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CNSINFECTIONSII
ReidHeffner,M.D.DepartmentofPathologyandAnatomicalSciences
December15,2016
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CNSINFECTIONSREFERENCES
• Robbins.Kumar.9th edition,2013,Chapter22
• Prusiner SB.Geneticandinfectiouspriondiseases.ArchNeurol 50:1129-1153,1993.
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CNSINFECTIONSContents
• Meningitis• Focalparenchymallesions
• Viralencephalitis• Parasiticdisease• Unconventional(slow)agents
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CNSInfectionsLearningobjectives
• Knowdefinitionsandterms• Knowessentialsofdiseasesdiscussed• Compareandcontrasteachdisease• Knowkeydiagnosticfeaturesofeachdisease
• Beabletoanswercaserelatedquestions
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CNSINFECTIONSLEARNINGOBJECTIVES
• Astudentshouldbefamiliarwiththefollowingterms:– Slowandlatentvirusinfection– XanthochromiaintheCSF– Cowdrytypeinclusions– Negribody– Glialnodule– Neuronophagia– Spongiformchange– Prion,PrPc,PrPsc
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CNSINFECTIONSCaseSummary
• Healthy70yearoldmansuddenlybecomesill• Confusion,fever,fatigue,headache• Diffuseweakness,↓DTRs,rash• EMGshowsaxonalneuropathy• Requiresintubation• Diesafter10days
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CASEDISCUSSIONQuestionstobeanswered
• Anyadditionalinformationneededtomakethediagnosis?
• Whatisthediagnosis?• Whatisthecause?• Whatistheprognosis?• Whatisthetreatment/prevention?
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TYPICALVIRALENCEPHALITISArbovirus Infections
Robbins,pp.826-827
• Representsthe“typical”viralencephalitis– ActuallyCNSviralinfectionismeningoencephalitis
• Mostcommontypeofencephalitis– Mostencephalitisisviral inorigin
• Manyagents• Usuallyinsummer,warmerweather• Suddenonset,fever,headache,drowsiness,stupor,coma
• Coursevariable
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“Typical”ViralEncephalitisPrimarilyagreymatterdisease
Brain is diffusely swollen and congested
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ViralEncephalitisHistologicFeatures
Lymphocytic perivascular cuffing
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ViralEncephalitisHistologicFeatures
Neuronophagia of dead cells
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ViralEncephalitisHistologicFeatures
Glial nodule with numerous rod cells
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WESTNILEFEVER
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WestNileFever
• WasconfinedtoMiddleEastforcenturies• FirstUScaseinsummerof1999– Thatyearwere59cases,7deaths– Thousandsofcrowsalsodied=firstclue– Probablycamefromimportedbird
• NowhasspreadthroughoutUS– Reservoirinbirds,mosquitotransmission
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WestNileFever
Culex mosquito
Reservoir in crows and other birds
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WestNileFever
• DiagnosisbasedonIgMantibodiesinCSF• Suddenonset,fever,headache– Rash,muscleweakness,myalgia,lymphadenopathy
• Mostcasesaremild– 15-20%mortalitywithdevelopmentofencephalitis
• Riskgreaterafterage50
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WestNilemorbilliformrash
Red, maculopapular, pruritic, trunk and extremities
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WestNileFeverJNeuropathology68:1053,2009
Brainstem encephalitis Severe axonal neuropathyAnterior horn cell neuronophagia and lossLooks like poliomyelitis
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WestNileFever
Lymphocytic cuffing, glial nodules, demyelinationMore prominent in the brainstem but affects other areas
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RABIES
Rabies is worldwide
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RABIESor([Fr]RAGE)
• Usuallyduetoananimalbite– Rabidanimalisaggressive– Dogs,cats,wildcarnivores
• Contactwithbatslesscommon– Spreadinaerosol
• Findtherabidanimalandtestit• Longincubationperiod
– Shorterwhenbiteisclosertohead• Humandiagnosiscanbemadewithcorneal
smear– Showrabiesantigenwithimmunofluorescence
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RABIES-CLINICALFACTS
• Headache,fever,paresthesiasorpainatwoundsite• Patientsthenbecomerestless,developseizures• Havelaryngealmusclespasmwith“hydrophobia”• Nearly100%mortalitywithouttherapy• Vaccineisavailable
– Canbegivenafterabitealongwithhumanrabiesimmuneglobulin
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RABIESPATHOLOGY
• Lymphocyticperivascularcuffing– Especiallybrainstem
• Negribodies=cytoplasmicviralinclusions– EspeciallyinhippocampusandPurkinjecells
EM showing rhabdovirus
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LATENTVIRUSINFECTIONSHerpesSimplexEncephalitis
• Mostcommonsporadic encephalitisinUS• UsuallyduetoHSV-1– HSV-2causesmeningitis
• 90%adultpopulationhasHSV-1antibodies• Primaryinfectionoccursinchildhood– Oftensubclinical
• Encephalitisrepresentsrecurrentinfection
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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
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HerpesSimplexEncephalitis
Herpes labialis (cold sore)Clusters of vesicles
Virus latent in V nerve gangliaReactivated→ travels out nerve
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HerpesSimplexEncephalitis
Area of increased density on CT which looks like hemorrhage Hemorrhagic lesions tend to be located
in temporal lobe or inferior frontal lobe
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HerpesSimplexEncephalitis
Encephalitis tends to produce marked brain edemaPatients in danger of dying from tonsillar herniation
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HerpesSimplexEncephalitis
Neutrophils predominate early
Cowdry inclusion bodyLarge, fills nucleus, red
EM shows herpes virus
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VARICELLA-ZOSTERINFECTIONS
• Varicella– Worldwide– Highlycontagious– Usuallyinchildren
• Ages2-8
– Rashbeginsontrunk• Spreadstomouth,face,limbs
– Usuallybenigncourse
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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
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SHINGLES-HERPESZOSTER
Vesicular rash following intercostal nervesRash often unilateral
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SHINGLES-HERPESZOSTER
• Inflammationinnerverootandganglia• Inclusions(nuclear)inneurons(likesimplex)• Maybenecrosisorhemorrhageinganglia
IHC showing virus in neurons
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IsZikagettingonyournerves?
• Associationwithmicrocephaly• NowlinkedtoGuillain-Barrésyndrome– 68ColumbianpatientswithG-Bsyndrome– 66patientshadZikavirusinfection
NEJM 2016; 375:1513-1523
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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
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Progressivemultifocalleukoencephalopathy
• Onset45-65years– YoungerpatientswhohaveAIDS
• Gradualdevelopmentofsymptoms• Dementiaandfocalfindings,especiallylossofvisualacuity
• CSFexamoftennormalornoncontributory• Subacutecoursewith3-6mo.survival
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PMLisademyelinatingdisease
Multiple small foci of demyelinationMany lesions located in occipital white matter
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PML
Demyelination with many gitter cellsBizarre atypical astrocytes
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PML
Intranuclear inclusions in oligodendrogliaComposed of numerous viral particlesInfected oligos die leading to demyelination
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CNSINFECTIONSCaseSummary
• Healthy70yoMsuddenlybecomesill• Confusion,fever,fatigue,headache• Diffuseweakness,↓DTRs,rash• EMGshowsaxonalneuropathy• Requiresintubation• Diesafter10days
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CASEDISCUSSIONQuestionstobeanswered
• Anyadditionalinformationneeded?• Whatisthediagnosis?• Whatisthecause?• Whatistheprognosis?• Whatisthetreatment/prevention?
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CASEDISCUSSIONQuestionstobeanswered
• Anyadditionalinformationneeded?– Season,othercases,appearanceofrash,viralstudies
• Whatisthediagnosis?–WestNilefever
• Whatisthecause?• Whatistheprognosis?– 15-20%mortalityifthereisencephalitis
• Whatisthetreatment/prevention?
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UNCONVENTIONAL(SLOW)INFECTIONS
• Longlatentperiodandcourse• SpongiformchangeinCNS• Agentshaveunconventionalproperties– LackDNA/RNA;containprotein(prions)
• Scrapie,kuru,C-J,madcowdisease
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Creutzfeldt-JakobDiseaseRobbins,pp.1380-1382
• Subacutespongiformencephalopathy• Diseasebothgeneticandinfectious• Agentisanabnormalproteinorprion• PrPsc derivedfromnormalproteinPrPc
• Resultsfromaconformationalchange
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Creutzfeldt-JakobDisease
• About10%casesareinherited– PRNPgeneonshortarmofchromosome20– PointmutationsingenecodingforPrPc
• C-Jdisease(SSE)isalsoinfectious(transmissible)– Prionsreplicate– PrPsc somehowrecruitsandtransformsPrPc
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Creutzfeldt-JakobDisease
• Onsetinmiddleagedpatients• Severedementiawithmemoryloss• Myoclonus• Ataxia• CSFcontainsexcessiveamtprotein14-3-3– 14-3-3familyofnormalproteins
• Fatalin6-24months
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Creutzfeldt-JakobDiseaseEarlyspongiformstage
SPONGE
Spongiform change with marked cellular edema in neurons and neuropil
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Creutzfeldt-JakobDiseaseLateStage
Cerebral atrophyStriking gliosis (PTAH) and marked neuronal loss
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Creutzfeldt-JakobDiseaseAmyloidformation
Prion protein undergoes a conformation change into a β-pleated sheet
Becomes insoluble amyloid Amyloid (congophilic) plaque
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Creutzfeldt-JakobDiseaseAmyloidformation
Amyloid plaque (silver stain)
EM shows amyloid as masses of filaments
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THE END