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NeurologicandPsychiatricManifestationsofConnectiveTissueDisordersinWomen
ShamikBhattacharyya,MD,MSBrighamandWomen’sHospital
HarvardMedicalSchool
ConnectiveTissueDiseases
• Oldertermdescribingdiseasesaffectingfascia,bone,cartilageandotherorgans.
• Heterogeneousgroupofdiseaseswithdiversepathophysiology– AutoimmunedisorderssuchassystemiclupuserythematosusandSjögrensyndrome
– InheriteddiseasessuchasMarfan syndromeandfibromusculardysplasia
WomenandAutoimmunity
78%ofpatientswithautoimmunedisordersarewomen.
Nat.Immunol.(2001);2:777-780
WhyWomen?
• Mechanismunclearbutlikelymediatedpartlybysexsteroids– Immunecellshavehormonereceptors– Hormoneproducingcellshavecytokinereceptors
• Morerobustantibodyproductioninwomen– InfectionproducesmoreTh2responseinwomencomparedtomen
– Numberofautoantibodiescorrelateswithriskofautoimmunity
NotalldiseasesMorecommoninmales• Myocarditis• Wegenergranulomatosis• Gastritis• TypeIDiabetes• AnkylosingSpondylitis• Idiopathicpulmonary
fibrosis
Morecommoninfemales• Thrombocytopeniapurpura• Myastheniagravis• Rheumatoidarthritis• Systemiclupus
erythematosus• Sjogren syndrome• Autoimmunehepatitis• Hashimoto’sthyroiditis
CellMediatedAntibodyMediated
Doesthispatienthaveneuropsychiatriclupus?
SystemicLupusErythematosus
• Chronic,multi-systemic,inflammatorydisorderofunclearetiology
• Disproportionatelyaffectswomen(80-90%)duringearlyadulthood
• MorefrequentinAfrican-Americans,Hispanics,andAsians
• Relativelycommon– 50/100,000peopleintheUS
DiagnosingLupusMalarrash Erythemaovermalarregionsofthefacesparingthenasolabial
folds
Discoidrash Raisederythematouspatcheswithkeratoticscalingandfollicularplugging
Photosensitivity Skinreactionfromsunlight(manytypes)
Oralulcers Usuallypainlessinoralcavityornasopharynx
Arthritis Nonerosive withtendernessorswelling
Pleuritis orpericarditis
Eitherbyhistoryorevidenceofpleural/pericardialeffusion
Renaldisorder Proteinuriaof0.5gramsdailyorcellularcasts
Neurologicdisorder Seizuresorpsychosiswithoutclearsecondaryprovocativefactor
Hematologicabnormality
Hemolyticanemiaorleukopeniaorlymphopeniaorthrombocytopenia
DiagnosingLupusPositiveanti-nuclearantibody
Generallyhigh-titer
Serology Positiveanti-dsDNA(doublestrandDNA),anti-Sm(Smnuclearantigen),orpositiveantiphospholipidantibodies
Fouroutofelevenrequiredfordiagnosis.
Breadthofcriteriareflectclinicalheterogeneityofdisease.
NeurologyinSLE
• Earlyindescriptionoflupus,neurologicalinvolvementrecognized.
• In1875,Hebra andKaposireportedstuporassociatedwithclinicalsymptomofSLE
• DiversemechanismsofneurologicalinjuryassociatedwithSLE
Nomenclature
• Historically,manytermsassociatedwithSLEaffectingthenervoussystem– Lupuscerebritis– Neurolupus– CNSlupus– Lupoid sclerosis
• Currentpreferredtermis: NeuropsychiatricSLE(NPSLE)
Nomenclature
19syndromesnamedtoprovidestandardizednomenclature- doesnotimplycausationbySLE.OthersyndromesnotnamedbuthavebeenobservedlikePosteriorReversibleEncephalopathySyndrome(PRES).
PathologyinNPSLE• In1968,JohnsonandEPRichardsonfromMGHdescribed24autopsyneuropathologicalstudiesfrompatientswithSLE:–Mostcommonfindingin80%wasmicoinfarcts withmicroglialnodules
– Nocasesofgeneralizedarteritisfound– “Alloftheobservedneuropathologicalchangescouldbeonavascularbasis…”
• Alargerpathologicalseries1988alsoshowednocasesofCNSvasculitisbutfoundfrequentembolicinfarctsfromLibman-Sacksendocarditis
PathophysiologyinNPSLE• H&Estudiesnotsensitivetodisordersaffectingneuronalfunction(suchasbysignalingchanges)
• Whataboutautoantibodies?SomerelevantonesforNPSLE– Anti-phospholipidantibodies– Anti-NMDARNR2subunit– Anti-RibosomalP
Anti-NMDARAntibodies
Proposedtobepathogenicparticularlyincognitivedisorders
Anti-NMDARNR2Ab
• SerumAbfoundinaboutonethirdofpatientswithSLE
• CanbedetectedinCSF• Atleast13cross-sectionalandlongitudinalstudieshaveexaminedrelationofAbtocognitivechanges–Mixedresults:6reportassociation,7norelation
• Investigationalmarkerofunclearrelevance
Anti-RibosomalPAb
• InitiallydescribedasbindingtoC-terminalofribosome,nowknowntobind:– NeuronalsurfacePantigen(NSPA),cellsurfaceproteinofunknownfunctioncausingcalciuminfluxandapoptosiswhenexposedtoanti-PAbinvitro.
• NSPAexpressedinregionsrelatedtomemoryformationandemotionalprocessing
Anti-RibosomalPAb
Antibodyusuallynotfoundincontrolsorotherautoimmuneconditions.HighlyspecificforSLE.
LimitedroleaspredictiveordiagnosticbiomarkerforsubtypeofSLE(notsensitiveorspecific).
NPSLE• PrevalenceofNPSLEsyndromesinSLE:56%(rangefrom12-95%)– 28%haveaneurologicalcomplaintattimeofdiagnosis
• Prevalenceofsyndromes:– Headache:28-57%–Mooddisorder:21%– Cognitivedisorder:20%– Seizure:10%– Cerebrovasculardisease:8%
Headache
Frequencyofheadacheissimilar tostudiesingeneralpopulation
HeadacheandSLEActivity
• MajorityofstudiesdonotfindrelationbetweenheadacheandSLEactivity(outof6studies,4havebeennegative)
• Norelationbetweenserumanti-cardiolipinAbsandheadache
“Lupusheadache”inisolationislikelynotamarkerofdiseaseactivity.TreatheadacheinSLEsymptomatically
Depression
• Prevalenceofmajordepressionin20-47%–Manymethodologicalflaws(typeofinterviewing,criteriaused,etc.)
Depression
• Unclearwhetherincreasedprevalencerelatedtodiseaseorchronicillnesswithdisability
• Elevateddiseaseactivityincreasestheoddsofmajordepressionmodestlyby10%.
PossiblyrelatedtoSLEbutmanyconfounders
Psychosis
• Inacohortof537patients,psychosisprevalence:17%– Psychosisatdiseaseonset:21%– PsychosisduringcourseofSLE:45%– Corticosteroidpsychosis:31%– Unrelated:2%
• Psychosiscorrelateswithelevateddiseaseactivity
Psychosis• Oftenwithprominentvisualhallucinations.Auditoryhallucinationsmorecommonwithsteroids.
• CSFusuallynormalbutcanshowelevatedprotein/mildpleocytosis
• MRIoftennormalbutcanshownon-specificlesions• AntiphospholipidAbsriskfactorforpsychosis
Oftenrelatedtodiseaseactivity.First,checkforsteroidpsychosis.Otherwise,treatSLEincludingwithsteroidsandantipsychotics.
Seizure
• Occurinabout20%ofpatientswithSLE• Canbegeneralizedorpartialonset• Multiplemechanisms– Acuteprovokingfactorssuchaselectrolyteabnormalitiesoruremia
– Stroke– PresenceofantiphospholipidAbsoranti-SmAb
SeizureManagement
• Majorityofpatientswithfirstseizurewillnotdevelopepilepsy
• Treatmentdecisionsimilartootherfirsttimeseizure– ImagingwithbrainMRI– EEG– UnclearroleoffurthertestingsuchasLPorotherantibodytesting
• NotallpatientswillneedAED
Stroke
• SecondleadingcauseofdeathinpatientswithSLE
• Twofoldincreasedriskofstroke(elevatedriskespeciallyinyoungerpopulation)
• Increasedprevalenceofconventionalriskfactors– Hypertension– Dyslipidemia– Diabetesmellitus
Screenforandtreatmodifiableriskfactors!
Mechanisms
• Smallvesselvasculopathy
Mechanisms
• Embolicinfarcts– Libman-Sacksendocarditis
• Microembolism prevalentinSLE–WithTCD,9-15%ofpatientshave“HITS”whenmonitoredforanhour
• Acceleratedatherosclerosis• CNSvasculitisisusuallynotfoundandisararecause
Stroke
• Anti-phospholipidantibodiesarepredictiveofischemicstroke– presentin65%ofpatientswithSLEandischemicstroke.
• Cancauseterritorialstrokesorsmallinfarcts
Stroke- Checkforanti-phospholipidAbs(lupusanticoagulant,anti-cardiolipin IgG/IgMisotype,anti-β2-glycoproteinIIgG/IgM)- Screenforinfective/Libman-Sacksendocarditis(ifimagingandsyndromesuggestive,proceedtoTEE;TTEsensitivityabout11%forLS)- SLENOTacontraindicationforIVtPA foracutestroke- Controlofmodifiableriskfactors- Secondarypreventionwithanti-plateletsoranticoagulationifanti-phospholipidsyndrome
PregnancyandAPS
• APSassociatedwithpregnancycomplications– Spontaneousfetalabortions– Pre-eclamspia/eclampsia– Fetalgrowthrestriction–Maternalthromboembolicdisease(5-12%inwomenwithAPSvs<0.1%ingeneralpopulation)
Management
• Riskofasymptomaticwomenwithincidentallyfoundantibodiesisunclear
• ForpregnantwomenwithpriorstrokeandpersistentAPLantibodies– LMWHanticoagulationduringpregnancy– Ifpreviouspregnancymorbidity(suchasfetalloss),low-doseaspirinisaddedtoregimen
DoesthispatienthaveneurologicalcomplicationsofSjögrensyndrome?
SjögrenSyndrome
• Siccasyndrome:Drymouthanddryeyes• Focallymphocyticinfiltrationofexocrineglandsparticularlysalivaryandlacrimalglands
• 20foldpredominanceofwomen• Averageageofdiagnosisis55years• Affects2-4millionpeopleinUS
DiagnosisDry ocularsymptomsforatleastthreemonths
Dry oralsymptomsforatleastthreemonths
Ocularexocrinedysfunctionsign – PositiveSchirmer TestorRoseBengalstainSalivary glanddysfunctionsign– Decreasedsalivaryfloworabnormalparotidsialography orabnormalsalivaryscintigraphyHistopathology ofsalivaryglandshowinglymphocyticfoci
Positiveserologyforanti-Ro/SSA oranti-La/SSB
4outofthesixcriteriarequiredEitherhistopathologyorpositiveserologyrequiredfordiagnosisInprimarySS,sensitivityforanti-Ro52%andanti-La34%!OftenoccursincontextofotherautoimmunediseasessuchasRAandSLE
Diagnosis
Diagnosis
SjögrenSyndrome
• Classificationcriteriafocusexclusivelyondryeyesanddrymouth
• Extra-glandularsignsarecommonanddisablinginSS– Thyroiddysfunction,45%ofpatients– Diffusearthralgias– Dryskin,dryrespiratorysystem(chroniccough)– Tubulointerstitial renaldysfunction– Increasedriskoflymphoma
NeurologyinSS
• Widespectrumofinvolvement.Prevalencedependsondefinition
• Mostcommon: Extremedebilitatingfatigue– Occursin50%– Causeisusuallyundetermined–Majorcontributortodecreasedfunctionalstatus– Oftendiagnosedinitiallywithfibromyalgiaorchronicfatigue
NeurologyinSS
• Commoncomplaintsofattentionandmemorydifficulty– Neuropsychologytestingoftenshowsfrontalexecutiveandverbalmemorydysfunction
• UnclearwhetherfromSS,psychologicalreactiontoit,oreffectoftreatment
• MRIoftenshowsincreasedburdenofwhitematterT2hyperintensities
ConcurrentNMO
• Canpresentasmyelitisorwithfocalbrainlesions.
• RecommendcheckingNMOAbandtreatinglikeNMO
NotallNMO
• Canhaveotherfocalneurologicpresentations– Tumefactivesteroidresponsivemasslikelesions– Recurrentmeningoencephalitis• Presentwithfevers,myalgias,anddelirium• CSFwithleukocytosisandelevatedprotein• Oftenresolvespontaneouslyorrespondtooralprednisonetreatment
PeripheralNeuropathy
• ManypatternsofneuropathyinSS– Puresensory• Non-lengthdependentganglionopathy (bestknown)• Painfuldistalneuropathy
– Symmetricsensorimotoraxonalneuropathy– Others:• Demyelinatingneuropathy• Cranialneuropathy(suchastrigeminalneuropathy)
Testing
• Sensitivityforserologyispoor:– Anti-Ro:40-50%– Anti-La:10-20%
• Schirmer testmaybepositiveinmajority• Lipbiopsyforsalivaryglandpathologyisalsopositiveinmajority
Intheabsenceofsiccasyndrome,unclearsignificanceofpositivetesting.SSoftenoccursinthecontextofotherautoimmunediseases.
Management
• Generallyhardtotreat• Symptomaticallytreatedwithneuropathicagents
• Unclearwhichimmunomodulatoryregimentouse:– Corticosteroids:30-40%responserate– IVIg:30-40%response– Rituximab– Infliximab
Doesthispatienthavefibromusculardysplasia?
Fibromuscular Dysplasia
• Adescriptivetermforcellgrowthinarterialwallresultinginangiographicbeading,narrowing,dissection,oraneurysm
• Cellhyperplasiamostcommoninmediabutcanalsooccurinintimaoradventitia
Circulation(2012);125:e636-639
Fibromuscular Dysplasia
• Unclearprevalenceingeneralpopulation.3.8%ofpotentialrenaldonorshaveangiographicFMD
• RegistrystartedinUSin2007forFMD– Ageatdiagnosis:51.9years– AgeoffirstFMDrelatedsymptoms:47.2years– Female:91%– Race:White95%,Black2.2%,Hispanic1.5%
Stroke(2012);125:3182-3190
Fibromuscular Dysplasia
Stroke(2012);125:3182-3190
PresentingSymptoms n(%)Hypertension 285(63.8)Headache 234(52.4)Pulsatiletinnitus 123(27.5)Dizziness 116(26.0)Cervicalbruit 99(22.2)Neckpain 99(22.2)Tinnitus 84(18.8)Chestpainorshortnessofbreath 72(16.1)
Flank/abdominalpain 70(15.7)Aneurysms 63(14.1)
Cervicalarterydissection 54(12.1)
Epigastricbruit 42(9.4)HemisphericTIA 39(8.7)Postprandialabdominalpain 35(7.8)
Stroke 31(6.9)
VascularBedInvolved n No.ofPatients
WithImaging %
Renalartery 294 369 79.7
Extracranialcarotidartery 251 338 74.3
Vertebralartery 82 224 36.6
Mesentericarteries 52 198 26.3
Intracranialcarotidarteries 35 206 17.0
Upper-extremityarteries
10 63 15.9
ExtracranialcarotidFMDcomparativelymorelikelytooccurinwomencomparedtomen(75%vs44%)
Fibromuscular Dysplasia
• Amongpatientswithextracranialcarotid/vertebralarterydisease,renalFMDpresentin64.5%
• Amongpatientswithrenalarterydisease,extracranal carotid/vertebralarterydiseasepresentin64.8%
• IntracranialFMDreportedin8%ofpatients
Stroke(2012);125:3182-3190
ClosingThoughts
• Neuropsychiatriclupusencompassesaheterogeneousgroupofdiseases
• Sjogren syndromeoftencausesdebilitatingfatigue– underappreciatedandunclearcause
• FibromusculardysplasiapresentsintheUSgenerallyasadiseaseofmiddleagedwomen
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