NeuropathyGROUP

EURO-NMD

MaryReilly(London)chairDavidePareyson(Milan)deputychairandleadforinheritedneuropathiesPietervanDoorn(Rotterdam)leadforinflammatoryneuropathiesDavidAdams(Paris)leadforTTR-FamilialAmyloidPolyneuropathyJanaHeberlova(Prague)leadforpaediatricneuropathiesPAGs’representative:Jean-PhilippePlançon(DanielTanesse&FrançoisePelcotdeputyrepresentatives)

Buildingbridgesandbreakingbarriersinrareneuromusculardiseases 2

Reportü  Mappingofcentresandactivities:Questionnairewentouttoallcentresto

collectmemberswithinterestinneuropathy–inherited–inflammatory–paediatrics

ü  Guidelinesregistrybeingdeveloped–gapanalysisü  InteractionswithPNS(MaryReilly,PietervanDoorn),CMTR(Davide

Pareyson)-EAN(PetervanDenBergh,DavidePareyson,AntonioToscano)ü  PlanningmeetingtookplaceduringthePNSBoardMeetinginBaltimore24th

Oct2017(Reilly,Pareyson,vanDoorn)&inParis3rdNov2017(Reilly,Pareyson,Adams,vanDenBergh)

ü  Updatesonrecentdevelopmentsintheneuropathyfieldü  SubgroupsandinteractionswithotherERNs:hTTR-amyloidosisü  InteractionswithPAGsü  ProposalforaNeuropathyDay

Buildingbridgesandbreakingbarriersinrareneuromusculardiseases 3

MapofNeuropathycentres/groups•  42/62answered(20stillmissing)•  42centresseeneuropathypatients•  39seeadultsand37seechildren•  42seeinheritedand41seeinflammatoryneuropathypatients

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ListofGuidelines,Consensusconferences,RecommendationsforNeuropathiesPOLYNEUROPATHYINGENERAL1) Practice Parameter: Evaluation of distal symmetric polyneuropathy: Role of laboratory and genetic testing (an evidence-based review)Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and AmericanAcademyofPhysicalMedicineandRehabilitation.Neurology2009;72:185–192.EnglandJDetal.(otherJournalsaswell=M&N,PMR)2)PracticeParameter:evaluationofdistalsymmetricpolyneuropathy:roleofautonomictesting,nervebiopsy,andskinbiopsy(anevidence-basedreview).ReportoftheAmericanAcademyofNeurology,AmericanAssociationofNeuromuscularandElectrodiagnosticMedicine,andAmericanAcademyofPhysicalMedicineandRehabilitation.Neurology.2009Jan13;72(2):177-84.EnglandJDetal.(otherJournalsaswell=M&N,PMR)3)Review:Distalsymmetricpolyneuropathy.CallaghanBC,PriceRS,FeldmanEL.JAMA2015;314(20):2172-2181

GBS1)EFNS/PNSguidelines:inpreparation(vanDoornPA,vandenBerghPYK,HaddenRetal)2)Nationalguideline:DutchmultidisciplinaryGBSguideline:ISBN978-90-816331-1-6.DutchSocietyofNeurology(vanDoornPAetal.2010)3)Guidelineforcollection,analysis:Guillain-BarrésyndromeandFishersyndrome;casedefinitionsandguidelinesforcollection,analysis,andpresentationofimmunizationsafetydata.SejvarJJetal.,TheBrightonGBSWorkingGroup.Vaccine2011;29:599-6124)PracticeParameter:PracticeParameter: immunotherapyforGuillain-Barrésyndrome.Reportof theQualityStandardsSubcommitteeoftheAmericanAcademyofNeurology.HughesRACetal.Neurology2003;61:736-7405)Consensus:SupportivecareforpatientswithGuillain-Barrésyndrome.HughesRACetal.ArchNeurol2005;62:1194-1198

CIDP1)Guidelines:EuropeanFederationofNeurological Societies/PeripheralNerveSocietyGuidelineonmanagementof chronic inflammatorydemyelinatingpolyradiculoneuropathy:ReportofajointtaskforceoftheEuropeanFederationofNeurologicalSocietiesandthePeripheralNerveSociety—FirstRevision.VandenBerghPYKetal.EuropeanJournalofNeurology2010,17:356–3632) Recommendations: Chronic inflammatory demyelinating polyneuropathy disease activity status: recommendations for clinical researchstandardsanduseinclinicalpractice.GorssonKetal.JPeripheralNervSyst2010;15:325-3333) Recommendations: Recommendations on diagnostic strategies for chronic inflammatory demyelinating polyradiculoneuropathy. TheFrenchCIDPStudyGroup.JNeurolNeurosurgPsychiatry2008;79:115–118.

MMN1)Guidelines:EFNS/PNSMMNGUIDELINEEuropeanFederationofNeurologicalSocieties/PeripheralNerveSocietyGuidelineonmanagementofmultifocalmotorneuropathy.ReportofaJointTaskForceoftheEuropeanFederationofNeurologicalSocietiesandthePeripheralNerveSociety–firstrevisionJointTaskForceoftheEFNSandthePNS†.JournalofthePeripheralNervousSystem2010;15:295–301.

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ListofGuidelines,Consensusconferences,RecommendationsforNeuropathiesPARAPROTEINEMICNEUROPATHY1)Guidelines:EFNS/PNSPDNGUIDELINEEuropeanFederationofNeurologicalSocieties/PeripheralNerveSocietyGuidelineonmanagementofparaproteinemicdemyelinatingneuropathies.ReportofaJointTaskForceoftheEuropeanFederationofNeurologicalSocietiesandthePeripheralNerveSociety– first revisionJointTaskForceof theEFNSand thePNS†. Journalof thePeripheralNervousSystem15:185–195(2010)2)Consensus:230thENMCInternationalWorkshop:ImprovingfutureassessmentandresearchinIgManti-MAGperipheralneuropathy: Aconsensus collaborative effort, Naarden, The Netherlands, 24–26 February 2017. Pruppers MHJ et al. Neuromuscular disorders2017;27:1065-1072

VASCULITICNEUROPATHY1)Guidelines:PNSNSVNGUIDELINEPeripheralNerveSocietyGuidelineontheclassification,diagnosis,investigation,andimmunosuppressivetherapyofnon-systemicvasculiticneuropathy:executivesummaryMichaelP.Collinsetal.JournalofthePeripheralNervousSystem15:176–184(2010)

IVIg1) Guidelines: EFNS TASK FORCE/CME ARTICLE EFNS guidelines for the use of intravenous immunoglobulin in treatment of neurologicaldiseasesEFNStaskforceontheuseofintravenousimmunoglobulinintreatmentofneurologicaldiseases.I.Elovaraetal.EuropeanJournalofNeurology2008,15:893–9082) Guidelines: Evidence-based guideline: Intravenous immunoglobulin in the treatment of neuromuscular disorders. Report of theTherapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. HS Patwa et al. Neurology2012;78:1009-1015

PLASMAPHERESIS1) Guidelines: Evidence-based guideline update: Plasmapheresis in neurologic disorders. Report of the Therapeutics and TechnologyAssessmentSubcommitteeoftheAmericanAcademyofNeurology.CorteseIetal.Neurology2011;76:294-300

OUTCOMEMEASUREMENTS1) Consensus: 196th ENMC international workshop: Outcome measures in inflammatory peripheral neuropathies 8–10 February 2013,Naarden,TheNetherlands.VanhoutteEKetal2013;23:923-934

NEUROPATHOLOGY(SKINANDSURALNERVEBIOPSY)1)EuropeanFederationofNeurologicalSocieties/PeripheralNerveSocietyGuidelineontheuseofskinbiopsyinthediagnosisofsmallfiberneuropathy.Reportofa joint task forceof theEuropeanFederationofNeurologicalSocietiesand thePeripheralNerveSociety.EuropeanJournalofNeurology2010,17:903–912.LauriaGetal.2)147thENMCinternationalworkshop:guidelineonprocessingandevaluationofsuralnervebiopsies,15-17December2006,Naarden,TheNetherlands.NeuromusculDisord.2008Jan;18(1):90-6.SommerCetal.

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ListofGuidelines,Consensusconferences,RecommendationsforNeuropathies

MOLECULARDIAGNOSISANDGENETICTESTINGINGENERAL1) EFNS guidelines for the molecular diagnosis of neurogenetic disorders: motoneuron, peripheral nerve and muscle disorders. European Journal ofNeurology2011,18:207–217.BurgunderJ-Metal.2)PracticeParameter:Evaluationofdistalsymmetricpolyneuropathy:Roleof laboratoryandgenetic testing (anevidence-basedreview)Reportof theAmericanAcademyofNeurology,AmericanAssociationofNeuromuscularandElectrodiagnosticMedicine,andAmericanAcademyofPhysicalMedicineandRehabilitation.Neurology2009;72:185–192.EnglandJDetal.(otherJournalsaswell=M&N,PMR)3) Practice Parameter: evaluation of distal symmetric polyneuropathy: role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-basedreview).ReportoftheAmericanAcademyofNeurology,AmericanAssociationofNeuromuscularandElectrodiagnosticMedicine,andAmericanAcademyofPhysicalMedicineandRehabilitation.Neurology.2009Jan13;72(2):177-84.EnglandJDetal.(otherJournalsaswell=M&N,PMR)

ATTR-RELATEDNEUROPATHY1)FirstEuropeanconsensusfordiagnosis,management,andtreatmentoftransthyretinfamilialamyloidpolyneuropathy.CurrOpinNeurol.2016Feb;29Suppl1:S14-26.AdamsDetal.2) Recommendations for presymptomatic genetic testing andmanagement of individuals at risk for hereditary transthyretin amyloidosis. Curr OpinNeurol.2016Feb;29Suppl1:S27-35.ObiciLetal.3)Guidelineoftransthyretin-relatedhereditaryamyloidosisforclinicians.OrphanetJournalofRareDiseases2013,8:31.AndoYetal.

CHARCOT-MARIE-TOOTHANDRELATEDNEUROPATHIES(dHMN,HNPP,HNA)1) 221st ENMC InternationalWorkshop: Foot Surgery in Charcot-Marie-Tooth disease June 10th-12th, 2016 Naarden, The Netherlands. NeuromusculDisord.2017Sep21.[Epubaheadofprint].ReillyMM,PareysonD,BurnsJ,LauráM,ShyME;ENMCCMTFootSurgeryStudyGroup,SinghD.2)GuidelinesformoleculardiagnosisofCharcot-Marie-Toothdisease.Neurología.2012;27(3):169—178.BercianoJetal.3)Diagnosticguidelinesforhereditaryneuralgicamyotrophyorheredofamilialneuritiswithbrachialplexuspredilection.OnbehalfoftheEuropeanCMTConsortium.NeuromusculDisord.2000Oct;10(7):515-7.KuhlenbäumerGetal.4)Guidelinesfordiagnosisofhereditaryneuropathywithliabilitytopressurepalsies.NeuromusculDisord.2000Mar;10(3):206-8.DubourgOetal.5)GuidelinesforthediagnosisofCharcot-Marie-Toothdiseaseandrelatedneuropathies.AdhocWorkingGroupofthePeripheralNervousSystemStudyGroup,ItalianNeurologicalSociety.ItalJNeurolSci.1999Aug;20(4):207-16.PareysonDetal.6)2ndWorkshopoftheEuropeanCMTConsortium:53rdENMCInternationalWorkshoponClassificationandDiagnosticGuidelinesforCharcot-Marie-Tooth Type 2 (CMT2-HMSN II) and Distal HereditaryMotor Neuropathy (distal HMN-Spinal CMT) 26-28 September 1997, Naarden, The Netherlands.NeuromusculDisord.1998Aug;8(6):426-31.DeJonghePetal.

PORPHYRIA1)Bestpracticeguidelinesonclinicalmanagementofacuteattacksofporphyriaandtheircomplications.AnnClinBiochem.2013May;50(Pt3):217-23.SteinP

Buildingbridgesandbreakingbarriersinrareneuromusculardiseases 7

Actionforguidelines

•  CollectionandcollationofGuidelines,Consensusconferences,Recommendations=TOBECOMPLETED

•  Analysisofexistingguidelines=TOBEDONE

•  GAPANALYSIS=ONGOING

•  PlannedGuidelines–  PNS/EAN:Guillain-BarrèSydrome,CIDP

–  TTR-relatedAmyloidosis?

•  Disseminationandapplication=ONGOING

Pareyson D, Saveri P, Pisciotta C. Current Opinion in Neurology 30:471–480 OCT 2017

Therapeutical approaches for Transthyretin-related Amyloidosis

ReportontwotrialswithgenesilencinginhATTR-neuropathy

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Compound-Study Inoserten–Neuro-TTR(Ionis) Patisiran–Apollo(Alnylam)Anti-SenseOligonucleotides RNAilipidnanoparticles

Mechanism BindtowildtypeandmutatedTTRmRNA

TTRreduction 75-79% 84%;87.8%meanmaxserumreduction

Route Subcutaneously-onceaweek Intravenously-every3weeks

StudyPhase Phase3completed,OLEongoing Phase3completed,OLEongoing

Ratiotreated:placebo 2:1 2:1

Duration 15months 18months

PrimaryEndpoints NorfolkQoL,mNIS+7 mNIS+7

Participants 172randomised,150completed17treateddroppedout

225randomised193completed29placebodroppedout

Outcome

Norfolk=12pointsdifferenceat15months;50%improved

Norfolk=21.1pointsdifferenceat18months;51.6%improved

mNIS+7=20pointsdifferenceat15months;47%stabilisedorimproved

mNIS+7=33.99pointdifferenceat18months;56%improved

Independentfromdiseasestage,presenceofcardiopathy,typeofmutation

Independentfromdiseasestage,presenceofcardiopathy,typeofmutation

Sideeffects Thrombocytopenia(4cases,1death);6renalproblems

Infusionrelatedreactions,peripheraledema

Buildingbridgesandbreakingbarriersinrareneuromusculardiseases

RecentandongoingRCT’sinGBSandCIDPCIDP:Path-trialLancetNeurologyNov2017IVIg-dosefindingstudy(DRIP)study.KristaKuitwaard,PietervanDoornetal.ProtocolacceptedJPNS.StudyreadyQ22018.GBS:SeconddoseIVIg.SID-GBS(largeRCTinNL,almostfinished)ICA-GBS(Willison),n=8GlasgowJPNS2017JET-GBS(Kuwabara)n=30?Japan,notpublishedyet.Phase2trialwithEculizumab,monoclonalantibodythatbybindingtoC5inhibitscomplementactivation.At24weeks,markedimprovementinmotorfunctionwasobservedinpatientstreatedwitheculizumab

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Buildingsubgroups:theexampleofamyloidosis

•  EURO-NMD– Neuropathy(Muscle);Pathology;Genetics;Neurophysiology;Imaging

•  OtherERNs:rarecardiacdiseases(cardiomyopathy);blooddisorders;autoinflammatorydiseases

•  PAGs•  InteractionswithInstitutions–HealthMinistryfornoveldrugaccess

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Neuropathyday

•  ONEdaydedicatedtoPeripheralNeuropathies

•  AllEurope,allcentres•  Openwardsandlaboratories•  Workshops,presentations,meetingswithpatients