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Small Fiber Poluneuropathy: An Update

Charles E. Argoff, M.D.

Professor of Neurology

Albany Medical College

Director, Comprehensive Pain Center

Albany Medical Center

Disclosures

•  Receive consulting fees from Pfizer, Nektar, Depomed, Salix, Daiichi Sankyo, Grunenthal, and Quest.

•  Receive honoraria from Allergan, Depomed, AstraZeneca, Daiichi Sankyo, BDSI, Collegium, and Avanir.

•  Stockholder of Pfizer and Depomed. •  Receives royalties from Elsevier.

PresentationObjectives

§  Todescribethedefinitionofsmallfiberpolyneuropathy

§  Todescribeapproachestomakingthediagnosisofsmallfiberpolyneuropathy

§  Todescribetherangeofmedicalconditionsassociatedwithsmallfiberpolyneuropathy

§  Todescribecurrentandemergingtreatmentsofsmallfiberpolyneuropathy

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Example:Mechanistic Characterization of Pain Any combination may be present

in a given individual Peripheral

(nociceptive)

■  Inflammation or mechanical damage in tissues

■ NSAID, opioid responsive

■ Responds to procedures

■ Classic examples ■  Acute pain due to

injury ■  Osteoarthritis ■  Rheumatoid arthritis ■  Cancer pain

Peripheral Neuropathic

■ Damage or dysfunction of peripheral nerves

■ Responds to both peripheral (NSAIDs, opioids, Na channel blockers) and central (TCA’s, neuroactive compounds) pharmacological therapy

■ Classic examples ■  Diabetic neuropathic

pain ■  Post-herpetic

neuralgia

Central Neuropathic or Centralized Pain

■ Characterized by central disturbance in pain processing (diffuse hyperalgesia/allodynia)

■ Responsive to neuroactive compounds altering levels of neurotransmitters involved in pain transmission

■ Classic examples ■  Fibromyalgia ■  Irritable bowel

syndrome ■  TMJD ■  Tension headache

Mixed Pain States

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Which person has pain?

Differential diagnosis- Widespread Pain

■ Rheumatic ■ Arthritis (OA, RA) ■ Polymyalgia Rheumatica ■ Osteomalacia ■ Myopathy ■ Spondyloarthropathies ■ Systemic Lupus

Erythematosus

■ Neurologic ■ Multiple sclerosis ■ Chiari malformation ■ Spinal stenosis ■ Radiculopathy ■ Polyeuropathy ■ Fibromyalgia

■ Endocrine ■ Hypothyroidism ■ Diabetes ■  IS SMALL FIBER

POLYNEUROPATHY OVERLOOKED?

Background

§  Peripheralneuropathyisexperiencedbyapproximately40millionpeopleintheUS

§  Manyperipheralneuropathiesaremixedneuropathieswithbothlargefiberandsmallfiberinvolvement

§  Increasinglyrecognizedisthedemonstrationofspecificinvolvementofsmallmyelinatedorunmyelinatedfibers,e.g.smallfiberneuropathies

Hovaguimian A, Gibbons CH. Diagnosis and Treatment of Pain in Small-fiber Neuropathy Curr Pain Headache Rep (2011) 15:193-200

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WhatisNeuropathicPain?

§  Painarisingasadirectconsequenceofdiseasesaffectingthesomatosensorysystem.Gradingsystem:definite,probable,possibleR-DTreedeetal.Neurology2008,ProposedbyIASPNeuropathicPainSpecialInterestGroup.

§  InPlainEnglish:Painfromthenerves,spinalcord,orbrain.Notoriginatinginthebones,muscles,organs.

CommonNeuropathicPainDiagnoses §  DiabeticPeripheralNeuropathy*

§  PostHerpeticNeuralgia*§  RadicularPain§  TraumaticPeripheralNerveInjury§  ComplexRegionalPainSyndrome§  ChronicPostopPain§  PhantomLimbPain§  HIVrelatedneuropathy§  SpinalCordInjury*§  Post-strokepain§  TrigeminalNeuralgia*§  SmallFiberPolyneuropathies

* FDA approved medications available

SmallFiberPolyneuropathyDefinition

§  Smallfiberneuropathies(SFN)resultfromdamagetotheperipheralnervesaffectingsmallmyelinatedA-DeltaandunmyelinatedCfibers.

§  Thefibersaffectedincludebothsmallsomaticaswellasautonomicfibers

§  Thermalperceptionandnociceptionaresubservedbysmallfibers

§  Entericfunctionisalsosubservedbysmallfibers

§  LARGEfibersareheavilymyelinatedandinvolvedinmusclecontrol,aswellastouch,vibrationadnpositionsense

Hovaguimian A, Gibbons CH. Diagnosis and Treatment of Pain in Small-fiber Neuropathy Curr Pain Headache Rep (2011) 15:193-200

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SmallFiberPolyneuropathyDefintion-2

§  MostSFNsoccurinalength-dependentfashion–firststockingdistributionchangesandthenlaterglovedistribution

§  Rarely,non-lengthdependentSFNcanresultsinsymptomsinvolvingtheface,trunk,proximallimbs,orothermorelocalizedareas

§  Thepathogenesisofinjurytosmallfibersisnotwellunderstood

§  SFNcanprogresstoinvolvelargefibersaswell

Hovaguimian A, Gibbons CH. Diagnosis and Treatment of Pain in Small-fiber Neuropathy Curr Pain Headache Rep (2011) 15:193-200

SmallFiberPolyneuropathy:BIGimpactonqualityoflife

§  OnlyonestudyasmeasuredtheimpactspecificallyonSFPNonqualityoflife

§  265patientsenrolled§  SFN-SIQ,VAS,36itemshortformhealthsurveyevaluated

§  SFPNpatientsdemonstratedamarkedoverallreductioninqualityoflife

§  PhysicalandmentalmeasuresweredecreasedChan AC, Wilder-Smith EP. Small fiber neuropathy: getting bigger! Muscle Nerve

53:671-682, 2016

DisordersAssociatedwithSFN

§  Diabetes§  ImpairedGlucose

Tolerance

§  MetabolicSyndrome

§  Sarcoidosis§  ThyroidDysfunction§  HIV§  VitaminB12Deficiency

§  VitaminB1Deficiency

§  Chemotherapydrugs§  AntiviralAgents§  CeliacDisease§  Sjogren’sSyndrome

§  ParaneoplasticSyndromes

§  Paraprotenemia§  RheumatoidArthritis

§  Idiopathic(upto50%!)

Hovaguimian A, Gibbons CH. Diagnosis and Treatment of Pain in Small-fiber Neuropathy Curr Pain Headache Rep (2011) 15:193-200

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DisordersAssociatedwithSFN-2

§  Guillain-BarreSyndrome

§  ChronicInflammatoryDemyelinatingPolyneuropathy(CIDP)

§  RestlessLegSyndrome§  HepatitisC§  SystemicLupus

Erythematosus

§  Amylodosis§  Fabry’sDisease§  EhlersDanlos

Syndrome§  HereditarySensory

Neuropathies§  HereditaryAutonomic

Neuropathies§  ?Centralpoststroke

pain(moretofollow)Hovaguimian A, Gibbons CH. Diagnosis and Treatment of Pain in Small-fiber

Neuropathy Curr Pain Headache Rep (2011) 15:193-200

DisordersassociatedwithSFN-3

§  Alcoholuse§  Rabies,varicellaor

Lymevaccine§  Anti-TNFinhibitors§  Metonidazole§  Linezolid§  Statins§  Sodium

channelopathies

§  Parkinsondisease§  Pompedisease§  Wilsondisease§  ALS§  FragileX§  Xlinked

adrenoleukodystrophy§  Chronicrenaldisease

Chan AC, Wilder-Smith EP. Small fiber neuropathy: getting bigger! Muscle Nerve 53:671-682, 2016

SFNPathophsyiology-PossibleroleofSodiumChannelmutations

§  Geneticvariantsinthestructure/functionofsodiumchannelsmayleadtoeitherlossofpainsensitivityorenhancedpain

§  InactivatingmutationsinSCN9A,whichencodesNav1.7isassociatedwithcongenitalinsensitivitytopain

§  GainoffunctionmutationsinSCN9AmayresultinSFN§  VariousmutationsinTRPA1orNAv1.8(SCN10A)andNav

1.9(SCN11A)alsomayleadtoSFN

§  Mightthisinformationleadtonewtreatments?

Bennett DL, Woods CG. Painful and painless channelopathies. Lancet Neurol 2014 Jun;13(6):587-99.

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Polyneuropathyiesmayinvolvesmallandlargenervefibers

Large-fiber neuropathy

Small-fiber neuropathy

Symptoms Numbness, pins and needles, tingling, poor balance

Pain: burning, electric shocks, stabbing pain, numbness

Exam Findings

Reflexes, proprioception Vibration, +/- motor

Thermal, pin-prick sensation, allodynia

Functional changes

Pressure, balance, fall risk Nociception; protective sensation

Diagnostic test

EMG/NCV, sural nerve biopsy

QST, nerve biopsy, Intraepidermal nerve fiber density (skin biopsy)

SFNSymptoms

§  Symptomsvarywidelyinseverity§  Oftenaffectedindividualsdescribeagradualonsetofvaguedistalsensorydisturbances

§  Examplesincludefeelinglikethereissandintheperson’sshoe,asockfeelingasifithaspebblesinit,pinsandneedlesensations,coldpainfulsensationsortingling.

Hovaguimian A, Gibbons CH. Diagnosis and Treatment of Pain in Small-fiber Neuropathy Curr Pain Headache Rep (2011) 15:193-200

SFNSymptoms-2

§  Burningpainintheextremities,sometimessevere

§  Allodyniaandhyperesthesia§  Socksorbedsheetsmaybepainful§  Symptomsareoftenworseatnight

Hovaguimian A, Gibbons CH. Diagnosis and Treatment of Pain in Small-fiber Neuropathy Curr Pain Headache Rep (2011) 15:193-200

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SFNSymptoms-3

§  Autonomicandentericdysfunctionincluding:dryeyes,drymouth,lightheadednesswithchangesinposture,syncope,abnormalitiesofsweating,erectiledysfunction,GIsymptomssuchasnauseaandemesis,constipation,diarrhea,changesinurinaryfrequencyincludingnocturia.

Hovaguimian A, Gibbons CH. Diagnosis and Treatment of Pain in Small-fiber Neuropathy Curr Pain Headache Rep (2011) 15:193-200

SFN-Diagnosis

§  Normalorpracticallynormalbasicphysicalandneurologicalexamination!!!

§  However,possiblefindingsincludedecreasedpinprick,diminishedthermalsensation,hyperalgesia,dryskin

§  Adetailedhistoryisvitaltomakingthediagnosis

§  Ancillarytestingmaybehelpfulaswell

Hovaguimian A, Gibbons CH. Diagnosis and Treatment of Pain in Small-fiber Neuropathy Curr Pain Headache Rep (2011) 15:193-200

SFN-Diagnosis-2

§  VariouswrittentoolssuchastheNeuropathicPainSymptomInventorymaybehelpful

§  QuantitativeSensoryTesting-thiscandetectthresholdsofthermalpain,thermalsensationandvibrationforexample.ContactHeatEvokedPotentialsattemptstolinkperipheralactivationtocentral.

§  QuantitativeSudomotorAxonReflextesting(QSART)

Hovaguimian A, Gibbons CH. Diagnosis and Treatment of Pain in Small-fiber Neuropathy Curr Pain Headache Rep (2011) 15:193-200

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DiagnosticStudiesandLimitationsStudies§  Bloodstudies§  X-ray,CT,MRI§  Electromyography

(EMG)§  Nerveconduction

velocity(NCV)§  Quantitativesensory

testing(QST)§  Skinbiopsy

LimitationsofEMG/NCV§  Insensitiveinacuteinjury§  Normalresultdoesnotrule

outneuropathicpain§  Cannotassessfunctionof

small-fibernervesinvolvedinmostneuropathicpain

Galer BS, Dworkin RH. A Clinical Guide to Neuropathic Pain. McGraw-Hill Companies; 2000.

SFN-Diagnosis-3§  SkinBiopsy-thishasbecomewidelyacceptedasa

techniquetoevaluatethestructureofsmallnervefibers.

§  Thestandardisa3-mmskinpunchbiopsythatcanbetakenfromanywhereoverthebody.

§  Duetotheneedtocomparetonormalvaluesthelowerextremityismostcommonlyassessed(alsolengthdependentSFNmorecommonthannon-lengthdependent)

§  Theresultsareexpressedasthenumberofintraepidermalfiberspermm

§  Thesensitivity(78-92%)andspecificity(65-90%)isfairlyhighforthistechnique

Hovaguimian A, Gibbons CH. Diagnosis and Treatment of Pain in Small-fiber Neuropathy Curr Pain Headache Rep (2011) 15:193-200

LossofskinnervefibersinPHN

The density of epidermal nerve endings in previously shingles-affected skin

0

1000

2000

3000

4000

Neurite densities from individual subjects in descending order (n = 38)

Neu

rite

s/m

m2 s

kin

surf

ace

area

Subjects without PHN

Subjects with PHN

Oaklander AL, Pain, 2001

Oaklander AL, et al Ann Neurol 1998; Oaklander AL, et al Pain 2001

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Smallfiberpolyneuropathy-blood/othertests

§  Metabolic:thyroidfunctions,HbA1C,FBS§  Nutritional:CBC,HepaticProfile,VitaminB1andB12

§  Infectious:CRP,HIV,Lyme,HBV,HCV§  Autoimmune:ESR,ANA,Anti-ENA,ANCA,anti-gliadin,RF,serumACE,?CXR

§  Paraneoplastic:Tumormarkers,LDH,Myelomascreen,SPE,anti-Huandanti-CV2/CRMP-5abChan AC, Wilder-Smith EP. Small fiber neuropathy: getting bigger! Muscle Nerve

53:671-682, 2016

Smallfiberpolyneuropathy-blood/othertests(continued)

§  Neurotoxins:urineandbloodtoxicology,reviewdrughistory

§  Herditary:alpha-galactosidaseA,globotriaosylceramidelevels,renalpanel,urineprotein,genetictestingforSCN9AorSCN10A

§  Lumbarpuncture:ifyoususpectinflammatory,auto-immuneorparaneoplasticetiologiesChan AC, Wilder-Smith EP. Small fiber neuropathy: getting bigger! Muscle Nerve

53:671-682, 2016

SFN-Treatment

§  Treatthetreatable!IfanunderlyingcauseofSFNcanbedetermined,optimaltreatmentofthecausativeconditionmaylessenthesymptomsofSFN

§  FewstudiesandnoguidelineshaveexaminedthepharmacologictreatmentofthepainassociatedwithSFN

§  Inonesuchstudy,bothgabapentinandtramadolwerefoundtobeeffectiveforSFN

Hovaguimian A, Gibbons CH. Diagnosis and Treatment of Pain in Small-fiber Neuropathy Curr Pain Headache Rep (2011) 15:193-200

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EFNS,EuropeanFederationofNeurologicalSocieties;IASP,InternationalAssociationfortheStudyofPain;NeuPSIG,NeuropathicPainSpecialInterestGroup

Neuropathicpainrecommendationsofvarioussocieties

OpioidTramadol

FirstlineSecondlineThirdline

TCAGBP/PGB

Lidocaine5%plaster

SNRI

(Opioid)

OpioidLamotrigineCapsaicin

CanadianPainSociety

TCAGBP/PGB

SNRILidocaine5%

Opioid

(exceptmethadone)

TCA,SNRIGBP/PGB

Lidocaine5%Opioid

(specificcircumstances)

EFNS,EuropeNeurology

IASPNeuPSIG

ParoxetineBupropionNMDA

antagonistFourthline Methadone

AttalN,etal.EurJNeurol.2006;13(11):1153-1169.DworkinRH,etal.Pain.2007;132(3):237-251.MoulinDE,etal.PainResManag.2007;12(1):13-21.

SFN-IsIVIG(intravenousimmunoglobulin)anEmergingTreatment?

§  Arecentreportdescribed3patientswithsarcoidosisandSFNwhowereexperiencingseverepainaswellasdysautonomia

§  EachpatienthadbiopsyprovenSFN

§  Eachpatienthadfailedtoresponseto“conventional”analgesic/symptomaticapproaches

§  EachpatientreceivedaninitialdoseofIVIG2g/kgfollowedby1g/kgdosesatregularintervals-eachwithdramaticresolutionofpainandautonomicsymptoms

§  Furtherlargerstudiesarewarranted

Parambi JG, Tavee JD, Zhou L, et al. Efficacy of intravenous immunoglobulin for small-fiber neuropathy associated with sarcoidosis. Resp Med 2011 Jan;105(1):101-5.

SFN-IsIVIG(intravenousimmunoglobulin)anEmergingTreatment?-2

§  LimiteddataforSjogren’ssyndrome-IVIG2g/kg§  Juvenileonsetunexplainedwidespreadpaintreatedwith

IVIGin15patientsbyOaklanderetal-treatedat2g/kg/monthatleast3times-62%demonstratedsignificantimprovement

§  Inanotherstudy,46patientswithSFPNassociatedwithdysautonomiaweretreatedwithoneormoreIVIGtreatment-forpatientswithpainintensitylevels≥3orwithsignificantdysautonomia,thetreatmentwashelpful

Oaklander A, Immunotherapy Prospects for Painful Small-fiber Sensory Neuroapthies and Ganglionopathies. Neurotherapeutics 2015

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SFPNandFibromyalgia

§  Approximately50%ofpatientswhohavebeendiagnosedwithFibromyalgiainseveralpublishedstudieshavedemonstratedfindingsconsistentwithSFPNondiagnosticbiopsies-studiestobereviewedonsubsequentslides

§  Whatdoesthatmean?§  WhatdoesthatmeanaboutinterpretingFMstudiesthathavealreadybeenpublished?

CWP,SFPNandFibromyalgiaI

§  27patientswithfibromyalgiawhosatisfiedthe2010ACRcriteriawerecomparedto30matchedcontrols

§  41%ofskinbiopsiesfromfibromyalgiasubjectscomparedto3%fromcontrolswerediagnosticforSFPN

§  TheMichiganNeuropathyScreeningInstrumentandUtahEarlyNeuropathyScalescoreswerehigherinfibromyalgiapatients

Oaklander AL, et al. Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia Pain 2013 Nov;154(11):2310-6.

CWP,SFPNandFibromyalgiaII§  25patientswithfibromyalgiawerecomparedto10depressedpatientsandcontrols

§  SmallfiberevaluationincludedQST,pain-relatedevokedpotentialsandquantifiedintraepidermalnervefiberdensityandregeneratingIENFofthelowerlegandupperthigh

§  ComparedwithcontrolsubjectsfibromyalgiapatientsBUTnotdepressedpatientshadimpairedsmallfiberfunction

Uceyler N, et al. Small fibre pathology in patients with fibromyalgia syndrome. Brain 2013 Jun;136(Pt6):1865-67.

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CWP,SFPNandFibromyalgiaII(continued)§  Skinbiopsyfindingsdemonstratedthattotaland

regeneratingIENFsatthelowerlegandupperthighwerereducedinpatientswithfibromyalgiacomparedwithcontrols

§  Areductioninunmyelinatednervefiberbundleswasseeninpatientswithfibromyalgiacomparedwithdepressedandcontrolsubjects

§  Theauthorsconcludedthattheresultspointtowardsaneuropathicnatureoffibromyalgia.

Uceyler N, et al. Small fibre pathology in patients with fibromyalgia syndrome. Brain 2013 Jun;136(Pt6):1865-67.

Summary

§  MultiplemedicalconditionsareassociatedwithSFN

§  Themechanism(s)ofSFNarenotcompletelyunderstoodandmayvarydependingontheindividual/specificassociateddisorder

§  RecognizingSFNanditsexistenceinperhapsmoreconditionsthanpreviouslyrecognizedmayleadtoimprovedtreatmentapproaches