9/4/2014

Acquired
Peripheral
Neuropathies
A/Prof Lyn Kiers
Director, Dept Clinical Neurophysiology,
Royal Melbourne Hospital

AxonalDegeneration(75%)
Abnormalaxonaltransport
Lackofgrowthfactors
Recoverbyregeneration

Demyelination(20%)
Primarydestructionofmyelin
sheath
Recoverbyremyelination

Cellbody neuronopathy(5%)
Sensory(DRG)ormotor(AHC)

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Commonestneuropathytype
Usuallychronic:weekstomonths
Predilectionforlargediameter,longnervefibres
Distalsymmetricpattern
Sensory>motor,areflexia
Specificaxonalneuropathiesinvolvesmalldiameter

fibres

Axonopathy Aetiology

Diabetes
Alcohol
Uraemia
Toxic/drugs
Paraneoplastic(some)
Nutritional

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Primarydestructionofthemyelinsheathleaving
theaxonintact
Secondaryaxonaldegenerationcommonlateinthe
diseasecourse
Clinicalfeatures

Weakness:Proximal&Distal>>Wasting
Exceptions:MAG&Hereditaryaremainlydistal
Sensory:Mild;Symmetric;Distal
Tendonreflexes:Reducedorabsentdiffusely

Immune/Inflammatory
GBS
CIDP
MultifocalMotorNp
ParaproteinemicNp
POEMS
HIV

Metabolic
Storagedisorders

Drugs/Toxins
Amiodarone
Chloroquine
Suramin
Bortezomib(mixed)
TNFalphablockers
hexacarbons
..

Mitochondrial
NARP,MNGIE

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Functionalinvolvement

Distribution

Oftenlargelyonemodality
Motor

Proximal&Distal;Arms
involvedearly
Face&Bulbarcommon
Asymmetric

InvolvementofAHC
Separate,distinctentities

Sensoryloss
Sensoryganglionopathy
Oftensevereespecially
proprioception/sensory
ataxia
Autonomic

Idiopathic
Immune
Sjogrens
Paraneoplastic antiHu,Ri,

CRMP5,Ma
Acutesensoryneuronopathy

Timecourse
Oftensubacute:Weeksto
months
Sensorydeficitoften
severe&poorlyresponsive
totherapy

Nerveconduction
Normalmotor/Fwave
NormalEMG
Absentsensorypotentials

Drugs
B6,cisPlatinum,

(doxorubicin)

Hereditary Fabrys

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Neuropathy Clinicalevaluation
Distal,symmetric,
sensory>motor
Earlyproximalweakness

Axonalneuropathy

Proprioceptiveloss,tremor,
ataxia
Painandautonomicfeatures

Sensoryneuronopathy
IgMantiMAGneuropathy
Smallfibreneuropathy
iediabetes,amyloid,Fabrys
Mononeuritismultiplex
Ie.Vasculitic,infiltration

Markedasymmetry
Weakness/sensorylossin
peripheralNdistribution
Palpablenervetrunks

Demyelinatingneuropathy

Inheritedneuropathy
Leprosy

Peripheralneuropathy Investigations

Stage1:

FBGU&E,LFT
FBE B12,folate
TFT
CXR
SPEP ESR,AutoAb

Stage2:
Nerveconduction

Stage3
CSF protein,cells
Heavymetals
QST/autonomic

testing/skinbiopsyifsmall
fibre
OralGTT,urineBJprotein

studies

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Electrodiagnosticstudies
Nerveconductionstudies
Reduced/Absentsensorypotentialslower>>upperlimbs
Lowamplitudedistalmotorresponses,mildlydelayedFwaves
Conductionvelocities:Mildlyreducedconsistentwithlossof
largemyelinatednervefibres

EMG
Neurogenic;distal>>proximalmuscles
Motorunits:Highamplitude;Longduration;Polyphasic;Rapid
firing
Fibrillations;Positivesharpwaves

NORMAL

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Nerveconductionstudies
Conductionvelocity:Veryslow(Upperextremity<37M/s)
Conductionblock:Failureofimpulseconductionalongan

anatomicallyintactaxon
Dispersionofmotorresponse
Prolongeddistallatencies&Fwaves

EMG
Reducedmotorunitrecruitment(fastfiringmotorunits)in

clinicallyweakmuscles

Normal Motor Conduction

Demyelinating Neuropathy

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Focal Conduction Block

SuralNerve biopsy
Onlyinselectcases
ifaetiologyunclear
Considering
treatablecause
Functionally
disabling
Moreusefulif:

Asymmetric

symptoms/signs
Sensorypresentation
AbnormalNCS

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SuralNervebiopsy diagnosticabnormalities

Vasculitis
Amyloidosis
Sarcoidosis
Leprosy
Tumourinfiltration
Inherited(egHNPPbutrarelyrequireddueto
geneticstudies 17pdeletionPMP22gene)

Case1 30yoman

4 month history of LL>UL weakness

Difficulty climbing stairs, standing from chair, buttoning his clothes,
carrying bags
Mild paraesthesia fingers
4/5 power biceps, triceps, finger abductors
4/5 hip flexion, ankle dorsiflexion
Reduced UL reflexes, absent LL reflexes
Decreased JPS great toe

Formulation:
Proximal>distal weakness
Hypo/Areflexia
Minimal sensory abnormality

= ? Demyelinating neuropathy

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Case1 30yoman

Nerveconductionstudies
ProlongeddistalandFwavelatencies
Slowconductionvelocities motor>sensory
Conductionblock/temporaldispersion

CSF raisedprotein
SerumproteinEP/Immunoelectrofixation
Autoantibodyprofile

Case2 70yolady

2yearsprogressivenumbnessandparaesthesiafeet
bilaterally
Slightparaesthesiafingertips

4/5powerEHL,EDL
Absentanklereflexes
Reducedpinprickandtemperaturesensationtolower1/3leg

Formulation:
Lengthdependentsensory>>motor=?Axonalneuropathy

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Case2 70yolady

Nerveconductionstudies
Reducedamplitudesural/superficialperoneal
MildslowingsensoryNCV
LowCMAPamplitudeinperonealnervesBL

SelectivebloodtestsmayincludeGTT,U&E,
B12,LFTs,ESR
Medicationhistory,alcohol

Case3 54yowoman

4monthhistoryofnumbnessandtinglingsensationsinD3/4
bilaterally
Spreadtoinvolveentirehands,and3Wlaterreported
troublewalkingandnumbnessoverchestandabdomen
Statedthatfloorfeltfunnyandshecouldntidentifyifit
washotorcold
After2monthsunabletoambulate

NormalpowerLLandUL
Areflexia
LossofVStowrists/knees;ImpairedJPSfingers/ankles
Widebasedunsteadygait,positiveRombergtest

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Case3 54yowoman

Profoundproprioceptiveloss,ataxia,areflexia
=sensoryneuronopathy/ganglionopathyorIgM(antiMAG)
paraproteinemicneuropathy

Nerveconductionstudies
Absent/reducedsensoryamplitudesinULandLL
Normalmotorresponses
B12,B6levels
CSF
AutoantibodiesincludingENA,antineuronalantibodies
?Lipbiopsy,Schirmerstest,CxR,cancerscreen

Case4 59yoman
8Mhistoryofnumbnesslateralaspectofleftleganddorsumof
foot;burningpain
2Mnumbness/paraesthesiarightthumbanddorsumofhand
1Mweaknesslefthand

4/5powerleftulnarinnervatedmuscles
4/5powerlefttoeextensionandankleeversion
ReducedLT/PPsensationleftperonealsensoryinnervationand
rightradialsensoryinnervation

Asymmetic,sequentialneurologicaldeficitsinthedistributionof
isolatedperipheralnerves=mononeuritismultiplex?Vasculitic?
MADSAM

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Case4 59yoman

Nerveconductionstudies
Reducedleftperonealmotoramplitudeandabsent
superficialperonealsensoryresponse
Reducedrightradialsensoryamplitude
Reducedleftulnarsensoryamplitudeandulnarmotor
amplitude,withuniformconductionslowing
Bloods ESR,CRP,autoantibodies,FBE,HepC,
paraproteins,ANCAetc
Nervebiopsy

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Guillain BarreSyndrome+variants(AMAN,
AMSAN)
CIDP+variants(MADSAM,DADS)
Paraproteinassociatedneuropathy
MGUSCIDP
POEMS

MultifocalMotorNeuropathywith
ConductionBlocks

Symmetricmotor&sensorydeficits
Proximal&distalweakness>wasting
Absentor reflexes
DistalLL>ULsensoryloss20%painful;autonomic/respuncommon

Gradualonsetovermonthsyears;progressive>2M

Naturalhistoryvariable

10%acuteonset

Chronicprogressive60%
Relapsingremitting30%
Monophasic10%
Spontaneousremissionnotuncommonbutdifficulttopredict

M>F,allages(mean50yrs)
<10%children

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NCS SegmentalDemyelination

Motorslowing,
Conductionblock,dispersion
Longdistal/Fwavelatencies
Absent/lowampl.SNAPs(UL>LL)

CSFproteinelevated;<10cells/mm

MRI

Nervebiopsy

Nerveroothypertrophy,enhancement
inflammation+atrophy
segmentaldemyelination/remyelination

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Prednisolone daily
IVIG ~4weekly
PlasmaExchange
IVMethylPrednisolone pulse

+/ Azathioprine
+/ CyclosporinA,Mycophenolate,Rituximab
?(Cyclophosphamide+/IVMP+/ PlasmaExchange)

Paraproteinemicneuropathies

MGUS,POEMS/OM,Waldenstroms
macroglobulinemia,lymphoma,amyloidosis
Distalpredominantlysymmetrical
sensorimotorneuropathy,or
polyradiculoneuropathyresemblingCIDP
(espIgAandIgG);specificfeaturesforIgM
RaisedCSFprotein
NCS 1/3demyelinating,2/3mixed
axonal/demyelinating

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Paraproteinemicneuropathies treatment

TreatMGUSneuropathyonlyifsignificant
neurologicdisability
IgG/IgAdemyelinatingneuropathiesrespond
totreatmentforCIDP
IgMneuropathyrespondspoorly
Rituximabsomebenefitinsomepatients
PE+IVcyclo;oralcyclo+prednisolone
monthlyto6months

HIVneuropathies

Distalsymmetricpolyneuropathy
Lumbosacralpolyradiculopathy(cauda
equinasyndrome;CMV)
Inflammatorydemyelinating
polyradiculoneuropathy
Sensoryneuronopathy
HIVtreatmentneuropathieseg.ddI,ddC,
d4T,lamivudineetc

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Demyelinating
Chloroquine
Tacrolimus
Perhexiline
Procainamide
TNFalphablockers
Mixed
Amiodarone
Suramin,Gold
Hexane,hexacarbons
Bortezomib
Axonal
Chloramphenicol
Ethionamide
Pyridoxine
Ethambutol

Axonal
Hydralazine
Isoniazid
Dapsone
NucleosidesddC,ddI.
Phenytoin
Thalidomide
Platinum,VP16,Taxols
Ethanol
Colchicine
Disulfiram
Nitrofurantoin
Vincaalkaloids
Statins
Leflunomide

ChemotherapyinducedPN

TAXOL

CISPLATINUM/CARBI

Sensory>motor

D0sedependent,severe

Largeandsmallfibre

pansensoryneuropathy
Proprioceptiveloss
Sensoryataxia,
pseudoathetosis
CrosslinksDNA
mechanismneuropathy
uncertain

Symptomsafter1st or2nd

treatment
Progressiondose
dependent
Disruptionof
microtubularfunction
mitoticspindle
dysfunction

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ChemotherapyinducedPN

Vincristine

Bortezomib

Mixedsensory,motor

Painfulsensoryaxonal

andautonomic
Distalweaknesslate
legs>arms
Cancauseprofound
weakness
Promotesmicrotubule
formation

neuropathy toxic
Immunemediated
motor>sensory
demyelinating
neuropathy;respondsto
immunetreatments
Proteasomeinhibition;
mechanismneuropathy
unclear

Oxaliplatininducedneurotoxicity

AcuteneurosensorySx
Beginduringinfusion,peak

within2448hrs
Coldinducedparaesthesias
Pharyngolaryngeal
dysaesthesias
Muscletightness(jawand
throat)
Legcramps
Resolvewithin1W
Recurwithsubsequent
infusions

Chronicneurotoxicity
ClinicalandEPfeatures

similartocisplatinumPN
Sensoryaxonalneuropathy

+/ neuronopathy
Accumulationofplatinum
basedcompoundwithinDRG
Coasting,thengradual
improvementafterdrug
discontinued

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TNFalphablockerdrugs

Demyelinatingneuropathyisrareadverse
event
Reportedwithinfliximab,etanerceptand
adalimumab
Developsearly(withinM)aftertreatment
introduction
ImmunomodulatingRxusuallyrequiredfor
neuropathycontrol,evenifdrugdiscontinued

Neuromuscular disease Centre, Washington University, St Louis, MO

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