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1 Neurosarcoidosis KellyMitchellMorningReport5December2006 2 AfewwordsaboutSarcoidosis MultisystemgranulomatousdisorderCharacterizedbythepresenceofnoncaseatinggranulomasininvolvedorgansTypicallyaffectsyoungadultsInitiallypresentswithoneofthefollowing BilateralhilaradenopathyPulmonaryreticularopacitiesSkin joint and oreyelesions 50 ofcasesareincidentaldiagnoses 3 Chestradiograph Bilateralenlargedhilarlymphnodesaswellasrightparatrachealandaortopulmonarylymphnodesarevisible Finelinearandreticularopacitiesarepresentintheperihilarlungparenchyma CourtesyofPaulStark MD 4 Left Thechestradiographshowsinterstitialdisease multiplesmallnodulesinthemid to upperzones withshrinkinghilarnodes StageIII Right HRCTshowsthebeadedorirregularthickeningofthebronchovascularbundles withnodulesalongbronchi vessels andsubpleuralregions CourtesyofTalmadgeEKingJr MD 5 Plainchestradiograph left andcomputedtomographicscan right fromapatientwithnodularsarcoidosis Transbronchiallungbiopsyrevealednoncaseatinggranulomas CourtesyofPeterClardy MD 6 Extrapulmonarymanifestations Sarcoidosiscaninvolveallorgansystemstoavaryingextentanddegree 7 ExtrapulmonaryManifestations Dermatologic upto20percentofpatientsmaculopapulareruptionisthemostcommonWaxy pinknodularlesionsarefrequentlydistributedontheface trunk andextensorsurfaceofthearmsandlegs Ophthalmologic upto20percent presentingsymptominfivepercent Anterioruveitis Posterioruveitis Retinalvasculitis Keratoconjunctivitis Conjunctivalfolliclessecondaryglaucoma cataractformation andblindnessarelatecomplicationsinuntreatedpatientsReticuloendothelialPeripherallymphadenopathy Hepatomegaly Noncaseatinggranulomasonliverbiopsy Splenicenlargement duetogranulomasinspleenMusculoskeletalAcutepolyarthritis ChronicarthritisDiffusegranulomatousmyositisisuncommon usuallyincurspoorprognosisExocrineswellingofthesalivaryglandsoccursinapproximatelyfourpercentofpatients 8 Extrapulmonarysarcoid RenalMostcommonlymanifestasabnormalitiesinCalciummetabolismCardiovascularGranulomatousinvolvementoftheventricularseptumandconductionsystemcanleadtoavarietyofarrhythmias includingcompleteheartblockandsuddendeath chronicpulmonaryhypertensionandcorpulmonalecanresultfromseverescarringofthepulmonaryparenchymaGastrointestinal Clinicallyrecognizablegastrointestinal GI diseaseoccursin0 1to0 9percentofpatientswithsarcoidosis althoughtheincidenceofsubclinicalinvolvementmaybemuchhigher ThestomachisthemostcommonlyinvolvedportionoftheGItractReproductive Sarcoidosiscaninvolvethetestes andmustbedifferentiatedfromtesticularcancerandtuberculosis Endocrine Sarcoidosiscancausediffusegoiteror rarely asolitarythyroidnoduleNeurologic Approximatelyfivepercentofpatientswithsarcoidosishaveneurologicinvolvement whichcanoccasionallybethepresentingsymptom Manifestationsofcentralnervoussystem CNS diseaseusuallyoccurearly whileperipheralnerveandskeletalmuscleinvolvementischaracteristicallyseeninthelaterstages 9 Neurosarcoid Neurologiccomplicationsoccurinapproximately5percentofpatientswithsarcoidosis 50percentofpatientswithneurosarcoidosispresentwithneurologicdifficultiesatthetimesarcoidosisisfirstdiagnosed One thirdofthosewithneurosarcoidosishaveordevelopmorethanoneneurologicmanifestation 10 ClinicalFeatures Anyportionofthecentralorperipheralnervoussystemcanbeaffectedbysarcoidosis CranialnervepalsiesAnycranialnervecanbeaffected Peripheralfacialnervepalsydevelopsinover50percentofpatientswithneurosarcoidosis OpticneuropathyandcranialnerveVIIIdysfunctioncanleadtointermittentorprogressivevisual auditory orvestibulardysfunction NeuroendocrinedysfunctionOneofmostcommonCNSparenchymalmanifestationsusuallyduetohypothalamicinflammation resultinginpolyuriaordisturbancesinsleep appetite temperature orlibido Directhypothalamicinvolvementcanleadtocentraldiabetesinsipidusorprimarypolydipsia hypercalcemia duetoproductionofcalcitriolbyactivatedmacrophages cancausenephrogenicdiabetesinsipidusSeizuresGranulomatousinflammationinaperivasculardistributioncanproducepartialorgeneralizedseizures orrestrictedorgeneralizedencephalopathy vasculopathy 11 Moreclinicalfeatures MyelopathyorradiculopathyDuetoGranulomatousinflammationaffectingthespinalcord canbeextramedullaryorintramedullary andthecaudaequinacanbeinvolved Hydrocephalusmaydevelopacutelyorsubacutely ifpresentisusuallyincidentallydetectedbyimagingstudies Meningealinvolvementcantaketheformofeitheranacuteasepticmeningitisorachronicmeningitis Meningealmasslesionsalsocandevelop Peripheralneuropathyelectromyographyusuallyrevealsanaxonalneuropathy acutegeneralizeddemyelinatingmotorneuropathysimilartotheGuillain Barr syndromealsohasbeendescribedCarpaltunnelsyndromeappearstobemorecommonamongpatientswithsarcoidosisthanthegeneralpopulationMuscularinvolvementincludesasymptomaticmicroscopicnodules isolatedpalpablenodules anacuteorchronicproximalmyopathy andmuscleatrophy 12 Diagnosis Concurrentinfectionormalignancymustbeexcluded Patientswhodevelopaneurologicillnessconsistentwithneurosarcoidosisbutarenotknowntohavesarcoidosispresentadiagnosticchallenge Don tforgettosuspectsarcoid 13 Clinicalevaluation Ifneurosarcoidosisissuspected thepatientshouldbeevaluatedforevidenceofextraneuraldiseasebecauseobtainingnervetissuefordiagnosticevaluationisoftendifficult Thoroughlyevaluateskin lymphnodes lungsEyesEndoscopicnasalandsinusexaminationComputedtomographicscanofthechesttolookforhilaradenopathyorparenchymalchangesInrarecases amagneticresonance gallium orfluorodeoxyglucosepositronemissiontomographicscan mayhighlightotherwiseoccultareasofinflammationthatmightbeamenabletobiopsyNotethatcorticosteroidseliminateevidenceofsystemicinflammation andthediagnosticevaluationshouldbepursuedinarapidfashionwhilewithholdingsteroidtherapyunlesssevereillnessmandatesitsuse 14 Diagnosis SerumangiotensinconvertingenzymemaybehelpfulifelevatedBUTnotspecificorsensitiveACEconcentrationmaynotnecessarilybeelevatedifthepatienthasisolatedneurosarcoidosis Neurologicevaluationshouldproceedifnoextraneuraltissueisavailableforbiopsy Unfortunately noneurodiagnostictestsarepathognomonicforneurosarcoidosisPresumptivediagnosisofneurosarcoidosisisoftenmadeonthebasisofMRIandlumbarpunctureresultsintheappropriateclinicalsetting 15 Neurodiagnostictesting ProcedureofchoiceforCNSdiseaseiscontrast enhancedMRIMeningealorparenchymalenhancementsuggestsactiveinflammationwithdisruptionofthebloodbrainbarrier andparenchymalormeningealmassesandhydrocephalusareeasilyidentified Studyof29patientswithneurosarcoidosis approximately40percentdemonstratedmeningealenhancementand ormultiplewhitematterlesionsonMRI 16 Neurodiagnostictesting Cerebrospinalfluid CSF abnormalitiesoccurfrequentlyinpatientswithCNSsarcoidosis elevatedopeningpressureinapproximately10percentofpatientstotalproteinisincreasedintwo thirdsofpatients typicallyupto250mg dLpleocytosisispresentinapproximately50percentofpatients usuallymononuclearGlucosecanbenormalorlow ascanbeseeninCNSinfectionsorcarcinomatousmeningitisoligoclonalbandsmaybepresentCSFACEconcentrationisoccasionallyelevated butreliablenormalvaluesarelackingandCSFACEmayalsobeincreasedwithinfectionorcarcinomatousmeningitisEMG evokedpotentials andangiography areoccasionallyindicatedtoexcludeotherconditionsandcanhelplocalizeneuromuscularlesions Ifthediagnosisremainsindoubt meningeal brain orspinalcordbiopsyisoccasionallyindicated Biopsytoestablishthediagnosis ratherthanempirictherapy shouldbeconsideredifthereisnodefinedsystemicdisease 17 TREATMENT CorticosteroidsBUTnorandomized doubleblind placebo controlledtreatmenttrialsforneurosarcoidosis doseanddurationoftherapyshouldbedictatedbydiseaseseverityandresponsetotherapyFrequentclinicalevaluationandperiodicassessmentoftheextentofMRIenhancement ifenhancementwaspresentonpretreatmentscans aregenerallyhelpfultomonitordiseaseassteroidsareweanedmonitoringofnerveconductionvelocitiesandtheelectromyogramisoccasionallyusefulBUTtitratingtherapytonormalizeCSFparametersisnotrecommendedbecauseexcessiveimmunosuppressionfrequentlyresultsfromthispractice 18 Alternativetherapies Patientswhodeteriorateinspiteofaggressivecorticosteroidtreatment whocannottoleratesteroids orwhohaveacontraindicationtocorticosteroidtreatmentBUTtherearenostudiescomparingvariousalternativetreatmentstooneanotherinpatientswithneurosarcoidosisOtherimmunosuppresants azathioprine methotrexate mycofenolate cyclophosphamide cyclosporin chlorambucilInfliximab Remicade isachimerichuman murineantihumanantibodythatspecificallyblockstheeffectoftumornecrosisfactor alpha TNF alpha Immunomodulatoryagentsusedinthemanagementofneurosarcoidosisincludehydroxychloroquine pentoxifyline thalidomide 19 Morealternatives SurgeryResectionofaCNSmasslesionisrarelyindicated andpatientsmaydeterioratefollowingattemptedresectionofamass Ventriculardraincanbelifesavinginpatientswithacutehydrocephalus Radiationtherapy forrefractorydiseaseconsideredifpatientsfailcorticosteroidtherapyandtrialsofatleasttwoalternativeagents 20 PROGNOSIS Approximately10percentofpatientsdieasadirectresultoftheinflammatoryprocessoritstreatment CNSparenchymaldiseaseorhydrocephalusandareoftenprofoundlyimmunocompromisedduetotreatment Patientswithaperipheralfacialnervepalsytendtoimproveovertwotofourweeks Opticneuropathycanimproveoverseveralweeks butsomepatientshaveaprogressivecourseendinginblindness Asepticmeningitisusuallyresolvesoverseveralweeks althoughanasymptomaticchronicpleocytosiscanpersist Peripheralneuropathicandmyopathicillnesstendstobechronica