrecurrentinfection

HerpesSimplexEncephalitisRobbins,pp.827-828

• Only15%pts.havehistoryoforallesions• Sudden onsetofheadache,fever,chills,lethargy• Maypresentasamass (space- occupying)lesion• CSFcontainspolys andredcellsearly

– Xanthochromialater(oldhemorrhage)– PCRhaslargelyreplacedbrainbiopsyfordiagnosis

• Rapidlyprogressive;20%mortality– Rxwithantiviralssuchasacyclovir

• InhibitsviralDNApolymerase

HerpesSimplexEncephalitis

Herpes labialis (cold sore)Clusters of vesicles

Virus latent in V nerve gangliaReactivated→ travels out nerve

HerpesSimplexEncephalitis

Area of increased density on CT which looks like hemorrhage Hemorrhagic lesions tend to be located

in temporal lobe or inferior frontal lobe

HerpesSimplexEncephalitis

Encephalitis tends to produce marked brain edemaPatients in danger of dying from tonsillar herniation

HerpesSimplexEncephalitis

Neutrophils predominate early

Cowdry inclusion bodyLarge, fills nucleus, red

EM shows herpes virus

VARICELLA-ZOSTERINFECTIONS

• Varicella– Worldwide– Highlycontagious– Usuallyinchildren

• Ages2-8

– Rashbeginsontrunk• Spreadstomouth,face,limbs

– Usuallybenigncourse

VARICELLA-ZOSTERINFECTIONS

• Herpeszoster– Latentinfection

• Trigeminalganglion,posteriorrootgangliaespecially

• Reactivationwithlowerimmunity,HIV,aging,cancer

– Worldwide,sporadic,nonseasonal– Usuallyinadults– Neuropathy

• Verypainfulwithfever• Permanentnervedamagecommon

Vesicular rash follows the path of involved nerve

SHINGLES-HERPESZOSTER

Vesicular rash following intercostal nervesRash often unilateral

SHINGLES-HERPESZOSTER

• Inflammationinnerverootandganglia• Inclusions(nuclear)inneurons(likesimplex)• Maybenecrosisorhemorrhageinganglia

IHC showing virus in neurons

IsZikagettingonyournerves?

• Associationwithmicrocephaly• NowlinkedtoGuillain-Barrésyndrome– 68ColumbianpatientswithG-Bsyndrome– 66patientshadZikavirusinfection

NEJM 2016; 375:1513-1523

Progressivemultifocalleukoencephalopathy (PML)

Robbins,pp.828-829

• Causeispapovavirus,DNAvirus,40nm– Threeknownstrains;JCismajorstrain

• 80%populationhasantibodies– Noclinicaldiseaseinvastmajority– Viruslatentinlymphoidorgans,bonemarrow

• PMLisanopportunisticinfection– AIDS,lymphoma,immunosuppression

• AfterMStreatmentwithnatalizumab (vs α4-integrin)– Poorcell-mediatedimmunity

Progressivemultifocalleukoencephalopathy

• Onset45-65years– YoungerpatientswhohaveAIDS

• Gradualdevelopmentofsymptoms• Dementiaandfocalfindings,especiallylossofvisualacuity

• CSFexamoftennormalornoncontributory• Subacutecoursewith3-6mo.survival

PMLisademyelinatingdisease

Multiple small foci of demyelinationMany lesions located in occipital white matter

PML

Demyelination with many gitter cellsBizarre atypical astrocytes

PML

Intranuclear inclusions in oligodendrogliaComposed of numerous viral particlesInfected oligos die leading to demyelination

CNSINFECTIONSCaseSummary

• Healthy70yoMsuddenlybecomesill• Confusion,fever,fatigue,headache• Diffuseweakness,↓DTRs,rash• EMGshowsaxonalneuropathy• Requiresintubation• Diesafter10days

CASEDISCUSSIONQuestionstobeanswered

• Anyadditionalinformationneeded?• Whatisthediagnosis?• Whatisthecause?• Whatistheprognosis?• Whatisthetreatment/prevention?

CASEDISCUSSIONQuestionstobeanswered

• Anyadditionalinformationneeded?– Season,othercases,appearanceofrash,viralstudies

• Whatisthediagnosis?–WestNilefever

• Whatisthecause?• Whatistheprognosis?– 15-20%mortalityifthereisencephalitis

• Whatisthetreatment/prevention?

UNCONVENTIONAL(SLOW)INFECTIONS

• Longlatentperiodandcourse• SpongiformchangeinCNS• Agentshaveunconventionalproperties– LackDNA/RNA;containprotein(prions)

• Scrapie,kuru,C-J,madcowdisease

Creutzfeldt-JakobDiseaseRobbins,pp.1380-1382

• Subacutespongiformencephalopathy• Diseasebothgeneticandinfectious• Agentisanabnormalproteinorprion• PrPsc derivedfromnormalproteinPrPc

• Resultsfromaconformationalchange

Creutzfeldt-JakobDisease

• About10%casesareinherited– PRNPgeneonshortarmofchromosome20– PointmutationsingenecodingforPrPc

• C-Jdisease(SSE)isalsoinfectious(transmissible)– Prionsreplicate– PrPsc somehowrecruitsandtransformsPrPc

Creutzfeldt-JakobDisease

• Onsetinmiddleagedpatients• Severedementiawithmemoryloss• Myoclonus• Ataxia• CSFcontainsexcessiveamtprotein14-3-3– 14-3-3familyofnormalproteins

• Fatalin6-24months

Creutzfeldt-JakobDiseaseEarlyspongiformstage

SPONGE

Spongiform change with marked cellular edema in neurons and neuropil

Creutzfeldt-JakobDiseaseLateStage

Cerebral atrophyStriking gliosis (PTAH) and marked neuronal loss

Creutzfeldt-JakobDiseaseAmyloidformation

Prion protein undergoes a conformation change into a β-pleated sheet

Becomes insoluble amyloid Amyloid (congophilic) plaque

Creutzfeldt-JakobDiseaseAmyloidformation

Amyloid plaque (silver stain)

EM shows amyloid as masses of filaments

THE END