cns infections ii - smbs.buffalo.edu€“ actually cns viral infection is meningoencephalitis ......
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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