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Myasthenia gravis

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Myasthenia gravis (MG) is a neuromuscular disease leading to fluctuating muscle ... What is Myasthenia gravis?-Cont. ... Myasthenia gravis: past, present, and future' ... – PowerPoint PPT presentation

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Title: Myasthenia gravis


1
Myasthenia gravis
  • Liang Gao
  • February 6, 2007

2
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)

3
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.

4
  • 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

5
  • 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

6
  • 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

7
  • Accelerated degradation of AChR molecules
    crosslinked by Ab
  • Functional AChR block

8
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

9
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

10
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

11
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

12
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

13
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/

14
Questions?
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