Pietro Cortelli

IRCCS Istituto delle Scienze Neurologiche di Bologna DIBINEM, Alma Mater Studiorum - Università di Bologna

HYSTORY•  1900descriptionofOPCA(Dejerine,Thomas)

•  1960descriptionofShy-Dragersyndrome

•  1964descriptionofSND(Adams,VanBogaert,VanderEecken)

Human α-synucleinopathies

•  Parkinson’sdisease(sporadic,geneticswitha-synorotherthanα-synmutation)

•  Dementiawithlewybodies–  PureDLB–  FamilialAlzheimerdisease(APP,PS-1,PS-2mutation,Downsyndrome)

•  MultiplesystemAtrophy(MSAp,MSAc)•  Pure/isolatedautonomicfailure(PAF)•  Disesasesthatmayhaveα-synimmunoreactivelesion

–  HallevordenSpatz,NeuroaxonalDystrophy,traumaticbarininjury,Pickdisease,ALS

MSA Neuropathology

Clinico-patologic overlap of neurodegenerative proteinopathies

MSASTUDYGROUPS

�  EuropeanMSAStudyGroup(1999,Innsbruck,27centres)

�  NorthAmericaMSAStudyGroup(2003,USA,11centres)

�  JapaneseMSAStudyGroup

�  ChineseMSAStudyGroup

�  MulticentreregistryoftheGermanCompetenceNetworkonParkinson’sdisease(2005,30centres)

EPIDEMIOLOGY

� Ararediseasewithannualincidenceabout0,6per100.000peryear

�  3per100.000peryearinpopulationolderthan50yrs

� Prevalencerangesfrom1,9to4,9per100.000inhabitants(similartothoseofHuntingtonandmotorneurondiseases)

CLINICALHALLMARKS

•  Parkinsonism

•  Cerebellarataxia

•  Autonomicfailure

•  Pyramidalsymptoms/signs

�  MSA-p=predominantparkinsonian(68%)

�  MSA-c=predominantcerebellar(32%)

NONMOTORSLEEP

AUTONOMIC

MOTORPARKINSONIANCEREBELLAR

CLINICALPRESENTATIONOFMSA

Milestones of disease advancement and total disease course. O'Sullivan S S et al. Brain 2008;131:1362-1372

© The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Dx= diagnosis of motor syndromes C= cognitive disability D= dysarthria or dysphagia F= frequent falls R= residential care U= urinary catheter W= wheelchair

DIAGNOSIS

�  NiallQuinn1989:“Thenatureofthebeast”

�  FirstConsensusCriteria1998

�  SecondConsensusCriteria2008(simpleandincludeneuroimagingfeatures)

�  Validation2009:sensitivitywithnewconsensus“possiblecategory”washigher,andPPVmarginallyhigher,thanforclinicaldiagnosiswitholdconsensus“possiblecategory”(sensitivityofnew=41%vs28%ofold)

Gilman, S. et al. Neurology 2008;71:670-676

Gilman, S. et al. Neurology 2008;71:670-676

Gilman, S. et al. Neurology 2008;71:670-676

Gilman, S. et al. Neurology 2008;71:670-676

Requiresneuropathologicfindingofwidespreadandabundantcentralnervoussystemglialcytoplasmicinclusions(GCIs)thatarepositivefora-synuclein,inassociationwithneurodegenerationinstriato-nigralorolivo-ponto-cerebellarstructures.

DEFINITEMSA

PROGNOSIS�  MoresevereanddisablingthanPD(4%ofprolonged

survival,Petrovich2012,Calandra2013)

�  Themostimportantearlyclinicalprognosticfeatureregardingsurvivalis“earlyautonomicdysfunction”

�  Suddendeathis7timesascommoninpatientswithautonomicpredominanceandmayoccureveninptwithtracheostomy

�  Female,olderageofonset,shorterintervaluntilclinicalmilestonesarereachedpredictshortersurvivaltime

�  NodifferencesbetweenMSA-pandMSA-c

Stridoriscategorizedasearlyifpresentingwithin3yearsofdiseaseonset.

p= 0.0139

CLINICALPRESENTATION&NATURALHISTORY

�  Motor(Parkinsonianorcerebellar)presentationismorecommonthanautonomicexcepturogenitaldysfunction

�  Onset55-60yrs(range=33-83yrs)

�  Meansurvival7-9yrswithsubstantialvariation

�  InEuropeandUSA,MSA-pismorecommonthanMSA-c(60%vs40%)

�  InJapanMSA-cismorecommonthanMSA-p(84%vs16%)

Rarepresentations

�  Severeautonomicfailure

�  NocturnalStridor

�  Dystonia(“Pisa” syndrome)

�  Lowerlimbtremor

Earlydiagnosis(<3yrs)

•  Diagnosisiseasybutafter5yearsofdisease!

•  Parkinsonianonset:“redflags”with>95%

specificityforMSA-Poccurafter3years

•  Cerebellaronset:SCA1,2,3,6,7,12,17;ataxiawith

oculomotorapraxia(aprataxinmutation;fragile-X-

associatedtremorataxiasyndrome;FMR1genemutation

in4%ofMSA-c)

•  Autonomiconset:synucleinopathies

RBD in MSA

•  May be the first symptoms of MSA •  Much less evident male preponderance and not related to any

demographic and clinical features and cognitive dysfunction •  May be associated with non REM sleep motor abnormalities, and

sleep related breathing disorders •  May evolves to a status dissociatus

Of the 348 (37%) converters over 953 subjects with iRBD only 18 (2%) evolves in MSA

TOOLSrecognizedbyconsensus2008

•  Clinical(history&Neurologicalexamination)•  PresenceanddurationofLevodoparesponse•  BrainMRI(atrophyofputamen,Middlecerebellarpeduncles,ponsorcerebellum)

•  FDG-PET(hypometabolisminputamenbrainstemorcerebellum)

•  PresynapticnigrostriataldopaminergicdenervationonSPECTorPET

RoutineBrainMRI

•  RoutineMRIrulesoutothercauseofnondoparesponsiveparkinsonism

(vascular,normalpressurehydrocephalus)andlesionsofthe

cerebellum

•  Severeponto-cerebellaratrophyinMSA-c

•  T2MRI:

–  “hotcrossbun”inthepons(observedalsoinSCA2and3,andvCJD)

–  SignallossindorsolateralputamenwithhyperintenselateralriminFLAIR(specificbutlittlesensitiveat1,5T,aspecificat3T)

BrainMRIDWI,spectroscopy,morphometry

•  FractionalanisotropyandapparentdiffusioncoefficientchangesarepresentpriorofT2MRIalterationsandareusefultodifferentiateMSAfromPDandincaseofcerebellarpresentation

•  Magneticresonancespectroscopy•  Voxelbasedmorphometryandtractographyarenot

appropriatefordiagnosticwork-upbutofferresearchinsights

•  Morphometricmeasurementsofmidbrain,ponscandistinguishMSA-pfromPSPandofsuperiorcerebellarpeduncleMSA-pfromPD

Functionalimaging

•  PETwith18F-dopa(presynapticdopaminergicmarker)andwithraclopride(D1striatal)poorlydistinghishMSA-pfromPDandotherparkinsonism

•  PET-FDGshowlowmetabolisminthebrainstemandcerebelluminMSA-c

•  SPECT-DATSCAN(dopaminetransporter,nigro-striatalpathway)isuselessinMSA-pmaybeusefulincaseofcerebellar(MSA-c),autonomicandsleeponset

•  SPECT-IBZM(D2striatalligand)littlevalue

OTHERTOOLS

•  Autonomicfunctiontests–  cardiovascularfunction–  Bladder

•  Sleepevaluation(polysomnography)•  Olfactoryevaluation

•  CardiacSPECT–MIBG(post-ganglioniccardiacdenervation)•  Transcranialsonography

INVESTIGATIONS

•  Eachofthemethodslistedhas

–  onlysuboptimalaccurancyattheonsetofthedisease

– moststudieshavebeendoneinclinicallydefiniteMSAwhen

investigationshavelittlesignificanceinthediagnosisofMSA

Theconundrumoftheearlydiagnosis(<3yrs)ofMSA

ONSET

•  SLEEP(RBD,others)

POSSIBLEDIAGNOSIS

•  iRBD,PD,DLB,MSA

Theconundrumoftheearlydiagnosis(<3yrs)ofMSA

ONSET

•  AUTONOMIC

POSSIBLEDIAGNOSIS

•  PAF,AAG,PD,DLB,MSA

Theconundrumoftheearlydiagnosis(<3yrs)ofMSA

ONSET

•  CEREBELLAR

POSSIBLEDIAGNOSIS

•  ILOCA,SCA,FXTAS,MSA-C

Cerebellarsigns

•  CerebellarAtaxiaoccursin64%ofMSA

•  Limbkineticataxia,scanningdysarthriaandcerebellar

oculomotordisturbancesarealsocommon

Theconundrumoftheearlydiagnosis(<3yrs)ofMSA

ONSET

•  PARKINSONISM

POSSIBLEDIAGNOSIS

•  PD,MSAP,PSP,CBD

Parkinsonism

•  Rigidity,bradykinesia,posturalinstabilityoccurin90%ofMSA•  Restingtremorislessfrequent(10-30%comparedto60-70%

ofPD)•  BenefitfromlevodopaisNOTsustainedbuttransientresponse

occurin30-40%ofMSAusinglargerdosagesthaninPD(facialdystoniaoccursmorefrequentlythanlimbdyskinesia)

•  Progressionisfast(UPDRSIIImotorscore28%peryearinMSAvs4%inPD,Seppi2005;UMSARSIhystoryreview35%,UMSARSIIImotorscore57%,Geser2006)

Cognitive and MSA

•  Cognitive impairment is not a feature of MSA and until recently would have been regarded as a reason to reconsider the diagnosis

•  Studies with neuropathological ascertainment

of MSA, cognitive impairment has been recorded in 14–18% of cases

Cognitive and MSA

Cognitive impairment, consisting of visuospatial and constructional dysfunction, impairment of verbal fluency, dysexecutive syndrome and depression has been described to be more severe and widespread in patients with MSA-P than in patients with MSA-C.

MakinganearlydiagnosisofMSAisdifficultbutyoucangetitifyouhaveknowledge

ofsleep,autonomic,cerebellarandparkinsonian

disorders!!!

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