Myasthenia gravis

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Myasthenia gravis

• Liang Gao
• February 6, 2007

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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)

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What is Myasthenia gravis?-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.

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• Each axon Branch contain acetylcholine (Ach)
  loaded synaptic vesicles
• Synaptic cleft contains acetylcholinesterase
  (AChE) and other proteins and proteoglycans
  involved in stabilizing the NMJ structure
• Postsynaptic membrane has characteristic deep
  folds the AChR is densely packed at the tops of
  the folds

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• 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

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• 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

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• Accelerated degradation of AChR molecules
  crosslinked by Ab
• Functional AChR block

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Results

• A reduction in the number or activity of the AChR
  molecules at the NMJ
• Decreased EPP, which may still be adequate at
  rest
• After repetitive activity of ACh release, the EPP
  may fall below the threshold needed to trigger
  the action potential

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Pathophysiology

• The antibodies are produced by plasmacells, that
  have been derived from B cells
• 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
• The thymus plays an important role in the
  development of T-cells, which is why myasthenia
  gravis is associated with thymoma
• Slight genetic predisposition particular HLA
  types seem to predispose for MG

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Diagnosis

• 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
• Physical examinationMuscle fatigability
• Blood testsAb
• Repetitive nerve stimulation--repeatedly
  stimulating a muscle with electrical impulses
• Pathological findings--Immunofluoresence shows
  IgG antibodies on the NMJ Muscle electron
  microscopy shows receptor infolding and loss of
  the tips of the folds

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Treatment

• Direct improvement of the weakness
• 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
  
• Reduction of the autoimmune process
• Treated patients with a combination of
  immunosuppressive drugs with a cholinesterase
  inhibitor

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Treatment-Cont.

• Serious Patents Plasmapheresis is used to remove
  the putative antibody from the circulation
  Intravenous immunoglobulins (IVIg) is used to
  bind the circulating antibodiesshort time
  benefits
• Thymectomy (removal of the thymus gland) can
  improve symptoms in more than half of
  patientspositive effects be seen within weeks to
  as much as 3-5 years after surgery

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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, 2006
• Scherer K, Bedlack RS, Simel DL. "Does this
  patient have myasthenia gravis?". JAMA 293
  1906-14, 2005
• Bedlack RS, Sanders DB. "How to handle
  myasthenic crisis. Essential steps in patient
  care.". Postgrad Med 107 211-4, 220-2. 2000
• Myasthenia Gravis, Foundation of America, INC
• http//www.myasthenia.org/
• The Myasthenia Gravis Associatoin
• http//www.mgauk.org/

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Questions?