Peripheral Neurology: GBS and MGPeripheral Neurology: GBS and MGPeripheral Neurology: GBS and MG

Ashok Verma, M.D., DMAshok Verma, M.D., DMProfessor of NeurologyProfessor of Neurology

Director, Kessenich Family MDA ALS CenterDirector, Kessenich Family MDA ALS Centerand MDA Clinicsand MDA Clinics

University of Miami Miller School of MedicineUniversity of Miami Miller School of Medicine

Guillain-Barre SyndromeGuillainGuillain--Barre SyndromeBarre Syndrome

LandryLandry’’s Paralysiss ParalysisGuillainGuillain--BarreBarre--Strohl SyndromeStrohl SyndromeAcute Inflammatory Demyelinating Acute Inflammatory Demyelinating Polyradiculoneuropathy (AIDP)Polyradiculoneuropathy (AIDP)

Most common cause of acute or subacute Most common cause of acute or subacute generalized paralysisgeneralized paralysisWorldWorld--wide prevalence (2/100,000)wide prevalence (2/100,000)Age, gender, seasonAge, gender, season

Guillain-Barre SyndromeGuillainGuillain--Barre SyndromeBarre Syndrome

EVENTS PRIOR TO GBSEVENTS PRIOR TO GBSEVENTS PRIOR TO GBSInfectionsInfections

Campylobacter jejuni,Campylobacter jejuni, Mycoplasma pneumoniaeMycoplasma pneumoniaeCytomegalovirus, EpsteinCytomegalovirus, Epstein--Barr virus, Influenza, Herpes, HIV, Barr virus, Influenza, Herpes, HIV, VacciniaVacciniaBorrelia burgdorferiBorrelia burgdorferiHepatitis Vaccine, RabiesHepatitis Vaccine, Rabies

Antecedent Events Antecedent Events Surgery/stressSurgery/stressPrior Hx of acute infectious process (1 Prior Hx of acute infectious process (1 –– 3 wks prior)3 wks prior)Recent immunization with Swine influenza (1976). Not as much of Recent immunization with Swine influenza (1976). Not as much of a a problem nowproblem nowHIGHER RISK PTS HIGHER RISK PTS

Lymphoma, Hodgkin's Disease, HIV, SLE Lymphoma, Hodgkin's Disease, HIV, SLE

Primary attack is on Primary attack is on the myelin sheaththe myelin sheath

Produces Produces random/segmental random/segmental demyelinationdemyelination

Guillain-Barre Syndrome Myelinopathy

GuillainGuillain--Barre SyndromeBarre Syndrome MyelinopathyMyelinopathy

NormalNormal

GBSGBS

Segmental demyelinationSegmental demyelination

Segmental demyelinationSegmental demyelination

Motor weakness: Proximal and distalMotor weakness: Proximal and distalImpaired reflexes: Early and prominentImpaired reflexes: Early and prominentSensory symptoms: Minimum loss, painSensory symptoms: Minimum loss, painAutonomic symptoms: CardiovascularAutonomic symptoms: Cardiovascular

Guillain-Barre Syndrome Clinical features

GuillainGuillain--Barre SyndromeBarre Syndrome Clinical featuresClinical features

Guillain-Barre Syndrome Clinical variants (focal/functional)

GuillainGuillain--Barre SyndromeBarre Syndrome Clinical variants (focal/functional)Clinical variants (focal/functional)

MillerMiller--Fisher syndrome (ophthalmoplegia, ataxia, Fisher syndrome (ophthalmoplegia, ataxia, areflexia)areflexia)Paraparetic formParaparetic formOculopharyngeal weknessOculopharyngeal weknessBifacial or abducens palsy with distal paresthesiaBifacial or abducens palsy with distal paresthesiaPharyngealPharyngeal--cervicalcervical--brachialbrachialPure sensory, autonomic, or ataxic formPure sensory, autonomic, or ataxic form

Guillain-Barre Syndrome Clinical variants (axonal)

GuillainGuillain--Barre SyndromeBarre Syndrome Clinical variants (axonal)Clinical variants (axonal)

Acute motor axonal neuropathy (AMAN) Acute motor axonal neuropathy (AMAN) (60% GM(60% GM11 ab, ab, C. jejuniC. jejuni infection)infection)Acute motor and sensory axonal neuropathy Acute motor and sensory axonal neuropathy (AMSAN)(AMSAN)Acute multifocal motor neuropathy?Acute multifocal motor neuropathy?

Guillain-Barre Syndrome Clinical course

GuillainGuillain--Barre SyndromeBarre Syndrome Clinical courseClinical course

Evolves from a few days to two weeksEvolves from a few days to two weeks25 25 -- 30% will require ventilatory assistance30% will require ventilatory assistanceImprovement occurs after plateau is reachedImprovement occurs after plateau is reached

GUILLAIN BARRE SYNDROME Investigations

GUILLAIN BARRE SYNDROMEGUILLAIN BARRE SYNDROME InvestigationsInvestigations

CSF analysis:CSF analysis:Increased protein concentration with a normal cell countIncreased protein concentration with a normal cell count-- -- albuminocytological dissociation (elevated CSF protein, typicallalbuminocytological dissociation (elevated CSF protein, typically y ranging from 46 to 300 mg/dl) ranging from 46 to 300 mg/dl)

EMG/NCS examination:EMG/NCS examination:Very often changes strongly suggestive of demyelination, such asVery often changes strongly suggestive of demyelination, such as conduction block, differential slowing, or focal slowing, are seconduction block, differential slowing, or focal slowing, are seen on en on assessment of one or more nerves.assessment of one or more nerves.

MRI with gadoliniumMRI with gadoliniumEnhancement of cauda equina roots in two third casesEnhancement of cauda equina roots in two third cases

H reflexH reflex F waveF wave

Guillain-Barre Syndrome Management

GuillainGuillain--Barre SyndromeBarre Syndrome ManagementManagement

There is no known prevention for sporadic GBS There is no known prevention for sporadic GBS The treatment of GBS has two components: The treatment of GBS has two components: (1) supportive care(1) supportive care

Respiratory support (about 25%)Respiratory support (about 25%)BP, electrolytes, infection, GI, PEBP, electrolytes, infection, GI, PESkin care to prevent ulcersSkin care to prevent ulcersPT after plateau of disease coursePT after plateau of disease course

(2) specific therapy (no change in mortality, but get better (2) specific therapy (no change in mortality, but get better faster and less severe disease)faster and less severe disease)Plasmapheresis (200 ml/kg wt, 40 ml/kg wt/day x 5 sessions on Plasmapheresis (200 ml/kg wt, 40 ml/kg wt/day x 5 sessions on alternate days)alternate days)IVIg therapy (2 gm/kg wt; 0.4gm/kg wt/day x 5 consecutive daysIVIg therapy (2 gm/kg wt; 0.4gm/kg wt/day x 5 consecutive days

Guillain-Barre Syndrome Prognosis and Recovery

GuillainGuillain--Barre SyndromeBarre Syndrome Prognosis and RecoveryPrognosis and Recovery

85% recover fully85% recover fully

10% variable residual deficits (outlook is worse for those pts 10% variable residual deficits (outlook is worse for those pts with severe proximal motor and sensory axonal damage (i.e., with severe proximal motor and sensory axonal damage (i.e., not just demyelinating)not just demyelinating)

3 3 –– 5% mortality (pulmonary, cardiovascular)5% mortality (pulmonary, cardiovascular)

5 5 -- 10% recurrence of neuropathy (subacute IDP, CIDP)10% recurrence of neuropathy (subacute IDP, CIDP)

Guillain-Barre Syndrome Salient features

GuillainGuillain--Barre SyndromeBarre Syndrome Salient featuresSalient features

Most common cause of acute or subacute generalized Most common cause of acute or subacute generalized weaknessweakness

Proximal and distal weaknessProximal and distal weakness

AreflexiaAreflexia

CSF, NCS and MRI help in diagnosisCSF, NCS and MRI help in diagnosis

Majority of GBS patients plateau within 2 wks followed by Majority of GBS patients plateau within 2 wks followed by recoveryrecovery

Greater potential for rapid recovery with RxGreater potential for rapid recovery with Rx

Myasthenia GravisMyasthenia Gravis

NormalNormal MGMG

BlockingBlocking

Binding, CrossBinding, Cross--linkinglinking

LyticLytic

Myasthenia Gravis Epidemiology

Myasthenia GravisMyasthenia Gravis EpidemiologyEpidemiology

50 to 125 cases/million or 30,000 cases in the United 50 to 125 cases/million or 30,000 cases in the United StatesStates

Occurs at any age with peaks in the 3rd and 6th decadesOccurs at any age with peaks in the 3rd and 6th decades

Women > Men from age 10Women > Men from age 10--4040

Men > Women over 40Men > Women over 40

Diseases Associated with Myasthenia Gravis

Diseases Associated with Diseases Associated with Myasthenia GravisMyasthenia Gravis

Thymic hyperplasiaThymic hyperplasiaThymomaThymomaThyroid disordersThyroid disordersRheumatoid arthritisRheumatoid arthritisSLESLEUlcerative colitisUlcerative colitisVitiligoVitiligoPemphigusPemphigusMultiple sclerosisMultiple sclerosis

Hemolytic anemiaHemolytic anemiaPernicious anemiaPernicious anemiaRed cell aplasiaRed cell aplasiaITPITPSarcoidosisSarcoidosisLeukemia/lymphomaLeukemia/lymphoma

Myasthenia Gravis Clinical features

Myasthenia GravisMyasthenia Gravis Clinical featuresClinical features

Weakness and fatigabilityWeakness and fatigabilityOcular: diplopia, ptosisOcular: diplopia, ptosisMasticatory: chewing difficultyMasticatory: chewing difficultyBulbar: dysarthria, dysphagiaBulbar: dysarthria, dysphagiaExtremities: proximal > distal limb weakness, neck Extremities: proximal > distal limb weakness, neck weaknessweaknessRespiratory muscles: dyspneaRespiratory muscles: dyspnea

Symptoms are worsened as day wears and by a Symptoms are worsened as day wears and by a rise in body temperature.rise in body temperature.

Myasthenia Gravis Grading system (Osserman)

Myasthenia GravisMyasthenia Gravis Grading system (Osserman)Grading system (Osserman)

Grade 0 Grade 0 -- RemissionRemissionGrade 1 Grade 1 -- OcularOcularGrade 2A Grade 2A -- Mild generalizedMild generalizedGrade 2B Grade 2B -- Moderate generalizedModerate generalizedGrade 3 Grade 3 -- Severe generalized (crisis)Severe generalized (crisis)Grade 4 Grade 4 –– Late generalizedLate generalized

Myasthenia Gravis Diagnosis

Myasthenia GravisMyasthenia Gravis DiagnosisDiagnosis

History History Neurological ExamNeurological ExamTensilon TestTensilon TestElectrodiagnostic studiesElectrodiagnostic studiesSerological test (AChR, MuSK Serological test (AChR, MuSK antibodies)antibodies)Chest CTChest CTThyroid function studiesThyroid function studies

Myasthenia Gravis Key points on neuro exam

Myasthenia GravisMyasthenia Gravis Key points on neuro examKey points on neuro exam

Measure palpebral fissure distance at rest and Measure palpebral fissure distance at rest and following one minute of upward gaze.following one minute of upward gaze.Test orbicularis oculi strength.Test orbicularis oculi strength.Test for diplopia by prolonged lateral gaze.Test for diplopia by prolonged lateral gaze.Test for dysarthria by having patient read aloud.Test for dysarthria by having patient read aloud.Test strength of neck and extremity muscles.Test strength of neck and extremity muscles.Should have normal pupillary reactions, sensation, Should have normal pupillary reactions, sensation, and DTRs.and DTRs.

Myasthenia Gravis Tensilon test

Myasthenia GravisMyasthenia Gravis Tensilon testTensilon test

Edrophonium inhibits cholinesterase to prolong Edrophonium inhibits cholinesterase to prolong Ach activity.Ach activity.Must have something Must have something objectiveobjective to measure:to measure:

Usually degree of ptosisUsually degree of ptosisOccasionally dysarthria/dysphagiaOccasionally dysarthria/dysphagiaNotNot extremity strength, fatigue or diplopiaextremity strength, fatigue or diplopia

Not required in all MG patients.Not required in all MG patients.Can rarely be Can rarely be ““positivepositive”” in other diseases.in other diseases.

Myasthenia Gravis Tensilon test

Myasthenia GravisMyasthenia Gravis Tensilon testTensilon test

Load 1 cc (10 mg) Tensilon in TB syringe.Load 1 cc (10 mg) Tensilon in TB syringe.Inject directly into antecubital vein in 3 steps: Inject directly into antecubital vein in 3 steps: 0.1 cc, 0.5cc, 1.0cc.0.1 cc, 0.5cc, 1.0cc.When patient feels effect (sweating, nausea, When patient feels effect (sweating, nausea, fasciculations), stop injection.fasciculations), stop injection.Consider cardiac/blood pressure monitoring in Consider cardiac/blood pressure monitoring in elderly patients.elderly patients.Use with caution in patients with prominent Use with caution in patients with prominent bulbar symptoms.bulbar symptoms.

Myasthenia Gravis Acetylcholine receptor antibody

Myasthenia GravisMyasthenia Gravis Acetylcholine receptor antibodyAcetylcholine receptor antibody

Most specific test for MGMost specific test for MG%+:%+:

85% generalized MG85% generalized MG60% ocular MG60% ocular MG

““BindingBinding”” RIA most often used RIA most often used (nl <0.03 to 0.5 nmol/L)(nl <0.03 to 0.5 nmol/L)Correlate poorly with disease severityCorrelate poorly with disease severityTherapeutic approach to antibody negative Therapeutic approach to antibody negative patients is the same.patients is the same.

Myasthenia Gravis MuSK antibody

Myasthenia GravisMyasthenia Gravis MuSK antibodyMuSK antibody

MuSK is a muscle MuSK is a muscle specific kinase essential specific kinase essential for the development of for the development of the the NMJ.the the NMJ.Seen in 40Seen in 40--70% of 70% of generalized generalized MG patients MG patients who are acetylcholine who are acetylcholine receptor Ab receptor Ab negativenegative..

Myasthenia Gravis Repetitive stimulation

Myasthenia GravisMyasthenia Gravis Repetitive stimulationRepetitive stimulation

Perform at 2Perform at 2--3 Hz using a supramaximal 3 Hz using a supramaximal stimulus.stimulus.**Decrement > 10% indicates neuromuscular Decrement > 10% indicates neuromuscular transmission defect.transmission defect.**Decrement more likely to be demonstrated in Decrement more likely to be demonstrated in weak muscles (usually proximal).weak muscles (usually proximal).Look for postLook for post--exercise facilitation and exhaustion, exercise facilitation and exhaustion, especially if no decrement at rest.especially if no decrement at rest.Decrement may improve with cold exposure Decrement may improve with cold exposure -- be be sure upper extremity temperature is at least 34sure upper extremity temperature is at least 3400C.C.

Myasthenia Gravis Needle EMG

Myasthenia GravisMyasthenia Gravis Needle EMGNeedle EMG

Insertional activity is typically normal.Insertional activity is typically normal.**Fasciculations may be present in patients on Fasciculations may be present in patients on Mestinon.Mestinon.Motor unit morphology and recruitment is Motor unit morphology and recruitment is normal.normal.Motor units characteristically show Motor units characteristically show variability in amplitude.variability in amplitude.**

Single Fiber EMGSingle Fiber EMGSingle Fiber EMG

Records individual muscle fiber potentials.Records individual muscle fiber potentials.Jitter measures variability of rise time of end plate Jitter measures variability of rise time of end plate potential to reach threshold.potential to reach threshold.Jitter is measured in microseconds as the mean Jitter is measured in microseconds as the mean consecutive difference (MCD).consecutive difference (MCD).Blocking = failure of NMJ transmission; EPP does Blocking = failure of NMJ transmission; EPP does not reach threshold.not reach threshold.Normal average MCD of 20 pairs in the EDC is < Normal average MCD of 20 pairs in the EDC is < 35 35 μμsec and normal blocking = 0%.sec and normal blocking = 0%.

Myasthenia Gravis Natural history

Myasthenia GravisMyasthenia Gravis Natural historyNatural history

Grob et al. 1,487 patients 1940Grob et al. 1,487 patients 1940--19851985(Ann N Y Acad Sci. 1987;505:472(Ann N Y Acad Sci. 1987;505:472--99. Review)99. Review)

Initial Symptoms:Initial Symptoms:Ocular 53%Ocular 53%

25% ptosis, 25% diplopia, 3% blurred vision25% ptosis, 25% diplopia, 3% blurred visionLeg/Arm/Neck Weakness 20%Leg/Arm/Neck Weakness 20%Bulbar 16%Bulbar 16%

6% dysphagia, 5% dysarthria, 4% chewing6% dysphagia, 5% dysarthria, 4% chewingRespiratory Muscle Weakness 1%Respiratory Muscle Weakness 1%Generalized fatigue 9%Generalized fatigue 9%

Myasthenia Gravis Natural history

Myasthenia GravisMyasthenia Gravis Natural historyNatural history

Grob et al. Ann N Y Acad Sci. 1987;505:472Grob et al. Ann N Y Acad Sci. 1987;505:472--99. Review99. Review

Ocular MGOcular MG40% remain ocular at one year40% remain ocular at one year13% ultimately remain ocular13% ultimately remain ocular

Time to Progression to Generalized MGTime to Progression to Generalized MG56% by 6 months56% by 6 months78% by 1 year78% by 1 year85% by 2 years85% by 2 years92% by 3 years92% by 3 years

Myasthenia Gravis Treatment

Myasthenia GravisMyasthenia Gravis TreatmentTreatment

Increase acetylcholine (anticholineesterases):Increase acetylcholine (anticholineesterases):MestinonMestinonNeostigmineNeostigmine

Decrease antibodies against the acetylcholine receptor Decrease antibodies against the acetylcholine receptor (immunosuppressants):(immunosuppressants):

PrednisonePrednisoneAzathioprineAzathioprineCyclosporineCyclosporineMycophenolate mofetilMycophenolate mofetilCyclophosphamideCyclophosphamidePlasmpheresisPlasmpheresisIVIGIVIG

Acute myasthenia gravis (crisis):Acute myasthenia gravis (crisis):Plasma exchange (200 Plasma exchange (200 –– 250 ml/kg wt over 5 250 ml/kg wt over 5 –– 7 sessions)7 sessions)IVIg (0.4 gm/kg wt/day 3 IVIg (0.4 gm/kg wt/day 3 --5 days)5 days)

ThymectomyThymectomy

MestinonMestinonMestinon

Oral acetylcholinesterase inhibitor which is used Oral acetylcholinesterase inhibitor which is used as first line therapy for MGas first line therapy for MGDose is variableDose is variable

60mg TID 60mg TID -- QIDQIDIf you need more, immunosuppressive therapy is If you need more, immunosuppressive therapy is warranted.warranted.Treat GI side effects with probanthine (30mg) or Treat GI side effects with probanthine (30mg) or hyocyamine sulfate (Levsin/Anaspaz, 0.125mg)hyocyamine sulfate (Levsin/Anaspaz, 0.125mg)IV dosing is 1/30th oral dosing (1mg IV=30mg IV dosing is 1/30th oral dosing (1mg IV=30mg po)po)

PrednisonePrednisonePrednisone

Start at 1Start at 1--1.5mg/kg wt/day for 21.5mg/kg wt/day for 2--4 weeks, then taper to 100mg qod.4 weeks, then taper to 100mg qod.

Maintain same dose until significant improvement (preferably Maintain same dose until significant improvement (preferably remission) then taper by 5 mg q 2 weeks as tolerated.remission) then taper by 5 mg q 2 weeks as tolerated.

Improvement usually begins in 2Improvement usually begins in 2--4 weeks.4 weeks.

Maximum benefit seen in 4Maximum benefit seen in 4--6 months.6 months.

Transient worsening occurs in 20% of patients during first week.Transient worsening occurs in 20% of patients during first week.

““RemissionRemission”” is often steroid dependent.is often steroid dependent.

Prednisone: Collateral programPrednisone: Collateral programPrednisone: Collateral program

1800 calorie/4 gram Na diet1800 calorie/4 gram Na diet

Avoid simple carbohydratesAvoid simple carbohydrates

Vitamin D 400Vitamin D 400--800 IU/day800 IU/day

Calcium supplementationCalcium supplementation1000mg/d pre1000mg/d pre--menopausal or malemenopausal or male1500mg/d post1500mg/d post--menopausalmenopausal

Initiate treatment with Fosamax if evidence of bone loss.Initiate treatment with Fosamax if evidence of bone loss.

Myasthenia Gravis IVIg and PE

Myasthenia GravisMyasthenia Gravis IVIg and PEIVIg and PE

Improvement seen in 1Improvement seen in 1--20 days.20 days.Duration of effect 1 Duration of effect 1 –– 4 months.4 months.Maintenance IVIg and PE.Maintenance IVIg and PE.

Intravenous Immunoglobulin Potential side effects

Intravenous ImmunoglobulinIntravenous Immunoglobulin Potential side effectsPotential side effects

Fever/chillsFever/chillsNausea/vomitingNausea/vomitingHeadacheHeadacheMyalgiasMyalgiasHypotensionHypotensionHypertensionHypertensionCHFCHFHepatitis CHepatitis C

Anaphylaxis in IgA Anaphylaxis in IgA deficiencydeficiencyAseptic meningitisAseptic meningitisRenal failureRenal failureStrokeStrokeDVTDVTAllergic reactionsAllergic reactions

Plasmapheresis Limitations

PlasmapheresisPlasmapheresis LimitationsLimitations

IV access IV access -- often requires large double lumen often requires large double lumen cathetercatheterComplications:Complications:

PneumothoraxPneumothoraxHypotensionHypotensionSepsisSepsisPulmonary embolismPulmonary embolism

ExpensiveExpensiveShortShort--term benefitterm benefit

Myasthenia Gravis Thymectomy

Myasthenia GravisMyasthenia Gravis ThymectomyThymectomy

Perlo et al. Perlo et al. Ann N Y Acad Sci.Ann N Y Acad Sci. 1971;183:3081971;183:308--1515

Time to remission in thymectomy patients:Time to remission in thymectomy patients:25% 1st year25% 1st year40% 2nd year40% 2nd year55% 3rd year55% 3rd year

Myasthenia Gravis Immunotherapy pearls

Myasthenia GravisMyasthenia Gravis Immunotherapy pearlsImmunotherapy pearls

Poor response to immunotherapy is often due to inadequate doses Poor response to immunotherapy is often due to inadequate doses for too for too short a duration.short a duration.

Patients with bulbar or generalized MG who are started on high dPatients with bulbar or generalized MG who are started on high dose ose prednisone should be hospitalized (because of early exacerbationprednisone should be hospitalized (because of early exacerbations).s).

Immuran takes at least 6 months to kick in and works about half Immuran takes at least 6 months to kick in and works about half the time the time (be patient).(be patient).

Medications with the shortest duration of action should be reducMedications with the shortest duration of action should be reduced first.ed first.

The faster the taper, the more likely the patient is to relapse.The faster the taper, the more likely the patient is to relapse.

Myasthenia Gravis Drugs to avoid

Myasthenia GravisMyasthenia Gravis Drugs to avoidDrugs to avoid

Calcium channel Calcium channel blockersblockersBetaBeta--blockersblockersQuinineQuinineQuinidineQuinidineProcainamideProcainamideLidocaineLidocaine

Aminoglycoside Aminoglycoside antibioticsantibioticsPolymixinPolymixinMorphineMorphineBarbituratesBarbituratesNeuromuscular Neuromuscular blocking agentsblocking agentsMagnesiumMagnesium

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