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 acetylcholine 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%: thymoma, 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 acetylcholine receptor: 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 Ptosis 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