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LowerMotorNeuronsMotorNeuronDisorders

NeuropathyNicholasJ.Silvestri,M.D.

AssistantProfessorofClinicalNeurology

Outline

• Motorneurons– Upperandlower

• Motorneurondisorders– Anteriorhorncelldiseases

• Peripheralnervedisorders– Nerveroot– Plexus– Nerve

MotorNeurons

• Uppermotorneurons:Cellbodiesinmotorcortex,axonsdescenddownthroughinternalcapsule,brainstem,andspinalcordtosynapseon…

MotorNeurons

• Lowermotorneurons:Cellbodiesareanteriorhorncells,axonsexitventralroots,joindorsalrootsatintervertebralforamenandtravelthroughnervestomuscles

Phenomenology• Uppermotorneuronsigns:

– Weaknessandslownessofmovement– Increasedtone(spasticity)– Hyperreflexia– Upgoingtoes(Babinski’ssign)

• Lowermotorneuronsigns:– Weakness– Decreasedtone– Hyporeflexia– Muscleatrophy– Fasciculationsandcramps

MotorNeuronDisorders

• Spinalmuscularatrophy• Amyotrophiclateralsclerosis

SpinalMuscularAtrophy

• TypeI(Werdnig-Hoffman)– Onsetbefore6monthsofage

• TypeII– Onsetbetween6and18monthsofage

• TypeIII(Kugelberg-Welander)– Onsetafter18monthsofage

• TypeIV– Adult-onset,thirdtofourthdecade

SpinalMuscularAtrophy

• Autosomalrecessiveinheritance• DuetohomozygousdeletionorpointmutationofSMN1geneonchromosome5

• SeverityofphenotyperelatedtonumberofSMN2copies

• Treatmentforalltypesislargelysupportive• Nusinersen approvedDec2016• GenetherapyinPhaseItrials

SpinalMuscularAtrophy

• SMAI:Werdnig-HoffmanDisease– Incidence4-10/100,000–Manifestsinfirst6monthsoflife– Hypotoniawithgeneralized(thoughproximallypredominant)weakness,tonguefasciculations,abdominalbreathing,weakcry,poorsuck

– Neversit– Only8%ofindividualsreachageof10years

SpinalMuscularAtrophy

• SMAII:Intermediateform– Onsetbetween6– 18monthsofage– Childcansitindependentlybutneverwalks– OtherwisesymptomsmimicSMAI– Posturalhandtremor– Pronetokyphoscoliosisandjointcontractures– Two-thirdsofindividualssurvivetoageof25years

SpinalMuscularAtophy

• SMAIII:Kugelberg-WelanderDisease– Onsetafter18monthsofage–Willsitandwalkbutneverrun– 40%stillwalkingat40yearsofage– Posturalhandtremor– Lifeexpectancynottypicallyaffected

AmyotrophicLateralSclerosis

• Neurodegenerativedisordercharacterizedbylossofmotorneuronsinthespinalcord,brainstem,andmotorcortex– Clinically,leadstoacombinationofUMNandLMNsymptomsandsigns

• Incidenceroughly1-2.5/100,000• Etiologyunknownandprogressionofthediseaseisrelentlessresultingindeath– 10%casesfamilial,e.g.C9orf72,SOD1mutations

TheIronHorse

ALS- Presentation

• 2/3patientswithlimb-onsetofsymptoms– Weaknessandwastingofdistallimbmusculature– Fasciculationsandcramps– Lackofsensorysymptoms

• 1/3patientswithbulbar-onsetofsymptoms– Dysphagia,dysarthria,dysphonia,chewingdifficulty

• Mostpatientseventuallydeveloprespiratorymuscleweakness– Dyspnea,orthopnea,signsofCO2retention– MostdeathsfromALSareduetorespiratoryfailure

ALS-Treatment• Riluzole:NMDAreceptorantagonist• Edaverone:Approvedlate2017– reducesoxidativestress

• Nutrition• Physicalandoccupationaltherapy• Speechandswallowingtherapy• Respiratorymanagement• Managementofsymptoms– Spasticity– Siallorhea

ALS- Prognosis

• Mediansurvivalfromtimeofdiseaseonsetrangesfrom24to36monthslookingatdatafromseveralstudiesofthenaturalhistoryofALS

• Mediansurvivalfromtimeofdiagnosisrangesfrom14to21monthsinthesamestudies

• 3yearsurvivalfromonsetroughly40%• 5yearsurvivalfromonsetroughly25%

OtherDisordersoftheAnteriorHornCell

• Progressivebulbarpalsy• Progressivemuscularatrophy• Kennedy’sdisease(x-linkedspinalmuscularbulbaratrophy)

• Infectiousetiologies– Poliovirus,enteroviruses,WestNilevirus,HIV

NerveRoot

• Degenerativediseaseofthespine• Discherniation• Inflammatoryorinfectious• Neoplastic

Radiculopathy

Radiculopathy

• Neckorbackpainusuallypresent• Painandmildsensorylossindistributionofnerveroot(dermatomalpattern)

• Weaknessrareduetomyotomaloverlapofmuscleinnervation

• Treatmenteithersurgicalorconservative• Mostcasesareself-limitedbutmayrecurwithtime

Plexus

CausesofPlexopathy

• Trauma– Birthtrauma

• Erb’spalsy:uppertrunkinjury• Klumpke’spalsy:lowertrunkinjury

• Inflammatory/Autoimmune– Parsonage-Turnersyndrome

• Neoplasticinvasion(lung,lymphatic,breast)• Radiationexposure• Structuralanomalies

Nerve

• Mononeuropathies• Polyneuropathies

Mononeuropathies

• Strictlydefinedasinjurytoasinglenerve• Commonexamples:

– Bell’spalsy(CNVII)– Carpaltunnelsyndrome(medianneuropathyatthewrist)– Ulnarneuropathyattheelbow– Saturdaynightpalsy(radialneuropathyatthespiralgroove)

– Commonperonealneuropathyatthefibularneck

Bell’sPalsy

• Annualincidence13-34cases/100,000population

• Norace,gender,orgeographicprediliction– Riskisthreetimesgreaterduringpregnancy(particularlyfirsttrimester)andfirstpost-partumweek

• Idiopathic,thoughmostcommonlythoughttobecausedbyHSV-1activation/infection– Otherviralinfections:VZV,CMV,EBV,etc

Bell’sPalsy

Polyneuropathy

• Typesoffibersinvolved:– Sensory

• Smallfibers(Adelta,Cfibers)• Largefibers

– Motor– Autonomic

• Smallfibers

• Pathophysiology– Axonal– Demyelinating

CausesofPolyneuropathy• AxonalNeuropathies

– Diabetesmellitus/dysglycemia– Amyloidosisorplasmacelldyscrasias– Vasculitis,e.g.polyarteritisnodosa,Churg-Strausssyndrome– Paraneoplastic– Nutritional,e.g.vitaminB1,B6,B12,Edeficiency– Infectious,e.g.viral(especiallyHIV)– Secondarytotoxins,e.g.arsenic,lead,thallium– Secondarytometabolicdisturbances,e.g.liverfailure,uremia,sepsis– Secondarytomedications,e.g.chemotherapeuticagents,antibiotics– Hereditary(Charcot-Marie-Toothdiseasetype2)– Immune-mediated,e.g.axonalvariantsofAIDPalsoknownasAMANand

AMSAN,alsoSjogren’sandothercollagenvasculardiseases– Idiopathic

CausesofPolyneuropathy

• Demyelinatingneuropathies– Immune-mediated:Guillain-BarreSyndrome(AIDP),CIDP(chronicinflammatorydemyelinatingpolyneuropathy)

– Hereditary:e.g.Charcot-Marie-Toothdiseasetypes1,3,and4

– Paraneoplastic:MGUS(IgM),hematologicmalignancies

– Infectious:diphtheria

Guillain-BarreSyndrome(AIDP)

• MostcommoncauseofacuteweaknessinWesterncountries

• Incidence:0.6to1.9/100,000population• Antecedentillness

– Viralsyndrome(URI,gastroenteritis)precedesillnessinabout2/3ofcases,typically1-3weeksbeforedevelopmentofneurologicalsymptoms

• Fairlyrapidlyprogressiveascendingweaknessandsensorysymptoms

Guillain-BarreSyndrome(AIDP)

• Motorsymptoms(weakness)usuallypredominateoversensorysymptoms

• Areflexiaonexamination• AlbuminocytologicdissociationinCSF– Nowhitebloodcells,elevatedprotein

• EMGandnerveconductionstudiesdemonstrateademyelinatingneuropathy

Guillain-BarreSyndrome(AIDP)

• Treatment– IVIgorplasmapheresis– Respiratorymanagement– Treatmentofdysautonomia– Physicalandoccupationaltherapy

Guillain-BarreSyndrome(AIDP)

• Course– Symptomsprogressoverthefirst1to2weeksinmostpatients

– 95%ofpatientsreachtheirnadirby4weeks– Plateauphasefor1to4weeks– Improvementensues,howeverratevariableanddependentonseverityofsymptomsatnadir(usuallyover2-12months)

– Relapsesin2to10%– CIDPin2%

Guillain-BarreSyndrome(AIDP)

• Prognosis–Majorityofpatients(80%)havenoorminorsequelae

– Permanentdisablingsymptomsin5-10%–Mortality<5%