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Myasthenia gravis


Myasthenia gravis Single fiber EMG recordings: (a) Normal; (b) Increased; Jitter (c) Blocking both increased jitters, and blocking is seen in the neuromuscular disorders. – PowerPoint PPT presentation

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Title: Myasthenia gravis

Myasthenia gravis
  • prevalence - 20 per 100,000
  • population-between 53,000 and 60,000 cases /USA

Pathophysiology of Myasthenia Gravis
Pathophysiology of Myasthenia Gravis
  • 85 of patients with MG have detectable serum
    antibodies against AChRs
  • 20 to 40 of the remaining patients are positive
    for anti-MuSK antibodies
  • about 10 of patients are double-seronegative MG
  • anti-LRP4 autoantibodies exist in serum samples
    of patients with double-seronegative MG.

Autoantibodies in Myasthenia Gravis
Antigen MG Control
Anti-AChR Human 85-90 TE671 80 0
Anti-Musk 2-5 of all MG, gt20 of AChR-SNMG 0
Anti-striated muscle 40 4
Anti-thyroid 44 14
Anti-nuclear 14-39 4
Anti-titin (MGT30) 85 (MGthymoma) 0
Anti-ryanodine receptor 50 (MGthymoma) 0
Evidence that MG is autoimmune disease
  • MG Patients have increased incidence of other
    immune-mediated diseases, such as rheumatoid
  • A transitory neonatal form of the disease occurs
    in MG.
  • Immunosuppressive treatment, including plasma
    exchange, produces improvement in most patients
  • An animal model of MG can be produced by
    immunization with purified AChR
  • Antibodies against human AChR are found in the
    serum of most patients

Evidence that MG is autoimmune disease
  • Myasthenic serum or IgG produces abnormal
    neuromuscular transmission when injected into
  • IgG and complement components are attached to the
    postsynaptic endplate membrane in myasthenic

Antibody-Mediated Mechanisms
  • Accelerated degradation of AChRs
  • Complement-Mediated AChR-loss
  • Blockade of AChRs

Possible Origin of Autoimmunity in MG
  • Cross reacting epitope
  • Idiotypic dysregulation
  • Abnormal antigen
  • Drug related antigen
  • Helper T-cell defect
  • Regulatory T-cell defect

AChR Seronegative Myasthenia Gravis
  • 10-15 of MG patients
  • Clinical presentation similar to seropositive
    generalized MG
  • Thymus usually normal
  • Reduced-AChRs probably due to antibodies, to
    another NMJ antigen, or signal transduction
    effect on AChR function

Autoimmune disorders applied to seropositive and
seronegative MG
Seropositive MG Seronegative MG
AChR antibodies Yes No
Improvement after plasma exchange Yes Yes
Defect transferable to mice by Ig Yes Yes
Transfer features
NMT defect Yes Yes
AChR reduction Yes No
Antibody attached to AChR Yes No
Immunization against antigen(s) Produces disease Not yet clear
  • AChR-positive MG (85-90)
  • AChR-negative MG
  • MuSK positive (around 20-40)
  • MuSK negative (double negative)

Clinical Presentation
  • Ptosis or diplopia was the initial symptom in two
  • Almost all have both within 2 years of disease
  • Difficulty chewing, swallowing, or talking is the
    initial symptom in one sixth of patients and limb
    weakness in one tenth.
  • Weakness typically fluctuates during the day .

Clinical Presentation
Disease course
  • MG is variable but usually progressive
  • Restricted to the ocular muscles in 10-40 of
  • Maximum weakness occurs during the first year in
    two thirds of patients.
  • Before corticosteroids were used for treatment,
    approximately one third of patients had
    spontaneous improvement, one third had
    progressive disease, and one third died of the

Factors that worsen myasthenic symptoms
  • Emotional upset,
  • Systemic illness (especially viral respiratory
  • Hypothyroidism / hyperthyroidism.
  • Pregnancy, the menstrual cycle,
  • Drugs affecting neuromuscular transmission
  • Fever.

Physical Findings
  • Ocular Muscles -Asymmetrical weakness of several
    muscles in both eyes is typical.
  • Ptosis is usually asymmetrical and varies during
    sustained activity
  • Oropharyngeal Muscles changes in the voice,
    difficulty chewing and swallowing
  • Limb Muscles Neck flexors are usually weaker than
    neck extensors, deltoids, triceps, and
    wrist/fingers extensors are often weaker than
    other muscles.

  • Weakness usually involves one or more ocular
    muscles without overt pupillary abnormality
  • Weakness is typically variable, fluctuating, and
  • After down gaze, upgaze produces lid overshoot
    ("lid twitch").
  • Pseudo-internuclear ophthalmoplegia-limited
    adduction is present, with nystagmoid jerks in
    abducting eye.
  • In asymmetrical ptosis, covering the eye with
    the ptotic lid may relieve contraction of the
    opposite frontalis.
  • Passively lifting a ptotic lid may cause the
    opposite lid to fall.
  • Cold applied to the eye may improve lid ptosis.

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    ?????, ?????, ?????, ?????, ?????
  • myasthenic crisis
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Clinical association of MuSK abs
  • Distinct population
  • Age at onset around third decade
  • More women than men
  • More bulbar patients
  • Response to plasma exchange
  • Incidence 20-40 of AChR negative MG
  • (Possible additional plasma factor involved ?)

The Thymus in Myasthenia Gravis
  • Breakdown in immune tolerance toward
    self-antigens in the thymus.
  • 10 of patients with MG have a thymic tumor most
    are benign.
  • 70 have hyperplastic changes (germinal centers)
    that indicate an active immune response
  • Virtually all patients with MG and thymoma have
    elevated concentrations of AChR-binding

(No Transcript)
Diagnostic Procedures-1
  • Edrophonium Chloride (Tensilon) Test
  • positive in more than 90 of patients with MG
  • Tensilon Test is not unique to MG
  • A dose of 2 mg is injected intravenously, and the
    response is monitored for 60 seconds. Then 3 and
    5 mg.

Diagnostic Procedures-2
  • Electromyography
  • 10 decrement in amplitude when the first
    stimulus is compared to the fourth or fifth
  • SFEMG is the most sensitive clinical test of
    neuromuscular transmission and shows increased
    jitter .

Diagnostic Procedures-2
(No Transcript)
  • Cholinesterase Inhibitors- Mestinon 30-60
  • Corticosteroids 75 of patients markdly
    improved ! Prednisone 1.5-2.0 mg/kg per day
  • Immunosuppressant Drugs-
  • Plasma Exchange ,IVIG
  • Thymectomy

  • Azathioprine
  • Onset action 4-8  
  • side effects allergic reaction,hepatic
    toxicity, leukopenia
  • Cyclosporin  Onset action 2-3 renal toxicity,
    hypertension, multiple potential drug
  • Cyclophosphamide  Onset action variabl  
  • side effects leukopenia, hair loss, cystitis

Efficacy of PE in myasthenia gravis Hadassah
  • 86 myasthenic patients were treated with repeated
    courses of PE (ranging from 6-126 exchanges
    during a period of 3 years)
  • The follow up period was 3 years
  • During this period the efficacy of PE was
    evaluated the response rate was over 85 of
    patients (improved).

Myasthenia gravis Myasthenic crisis
Before Plasmapheresis
After Plasmapheresis
Current therapy of myasthenia gravis
  • What do we treat patients with MG when the
    conventional therapy fails?

mAb therapy for neuro-inflammatory diseases
  • Monoclonal antibodies (mAbs) represent an
    emerging and rapidly growing field of therapy in
    neuro-inflammatory diseases .
  • Most of them have been developed in systemic
    autoimmune diseases and Oncology.
  • There are currently more the 240 mAbs in clinical

mAb therapy for neuro-inflammatory diseases
  • Monoclonal antibodies mode of action
  • Depletion of specific cells
  • Blocking specific molecules expressed on the cell
  • Neutralizing soluble serum factors

Monoclonal Abs directed at specific immunologic
aspects of MG
  • Abnormal B cells activation
  • Complement activation
  • BAFF disregulation
  • Helper and Regulatory T-cell defect

Monoclonal Abs directed at specific immunologic
aspects of MG.
Dalakas , Ann N Y Acad Sci, 2012
Examples of Therapeutic Monoclonal Antibodies
Name Antigenic target Clinical use
Muromomab CD3 Transplant rejection
Daclizumab CD25 Transplant rejection,adult T-cell leukemia
Rituximab CD20 B-cell lymphoma, AUTOIMMUNITY
Infliximab TNF Crohns disease, RA
Alemtuzumab CD52 CLL,MS
Adalimumab TNF RA
Efalizumab CD11a Psoriasis
Natalizumab ABT-874 a-4 integrin Anti IL-12 MS, Crohns disease Not yet identified
Toralizuma CD40L, CD154 ineffective in SLE
No candidate Non Fc-binding Not yet identified
Eculizumab Anti-C5 paroxysmal nocturnal hemoglobinuria and atypical hemolytic-uremic syndrome
Abatacept Anti-CTLA4 ineffective in SLE
Targeting B-cells
  • AChR MG is the prototypic antibody mediated
    disease with clear evidence that AChR antibodies
    induce the disease in animal models and in
  • Both AChR and MuSK antibody positive patients
    respond to plasma exchange.
  • Anti-MuSK patients do not appear to respond to
  • Anti-MuSK antibodies are IgG4 which do not
    activate complement.
  • Anti-AChR are IgG1 and IgG3 that activate

Targeting B-cells
  • B-cell targeting therapies
  • Rituximab
  • Ocrelizumab
  • Ofatumumab

Rituximab Anti-CD20
Target CD-20 receptor
Other names Mabthera Rituxan, and Zytux
Rationale B cells involvement in autoimmune diseases antibody mediated , B cells role as APCs and cytokines production
Mode of action The antibody binds to CD20 expressed on B cells, from early pre-B cells to later in differentiation, but absent on terminally differentiated plasma cells. eliminates nearly all CD20-expressing B cells by CDC and ADCC as well as induction of apoptosis
Safety and tolerability Severe infusion reaction, cardiac arrest, Infections PML. Resistance development, most likely due to less efficient antibody-dependent cytotoxicity or to generation of human antichimeric antibodies (HACA).
The role of B-cell activating factor (BAFF) in
myasthenia gravis
  • B-cell activating factor (BAFF) is important in
    the differentiation and maturation of B cells and
    plasma cells.
  • Although the mechanism(s) by which BAFF and its
    receptors help regulate B-cell function and
    tolerance is not known, it may play a significant
    role in the immune process involved in myasthenia
  • Serum BAFF levels were found to be significantly
    higher in MG patients compared to controls
    including those with MS There was no correlation
    to disease severity but a trend for levels to be
    higher in AChR patients.
  • There is also evidence that BAFF is upregulated
    in germinal follicle like structures in
    myasthenic thymuses.

Belimumab Anti-BAFF
Target BAFF
Other names Anti-BAFF
Rationale BAFF- is important in the differentiation and maturation of B cells and plasma cells
Mode of action inhibits BAFF action via binding circulating BAFF and reducing the number of circulating B-cells but not to the extent as rituximab
Safety and tolerability approved in the US, Canada and Europe for the treatment of systemic lupus erythematosis A phase II trial in rheumatoid arthritis was encouraging but no phase III trial is underway. A phase II trial in MG has been announced
Therapy that targets complement
  • Complement mediated damage to the post-synaptic
    junction has been demonstrated to bind to the
    AChR-antibody complex inducing membrane-attack-com
    plex damage to the membrane reducing
    post-synaptic folds, widening the synaptic cleft
    and reducing the numbers of receptors.

Eculizumab Anti-C5
Target complement protein C5
Other names Soliris
Rationale Complement mediated damage to the post-synaptic junction has been demonstrated to bind to the AChR-antibody complex inducing membrane-attack-complex damage to the membrane reducing post-synaptic folds, widening the synaptic cleft and reducing the numbers of receptors.
Mode of action a recombinant humanized monoclonal IgG 2/4 antibody that binds to complement protein C5 which prevents the generation of the terminal complement C5b-9 complex
Safety and tolerability nausea, back pain, nasopharyngitis, and headache vulnerable to infection with encapsulated organisms. meningococcal vaccination is recommended at least 2 weeks prior to receiving eculizumab
Agents targeting T cell intracellular signaling
pathways, and costimulation
  • IL-2 mediate cell proliferation and
  • Daclizumab binds to CD25 (IL-2 receptor
    antagonist) and inhibits T cell proliferation.
  • Daclizumab is very well tolerated, has been
    approved for one form of leukemia, and has been
    very promising in patients with multiple
    sclerosis in at least two clinical trials.
  • Daclizumab An excellent agent to consider for MG

Daclizumab Anti-CD25
Target IL-2 receptor a chain (CD25)
Other names Anti-CD25, Zenapax
Rationale IL-2 mediate cell proliferation and differentiation.
Mode of action Prevents IL-2 binding without triggering of complement- or cell-mediated cell depletion, modulation of the IL-2 receptor complex or induction of intracellular signaling events a marked expansion of regulatory CD56bright NK cells
Safety and tolerability Gastrointestinal (e.g. nausea, diarrhoea), metabolic and nutritional disorders
Association of Myasthenia Gravis with Other
  • Hyperthyroidism
  • Rheumatoid arthritis. 2
  • Seizures
  • diabetes mellitus 7
  • thyroid disease 6
  • nonthymus neoplasm 3,

Transitory Neonatal Myasthenia.
  • 10-20 of newborns of MG mothers
  • frequency and severity correlate with antibody
  • Hypotonia and poorly fed during the first 3 days.
    symptoms may be delayed for 1-2 days. Usually
    last less than 2 weeks but may continue for as
    long as 12 weeks.

Genetic Myasthenic Syndromes
  • not immune mediated
  • 21 male predominance.
  • ophthalmoparesis and ptosis during infancy. Limb
    weakness is usually mild compared with
  • Respiratory distress is unusual.
  • ChE inhibitors improve limb muscle weakness in
    many forms of congenital genetic myasthenia

Lambert-Eaton Myasthenic Syndrome
  • A pre-synaptic abnormality of ACh release
  • In association with malignancy, usually small
    cell lung cancer (SCLC).
  • Abs against the voltage-gated calcium channels
    (VGCCs) on nerve terminals
  • reduced tendon reflexes and enhanced by repeated
    muscle contraction or repeated tapping of the
  • autonomic dysfunction dry mouth, impotence and
    postural hypotension.
  • Treatment with Guanidine hydrochloride increases
    the release of ACh

Drug alert for patients with myasthenia gravis
  • Interferon-a, botulinum toxin, and
    d-penicillamine should never be used in
    myasthenic patients.
  • The following drugs produce worsening of
    myasthenic weakness in most patients who receive
    them. Use with caution and monitor patient for
    exacerbation of myasthenic symptoms.
  • Succinylcholine, d-tubocurarine, or other
    neuromuscular-blocking agents
  • Quinine, quinidine, and procainamide
  • Aminoglycoside antibiotics, particularly
    gentamicin, kanamycin, neomycin, and streptomycin
  • Beta blockers (systemic and ocular preparations)
    propranolol, timolol maleate eyedrops
  • Calcium-channel blockers
  • Magnesium salts (including laxatives and antacids
    with high Mg2 concentrations)
  • Iodinated contrast agents
  • Many other drugs are reported to exacerbate the
    weakness in some patients with MG. All patients
    with MG should be observed for increased weakness
    whenever a new medication is started.

  • A toxin produced by the anaerobic bacterium,
    Clostridium botulinum,
  • Blocks the release of ACh from the motor nerve
  • Intoxication usually follows ingestion of
    contaminated foods that were inadequately
  • First Nausea and vomiting and then neuromuscular
    symptoms 12-36 hours after ingestion
  • Clinical symptoms
  • blurred vision, dysphagia, and dysarthria.
  • Pupillary responses to light are impaired.
  • tendon reflexes are variably reduced.
  • Fatal respiratory paralysis may occur rapidly.
  • Autonomic dysfunction, such as dry mouth,
    constipation, or urinary retention in most.
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