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