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Short Presentation f..


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Short Presentation f..

  1. 1. Myasthenia gravis Liang Gao February 6, 2007
  2. 2. What is Myasthenia gravis? <ul><li>Myasthenia gravis (MG) is a neuromuscular disease leading to fluctuating muscle weakness and fatigability </li></ul><ul><li>14 per 100,000 (in the U.S.), one of the lesser known autoimmune disorders </li></ul><ul><li>Caused by the failure of neuromuscular transmission </li></ul><ul><li>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) </li></ul>
  3. 3. What is Myasthenia gravis?-Cont. <ul><li>Biding of autoantibodies to proteins involved in signaling at the neuromuscular junction (NMJ) </li></ul><ul><li>AChR ( Acetylcholine Receptor) & Muscle-specific tyrosine kinase (MuSK) involved in AChR clustering </li></ul><ul><li>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. </li></ul>
  4. 4. <ul><li>Each axon Branch contain acetylcholine (Ach) loaded synaptic vesicles </li></ul><ul><li>Synaptic cleft contains acetylcholinesterase (AChE) and other proteins and proteoglycans involved in stabilizing the NMJ structure </li></ul><ul><li>Postsynaptic membrane has characteristic deep folds: the AChR is densely packed at the tops of the folds </li></ul>
  5. 5. <ul><li>Nerve action potential reaches the synaptic button--voltage-gated Ca2+ channels open </li></ul><ul><li>Ca2+ influx -- synaptic vesicles with ACh release </li></ul><ul><li>ACh binds to AChR--triggering the opening of its Na+ channels and influx of Na+ </li></ul><ul><li>Endplate potential (EPP) activates voltage-gated Na+ channels, leading to further influx of Na+ and spreading of the action potential along the muscle fiber </li></ul><ul><li>Anti-AChR Abs affect neuromuscular transmission by at least 3 mechanisms: </li></ul>
  6. 6. <ul><li>Ab binding to the AChR activates the complement cascade </li></ul><ul><li>Formation of membrane attack complex (MAC) and localized destruction of the postsynaptic NMJ membrane. </li></ul><ul><li>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 </li></ul>
  7. 7. <ul><li>Accelerated degradation of AChR molecules crosslinked by Ab </li></ul><ul><li>Functional AChR block </li></ul>
  8. 8. Results <ul><li>A reduction in the number or activity of the AChR molecules at the NMJ </li></ul><ul><li>Decreased EPP, which may still be adequate at rest </li></ul><ul><li>After repetitive activity of ACh release, the EPP may fall below the threshold needed to trigger the action potential </li></ul>
  9. 9. Pathophysiology <ul><li>The antibodies are produced by plasmacells , that have been derived from B cells </li></ul><ul><li>These plasmacells are activated by T-helper(CD4+ T) cells , which in turn are activated by binding to acetylcholine receptor antigenic peptide sequences ( epitopes ) that rest within the histocompatibility antigens of antigen precenting cells </li></ul><ul><li>The thymus plays an important role in the development of T-cells, which is why myasthenia gravis is associated with thymoma </li></ul><ul><li>Slight genetic predisposition : particular HLA types seem to predispose for MG </li></ul>
  10. 10. Diagnosis <ul><li>Difficult for diagnosis, as the symptoms can be subtle and hard to distinguish from both normal variants and other neurological disorders and always take years for the right diagnosis </li></ul><ul><li>Physical examination—Muscle fatigability </li></ul><ul><li>Blood tests—Ab </li></ul><ul><li>Repetitive nerve stimulation--repeatedly stimulating a muscle with electrical impulses </li></ul><ul><li>Pathological findings--Immunofluoresence shows IgG antibodies on the NMJ & Muscle electron microscopy shows receptor infolding and loss of the tips of the folds </li></ul>
  11. 11. Treatment <ul><li>Direct improvement of the weakness </li></ul><ul><li>Improved muscle function by cholinesterase inhibitors --slow the natural enzyme cholinesterase that degrades acetylcholine in the motor end plate; the neurotransmitter is therefore around longer to stimulate its receptor </li></ul><ul><li>Reduction of the autoimmune process </li></ul><ul><li>Treated patients with a combination of immunosuppressive drugs with a cholinesterase inhibitor </li></ul>
  12. 12. Treatment- Cont. <ul><li>Serious Patents: Plasmapheresis is used to remove the putative antibody from the circulation& Intravenous immunoglobulins (IVIg) is used to bind the circulating antibodies—short time benefits </li></ul><ul><li>Thymectomy (removal of the thymus gland) can improve symptoms in more than half of patients—positive effects be seen within weeks to as much as 3-5 years after surgery </li></ul>
  13. 13. Reference: <ul><li>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, 2006 </li></ul><ul><li>Scherer K, Bedlack RS, Simel DL. &quot;Does this patient have myasthenia gravis?&quot;. JAMA 293: 1906-14, 2005 </li></ul><ul><li>Bedlack RS, Sanders DB. &quot;How to handle myasthenic crisis. Essential steps in patient care.&quot;. Postgrad Med 107: 211-4, 220-2. 2000 </li></ul><ul><li>Myasthenia Gravis, Foundation of America, INC </li></ul><ul><li> </li></ul><ul><li>The Myasthenia Gravis Associatoin </li></ul><ul><li> </li></ul>
  14. 14. Questions?