Myasthenia gravisMyasthenia gravis

Liang GaoLiang GaoFebruary 6, 2007February 6, 2007

What is Myasthenia gravis?What is Myasthenia gravis?

Myasthenia gravis (MG) is a neuromuscular disease leading to fluctuating muscle weakness and fatigability

14 per 100,000 (in the U.S.), one of the lesser known autoimmune disorders

Caused by the failure of neuromuscular transmission

Symptoms: characteristic muscle weakness that worsens after use of affected muscles. 2/3 of patients, the extrinsic ocular muscles (EOMs) present the initial symptoms. The symptoms usually progress to the other bulbar muscles and limb muscles, resulting in generalized MG (gMG)

What is Myasthenia gravis?-What is Myasthenia gravis?-Cont.Cont.

Biding of autoantibodies to proteins involved in signaling at the neuromuscular junction (NMJ)

AChR (Acetylcholine Receptor) & Muscle-specific tyrosine kinase (MuSK) involved in AChR clustering

People treated with penicillamine can develop MG symptoms--antibody titer is usually similar to that of MG, but both the symptoms and the titer disappear when drug administration is discontinued.

Each axon Branch contain acEach axon Branch contain acetylcholine (Ach) loaded synetylcholine (Ach) loaded synaptic vesiclesaptic vesicles

Synaptic cleft contains acetylcholinesterase (AChE) and other proteins and proteoglycans involved in stabilizing the NMJ structure

Postsynaptic membrane has Postsynaptic membrane has characteristic deep folds: thcharacteristic deep folds: the AChR is densely packed at e AChR is densely packed at the tops of the foldsthe tops of the folds

Nerve action potential reaches the synaptic button--voltage-gated Ca2+ channels open

Ca2+ influx -- synaptic vesicles with ACh release

ACh binds to AChR--triggering the opening of its Na+ channels and influx of Na+

Endplate potential (EPP) activates voltage-gated Na+ channels, leading to further influx of Na+ and spreading of the action potential along the muscle fiber

Anti-AChR Abs affect neuromuscular transmission by at least 3 mechanisms:

Ab binding to the AChR activates the complement cascade

Formation of membrane attack complex (MAC) and localized destruction of the postsynaptic NMJ membrane.

A simplified, altered morphology of the postsynaptic membrane of the NMJ of MG patients, which lacks the normal deep folds and has a relatively flat surface

Accelerated degradation of AChR molecules crosslinked by Ab

Functional AChR block

ResultsResults

A reduction in the number or activity of thA reduction in the number or activity of the AChR molecules at the NMJe AChR molecules at the NMJ

Decreased EPP, which may still be adequaDecreased EPP, which may still be adequate at restte at rest

After repetitive activity of ACh release, the After repetitive activity of ACh release, the EPP may fall below the threshold needed tEPP may fall below the threshold needed to trigger the action potentialo trigger the action potential

PathophysiologyPathophysiologyThe antibodies are produced by The antibodies are produced by plasmacellsplasmacells, that have bee, that have been derived from n derived from B cellsB cells

These plasmacells are activated by These plasmacells are activated by T-helper(CD4+ T) cellsT-helper(CD4+ T) cells, , which in turn are activated by binding to acetylcholine recewhich in turn are activated by binding to acetylcholine receptor antigenic peptide sequences (ptor antigenic peptide sequences (epitopesepitopes) that rest withi) that rest within the histocompatibility antigens ofn the histocompatibility antigens of antigen precenting cells

The thymus plays an important role in the development of The thymus plays an important role in the development of T-cells, which is why myasthenia gravis is associated with tT-cells, which is why myasthenia gravis is associated with thymomahymoma

Slight Slight genetic predispositiongenetic predisposition: particular : particular HLAHLA types seem to types seem to predispose for MG predispose for MG

DiagnosisDiagnosis

Difficult for diagnosis, as the symptoms can be subtle and hDifficult for diagnosis, as the symptoms can be subtle and hard to distinguish from both normal variants and other neuard to distinguish from both normal variants and other neurological disorders and always take years for the right diagrological disorders and always take years for the right diagnosis nosis Physical examination—Muscle fatigabilityPhysical examination—Muscle fatigabilityBlood tests—AbBlood tests—AbRepetitive nerve stimulation--repeatedly stimulating a musRepetitive nerve stimulation--repeatedly stimulating a muscle with electrical impulses cle with electrical impulses Pathological findings--Immunofluoresence shows IgG antibPathological findings--Immunofluoresence shows IgG antibodies on the NMJ & Muscle electron microscopy shows receodies on the NMJ & Muscle electron microscopy shows receptor infolding and loss of the tips of the folds ptor infolding and loss of the tips of the folds

TreatmentTreatment

Direct improvement of the weakness Direct improvement of the weakness Improved muscle function by Improved muscle function by cholinesterase inhicholinesterase inhibitorsbitors--slow the natural enzyme cholinesterase t--slow the natural enzyme cholinesterase that degrades acetylcholine in the motor end plathat degrades acetylcholine in the motor end plate; the neurotransmitter is therefore around longee; the neurotransmitter is therefore around longer to stimulate its receptor r to stimulate its receptor

Reduction of the autoimmune process Reduction of the autoimmune process Treated patients with a combination of Treated patients with a combination of immunosimmunosuppressive drugsuppressive drugs with a with a cholinesterase inhibitorcholinesterase inhibitor

Treatment-Treatment-Cont.Cont.

Serious Patents: Serious Patents: PlasmapheresisPlasmapheresis is used to remo is used to remove the putative antibody from the circulation& ve the putative antibody from the circulation& IntIntravenous immunoglobulins (IVIg)ravenous immunoglobulins (IVIg) is used to bind is used to bind the circulating antibodies—short time benefitsthe circulating antibodies—short time benefits

ThymectomyThymectomy (removal of the thymus gland) can i (removal of the thymus gland) can improve symptoms in more than half of patientsmprove symptoms in more than half of patients—positive effects be seen within weeks to as muc—positive effects be seen within weeks to as much as 3-5 years after surgery h as 3-5 years after surgery

Reference:Reference:

Bianca M. Conti-Fine, Monica Milani, and Henry J. Kaminski. “Myasthenia gravis: past, present, and future”. The Journal of Clinical Investigation, Volume 116, Number 11, 2006Scherer K, Bedlack RS, Simel DL. "Does this patient have mScherer K, Bedlack RS, Simel DL. "Does this patient have myasthenia gravis?". yasthenia gravis?". JAMAJAMA 293: 1906-14, 2005 293: 1906-14, 2005Bedlack RS, Sanders DB. "How to handle myasthenic crisis.Bedlack RS, Sanders DB. "How to handle myasthenic crisis. Essential steps in patient care.". Essential steps in patient care.". Postgrad MedPostgrad Med 107: 211-4, 107: 211-4, 220-2. 2000220-2. 2000Myasthenia Gravis, Foundation of America, INCMyasthenia Gravis, Foundation of America, INChttp://www.myasthenia.org/http://www.myasthenia.org/The Myasthenia Gravis AssociatoinThe Myasthenia Gravis Associatoinhttp://www.mgauk.org/http://www.mgauk.org/

Questions?Questions?