MyastheniaMyasthenia GravisGravis DiagnosisDiagnosis andand managementmanagement

Dr.Dr. ThaninThanin AsawavichienjindaAsawavichienjinda,, M.D.M.D. MyastheniaMyasthenia GravisGravis

• A neuromuscular disorder characterized by weakness and fatigability of skeletal muscles • The underlying defect: A decrease in the number of available receptors (AChRs) at neuromuscular junctions due to an antibody-mediated autoimmune attack. •• PreferablePreferable name:name: AutoimmuneAutoimmune myastheniamyasthenia • Treatment now available for MG is highly effective, although a specific cure has remained elusive

Harrison 2001 MyastheniaMyasthenia Gravis:Gravis: EpidemiologyEpidemiology

•• InIn thethe USA,USA, thethe prevalenceprevalence isis 14.214.2 cases/1cases/1 millionmillion peoplepeople •• AppearAppear atat anyany ageage •• InIn women,women, thethe onsetonset betweenbetween 2020 andand 4040 yearsyears ofof ageage •• AmongAmong men,men, atat 4040--6060 • Overall, women are affected more frequently than men, in a ratio of approximately 3:2. •• FamilialFamilial occurrenceoccurrence isis rarerare

JOAO 2004 MyastheniaMyasthenia Gravis:Gravis: EpidemiologyEpidemiology

•• AnnualAnnual incidence:incidence: 0.250.25--2/100,0002/100,000 •• SpontaneousSpontaneous remission:remission: 20%20% •• WithoutWithout treatment,treatment, 2020--30%30% diedie inin 1010 yearsyears •• MGMG isis aa heterogeneousheterogeneous disorderdisorder –– 90%90% nono specificspecific causecause •• Genetic predisposing factor: HLA association; HLA-BW46 in chinese ocular MG –– ThymicThymic tumor:tumor: 10%10% Lancet 2001 MyastheniaMyasthenia Gravis:Gravis: PathophysiologyPathophysiology • Autoimmune response mediated by specific anti-AChR antibodies • Pathogenic antibodies are IgG and are T cell dependent, SensitizedSensitized TT--helperhelper cellscells • Autoimmune response, the thymus appears to play a role • 75%: thymus abnormal – 65%: hyperplasia – 10%: , rarelyrarely inin children;children; oftenoften (20%)(20%) inin patientspatients agedaged 3030--4040 yearsyears

NEJM 1994; Neurologic clinics 1994; BJA 2002; JOAO 2004 MyastheniaMyasthenia Gravis:Gravis: PathophysiologyPathophysiology – Postsynaptic nicotinic : reduce the number of functional receptors • loss of structural integrity of receptors: by Ab and complement – Morphologic changes of simplification of the pattern of postsynaptic membrane folding; – An increased gap between the nerve terminal and the post synaptic muscle membrane • Blockade • ⇑ Turnover of AchRs: Accelerated degradation of acetylcholine receptors NEJM 1994, 1997; Neurologic clinics 1997; BJA 2002; JOAO 2004 MyastheniaMyasthenia Gravis:Gravis: PathophysiologyPathophysiology •• ReducedReduced AchRAchR densitydensity –– resultsresults inin endend--plateplate potentialspotentials ofof diminisheddiminished amplitudeamplitude whichwhich failfail toto triggertrigger actionaction potentialspotentials inin somesome fibersfibers causingcausing aa failurefailure inin initiationinitiation ofof musclemuscle fibrefibre contractioncontraction –– powerpower ofof thethe wholewhole musclemuscle isis reducedreduced •• TheThe amountamount ofof AChACh releasedreleased perper impulseimpulse normallynormally declinesdeclines onon repeatedrepeated activityactivity (termed(termed

presynapticpresynaptic rundown)rundown) NEJM 1994; BJA 2002 MyastheniaMyasthenia Gravis:Gravis: ClinicalClinical FeaturesFeatures

––FluctuatingFluctuating weaknessweakness ofof voluntaryvoluntary musclesmuscles (fatigability)(fatigability) ••WorsenWorsen afterafter exertionexertion andand improveimprove withwith restrest ––NoNo abnormalityabnormality ofof cognition,cognition, sensorysensory function,function, oror autonomicautonomic functionfunction

JOAO 2004 MyastheniaMyasthenia Gravis:Gravis: ClinicalClinical FeaturesFeatures

•• InitialInitial symptomssymptoms involveinvolve thethe ocularocular musclesmuscles inin 60%60% •• AllAll patientspatients willwill havehave ocularocular involvementinvolvement withinwithin 22 yearsyears ofof diseasedisease onsetonset

JOAO 2004 MyastheniaMyasthenia Gravis:Gravis: ClinicalClinical FeaturesFeatures

•• OcularOcular manifestationsmanifestations –– PtosisPtosis,, uniuni-- oror bilateralbilateral isis veryvery commoncommon andand maymay occuroccur whilewhile patientspatients reading,reading, oror duringduring longlong periodperiod ofof drivingdriving

JOAO 2004 PtosisPtosis and impaired orbicularis oculi MyastheniaMyasthenia Gravis:Gravis: ClinicalClinical FeaturesFeatures

•• OcularOcular manifestationsmanifestations –– DiplopiaDiplopia:: ExtraocularExtraocular musclemuscle weaknessweakness maymay alsoalso presentpresent asymmetricallyasymmetrically

JOAO 2004 EOMEOM MyastheniaMyasthenia Gravis:Gravis: ClinicalClinical FeaturesFeatures

•• BulbarBulbar involvementsinvolvements –– DifficultyDifficulty chewing,chewing, speaking,speaking, oror swallowing:swallowing: initialinitial symptomssymptoms inin 17%17% ofof patientspatients •• Fatigability and weakness during mastication •• Unable to keep jaw closed after chewing •• Slurred and nasal speech

Neurologic clinics 1997; JOAO 2004 Nasal voice MyastheniaMyasthenia Gravis:Gravis: ClinicalClinical FeaturesFeatures

•• LimbLimb musclesmuscles weakness:weakness: –– InitialInitial symptomssymptoms inin fewerfewer thanthan 10%10% –– UpperUpper extremitiesextremities weaknessweakness isis moremore commoncommon thanthan lowerlower extremities,extremities, asymmetricalasymmetrical –– InvolveInvolve proximalproximal musclesmuscles thanthan distaldistal –– InvolveInvolve neckneck muscles:muscles: neckneck flexionflexion weakerweaker thanthan neckneck extensionextension

Neurologic clinics 1997; JOAO 2004 MyastheniaMyasthenia Gravis:Gravis: ClinicalClinical FeaturesFeatures

•• RespiratoryRespiratory insufficiencyinsufficiency –– TheThe initialinitial presentationpresentation isis rarerare –– OccurringOccurring precipitouslyprecipitously inin aa patientpatient withwith recentrecent worseningworsening ofof symptomssymptoms

Neurologic clinics 1997 MyastheniaMyasthenia Gravis:Gravis:

•• PrecipitatingPrecipitating eventsevents –– SystemicSystemic illnessillness –– ViralViral upperupper respiratoryrespiratory tracttract infectioninfection –– ReceivingReceiving generalgeneral anesthesiaanesthesia –– ReceivingReceiving neuromuscularneuromuscular blockingblocking agentsagents –– Pregnancy,Pregnancy, menstrualmenstrual cyclecycle –– ExtremeExtreme heatheat –– StressStress

Neurologic clinics 1997 MedicationsMedications induceinduce oror exacerbateexacerbate MGMG

•• DefiniteDefinite associationassociation –– PenicillaminePenicillamine,, corticosteroidscorticosteroids •• ProbableProbable associationassociation –– AnticonvulsantsAnticonvulsants ((phenytoinphenytoin));; –– AntiAnti--infectivesinfectives ((aminiglycosidesaminiglycosides,, ciprofloxacin)ciprofloxacin);; –– BetaBeta--adrenergicadrenergic receptorreceptor--blockingblocking drugs;drugs; –– LithiumLithium carbonate;carbonate; –– ProcainamideProcainamide HClHCl

Archives of Internal Med 1997 MedicationsMedications induceinduce oror exacerbateexacerbate MGMG

•• PossiblePossible associationassociation – Anticholinergic drugs (artane); – Anti-infectives (ampicillin, imipenem, erythromycin, pyrantel); – Cardiovascular drugs (propafenone HCl, verapamil); – Cholroquine phosphate; – Neuromuscular-blocking drugs (vecuronium, succinylcholine); – Ocular drugs (proparacaine HCl, tropicamide); – Miscellaneous drugs (acetazolamide, carnitine, interferon alfa, trandermal nicotine) Archives of Internal Med 1997 MG:MG: ClassificationClassification

•• OssermanOsserman ClassificationClassification GradeGrade I:I: involveinvolve focalfocal diseasedisease (restricted(restricted toto ocularocular muscle)muscle) GradeGrade II:II: generalizedgeneralized diseasedisease IIaIIa:: mildmild IIbIIb:: moderatemoderate GradeGrade III:III: severesevere generalizedgeneralized diseasedisease GradeGrade IV:IV: aa crisiscrisis withwith lifelife--threateningthreatening impairmentimpairment ofof respirationrespiration

NEJM 1994 MG:MG: ClassificationClassification •• MGMG FoundationFoundation ofof AmericaAmerica ClinicalClinical ClassificationClassification Grade I: Any ocular muscle weakness Grade II: Mild weakness affecting other than ocular muscles IIa: limb and/or axial weakness; less oropharyngeal involvement IIb: oropharyngeal and/or respiratory weakness Grade III: Moderate weakness affecting other than ocular muscles (a,b) Grade IV: Severe weakness affecting other than ocular muscles (a,b) Grade V: Defined by tracheal intubation

BMC musculoskeletal disorders 2004 MyastheniaMyasthenia Gravis:Gravis: ClinicalClinical FeaturesFeatures

•• ClinicalClinical coursecourse –– MostMost progressprogress ifif nono treatmenttreatment –– 66%:66%: maximummaximum weaknessweakness duringduring thethe firstfirst yearyear –– SpontaneousSpontaneous improvementimprovement occursoccurs earlyearly inin thethe coursecourse –– OcularOcular typetype •• 66% develop generalized disease in one year •• 14% not progress after 2 years

Neurologic clinics 1997 MyastheniaMyasthenia Gravis:Gravis: ClinicalClinical FeaturesFeatures

•• ClinicalClinical coursecourse –– ActiveActive stagestage (5(5--77 y)y):: fluctuationfluctuation andand progressionprogression forfor severalseveral years:years: thymectomythymectomy benefitbenefit –– InactiveInactive stagestage (10(10 y)y) :: fluctuationfluctuation whilewhile intercurrentintercurrent illnessillness oror otherother identifiableidentifiable factorsfactors (drugs,(drugs, pregnancy):pregnancy): thymectomythymectomy nono benefitbenefit –– BurntBurnt--outout stagestage:: afterafter 1515--2020 years;years; fixedfixed weaknessweakness withwith atrophicatrophic musclesmuscles

Neurologic clinics 1997 MyastheniaMyasthenia Gravis:Gravis: DiagnosisDiagnosis

•• ClinicalClinical manifestations:manifestations: chronicchronic intermittentintermittent musclemuscle weakness;weakness; fatigabilityfatigability •• ProvocativeProvocative test:test: –– Physiologic:Physiologic: •• Look up for several minutes; counting aloud to 100; repetitively testing the proximal muscles –– Pharmacologic:Pharmacologic: •• Curare test: to demonstrate generalized MG (Neurologic( clinics 1994) JOAO 2004 EnhancedEnhanced ptosisptosis Provocative test MyastheniaMyasthenia Gravis:Gravis: DiagnosisDiagnosis

•• PharmacologicalPharmacological teststests MyastheniaMyasthenia Gravis:Gravis: DiagnosisDiagnosis

•• TensilonTensilon test:test: –– UsingUsing edrophoniumedrophonium chloride:chloride: shortshort actingacting acetylcholinesteraseacetylcholinesterase inhibitorinhibitor –– 1010 mgmg ofof edrophoniumedrophonium (0.15(0.15--0.20.2 mg/kg)mg/kg) usedused –– AA smallsmall testtest dosedose (2(2 mg)mg) iv;iv; afterafter 11 min.min. nono improvementimprovement andand sideside effect,effect, thethe remainderremainder givengiven slowlyslowly –– TheThe effecteffect ofof edrophoniumedrophonium:: inin 3030 sec.sec. andand lastlast fewerfewer thanthan 1010 min.min.

JOAO 2004 MyastheniaMyasthenia Gravis:Gravis: DiagnosisDiagnosis

•• TensilonTensilon test:test: –– HavingHaving falsefalse positivepositive (LEMS,(LEMS, MND,MND, MS,MS, tumor,tumor, DMDM cranialcranial neuropathy,neuropathy, mitochondrialmitochondrial myopathymyopathy)) andand falsefalse negativenegative –– SideSide effects:effects: N/V,N/V, tearing,tearing, salivation,salivation, musclemuscle fasciculation,fasciculation, abdominalabdominal cramp,cramp, bronchospasmbronchospasm,, bradycardiabradycardia,, cardiaccardiac arrestarrest –– CardiacCardiac monitoringmonitoring –– AtropineAtropine available:available: 0.60.6 mgmg IVIV

JOAO 2004 MyastheniaMyasthenia Gravis:Gravis: DiagnosisDiagnosis

•• NeostigmineNeostigmine testtest –– LongerLonger actingacting –– 1.51.5 mgmg IMIM oror 0.50.5 mgmg IVIV –– ActionAction beginsbegins inin 1515--3030 minsmins andand lastslasts upup toto 33 hourshours

Neurologic clinics 1997 MyastheniaMyasthenia Gravis:Gravis: DiagnosisDiagnosis

•• ElectrophysiologicalElectrophysiological teststests MyastheniaMyasthenia Gravis:Gravis: DiagnosisDiagnosis

•• RepetitiveRepetitive nervenerve stimulationstimulation –– 33 HzHz isis usedused forfor 6060 sec.sec. –– AA greatergreater thanthan 15%15% decrementdecrement ofof thethe amplitudeamplitude ofof CMAPCMAP isis consideredconsidered positivepositive –– TheThe yieldyield ofof thethe testtest increasesincreases ifif proximalproximal nervesnerves areare stimulatedstimulated –– MayMay bebe abnormalabnormal inin ALS,ALS, peripheralperipheral neuropathy,neuropathy, radiculopathyradiculopathy,, MSMS

Neurologic clinic 1997; JOAO 2004 MyastheniaMyasthenia Gravis:Gravis: DiagnosisDiagnosis •• SFEMGSFEMG –– SignalsSignals areare recordedrecorded onlyonly fromfrom musclemuscle fibersfibers closeclose toto thethe recordingrecording surfacesurface ofof thethe needleneedle electrodeelectrode –– MeasureMeasure thethe relativerelative firingfiring (action(action potentials)potentials) ofof adjacentadjacent musclemuscle fibersfibers fromfrom thethe samesame motormotor unitunit duringduring voluntaryvoluntary activityactivity –– TheThe variationvariation (time)(time) inin firingfiring betweenbetween thesethese firingfiring isis calledcalled jitterjitter ((µµsec)sec)

Neurologic clinics 1997 MyastheniaMyasthenia Gravis:Gravis: DiagnosisDiagnosis

•• SFEMGSFEMG –– NormalNormal jitterjitter rangesranges fromfrom 1010--5050 µµsecsec –– IncreasedIncreased jitterjitter isis seenseen inin MGMG (100(100 µµsecsec oror greater)greater) –– NeuromuscularNeuromuscular blockblock occursoccurs asas endend--plateplate potentialspotentials failfail toto reachreach adequateadequate thresholdthreshold toto generategenerate actionaction potentialpotential –– TimeTime forfor endend--plateplate potentialpotential toto reachreach thethe thresholdthreshold forfor actionaction potentialpotential generationgeneration isis longerlonger

Neurologic clinics 1997 MyastheniaMyasthenia Gravis:Gravis: DiagnosisDiagnosis •• SFEMGSFEMG –– MostMost sensitivesensitive –– DifficultDifficult toto performperform –– NeedNeed experienceexperience ofof thethe EMGerEMGer

INDAPS 2004 MyastheniaMyasthenia Gravis:Gravis: DiagnosisDiagnosis •• SFEMGSFEMG –– MayMay bebe abnormalabnormal (F+)(F+) inin neuropathies,neuropathies, mitochondrialmitochondrial myopathiesmyopathies,, nervenerve injury,injury, anterioranterior hornhorn cellcell disordersdisorders –– MayMay havehave falsefalse negativesnegatives inin mildmild affected,affected, oror onon immunosuppressiveimmunosuppressive treatmenttreatment

Neurologic clinics 1997 MyastheniaMyasthenia Gravis:Gravis: DiagnosisDiagnosis

•• ImmunologicalImmunological teststests MyastheniaMyasthenia Gravis:Gravis: DiagnosisDiagnosis

•• AntibodyAntibody toto acetylcholineacetylcholine receptorreceptor –– PresentPresent inin almostalmost allall patientspatients withwith thymomathymoma –– AbsentAbsent inin ocularocular typetype –– AbsentAbsent inin 20%20% ofof generalizedgeneralized MGMG

JOAO 2004 MyastheniaMyasthenia Gravis:Gravis: DiagnosisDiagnosis

•• SleepSleep testtest andand restrest testtest –– RestRest testtest forfor ocularocular ((ptosisptosis)) typetype (AAO 2002) MyastheniaMyasthenia Gravis:Gravis: DiagnosisDiagnosis

•• IceIce testtest –– MusclesMuscles inin MGMG functionfunction betterbetter inin aa lowerlower temperaturetemperature •• Decreased acetylcholinesterase activity •• Increased depolarizing effect of acetylcholine at motor endplates –– ApplyingApplying iceice packpack onon thethe eyelideyelid duringduring closingclosing forfor 22 minsmins.. –– Positive:Positive: lidlid fissurefissure increasesincreases byby 22 mmmm oror moremore fromfrom baselinebaseline (Curr Opin Neurol 2001)

JOAO 2004 ice test rest test

Before ice test After ice test MyastheniaMyasthenia Gravis:Gravis: DiagnosisDiagnosis

OcularOcular MGMG SensitiveSensitive •• TensilonTensilon testtest 86%86% (F +) (side effect) •• RNSRNS (EOM)(EOM) 48%48% (F+) (invasive) •• AchRAchR--AbAb:: 4545--65%65% (rare F +) (expensive) •• SFEMGSFEMG (gold(gold standard)standard) 95%95% (F +) (pain) (orbicularis oculi and frontalis) •• SleepSleep testtest simple and safe but takes time (30 mins.) and place •• RestRest testtest 50%50% nono F+F+ (AAO 2000) •• IceIce testtest forfor ptosisptosis:: 95%95% nono F+F+(Curr Opin Neurol 2001)

Neurologic clinics 1997; J med Assoc Thai 2001; JOAO 2004 MyastheniaMyasthenia Gravis:Gravis: DiagnosisDiagnosis

GeneralizedGeneralized MGMG SensitiveSensitive •• TensilonTensilon testtest 9595 •• RNSRNS higher than in ocular MG (F+) •• AchRAchR--AbAb:: 90%90% (rare F +) •• SFEMGSFEMG 100%100% (F +)

JOAO 2004 MyastheniaMyasthenia Gravis:Gravis: DifferentialDifferential DiagnosisDiagnosis •• FromFrom generalizedgeneralized MGMG – ALS: Asymmetric muscle weakness and atrophy – Other NMJ disorders • Lambert Eaton myasthenic syndrome • Congenital myasthenic syndrome • Neurotoxins – Botulism: Generalized limb weakness – Venoms: snakes, scorpions, spiders – Inflammatory demyelinating diseases • GBS: ascending limb weakness • Miller Fisher syndrome • Chronic – Inflammatory muscle disorders: Painful proximal symmetric limb weakness; no ocular involvement – Periodic paralysis: Intermittent generalized muscle weakness; no ocular involvement JOAO 2004 MyastheniaMyasthenia Gravis:Gravis: DifferentialDifferential DiagnosisDiagnosis

•• FromFrom BulbarBulbar MyastheniaMyasthenia – Brainstem stroke – Pseudobulbar palsy

•• FromFrom OcularOcular MyastheniaMyasthenia – MS: UMN; bilateral internuclear ophthalmoplegia – Mitochondrial cytopathy (chronic progressive external ophthalmoplegia) – Oculopharyngeal muscular dystrophy – Thyroid ophthalmopathy

JOAO 2004 MyastheniaMyasthenia GravisGravis

•• ManagementManagement –– DiagnosisDiagnosis –– SearchingSearching forfor associatedassociated diseasesdiseases –– TreatmentsTreatments –– AvoidingAvoiding andand treatingtreating precipitatingprecipitating factorsfactors MyastheniaMyasthenia Gravis:Gravis: •• AssociatedAssociated diseasesdiseases –– ThymomaThymoma –– NonthymusNonthymus neoplasmneoplasm inin 3%3% –– DMDM inin 7%7% –– ThyroidThyroid diseasedisease inin 6%6% –– RheumatoidRheumatoid arthritisarthritis inin fewerfewer thanthan 2%2% –– PerniciousPernicious anemia,anemia, pancytopeniapancytopenia,, thrombocytopeniathrombocytopenia andand SLESLE inin fewerfewer thanthan 1%1% –– PolymyositisPolymyositis,, dermatomyositisdermatomyositis,, psoriasis,psoriasis, sclerodermascleroderma (BJA 2002) Neurologic clinics 1997 Harrison 2001 MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment

•• TheThe goalgoal isis toto achieveachieve remissionremission –– SymptomsSymptoms freefree andand takingtaking nono medicationmedication •• By increased neuromuscular transmission •• Reduce autoimmunity JOAO 2004 •• Others:Others: havinghaving aa normalnormal qualityquality ofof lifelife eveneven ifif somesome signssigns remainingremaining andand cholinesterasecholinesterase inhibitorsinhibitors takingtaking Neurologic clinics 1994 MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment

•• NoNo singlesingle treatmenttreatment isis idealideal forfor allall patientspatients –– EachEach patientpatient needsneeds anan individualindividual planplan –– TreatmentTreatment maymay havehave toto bebe changedchanged timetime toto timetime •• ObtainObtain thethe bestbest responseresponse whilewhile keepingkeeping thethe riskrisk andand sideside effectseffects asas lowlow asas possiblepossible

Neurologic clinics 1994 Ocular MG

15% never spread out (Neurologic clinics 1994) Spontaneous remission (JOAO 2004) Good response to pyridostigmine If spread out, in 2 y - thymectomy If not response to pyridostigmine Add prednisolone: 10-30 mg/d for 2-3 months or incrementing dose; after maximum benefit slow tapering If not effective, getting along with dysfunction; maneuvers and simple mechanical devices used Or high-dose daily prednisolone + azathioprine or even thymectomy If ptosis is fixed; surgical shortening of the eyelid to be considered (JOAO 2004; Neurologic clinics 1994)

Harrison 2001 Before After treatment Generalized MG No bulbar involvement: remission Thymectomy: Indications

- Thymoma - Those are medically stable and aged

60 years or younger (puberty) (Neurologic( clinics 1994; NEJM 1994) 35% have clinical remission; 50%: improvement (Neurologic( clinics 1994; NEJM 1994) Clinical improvement in 6-12 m. after (JOAO( 2004) 1-2 years after surgery, immunosuppressive therapy to be considered if functional limitations (Neurologic( clinics 1994)

Harrison 2001 MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment •• GeneralizedGeneralized MGMG withwith onsetonset inin childhoodchildhood –– MoreMore benignbenign thanthan inin adult;adult; lessless associatedassociated withwith thymomathymoma,, andand remitremit spontaneouslyspontaneously –– ChEChE inhibitorsinhibitors onlyonly applyapply otherwiseotherwise disablingdisabling signssigns exist,exist, steroidsteroid willwill bebe recommendedrecommended –– ThymectomyThymectomy ifif notnot respondrespond toto prednisoloneprednisolone

Neurologic clinics 1994 MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment

•• GeneralizedGeneralized MGMG withwith latelate--lifelife onsetonset –– LessLess likelylikely toto improveimprove afterafter thymectomythymectomy –– SurgerySurgery carriescarries greatergreater riskrisk –– TreatmentTreatment withwith ChEChE inhibitorsinhibitors –– SevereSevere casescases worthworth toto useuse prednisoloneprednisolone andand azathioprineazathioprine

Neurologic clinics 1994 Myasthenic crisis Sudden worsening of respiratory function + profound muscle weakness - Negative inspiratory force of less than -20 cmH2O - Tidal volume of less than 4mL/kg - Force vital capacity < 15 mL/kg (normal 50- 60 in female, 70 in male)

Neurologic emergency

Causes: concurrent infection, medications, drug withdrawal (JOAO( 2004) DDx from cholinergic crisis: clinical and tensilon test

Management -Stop every medications -Assisted ventilation -Treating ppf. -If not improve -IVIg or plasmapheresis (JOAO( 2004) Harrison 2001 MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment

•• AcetylcholinesteraseAcetylcholinesterase inhibitorsinhibitors –– SymptomaticSymptomatic improvementimprovement forfor aa periodperiod ofof timetime –– InitialInitial therapytherapy –– OnsetOnset inin 3030 minsmins.. –– PeakPeak effecteffect atat 22 hrs.hrs. –– HalfHalf lifelife approximatelyapproximately 44 hrs.hrs. –– LowerLower risksrisks andand sideside effectseffects thanthan others:others: abdominalabdominal cramping,cramping, n/vn/v increasedincreased salivation,salivation, andand diarrheadiarrhea

NEJM 1994; Neurologic clinics 1997 MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment •• AcetylcholinesteraseAcetylcholinesterase inhibitorsinhibitors –– BenefitBenefit mostmost patientspatients butbut incompleteincomplete afterafter weeksweeks oror monthsmonths treatment;treatment; requirerequire furtherfurther therapeutictherapeutic measuresmeasures –– NoNo fixedfixed dosagedosage scheduleschedule suitssuits allall patientspatients –– TheThe needneed forfor ChEChE inhibitorsinhibitors variesvaries fromfrom dayday--toto--dayday andand duringduring thethe samesame dayday –– AA sustainedsustained--releaserelease preparationpreparation usedused onlyonly atat bedtimebedtime

NEJM 1994; Neurologic clinics 1997 MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment

•• AcetylcholinesteraseAcetylcholinesterase inhibitorsinhibitors –– PyridostigminePyridostigmine bromidebromide isis usedused •• Starting with 30 mg every 4 to 6 hours; titrated depending on clinical symptoms and patient tolerability •• Cholinergic crisis if too much of this medication (max. Dose = 450 mg/d) •• Lowest amount with maximum benefit •• 30 minutes before eating for patients with oropharyngeal weakness

60 mg pyridostigmine = 15 mg neostigmine Dose im form (2 ml = 5 mg) = 1/30 of oral dose Neurologic clinics 1997; JOAO 2004 MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment •• ImmunosuppressiveImmunosuppressive therapytherapy – Indications • Not adequately controlled by anticholinesterase drugs and sufficently distressing to outweigh the risks of possible side effects of immunosuppressive drugs in ocular MG • Severe but not ready to have surgery • Not improve after thymectomy: may delay 3 y after surgery • Crisis not respond to plasma exchange or IVIg • In inactive and burnt-out stage

NEJM 1994 MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment

•• ImmunosuppressiveImmunosuppressive therapytherapy –– Steroid:Steroid: reducereduce AchRAchR--AbAb titertiter ••MostMost useuse ••TypicalTypical dosagedosage isis 11 mg/kgmg/kg dailydaily asas aa singlesingle oraloral dosedose

JOAO 2004 MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment

•• ImmunosuppressiveImmunosuppressive therapytherapy –– Steroid:Steroid: •• Start on a low dose and gradually titrate the dose up – 5 mg daily and increased by 5 mg every 4-7 days until clinical benefit achievement; – Remain on this dose for 2 mo. – Then, switch to alternate-day therapy – Once, the condition stable, taperd downward by 5 mg every month – Patients may relapse after tapered off – Most patients require long-term low-dose

JOAO 2004 MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment •• ImmunosuppressiveImmunosuppressive therapytherapy –– Steroid:Steroid: – Have benefit in 6 to 8 weeks after initiation – Adverse effects: acne, bruising, cataracts, electrolyte imbalance, hirsutism, hyperglycemia, HT, avascular necrosis of the femoral head, obesity, osteoporosis, myopathy •• High-dose daily prednisolone (60-80 mg; 1-1.5 mg/kg/d) – Rapid improvement – Institution in the first 2-3 weeks – Exacerbation of weakness managed by ChE-inhibitors or plasmapheresis

JOAO 2004 MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment

•• ImmunosuppressiveImmunosuppressive therapytherapy –– AzathioprineAzathioprine:: •• Most use •• To reduce adverse steroid effects •• To whom steroids are contraindicated •• Starting dose is 50 mg daily for the first week, then increased 50 mg every week •• Titrating up to a maximum of 2-3 mg/kg/d in two or three divided doses

NEJM 1994; JOAO 2004 MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment

•• ImmunosuppressiveImmunosuppressive therapytherapy –– AzathioprineAzathioprine:: •• Clinical benefit shown in 4-6 months or longer (max effect 12-24 mos.) •• Once improvement; maintain as long as 4-6 mos. •• Adverse effects: neutropenia, hepatotoxicity; increase risk of malignancy; idiosyncratic influenza-like reaction

NEJM 1994; JOAO 2004 MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment

•• PlasmapheresisPlasmapheresis (plasma(plasma exchange)exchange) andand IVIgIVIg:: IndicationsIndications – Severe MG and exacerbations – Preparing for thymectomy or post operative period – Covering period before immunosuppressive therapy becomes fully active

INDAPS 2004 MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment •• PlasmapheresisPlasmapheresis (plasma(plasma exchange):exchange): doubledouble filtrationfiltration plasmaplasma exchangeexchange andand immunoadsorptionimmunoadsorption plasmaphoresisplasmaphoresis –– UndergoingUndergoing aa 22--weekweek coursecourse ofof 55--66 exchangesexchanges (1(1 plasmaplasma volumevolume == 4040--5050 ml/kg;ml/kg; 22--33 litersliters each)each) –– EffectiveEffective butbut transienttransient inin itsits response:response: ImprovementImprovement inin thethe thirdthird exchangeexchange andand lastslasts 66--88 weeksweeks –– ToTo removeremove thethe circulatingcirculating immuneimmune complexescomplexes andand AchRAchR--AbAb NEJM 1994; Neurologic clinics 1997; JOAO 2004 MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment

•• PlasmapheresisPlasmapheresis (plasma(plasma exchange):exchange): –– Limitation:Limitation: tootoo smallsmall oror fragilefragile venousvenous accessaccess –– ComplicationsComplications (catheters):(catheters): pneumothoraxpneumothorax,, bleeding,bleeding, sepsis,sepsis, –– AdverseAdverse effects:effects: hypotension,hypotension, hypercoagulationhypercoagulation,, hypoalbuminemiahypoalbuminemia,, hypocalcemiahypocalcemia,, pulmonarypulmonary embolism,embolism, arrhythmia,arrhythmia, (frequent(frequent exchanges)exchanges) anemia,anemia, lowlow plateletsplatelets

NEJM 1994; Neurologic clinics 1997; JOAO 2004 MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment

•• IVIgIVIg therapytherapy –– Dose:Dose: 22 g/kgg/kg overover 22--55 daysdays –– ClinicalClinical improvementimprovement inin 11--22 weeksweeks andand lastslasts weeksweeks toto monthsmonths

NEJM 1994; Neurologic clinics 1997; JOAO 2004 MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment

•• IVIgIVIg:: SideSide effecteffect profile(someprofile(some productproduct containcontain IgAIgA)) –– AllergicAllergic response:lowresponse:low gradegrade fever,fever, chills,chills, myalgiamyalgia –– Diaphoresis,Diaphoresis, fluidfluid overload,overload, HTHT –– Nausea,Nausea, vomiting,vomiting, rash,rash, neutropenianeutropenia –– Headache,Headache, asepticaseptic meningitismeningitis –– HyperviscosityHyperviscosity:: stroke,stroke, MI,MI, ATNATN (most(most seriousserious withwith compromizedcompromized renalrenal glomerularglomerular filtration;filtration; DM)DM) NEJM 1994; Neurologic clinics 1997; JOAO 2004 MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment

•• IVIgIVIg:: SideSide effecteffect profileprofile –– AnaphylacticAnaphylactic reaction:reaction: withwith IgAIgA deficiencydeficiency –– TransmissionTransmission withwith (very(very low)low) •• Hepatitis •• HIV

NEJM 1994; Neurologic clinics 1997; JOAO 2004 MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment

•• SurgicalSurgical interventionintervention –– ThymectomyThymectomy •• Acetylcholine-receptor antibody levels fall after thymectomy •• Mechanisms – Eliminate a source of continued antigenic stimulation – Subside immune response – Correct a disturbance of immune regulation

NEJM 1994 MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment

•• SurgicalSurgical interventionintervention –– ThymectomyThymectomy •• Not recommended in – Patients with purely ocular MG – Childhood, some do not recommended because of less severity than in adults and common remission spontaneously – Late-onset

Neurologic clinics 1994; NEJM 1994 Curr Opinion in Neurol 2001 MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment

•• FutureFuture treatmenttreatment –– BB--cellcell--directeddirected approachesapproaches ••BB--cellscells produceproduce pathogenicpathogenic antibodiesantibodies –– TT--cellcell--directeddirected approachesapproaches ••PivotalPivotal rolerole inin autoimmuneautoimmune antibodyantibody responseresponse

NEJM 1994 PreparationPreparation forfor thymectomythymectomy PreparationPreparation forfor thymectomythymectomy

•• NoNo emergencyemergency performanceperformance ofof thymectomythymectomy •• PreoperativePreoperative preparationpreparation –– OptimizedOptimized strengthstrength andand respiratoryrespiratory functionfunction –– AvoidedAvoided immunosuppressiveimmunosuppressive agentsagents (risk(risk ofof infection)infection) –– IfIf VCVC << 22 liters,liters, plasmapheresisplasmapheresis carriedcarried outout

NEJM 1994 PreparationPreparation forfor thymectomythymectomy

•• PostoperativePostoperative managementmanagement –– MayMay havehave weaknessweakness •• Pain •• Myasthenic crisis: ChE-Is withdrawal •• Cholinergic crisis: disease improvement •• May test with tensilon –– ChEChE inhibitorsinhibitors maymay bebe reducedreduced forfor aa fewfew daysdays afterafter thymectomythymectomy –– PostoperativePostoperative ChEChE medicationmedication givengiven IVIV atat aa dosedose ofof ¾¾ ofof thethe preoperativepreoperative requirementrequirement

NEJM 1994 AnaestheticAnaesthetic managementmanagement inin MGMG AnaestheticAnaesthetic managementmanagement inin MGMG

•• LocalLocal andand regionalregional anaesthesiaanaesthesia shouldshould bebe employedemployed •• GAGA requiresrequires meticulousmeticulous prepre andand perioperativeperioperative carecare

BJA 2002 AnaestheticAnaesthetic managementmanagement inin MGMG

•• PreoperativePreoperative consideration:consideration: majormajor electiveelective surgicalsurgical proceduresprocedures –– AdmittedAdmitted 4848 hrshrs priorprior toto surgerysurgery –– AssessmentAssessment andand monitoringmonitoring ofof respiratoryrespiratory (FVC)(FVC) andand bulbarbulbar functionfunction –– AdjustmentAdjustment ofof ChEChE inhibitorsinhibitors andand steroidsteroid ifif indicatedindicated –– ChestChest physiotherapyphysiotherapy startedstarted –– PlasmaPlasma exchangeexchange oror IvIgIvIg ifif necessarynecessary

BJA 2002 AnaestheticAnaesthetic managementmanagement inin MGMG

•• PreoperativePreoperative consideration:consideration: majormajor electiveelective surgicalsurgical proceduresprocedures –– SedativeSedative medicationsmedications savesave ifif nono respiratoryrespiratory comprimisecomprimise –– AntimuscarinicAntimuscarinic agentsagents helpfulhelpful inin reducingreducing secretionssecretions –– SteroidSteroid continuedcontinued prepre--operativelyoperatively –– HydrocortisoneHydrocortisone administeredadministered onon thethe dayday ofof surgerysurgery –– ChEChE inhibitorsinhibitors withheldwithheld onon thethe morningmorning ofof surgerysurgery

BJA 2002 AnaestheticAnaesthetic managementmanagement inin MGMG

•• InductionInduction andand maintenancemaintenance ofof anaesthesiaanaesthesia –– RoutineRoutine monitoringmonitoring –– SupplementSupplement withwith invasiveinvasive bloodblood pressurepressure measurementmeasurement –– NasotrachealNasotracheal tubetube isis preferedprefered –– PatientsPatients moremore sensitivesensitive toto neuromuscularneuromuscular blockingblocking agentsagents

BJA 2002 AnaestheticAnaesthetic managementmanagement inin MGMG

•• PostoperativePostoperative managementmanagement –– NursedNursed inin aa highhigh dependencydependency areaarea andand adequateadequate analgesiaanalgesia provided:provided: NSAIDNSAID andand parenteralparenteral opioidsopioids –– ChEChE inhibitorsinhibitors restartedrestarted atat aa reducereduce dosedose inin thethe immediateimmediate postpost--operativeoperative periodperiod andand increasingincreasing ifif necessarynecessary

BJA 2002 SeronegativeSeronegative MGMG SeronegativeSeronegative MGMG

•• FoundFound inin approximatelyapproximately 15%15% ofof patientspatients withwith generalizedgeneralized MGMG •• ClinicallyClinically indistinguishableindistinguishable fromfrom AchRAchR-- AbAb--positivepositive patientspatients •• BeBe diagnoseddiagnosed usingusing SFEMGSFEMG •• 70%70% ofof SNMGSNMG patientspatients havehave AbAb toto thethe musclemuscle--specificspecific receptorreceptor tyrosinetyrosine kinasekinase ((MuSKMuSK))

Curr Opin Neurol 2001 ThymomaThymoma--associatedassociated MGMG

•• MuscleMuscle antibodiesantibodies predictpredict thethe presencepresence ofof thymomathymoma SensSens.. Spec.Spec. ––RyanodineRyanodine receptorreceptor AbAb 70%70% ––TitinTitin AbAb 95%95% ––BothBoth 70%70% 70%70%

Curr Opin Neurol 2001 LateLate--onsetonset MGMG LateLate--onsetonset MGMG

•• OnsetOnset afterafter thethe ageage ofof 5050 •• MaleMale == femalefemale •• MostMost areare nonthymomanonthymoma •• MoreMore severesevere thanthan earlyearly--onsetonset MGMG •• HavingHaving circulatingcirculating AbAb toto AchRAchR butbut lowerlower conc.conc. thanthan inin earlyearly--onsetonset MGMG •• TitinTitin AbAb associatesassociates withwith severityseverity •• DifficultyDifficulty inin treatmenttreatment Archives of Neurol 1999 LateLate--onsetonset MGMG

•• DifficultyDifficulty inin treatmenttreatment –– TemporaryTemporary responseresponse toto ChEChE--inhibitorsinhibitors –– PlasmaPlasma exchangeexchange producesproduces moremore complicationscomplications –– ThymectomyThymectomy givesgives poorerpoorer resultsresults –– SteroidsSteroids givegive manymany complicationscomplications –– TreatmentTreatment hashas toto bebe tailoredtailored

Archives of Neurol 1999 MGMG andand pregnancypregnancy MGMG andand pregnancypregnancy •• PregnancyPregnancy isis associatedassociated withwith physiologicphysiologic immunosuppressionimmunosuppression:: depressdepress leukocyteleukocyte functionfunction •• PregnancyPregnancy aggravatesaggravates MGMG •• So,So, clinicalclinical coursecourse unpredictable:unpredictable: rulerule ofof threethree •• OneOne pregnancypregnancy notnot predictpredict thethe coursecourse inin subsequentsubsequent pregnanciespregnancies •• ExacerbationExacerbation occuroccur equallyequally inin allall trimesterstrimesters •• TherapeuticTherapeutic terminationtermination notnot demonstratedemonstrate aa consistentconsistent benefitbenefit inin casescases ofof firstfirst trimestertrimester exacerbationexacerbation

BMC musculoskeletal disorders 2004 MGMG andand pregnancypregnancy •• UseUse minimualminimual dosagedosage ofof drugsdrugs •• ChEChE--inhibitors:inhibitors: inin creasedcreased uterineuterine contractioncontraction •• AvoidAvoid otherother immunosuppressiveimmunosuppressive drugsdrugs exceptexcept steroidsteroid •• NormalNormal deliverydelivery donedone •• NoNo problemsproblems inin breastbreast feedingfeeding •• TransientTransient neonatalneonatal myasthenia:myasthenia: – Found by 9-30% – Good response to ChE-inhibitors – Complete recovery in 2-4 mo

BMC musculoskeletal disorders 2004 MyasthenicMyasthenic crisiscrisis MyasthenicMyasthenic crisiscrisis

•• RarelyRarely atat thethe initialinitial presentationpresentation •• KnownKnown MGMG maymay reachreach aa crisiscrisis •• DefinedDefined asas suddensudden worseningworsening ofof respiratoryrespiratory functionfunction and/orand/or profoundprofound musclemuscle weaknessweakness •• BeingBeing aa neurologicneurologic emergencyemergency •• Causes:Causes: concurrentconcurrent infection,infection, medications,medications, drugdrug withdrawalwithdrawal

JOAO 2004 MyasthenicMyasthenic crisiscrisis

•• DDxDDx fromfrom cholinergiccholinergic crisiscrisis –– AbdominalAbdominal pain,pain, diarrhea,diarrhea, hypersecretionhypersecretion,, pinpointpinpoint pupilpupil –– NegativeNegative oror worseworse byby tensilontensilon testtest •• Hold ChE-Is •• Atropine 2 mg/hr –– TensilonTensilon testtest toto considerconsider thethe needneed ofof ChEChE-- IsIs MyasthenicMyasthenic crisiscrisis •• ManagementManagement –– StopStop everyevery medicationsmedications –– AssistedAssisted ventilationventilation •• Respiratory support required if

– Negative inspiratory force of less than -20 cm H2O – Tidal volume of less than 4mL/kg – Force vital capacity < 15 mL/kg (normal 50-60 [f], 70 [m]) –– TreatingTreating ppfppf.. –– TensilonTensilon testtest toto estimateestimate ChEChE--IsIs requirementrequirement –– IfIf notnot improveimprove •• IVIg or plasmapheresis JOAO 2004

Lancet 2001 MyastheniaMyasthenia Gravis:Gravis: EtiologyEtiology

•• ImmunopathogenesisImmunopathogenesis –– MGMG isis duedue toto antibodyantibody--mediatedmediated processesprocesses •• Ab is present •• Ab interacts with the target antigen, acetylcholine receptor •• Passive transfer reproduces disease feature •• Immunization with the antigen produces a model disease •• Reduction of antibody levels ameliorates the disease NEJM 1997

MyastheniaMyasthenia Gravis:Gravis: InvestigationInvestigation

•• ForFor associatedassociated diseasesdiseases –– AutoimmuneAutoimmune thyroiditisthyroiditis –– GraveGrave’’ss diseasedisease –– SLESLE –– CXRCXR –– CTCT chestchest scan:scan: maymay missmiss smallsmall thymomathymoma nodulesnodules JOAO 2004 •• RuleRule outout geneticgenetic MG,MG, LambertLambert--EatonEaton myasthenicmyasthenic syndromesyndrome Neurologic clinics 1994 MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment •• OcularOcular MGMG –– GoodGood responseresponse toto pyridostigminepyridostigmine –– StartingStarting withwith 3030 mgmg everyevery 44 toto 66 hourshours –– TitratedTitrated dependingdepending onon clinicalclinical symptomssymptoms andand patientpatient tolerabilitytolerability –– AdverseAdverse effects:effects: abdominalabdominal cramping,cramping, increasedincreased salivation,salivation, nauseanausea andand diarrheadiarrhea –– LowestLowest amount,amount, maximummaximum benefitbenefit –– UsuallyUsually spontaneousspontaneous remissionremission

JOAO 2004 MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment •• OcularOcular MGMG ––IfIf spreadspread out,out, willwill occuroccur inin 11--22 yearsyears afterafter onsetonset ––So,So, closedclosed followfollow upup inin thethe firstfirst 22 yearsyears isis necessarynecessary toto detectdetect weaknessweakness earlyearly –– thymectomythymectomy isis recommendedrecommended

Neurologic clinics 1994 MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment

•• ImmunosuppressiveImmunosuppressive therapytherapy –– CyclosporineCyclosporine •• Inhibits T-cell activation •• For failure to respond to combination therapy with prednisolone and azathioprine or intolerability of azathioprine •• Starting dose: 25 mg twice daily •• Titrating up to 3-6 mg/kg/d

NEJM 1994; JOAO 2004 MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment

•• ImmunosuppressiveImmunosuppressive therapytherapy –– CyclosporineCyclosporine •• Combination therapy is more efficacious; reduced dosage and fewer adverse effects •• Time to onset of effect: 2-12 wk •• Time to maximal effect: 3-6 mo •• Adverse effects: nephrotoxicity, HT

NEJM 1994; JOAO 2004 MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment

•• ImmunosuppressiveImmunosuppressive therapytherapy ––CyclophosphamideCyclophosphamide ••UsedUsed onlyonly othersothers failedfailed oror notnot toleratedtolerated ••StartingStarting dose:dose: 2525 mgmg dailydaily ••GraduallyGradually increasedincreased upup toto 22--55 mg/kg/dmg/kg/d ••AdverseAdverse effect:effect: hemorrhagichemorrhagic cystitiscystitis

JOAO 2004 MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment

•• ImmunosuppressiveImmunosuppressive therapytherapy ––MycophenolateMycophenolate MofetilMofetil ••NovelNovel agent,agent, benefitbenefit inin transplantationtransplantation medicinemedicine ••StartingStarting atat 250250 mgmg twicetwice dailydaily ••StandardStandard dailydaily dosage:dosage: 11--22 g.g. ••CBCCBC checkedchecked everyevery weekweek forfor thethe firstfirst month;month; everyevery twotwo weeksweeks forfor thethe nextnext 66--88 weeks;weeks; andand monthlymonthly thereafterthereafter

JOAO 2004

MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment •• GeneralizedGeneralized MGMG withwith onsetonset inin adultadult lifelife –– Mild:Mild: nono symptomssymptoms relatedrelated toto breathing,breathing, coughingcoughing andand swallowingswallowing •• ChE inhibitors •• If optimal dosage, thymectomy to be considered •• Or additional prednisolone, if no remission in 1 year - thymectomy –– BalbarBalbar involvementinvolvement •• ChE inhibitors + high dose prednisolone •• Thymectomy to be considered Neurologic clinics 1994 MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment •• GeneralizedGeneralized MGMG –– CombinationCombination withwith pyridostigminepyridostigmine andand prednisoloneprednisolone •• Starting with low dose •• Starting with high dose: 1-1.5 mg/kg/d – Patients be worse – Should be admitted for 2 weeks – Clinical benefit in 1-2 months afterward – Adverse effects: acne, bruising, cataracts, electrolyte imbalance, hirsutism, hyperglycemia, HT, avascular necrosis of the femoral head, obesity, osteoporosis, myopathy

JOAO 2004 MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment •• GeneralizedGeneralized MGMG withwith onsetonset inin childhoodchildhood – Distiquishing acquired autoimmune MG from genetic MG – not respond to immunotherapy – Seronegative in acquired MG possible – Positive treatment response with plasma exchange, IvIg is ; but negative not excluded – More benign than in adult; less associated with thymoma, and remit spontaneously – ChE inhibitors only apply otherwise disabling signs exist, steroid will be recommended – Thymectomy if not respond to prednisolone Neurologic clinics 1994 MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment

•• GeneralizedGeneralized MGMG ––ToTo reducereduce adverseadverse steroidsteroid effectseffects ––AddAdd withwith oror switchswitch toto azathioprineazathioprine

JOAO 2004 MyastheniaMyasthenia Gravis:Gravis: TreatmentTreatment •• OcularOcular MGMG –– IfIf notnot goodgood responseresponse toto pyridostigminepyridostigmine:: notnot leadlead toto normalnormal socialsocial andand workingworking lifelife •• Add low dose prednisolone: 10-30 mg/d for 2- 3 months or incrementing dose; after maximum benefit slow tapering •• If not effective, getting along with dysfunction; maneuvers and simple mechanical devices used •• Or high-dose daily prednisolone with/without azathioprine or even thymectomy •• If ptosis is fixed; surgical shortening of the eyelid to be considered

JOAO 2004; Neurologic clinics 1994 MyastheniaMyasthenia Gravis:Gravis: PathophysiologyPathophysiology MyastheniaMyasthenia Gravis:Gravis: PathophysiologyPathophysiology

•• SerumSerum concentrationconcentration ofof acetylcholineacetylcholine-- receptorreceptor antibodyantibody notnot correlatecorrelate withwith thethe clinicalclinical severityseverity •• DegreeDegree ofof reductionreduction ofof acetylcholineacetylcholine receptorsreceptors correlatecorrelate withwith thethe severityseverity

NEJM 1997 MyastheniaMyasthenia Gravis:Gravis: PathophysiologyPathophysiology

•• ImmunopathogenesisImmunopathogenesis ––AntibodyAntibody negativenegative MGMG ••FoundFound inin 1010--20%20% ••Causes:Causes: – Too low an affinity for detection in the soluble assay system – Antibody may be directed at epitopes not present in the soluble acetylcholine-receptor extract

NEJM 1997 MedicationsMedications induceinduce oror exacerbateexacerbate MGMG

•• AntiAnti--infectiveinfective AgentsAgents –– AminoglycosidesAminoglycosides –– KanamycinKanamycin sulfatesulfate –– AmpicillinAmpicillin sodiumsodium –– ErythromycinErythromycin –– CiprofloxacinCiprofloxacin HCLHCL –– ImipenemImipenem –– PyrantelPyrantel

JOAO 2004 MedicationsMedications induceinduce oror exacerbateexacerbate MGMG

•• CardiovascularCardiovascular AgentsAgents – Propanolol HCL – Acebutolol HCL – Oxyprenolol HCL – Practolol – Timolol maleate ( β blocker) – Quinidine (anti-arrhythmic) – Procainamide HCL (anti-arrhythmic) – Propafenone HCL (anti-arrhythmic)

JOAO 2004 MedicationsMedications induceinduce oror exacerbateexacerbate MGMG •• OtherOther AgentsAgents –– ChloroquineChloroquine –– CorticosteroidsCorticosteroids –– DD--penicillaminepenicillamine –– InterferonInterferon αα –– MydriaticsMydriatics –– PhenytoinPhenytoin sodiumsodium –– TrihexyphenidylTrihexyphenidyl HCLHCL (artane) –– TrimethadioneTrimethadione –– VerapamilVerapamil HCLHCL

JOAO 2004 J med Assoc Thai 2001 กลับสูเมนูหลัก