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Clinical aspects of myasthenia gravis


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Title: Clinical aspects of myasthenia gravis

Clinical aspects of myasthenia gravis
Athens 20 February 2010
  • Amelia Evoli
  • Neuroscience Department
  • Catholic University, Roma, Italy

Myasthenia gravis (MG) is a disease of
neuromuscular transmission
The neuromuscular junction (NMJ) is a highly
efficient synapse which converts the nerve
impulse into muscle contraction
At the NMJ the motor nerve terminal and the
muscle membrane are juxtaposed. The nerve
terminal contains vesicles filled with ACh and
the muscle membrane is folded into many synaptic
folds which greatly increase its area.
The specialized region of muscle
membrane at the NMJ is called motor end plate
Neuromuscular transmission
When a nerve impulse reaches the nerve terminal,
a high number of synaptic vesicles simultaneously
open (a massive amount of ACh is released in the
synaptic space)
  • ACh binding to AChRs results in the opening of
    ion channels
  • the huge influx of sodium leads to a local
    depolarization ("end plate potential" - EPP)
  • If the EPP is sufficiently large, an action
    potential is produced and muscle contraction
  • ACh is metabolized by acetyl cholinesterase

Safety factor of neuromuscular transmission
  • At the normal NMJ, the amplitude of the end-plate
    potential is much larger than the threshold that
    is needed to activate muscle contraction.
  • That is due to the fact that
  • the number of ACh vesicles released by each
    nerve impulse
  • the number of activated ACh receptors
  • are considerably greater than the amounts
    required to depolarize the muscle membrane to the
  • This represents the safety factor of the
    neuromuscular transmission

Diseases of neuromuscular junction are
characterized by a reduced safety factor A
decrease of ACh release or a reduced ACh receptor
opening can be responsible As the safety factor
alteration is more evident when there is
over-activation of the neuromuscular
transmission, the most typical symptom is muscle
Neuromuscular transmission disorders
Autoimmune Myasthenia gravis Lambert-Eaton
myasthenic syndrome Peripheral nerve
hyperexcitability syndromes Toxic Toxins (a- and
b-neurotoxins) - produced by bacteria - present
in venoms Drugs and poisons Congenital Congenital
myasthenic syndromes
Myasthenia gravis
  • It is the most frequent disorder of NMJ
  • annual incidence of 4-11/million and prevalence
  • Clinical aspects
  • muscle weakness with fatigability
  • typical pattern of weakness in most cases
  • fluctuating course with remissions and relapses
  • association with thymus alterations
    (hyperplasia, thymoma)

Myasthenia gravis can occur at any age
Myasthenia gravis is a post-synaptic disorder of
the neuromuscular junction
  • It is an autoimmune disorder, in which
  • specific autoantibodies are directed against
    different proteins at the motor end plate
  • the autoimmune attack results in a reduced
    response to nerve-released acetylcholine
  • the impairment of neuro-muscular transmission
    underlies muscle weakness and fatigability

Ion channels and associated proteins at the
neuromuscular junction
In myasthenia gravis, pathogenic antibodies are
directed against the acetylcholine receptor
(AChR) or the muscle specific kinase (MuSK)
The acetylcholine receptor is the main antigen in
Ab binding site
AChR structure
  • Main effects of anti-AChR antibodies
  • increased receptor degradation
  • complement-mediated lysis of the postsynaptic
    membrane membrane

Loss of AChRs and simplification of the
postsynaptic membrane
Weakness depending on exertion is the hallmark
of MG
Normally, the amount of ACh released by each
nerve activation decreases during a series of
nerve stimuli (which is the equivalent of
sustained activity)
In MG, release of ACh is normal However, as
AChRs are reduced this physiologic decrease in
ACh release means that an insufficient number of
AChRs open to adequately depolarize the muscle
membrane. Neuromuscular transmission failure at
an increasing number of junctions causes
progressive muscle weakness
A decremental pattern during low-rate repetitive
nerve stimulation is typical of MG
MG with anti-AChR Abs is frequently associated
with thymus alterations
  • thymus hyperplasia is very common in the
    early-onset disease
  • thymoma in found in 10-15 of patients, more
    frequently in the 5th-7th decades
  • the thymus is thought to play a role in MG
    pathogenesis and thymectomy is an established
    therapy for the disease
  • the response to thymectomy varies in different
    patient groups

Thymic hyperplasia in early-onset MG
The hyperplastic thymus is considered the site
where the tolerance to AChR is broken and the
production of anti-AChR antibodies is started.
Early-onset MG generally shows a good response
to thymectomy - clinical improvement - serum
anti-AChR Ab reduction
MG associated with thymoma
Thymoma is a slow-growing tumor originating from
thymic epithelial cells It can vary markedly in
size and local invasiveness

The role of thymoma in MG is not completely
clear - the response to thymectomy is less good
than in patients with thymus hyperplasia - the
onset of MG can even occur after thymoma treatment
Whenever feasible, surgery is indicated in
patients with thymoma
In late-onset MG the thymus is in most cases
normal-for age
  • - At this age, thymus parenchyma is mostly
    replaced by fat tissue
  • - Small islands of epithelial cells and lymphoid
    infiltrates can be found
  • Thymectomy
  • Its effectiveness is uncertain
  • It is performed in the presence of thymoma

Anti-AChR positive generalized MG
Early-onset Thymoma associated Late-onset
Age of onset lt 50 years 40-60 years (in most cases) 50 years
MF 14 11 1.71
Thymic pathology hyperplasia AB,B thymoma no
anti-titin Abs uncommon 70-90 gt50
anti-RyR Abs uncommon 50-75 30-40
Remarkable variability of weakness extension and
Two peak ages of onset
  • High frequency of thymus pathology
  • hyperplasia in 60-70 of EOMG cases
  • thymoma in 10-15 of MG patients
  • Other auto-antibodies
  • anti-thyroid Abs in early-onset MG
  • Anti-muscle abs in late-onset and thymoma MG

Antibody status in myasthenia gravis
  • Anti-AChR antibodies are present
  • in 85-90 of patients with generalized MG
    (nearly 100 thymoma cases)
  • 50 of patients with ocular myasthenia
  • Anti-AChR negative MG includes
  • - MG with anti-MuSK Abs which is a
    distinct disease entity
  • - seronegative MG - SNMG (with no Abs on the
    standard assays)
  • SNMG appears to belong to the same spectrum as
  • ocular or generalized
  • often associated with thymus hyperplasia

Anti-MuSK positive myasthenia gravis
  • MuSK (muscle-specific protein kinase)
  • is a component of agrin-receptor
  • interacts with agrin and rapsyn
  • is required to cluster AChRs both in the
    embryonic and adult muscle

Region Extra-cellular
Anti-MuSK positive myasthenia gravis
  • Antibodies to MuSK are typically found in
    generalized disease, with prevalent involvement
    of facial and oro-pharyngeal muscles
  • More rarely, these Abs are associated with more
    focal weakness mainly involving neck, laryngeal
    and respiratory muscles
  • Anti-MuSK MG differs from the anti-AChR disease
  • weakness fluctuations are uncommon
  • the response to AChE-I is frequently
  • thymus alterations are very uncommon and
    thymectomy does not seem to improve the course of
    the disease.

Myasthenia gravis clinical forms
Anti-AChR positive Anti-AChR positive Anti-AChR positive Anti-AChR positive Anti-AChR negative Anti-AChR negative
Early-onset Thymoma Late-onset Seronegative MuSK-MG
Weakness extension Ocular Generalized Generalized (mostly) Generalized Ocular or generalized Generalized
Age of onset Any lt 50 years 40-60 yrs (mostly) gt 50 yrs Any Any
MF 1.51 14 11 1.51 12 14.5
Thymus Pathology - Hyperplasia AB, B thymomas - Hyperplasia (35-50) -
Ocular myasthenia
  • extrinsic ocular muscles are commonly affected,
    both at the onset and in the subsequent disease
  • only in a minority of patients the disease
    remains confined to ocular muscles
  • in most cases, generally within 2 years from the
    onset, the disease becomes generalized

Generalized MG
  • Treatment is aimed at
  • relieving symptoms
  • preventing generalization

Generalized MG
Generalized myasthenia gravis
  • Ocular, facial, oro-pharyngeal, axial and limb
    muscles can be variably affected in different
  • bulbar and axial muscles are prevalently
    affected in late-onset MG
  • limb muscle involvement is more typical of the
    early-onset disease
  • Respiratory crises requiring assisted ventilation
    are less frequent, thanks to the early use of
    immunosuppressive therapy

MGFA Classification
(Jaretzki, 2000)
Group I Ocular myasthenia
Group II Mild myasthenia
IIa Prevalent on limb and axial muscles
IIb Prevalent on bulbar muscles
Group III Moderate myasthenia
Group IV Severe myasthenia
Group V Respiratory crisis
The extent and progression of MG are important
parameters related to treatment choices
Ossermans classification Ossermans classification
Group 1 Ocular myasthenia
Group 2A Mild generalized
Group 2B Moderate generalized
Group 3 Acute severe generalized
Group 4 Late severe generalized
MGFA clinical classification
Grade I Ocular
Grade II Mild weakness prevalent on limb (IIa) or bulbar muscles (IIb)
Grade III Moderate (IIIa/IIIb)
Grade IV Severe (IVa/IVb fed by a nasogastric tube)
Grade V Respiratory crisis
Jaretzki, 2000
Maximum disease severity
Patients treated between 1998 and 2008
Myasthenia gravis Current treatment
  • Symptomatic therapy
  • Acetyl-Cholinesterase Inhibitors (piridostigmine
    - Mestinon
  • Increase ACh availability
  • Thymectomy
  • In patients with thymic hyperplasia
  • Removes the possible site of auto-sensitization
    against AChR and a relevant site of anti-AChR
    antibody production
  • In patients with thymoma
  • Removes a potentially invasive tumor
  • Immunosuppressive therapy
  • Inhibits lymphocyte proliferation and antibody
  • Short-term treatments
  • Plasma-exchange
  • Removes serum antibodies and cytokines
  • IVIG
  • Interferes with antibody production and activity

Myasthenia gravis General principles of treatment
  • Chronic autoimmune disease
  • indication for immunosoppressive therapy (IS)
  • IS therapy has changed both the prognosis and
    history of MG
  • However, IS therapy is not performed in all
  • Spontaneous remission in 10-20
  • Mild clinical forms
  • Remission induced by thymectomy

It modifies the disease course
Myasthenia gravisSymptomatic treatment with
  • First-line treatment
  • Although generally effective, AChE-Is provide a
    stable disease control in a minority of patients
  • In patients with anti-MuSK Abs AChE-Is are
    generally scarcely effective and may even worsen
  • Individual response is variable
  • Muscarinic/nicotinic side effects
  • Overmedication can be responsible for cholinergic

AChE-Is do not interfere with antibody synthesis
Myasthenia Gravis - Thymectomy
  • In patients with thymoma
  • In generalized early-onset anti-AChR MG
  • Positive results in 78-87 of cases, with a
    significantly increased remission rate
  • The indication for thymectomy is controversial
  • infantile MG (minimum age for thymectomy)
  • late-onset MG (maximum age for thymectomy)
  • ocular myasthenia
  • anti-AChR negative MG (especially in patients
    with anti-MuSK Abs)

Thymectomy requires a stable control of MG
Immunosuppressive therapy
  • Performed in 70-80 of patients
  • Indicated in the presence of disabling weakness,
    when AChE-Is fail to control symptoms, in
    association or as an alternative to thymectomy
  • Effective in gt 80 of cases
  • It has markedly improved the disease outcome
  • Main disadvantages
  • Unspecific
  • Need for prolonged therapy (relapses at
    treatment tapering or withdrawal)
  • Potentially serious side effects

Immunosuppressive therapy
  • Corticosteroids
  • Prednisone, Prednisolone
  • Cytostatic drugs
  • Azathioprine, Mycophenolate mofetil,
    Cyclosphosphamide, Methotrexate
  • Calcineurine Inhibitors
  • Cyclosporine A, Tacrolimus
  • Rituximab

Which immunosuppressive therapy and why?
  • The treatment approach is determined by
  • severity, distribution and rate of weakness
  • disease characteristics
  • patient characteristics (age, lifestyle,
    associated conditions)
  • The initial goal of therapy is to reduce weakness
    as much as and as quickly as possible, especially
    when oropharyngeal and respiratory muscles are
  • Thereafter the major goal is to reduce
    medications to the least amount that maintains
    the maximal benefit (satisfactory control of

Corticosteroids are generally the first treatment
owing to their rapid-onset effect For long-term
therapy, combined treatment is preferred to
reduce medications
Immunosuppressive therapy - Corticosteroids
  • In patients with ocular myasthenia low-dose
    prednisone is the first-line treatment
  • In generalized MG treatment
  • Corticosteroids are commonly used as initial
  • Prednisone 0.8-1.5mg/kg/die gradual shift to
    alternate day treatment progressive dose
  • Steroid treatment can induce an early
    deterioration of MG that can be prevented or
    effectively treated with P-E/IVIG
  • In long-term treatment side effects are quite

In patients who need high maintenance doses the
association of a steroid-sparing
immunosuppressant is recommended
Immunosuppressive drugs
  • Different class of immunosuppressants are
    currently used in MG
  • These drugs produce marked, sustained improvement
    in most patients, including many who have not
    responded well to steroids or thymectomy.
  • Disadvantages include
  • delayed onset of improvement
  • potential severe side-effects

Immunosuppressants can be used in monotherapy or
with prednisone The combined treatment is
associated with better therapeutic results and a
reduced rate of side effects
Immunosuppressive drugs
  • Azathioprine (1st choice)
  • initial dose 2.5-3 mg /Kg/daily
  • maintenance dose 1 mg/Kg
  • Cyclosporine A
  • initial dose 3-5 mg /Kg/daily
  • maintenance dose 2-3 mg/Kg/die
  • Mycophenolate mofetil
  • 2-2.5 g/daily
  • Tacrolimus
  • initial dose 3-4 mg/day
  • maintenance dose 1-2 mg/day
  • Cyclophosphamide (same doses as azathioprine)

Emerging immunosuppressive therapies
  • Rituximab, a monoclonal antibody which depletes B
  • 375mg/m2 i.v. on a weekly schedule for 4 weeks
  • 1 gr in 2 infusions with an interval of 2 weeks
  • In small series and case reports, rituximab
    appears to be effective in anti-AChR and
    anti-MuSK-positive MG
  • Future developments of specific immunotherapy for
    myasthenia gravis may be effective through
  • increasing immune regulatory mechanisms
  • inducing specific tolerance
  • targeting antigen-specific B and T lymphocytes

Short-term treatments
  • Plasma-exchange (P-E)
  • Therapeutic protocol 3-6 exchanges on alternate
  • effective in 90 of cases
  • short latency
  • Intravenous immunoglobulin (IVIG)
  • Therapeutic protocol 2 g/kg in 2/5 days
  • effective in 80 of cases
  • longer latency (compared to P-E)
  • P-E and IVIG are used in
  • treating exacerbation phases
  • preparation for thymectomy
  • Their effect is temporary and their use does not
    replace pharmacological immunosuppressive therapy

Ocular myasthenia
Unsatisfactory response
Diagnosis of thymoma
Prednisone (25-50mg e.o.d.)
Progressive dose reduction to the minimum
effective dose or withdrawal
Unsatisfactory response or (more commonly) high
maintenance doses
Consider the association with immunosuppressants
Generalized myasthenia
mild MG indication for thymectomy (thymoma,
early-onset MG)
Satisfactory control of symptoms
ACHE- Is, thymectomy
Disabling symptoms
IS therapy
moderate/severe MG indication for thymectomy
ACHE-Is, IS therapy plasma- exchange, IVIG
IS therapy
When thymectomy is not indicated (late-onset
ACHE-Is in patients with mild disease IS therapy
in cases with disabling symptoms
Plasma-exchange, IVIG in treating disease
Considerations on MG treatment
  • Myasthenia gravis is one of the best treatable
    conditions and, though current treatment has
    limitations, it has greatly improved the course
    of the disease.
  • However, treatment is often long-term and
    entails the risk of side effects. Consequently, a
    constant cooperation between the patient and
    his/her neurologist is required.
  • The main goal of therapy is to induce remission.
    But MG is a markedly heterogeneous disease and
    many factors can influence the response to
  • A good control of the disease with no/minor side
    effects is undoubtedly a therapeutic success.

Hellenic Myasthenia Gravis Association (HMGA)