BASICS

DESCRIPTION

• Myasthenia gravis (MG) is the most common disorder of the neuromuscular junction. MG causes painless, variable, fatigable muscle weakness. Weakness can involve ocular, bulbar, limb, and respiratory muscles. Extraocular muscles are most commonly affected and patients often present with ptosis and/or diplopia.

• MG is the best characterized autoimmune disease.

• 2 clinical forms of MG:

– Ocular MG (15%): Weakness is limited to the eyelids and extraocular muscles

– Generalized MG (85%): Variable involvement of bulbar, limb, and respiratory muscles as well

• 2 serological forms of MG:

– Seropositive: Patients have detectable antibodies to the acetylcholine receptor (AChR) or to the muscle-specific receptor tyrosine kinase (MuSK).

– Seronegative: Patients do not have detectable antibody levels

50% of patients with ocular myasthenia are seropositive.

90% of patients with generalized myasthenia are seropositive

• The thymus is abnormal in most patients with MG.

EPIDEMIOLOGY

• Occurs at any age

• Bimodal distribution:

– Early peak (40%) in the second and third decades.

– Female:Male ratio is 2:1.

– Late peak (60%) in the sixth to eighth decades.

Female:Male ratio is 1:2

Incidence

30 new cases per million (1)

Prevalence

• 15 per 100,000 in the US

• Approximately 60,000 patients with MG in the US

• Prevalence of MG has increased over the past 50 years

RISK FACTORS

• Familial MG

• Factors that worsen MG symptoms include stress, heat, infection, thyroid disease, pregnancy, menstruation, fever, and drugs.

– Consider annual vaccination against influenza for MG patients.

Genetics

• No known Mendelian inheritance of MG

• Family members of patients with MG are 1,000 times more likely to develop the disease than is the general population.

• Transient neonatal MG seen in 10–20% of infants born to myasthenic mothers.

– Transplacental passage of anti-AChR antibodies

– Resolution in weeks to months

GENERAL PREVENTION

• Drugs may unmask or exacerbate MG

– Aminoglycoside antibiotics and penicillamine

– Statin treatment may be associated with a myasthenic syndrome or exacerbation of myasthenia symptoms.

PATHOPHYSIOLOGY

• Circulating anti-AChR antibodies (80%)

– Antibodies bind to the AChR of junctional folds, cause complement-mediated destruction of the folds; results in “simplification” of postsynaptic region.

• Circulating anti-MuSK antibodies (10%)

– MuSK-positive patients more likely to have early bulbar and respiratory symptoms

– Women more commonly affected

• Seronegative patients clinically similar to patients with AChR antibodies

ETIOLOGY

• Thymus plays important role in early-onset MG associated with anti-AChR antibodies.

– Gland enlarged with lymphocytic infiltrates, germinal centers, and myoid cells which express AChRs

COMMONLY ASSOCIATED CONDITIONS

• Thymus abnormal in most patients with MG:

– Lymphoid follicular hyperplasia in 70%

– Thymoma present in to 10–15% of patients with MG

Most thymic tumors in patients with MG are benign

The peak incidence occurs in the fourth to sixth decades, with no sex predilection

• Autoimmune thyroid disease (8% of MG patients)

DIAGNOSIS

HISTORY

• Patients with MG complain of muscle weakness

– In most patients, ptosis or diplopia is the initial symptom.

– Difficulty chewing, swallowing, or talking.

– Patients may complain of choking or coughing after eating, escape of liquids through the nose when swallowing

– Voice may become nasal or hoarse

– Limb weakness

– Respiratory dysfunction is rarely the presenting symptom of MG

• Weakness usually fluctuates, worsening at the end of the day or with prolonged use of the muscles

• Sensory complaints not typical of MG

PHYSICAL EXAM

• Ptosis

– Unilateral or bilateral

– Often fatigable

– Can be demonstrated by observing progressive ptosis during sustained upgaze

– Patients often compensate for ptosis by using their frontalis muscle

– Cold applied to the eyelid may improve ptosis (“ice-pack test”)

– With rapid shift from downgaze to upgaze, may see excessive lid elevation, followed by drooping (Cogan’s lid twitch sign)

• Ocular motility limitations

– Asymmetric weakness of several muscles in both eyes typical

– Medial rectus muscle often involved (“pseudo INO”)

– Pupil is not involved

• Weak orbicularis oculi

– Examiner can easily pry open forcibly closed eyelids

– When the patient tries to keep the eyes closed, slight involuntary opening may occur (“peek sign”)

• Examiner may be able to manually open the jaw against resistance.

DIAGNOSTIC TESTS & INTERPRETATION

Lab

• Anti-AChR antibodies

– Binding (sufficient in most cases), blocking, and modulating antibodies can be assayed.

– 80–85% of all patients with MG seropositive

Generalized MG: 85% (2)[C]

Ocular MG: 50%

MG and thymoma: Almost 100%

• Anti-MuSK antibodies

– Present in up to 50% of generalized MG patients seronegative for anti-AChR antibodies; absent in ocular MG

• Thyroid function tests

• Thyroid antibody test

Imaging

• CT or MRI of anterior mediastinum

– Thymoma

Diagnostic Procedures/Other

• Ice test frequently performed in office with improvement of ptosis 2+ mm highly suggestive for MG.

• Edrophonium chloride (Tensilon) test

– Acetylcholinesterase inhibitor

– Allows ACh to interact longer with postsynaptic membrane, resulting in greater end-plate depolarization

– Examiner looks for transient improvement in muscle strength (e.g., resolution of ptosis)

– Initial dose 2 mg IV, can be followed by another 2 mg every 1 minute up to maximum of 10 mg

– Sensitivity 80–90%

– Atropine must be available during the edrophonium test.

– Patients should avoid taking oral anticholinesterase inhibitors for 24 hours prior to the test.

– With availability of serologic tests, edrophonium test is rarely performed.

• Neurophysiological tests

– Routine EMG is not helpful in ocular MG

– Repetitive nerve stimulation (RNS) has a sensitivity of about 55%.

– Single-fiber EMG is more sensitive (90–95%), but less specific than RNS.

Pathological Findings

• Muscle electron microscopy

– “Simplification” of postsynaptic region

• Immunofluorescence

– IgG antibodies and complement on receptor membranes

DIFFERENTIAL DIAGNOSIS

• Conditions that mimic ocular MG:

– Chronic progressive external ophthalmoplegia

– Myotonic dystrophy

– Cranial neuropathies

– Guillain Barré Syndrome (Fisher variant)

– Thyroid ophthalmopathy

• Conditions that mimic generalized MG:

– Amyotrophic lateral sclerosis (ALS)

– Lambert-Eaton myasthenic syndrome

– Botulism

TREATMENT

MEDICATION

First Line

• Controlled clinical trials for any treatment of MG are rare.

• Acetylcholinesterase inhibitors

– No placebo-controlled randomized studies

– May provide symptomatic relief

– Short half-lives necessitate frequent dosing

– Side effects include diarrhea, sweating, salivation, and tearing

– Rarely effective for ocular MG

– Pyridostigmine bromide (Mestinon)

– Available as 60 mg tablet, 180 mg sustained-release tablet, and 60 mg/5 mL syrup

– Initial dose in adults is 30 mg t.i.d.

– Increase dose in 30 mg increments as needed, to maximum 120 mg q3–4 h

– Neostigmine methylsulfate (Prostigmin)

Available in 0.25, 0.5, and 1 mg/mL concentrations

Initial dose 0.5 mg subcutaneously or IM q3h

• Corticosteroids

– Limited evidence from randomized controlled trials (3)[A]

– Marked improvement in over 75% of MG patients

– Ptosis and ophthalmoparesis usually respond only to immunosuppression

– Early use of steroids in ocular MG may prevent generalization (4)[C]

– Prednisone

Initial dose 60–80 mg/d PO

Taper very slowly

Switch to alternate day regimen within 2 weeks

May also start at 20 mg/d and gradually increase dose

Second Line

• Azathioprine: 100–200 mg/d PO

– Most commonly used second line immunomodulator

– Side effects include hepatotoxicity, cytopenia, and lymphoproliferative disease.

– Regular monitoring of complete blood count, liver function tests, and renal function tests

• Mycophenolate mofetil: 1 g PO or IV b.i.d.

– Selectively inhibits proliferation of activated B and T lymphocytes

ADDITIONAL TREATMENT

General Measures

• Assistive devices

– Ptosis “crutches” and lid adhesives are usually not well tolerated

– An eye patch or lens occluder eliminates diplopia

– Prism is helpful only if the ocular misalignment is stable

Issues for Referral

Because of the likelihood of generalization and complexity of management, patients with MG should be followed by a neurologist.

SURGERY/OTHER PROCEDURES

• Thymoma

– Surgery with or without radiotherapy

– Value of thymectomy in patients without thymoma unclear

No randomized trials to date

In general, thymectomy is offered to younger (under age 60) anti-AChR antibody-positive patients with generalized MG.

• Neuromuscular blocking agents should be avoided by anesthesiologists.

IN-PATIENT CONSIDERATIONS

Admission Criteria

• Plasmapheresis

• IVIG

• Pulmonary infections

• Myasthenic or cholinergic crises

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