Myasthenia Gravis

Essentials of Diagnosis

• Fluctuating weakness of voluntary muscles, producing symptoms such as

  • Diplopia

  • Ptosis

  • Difficulty in swallowing

• Activity increases weakness of affected muscles

• Short-acting anticholinesterases transiently improve the weakness

General Considerations

• Occurs at all ages, sometimes in association with

  • Thymic tumor

  • Thyrotoxicosis

  • Rheumatoid arthritis

  • Lupus erythematosus

• Onset is usually insidious, but the disorder is sometimes unmasked by a coincidental infection

• Exacerbations may occur before the menstrual period and during or shortly after pregnancy

• Symptoms are due to blocks of neuromuscular transmission caused by autoantibodies binding to acetylcholine receptors

• The external ocular muscles and certain other cranial muscles, including the masticatory, facial, and pharyngeal muscles, are especially likely to be affected

• The respiratory and limb muscles may also be involved

Demographics

• Most common in young women with HLA-DR3

• If thymoma is associated, older men are more commonly affected

Symptoms and Signs

• Initial symptoms

  • Ptosis

  • Diplopia

  • Difficulty in chewing or swallowing

  • Respiratory difficulties

  • Limb weakness

  • Some combination of these problems

• Weakness

  • May remain localized to a few muscle groups, especially the ocular muscles

  • May become generalized

• Symptoms often fluctuate in intensity during the day

• This diurnal variation is superimposed on a tendency to longer-term spontaneous relapses and remissions that may last for weeks

• Clinical examination confirms the weakness and fatigability of affected muscles

• Extraocular palsies and ptosis, often asymmetric, are common

• Pupillary responses are normal

• The bulbar and limb muscles are often weak, but the pattern of involvement is variable

• Sustained activity of affected muscles increases the weakness, which improves after a brief rest

• Sensation is normal

• Usually no reflex changes

Differential Diagnosis

• Lambert-Eaton myasthenic syndrome (usually paraneoplastic)

• Botulism

• Aminoglycoside-induced neuromuscular weakness

Laboratory Tests

• Elevated level of serum acetylcholine receptor antibodies has a sensitivity of 80–90%

• Certain patients have serum antibodies to muscle-specific tyrosine kinase (MuSK), which should be determined

  • These patients are more likely to have facial, respiratory and proximal muscle weakness than those with antibodies to acetylcholine receptors

• Other associated antibodies

  • Low-density lipoprotein receptor-related protein 4 (LRP4)

  • Agrin

  • Tests for these antibodies are not widely commercially available

Imaging Studies

• CT scan of the chest with and without contrast

  • Should be obtained to demonstrate a coexisting thymoma

  • However, normal studies do not exclude this possibility

Diagnostic Procedures

• Electrophysiology

  • Demonstration of a decrementing muscle response to repetitive 2- or 3-Hz stimulation of motor nerves indicates a disturbance of neuromuscular transmission

  • Such an abnormality may even be detected in clinically strong muscles with certain provocative procedures

• Needle electromyography

  • Shows a marked variation in configuration and size of individual motor unit potentials in affected muscles

  • Single-fiber electromyography reveals an increased jitter, or variability, in the time interval between two muscle fiber action potentials from the same motor unit

Medications

• Drugs, such as aminoglycosides, that may exacerbate myasthenia gravis should be avoided

• Anticholinesterase drugs provide symptomatic benefit without influencing the course of the disease

• Neostigmine, pyridostigmine, or both can be used

  • Dose is determined on an individual basis

  • Usual dose of neostigmine, 7.5–30 mg four times daily orally (average, 15 mg)

  • Usual dose of pyridostigmine, 30–180 mg four times daily orally (average, 60 mg)

  • Overmedication may temporarily increase weakness

• Corticosteroids

  • Indicated if there has been a poor response to anticholinesterase drugs

  • Start while the patient is in the hospital, since weakness may initially be aggravated

  • Prednisone can be started at 20 mg orally daily and increased by 10 mg increments weekly to a target of 1 mg/kg/day (maximum daily dose 100 mg)

  • For patients who are hospitalized with severe myasthenia and are receiving intravenous immunoglobulin or plasmapheresis, 1 mg/kg/day (maximum daily dose 100 mg) of prednisone can be given initially because the more rapid onset of action of immunoglobulin or plasmapheresis mitigates the initial dip in strength due to corticosteroids

  • Once patient is stabilized at the initial high dose, corticosteroids can gradually be tapered to a relatively low maintenance level (eg, 10 mg prednisone orally daily) as improvement occurs; total withdrawal is difficult, however

  • Can be prescribed as alternate-day or daily treatment, with alternate-day therapy potentially mitigating side effects

• Azathioprine

  • May be effective in allowing a lower dose of corticosteroids

  • Usual dose, 2–3 mg/kg/day orally after a lower initial dose

  • Other immunosuppressive agents that are used to reduce the corticosteroid dose include

  • Mycophenolate mofetil

  • Rituximab

  • Cyclosporine

  • Methotrexate

  • Tacrolimus

• Plasmapheresis or intravenous immunoglobulin therapy

  • May be helpful in patients with major disability

  • May also be useful for stabilizing patients before thymectomy and for managing acute crisis

  • Have similar efficacy

• Eculizumab, a complement inhibitor

  • Approved by the FDA for disease refractory to at least two alternate immunosuppressive therapies

  • Dosage: 900 mg intravenously weekly for 4 doses, followed by 1200 mg at week 5, then 1200 mg every 2 weeks

  • Vaccination against meningococcus is required prior to receiving eculizumab

Surgery

• Thymectomy

  • Usually leads to symptomatic benefit or remission

  • Should be considered in all patients younger than age 65, unless weakness is restricted to the extraocular muscles

• If the disease is of recent onset and only slowly progressive, operation is sometimes delayed for a year or so, in the hope that spontaneous remission will occur

Complications

• Aspiration pneumonia

• Life-threatening exacerbations of myasthenia (so-called myasthenic crisis) may lead to respiratory weakness requiring immediate admission to the intensive care unit

Prognosis

• The disorder follows a slowly progressive course and may have a fatal outcome owing to respiratory complications such as aspiration pneumonia

When to Refer

• All patients

When to Admit

• Patients with acute exacerbation or respiratory involvement

• Patients requiring plasmapheresis

• For thymectomy