PATHO-PHYSIOLOGY

Witheverynerveimpulse,theamountofAChreleasedbythepresynapticmotorneuronnormally
decreasesbecauseofatemporarydepletionofthepresynapticAChstores(aphenomenonreferredtoas
presynapticrundown).
InMG,thereisareductioninthenumberofAChRsavailableatthemuscleendplateandflatteningof
thepostsynapticfolds.Consequently,evenifanormalamountofAChisreleased,fewerendplate
potentialswillbeproduced,andtheymayfallbelowthethresholdvalueforgenerationofanaction
potential.Theendresultofthisprocessisinefficientneuromusculartransmission.Inefficient
neuromusculartransmissiontogetherwiththenormallypresentpresynapticrundownphenomenonresults
inaprogressivedecreaseintheamountofmusclefibersbeingactivatedbysuccessivenervefiberimpulses.
ThisexplainsthefatigabilityseeninMGpatients.
PatientsbecomesymptomaticoncethenumberofAChRsisreducedtoapproximately30%ofnormal.
Thecholinergicreceptorsofsmoothandcardiacmusclehaveadifferentantigenicitythanskeletalmuscle
andusuallyarenotaffectedbythedisease.
ThedecreaseinthenumberofpostsynapticAChRsisbelievedtobeduetoanautoimmuneprocess
wherebyantiAChRantibodiesareproducedandblockthetargetreceptors,causeanincreasetheturnover
ofthereceptors,anddamagethepostsynapticmembraneinacomplementmediatedmanner.
Clinicalobservationssupporttheideathatimmunogenicmechanismsplayimportantrolesinthe
pathophysiologyofMG.Suchobservationsincludethepresenceofassociatedautoimmunedisorders(eg,
autoimmunethyroiditis,systemiclupuserythematosus[SLE],andrheumatoidarthritis[RA])inpatients
withMG.
Moreover,infantsborntomyasthenicmotherscandevelopatransientmyasthenialikesyndrome.
PatientswithMGwillhaveatherapeuticresponsetovariousimmunomodulatingtherapies,including
plasmapheresis,corticosteroids,intravenousimmunoglobulin(IVIg),otherimmunosuppressants,and
thymectomy.
AntiAChRantibodyisfoundinapproximately8090%ofpatientswithMG.Experimental
observationssupportinganautoimmuneetiologyofMGincludethefollowing:
InductionofamyasthenialikesyndromeinmicebyinjectingalargequantityofimmunoglobulinG(IgG)
fromMGpatients(ie,passivetransferexperiments)
DemonstrationofIgGandcomplementatthepostsynapticmembraneinpatientswithMG
InductionofamyasthenialikesyndromeinrabbitsimmunizedagainstAChRbyinjectingthemwithAChR
isolatedfromTorpedocalifornica(thePacificelectricray)
TheexactmechanismoflossofimmunologictolerancetoAChR,aselfantigen,isnotunderstood.
ThymusisthecentralorganinTcellmediatedimmunity,andthymicabnormalitiessuchasthymic
hyperplasiaorthymomaarewellrecognizedinmyasthenicpatients.
AntibodyresponseinMGispolyclonal.Inanindividualpatient,antibodiesarecomposedofdifferent
subclassesofIgG.Inmostinstances,1antibodyisdirectedagainstthemainimmunogenicregion(MIR)on
thealphasubunit.ThealphasubunitisalsothesiteofAChbinding,thoughthebindingsiteforAChisnot
thesameastheMIR.BindingofAChRantibodiestoAChRresultsinimpairmentofneuromuscular
transmissioninseveralways,includingthefollowing:
Crosslinking2adjacentAChRswithantiAChRantibody,thusacceleratinginternalizationand
degradationofAChRmolecules
Causingcomplementmediateddestructionofjunctionalfoldsofthepostsynapticmembrane
BlockingthebindingofAChtoAChR
DecreasingthenumberofAChRsattheNMJbydamagingthejunctionalfoldsonthepostsynaptic
membrane,therebyreducingthesurfaceareaavailableforinsertionofnewlysynthesizedAChRs
PatientswithoutantiAChRantibodiesarerecognizedashavingseronegativeMG(SNMG).Many
patientswithSNMGhaveantibodiesagainstmusclespecifickinase(MuSK).MuSKplaysacriticalrolein
postsynapticdifferentiationandclusteringofAChRs.PatientswithantiMuSKantibodiesare

predominantlyfemale,andrespiratoryandbulbarmusclesarefrequentlyinvolved.Anothergrouphas
reportedpatientswhoexhibitprominentneck,shoulder,andrespiratoryweakness. [11,12]
TheroleofthethymusinthepathogenesisofMGisnotentirelyclear,but75%ofpatientswithMG
havesomedegreeofthymusabnormality(eg,hyperplasiaorthymoma).Histopathologicstudieshave
shownprominentgerminalcenters.Epithelialmyoidcellsnormallypresentinthethymusdoresemble
skeletalmusclecellsandpossessAChRsontheirsurfacemembrane.Thesecellsmaybecomeantigenic
andunleashanautoimmuneattackonthemuscularendplateAChRsbymolecularmimicry.
ThequestionofwhyMGafflictstheextraocularmusclesfirstandpredominantlyremains
unanswered.Theanswerprobablyhastodowiththephysiologyandantigenicityofthemusclesin
question.