Myasthenia Gravis

Myasthenia gravis (MG) is a relatively rare autoimmune disorder in which

antibodies form against acetylcholine nicotinic postsynaptic receptors at the
neuromuscular junction of skeletal muscles (see the image below). MG is
sometimes identified as having an ocular and generalized form, although one
is not exclusive of the other and the ocular form is considered an initial,
milder form of illness that progresses to the more severe generalized form in
most but not all patients.

Causes and Risk Factors for Myasthenia Gravis

MG usually is caused by a malfunction of the immune system. The causative

factor is unknown, but the disorder may have a genetic link. Causes include
a genetic defect, which results in congenital MG, and the circulation of
maternal antibodies through the placenta, which result in transient neonatal
MG.
Acetylcholine (ACh) is a neurotransmitter that is involved in the transfer of
information to muscle tissue. In myasthenia gravis, cells that bind to other
cells to neutralize or destroy them (called antibodies) destroy acetylcholine
receptor sites (AChR) in areas of muscle tissue that receive nerve impulses
(called neuromuscular junctions), preventing nerve impulses from reaching
the muscles. This results in weakness and rapid fatigue in affected muscles.
MG may be associated with other autoimmune diseases. Patients with family
members who suffer from disorders such as rheumatoid arthritis,
scleroderma, and lupus may have an increased risk for myasthenia gravis.
The thymus is an organ that produces cells involved in immune responses. It
is located below the larynx and above the heart. Approximately 15 percent of
MG patients have a tumor of the thymus (thymoma) and 6080 percent have
abnormal enlargement (hyperplasia) of the thymus

Signs and symptoms

The presentation of MG has the following characteristics:

The usual initial complaint is a specific muscle weakness rather than

generalized weakness
Extraocular muscle weakness or ptosis is present initially in 50% of
patients and occurs during the course of illness in 90%
The disease remains exclusively ocular in only 16% of patients
Rarely, patients have generalized weakness without ocular muscle
weakness
Bulbar muscle weakness is also common, along with weakness of head
extension and flexion
Limb weakness may be more severe proximally than distally
Isolated limb muscle weakness is the presenting symptom in fewer
than 10% of patients
Weakness is typically least severe in the morning and worsens as the
day progresses
Weakness is increased by exertion and alleviated by rest
Weakness progresses from mild to more severe over weeks or months,
with exacerbations and remissions
Weakness tends to spread from the ocular to facial to bulbar muscles
and then to truncal and limb muscles
About 87% of patients have generalized disease within 13 months after
onset
Less often, symptoms may remain limited to the extraocular and eyelid
muscles for years
The following factors may trigger or worsen exacerbations:
Bright sunlight
Surgery
Immunization
Emotional stress
Menstruation
Intercurrent illness (eg, viral infection)
Medication (eg, aminoglycosides, ciprofloxacin, chloroquine, procaine,
lithium, phenytoin, beta-blockers, procainamide, statins)

Classifications
The Myasthenia Gravis Foundation of America Clinical Classification divides
MG into 5 main classes and several subclasses:

Class I: Any ocular muscle weakness; may have weakness of eye

closure; all other muscle strength is normal
Class II: Mild weakness affecting other than ocular muscles; may also
have ocular muscle weakness of any severity

Class IIa: Predominantly affecting limb, axial muscles, or both; may

also have lesser involvement of oropharyngeal muscles
Class IIb: Predominantly affecting oropharyngeal, respiratory muscles,
or both; may also have lesser or equal involvement of limb, axial muscles,
or both
Class III: Moderate weakness affecting other than ocular muscles;
may also have ocular muscle weakness of any severity
Class IIIa: Predominantly affecting limb, axial muscles, or both; may
also have lesser involvement of oropharyngeal muscles
Class IIIb: Predominantly affecting oropharyngeal, respiratory
muscles, or both; may also have lesser or equal involvement of limb, axial
muscles, or both
Class IV: Severe weakness affecting other than ocular muscles; may
also have ocular muscle weakness of any severity
Class IVa: Predominantly affecting limb, axial muscles, or both; may
also have lesser involvement of oropharyngeal muscles
Class IVb: Predominantly affecting oropharyngeal, respiratory
muscles, or both; may also have lesser or equal involvement of limb, axial
muscles, or both; use of a feeding tube without intubation
Class V: Defined by the need for intubation, with or without
mechanical ventilation, except when used during routine postoperative
management

Diagnosis
The antiacetylcholine receptor (AChR) antibody test for diagnosing MG has
the following characteristics:

High specificity (up to 100%)

Positive in as many as 90% of patients who have generalized MG
Positive in only 50-70% of patients who have purely ocular MG
False-positive anti-AChR antibody test results have been reported in patients
with the following:

Thymoma without MG
Lambert-Eaton myasthenic syndrome
Small cell lung cancer
Rheumatoid arthritis treated with penicillamine
1-3% of the population older than 70 years
Assays for the following antibodies may also be useful:

Anti-MuSK antibody (present in about half of patients with negative

results for anti-AChR antibody)
Anti-lipoprotein-related protein 4 (LRP4) antibody
Anti-agrin antibody
Antistriational antibody (present in almost all patients with thymoma
and MG, as well as in half of MG patients with onset of MG at 50 years or
older)
Other studies are as follows:

Plain chest radiographs may identify a thymoma as an anterior

mediastinal mass
Chest computed tomography is important to identify or rule out
thymoma or thymic enlargement in all cases of MG
In strictly ocular MG, magnetic resonance imaging of the brain and
orbit is helpful to evaluate for mass lesions compressing the cranial nerves
or a brainstem lesion that may masquerade as ocular MG
Electrodiagnostic studies (repetitive nerve stimulation and single-fiber
electromyography)

Management
With recent advances in understanding the various underlying antibodies
that cause myasthenia gravis and differences in how they present clinically
and respond to various therapies, it is suggested that patients with
myasthenia gravis should be classified into subgroups. Subgroups based on
serum antibodies and clinical features may include early-onset, late-onset,
and patients with thymoma, MuSK, LRP4, antibody-negative, and ocular
forms of myasthenia gravis.
Therapy for MG includes the following:

Anticholinesterase (AchE) inhibitors

Immunomodulating agents
Intravenous immune globulin (IVIg)
Plasmapheresis
Thymectomy
Initial treatment for mild MG
Pyridostigmine is used for maintenance therapy
Neostigmine is generally used only when pyridostigmine is unavailable
Corticosteroid therapy provides a short-term benefit

Azathioprine, usually after a dose of corticosteroids, is the mainstay of

therapy for difficult cases
Cyclosporine A and occasionally methotrexate and cyclophosphamide
are used for severe cases
Moderate or severe MG worsening into crisis (no value in mild disease)
Elderly patients
Patients with complex comorbid diseases (eg, acute respiratory failure)
Patients with severe weakness poorly controlled with other agents
Plasmapheresis- generally reserved for myasthenic crisis and
refractory cases
Also effective in preparation for surgery
Improvement is noted in a couple of days, but does not last for more
than 2 months
Can be used long-term on a regular weekly or monthly basis can be
used if other treatments cannot control the disease
Thymectomy

The standard of care for all patients with thymoma and for patients
aged 10-55 years without thymoma but with generalized MG
Proposed as a first-line therapy in most patients with generalized
myasthenia
In ocular MG, should be delayed at least 2 years to allow for
spontaneous remission
Not recommended in patients with antibodies to muscle-specific kinase
(MuSK)
Controversial in prepubescent patients and, to a lesser extent, patients
older than 55 years