Myasthenia Gravis

General Principles

Definition

Myasthenia gravis (MG) is an autoimmune disorder that involves antibody-mediated postsynaptic dysfunction of the neuromuscular junction of skeletal muscle resulting in fatigable weakness.

Classification

  • Generalized disease is most common and affects a variable combination of ocular, bulbar, respiratory, and appendicular muscles.
  • Ocular MG is confined to eyelid and oculomotor function. It accounts for 10%–40% of all MG cases.

Epidemiology

Bimodal distribution with peak incidence in women in the second and third decades and in men in the sixth and seventh decades.

Pathophysiology

MG is an acquired autoimmune disorder resulting from the production of autoantibodies against the postsynaptic acetylcholine receptor (AChR) or, less commonly, against receptor-associated proteins, including muscle-specific receptor tyrosine kinase (MuSK) or low-density lipoprotein receptor-related protein 4. However, despite the identification of these additional antigens, “seronegative” forms still account for up to 10% of MG patients.

Associated Conditions

  • MG is often associated with thymus hyperplasia; 10% may have a malignant thymoma. Hyperplasia is more common in those younger than 40 years. Thymoma is more common in MG patients older than 30 years.
  • Autoimmune thyroiditis (hyper- more common than hypo-) is present in approximately 15% of patients with MG. MG patients also have an increased risk of other autoimmune diseases including lupus, rheumatoid arthritis, polymyositis, and pernicious anemia.

Diagnosis

Clinical Presentation

History

  • The cardinal feature of MG is fluctuating weakness that is worse after exercise or prolonged activity and improves with rest.
  • More than 50% of patients present with ptosis that may be asymmetric.
  • Other common complaints include blurred vision or diplopia, trouble smiling, and difficulties with chewing, swallowing, and speaking (e.g., winded at end of sentences, “staccato” [interrupted] speech, nasal speech, or weak voice).
  • Weakness of neck flexors and extensors and proximal arm weakness are common. MG is one of the few neuromuscular disorders to cause prominent neck extensor weakness, creating a “head drop.”
  • Myasthenic crisis consists of respiratory failure or the need for airway protection and occurs in approximately 15%–20% of MG patients.1 Patients with bulbar and respiratory muscle weakness are particularly prone to respiratory failure, which may develop rapidly and unexpectedly.
  • Respiratory infection, surgery (e.g., thymectomy), medications (e.g., aminoglycosides, quinine, quinolones, β-blockers, lithium, magnesium sulfate), pregnancy, and thyroid dysfunction can precipitate crisis or exacerbate symptoms. However, it is important to note that none of these medications should be withheld if required to treat a concurrent illness. Anticholinergic medications are a notable exception to this rule for obvious reasons, and in the absence of a life-threatening indication, their use should be avoided.

Physical Examination

  • Presenting signs include ptosis, diplopia, dysarthria, dysphagia, extremity weakness, and respiratory difficulty.
  • Fatigability on examination is a useful diagnostic feature.
  • Ptosis may worsen after prolonged upward gaze (usually by 60 seconds). Patients may also begin to develop diplopia after sustained gaze in one direction.
  • Carefully evaluate the airway, handling of secretions, ventilation, and the work of breathing.
  • NIF and FVC are useful at the bedside to assess for respiratory muscle weakness. The breath count test described earlier in the GBS section is also useful in this population. The same general rules for ventilatory support (i.e., inability to protect airway or ventilate adequately) apply.

Differential Diagnosis

  • Lambert–Eaton myasthenic syndrome (LEMS) is an autoimmune disease affecting the presynaptic voltage-gated calcium channels of the neuromuscular junction. It is frequently associated with malignancy (small-cell lung cancer). LEMS also presents with fluctuating weakness, but improves with exercise. Weakness in LEMS is classically more prominent in the legs relative to the arms, and unlike MG, oculobulbar deficits are uncommon. A quick bedside examination finding that may be present is to evaluate for facilitation of reflexes that are absent or diminished at rest but present or increased after 10 seconds of isometric exercise.
  • Amyotrophic lateral sclerosis (ALS) may present with bulbar weakness and a “head drop.” However, ALS can be differentiated from MG by presence of upper motor neuron signs in the former. Electrodiagnostic studies are also very useful in distinguishing the two.
  • The differential also includes botulism (covered in more detail below), congenital forms of myasthenia, mitochondrial disorders (e.g., chronic progressive external ophthalmoplegia), and acquired and hereditary myopathies or other motor neuronopathies (other than ALS).

Diagnostic Testing

A good rule of thumb is to have two lines of diagnostic evidence (usually serologic and electrodiagnostic) in the appropriate clinical context to make a diagnosis of autoimmune MG.

Laboratory Studies

  • Serum AChR binding antibodies are detected in 85%–90% of adult generalized MG patients and in 50%–70% of ocular MG patients.
  • MuSK antibodies are detected in about 30%–70% of AChR antibody–negative MG patients.
  • Thyroid function should be checked to evaluate for autoimmune thyroiditis.

Imaging

Chest CT is indicated to screen for a thymoma.

Diagnostic Procedures

Electrodiagnostic studies are an important step in diagnosing MG.

  • Myasthenic weakness is often improved by cold. Although the history obtained from the patient may suggest this phenomenon, the “ice pack test” is an easy and safe, objective “bedside” measure of this phenomenon and is often helpful in the evaluation of ocular MG. Repetitive nerve stimulation typically shows a decrement in the amplitude of the compound muscle action potential in MG. If the patient is taking pyridostigmine, it should be held (if possible) because it could mask a decrement.
  • In LEMS, the response is incremental.
  • Single-fiber EMG has a sensitivity of >95% for both generalized and ocular MG when performed on facial muscles.
  • Edrophonium testing is no longer routinely used.

Treatment

  • Treatment of MG is individualized and depends on the severity of the disease, age, comorbidities, and response to therapy.
  • Myasthenic crisis requires prompt recognition and aggressive support.
    • Consider ICU level care and elective intubation for FVC <20 mL/kg or NIF >−30 cm H2O (similar parameters to the “20/30” rule used for GBS).
    • Given the potential for fairly rapid improvement with acute immunomodulatory therapies (see below), noninvasive ventilation (e.g., bilevel positive airway pressure) can also be considered, in patients with adequate airway protection, as a means to avoid invasive ventilation.
    • Treat superimposed infections and metabolic derangements.
    • Plasmapheresis and IVIG are both used to treat MG crises/exacerbations and have equal efficacy with a similar rate of adverse effects.2 However, expert guidelines support the use of plasmapheresis over IVIG in myasthenic crisis, given its greater short-term efficacy and quicker onset of action, unless there are comorbidities or elements of the individual’s medical history that make IVIG the better option.3
    • Because the effects of PLEX or IVIG are relatively rapid in onset but short-lived, corticosteroids are typically started soon after initiating PLEX, usually at a dose of 10–20 mg/d and slowly titrated (e.g., by 5 mg every 3 days) to a dose of 50 mg/d.
    • Anticholinesterases should be temporarily withdrawn from patients who are receiving ventilation support to avoid cholinergic stimulation of pulmonary secretions.
    • Neuromuscular blocking agents should be avoided.

Medications

First Line

  • Anticholinesterase drugs can produce symptomatic improvement in most forms of MG (anti-MuSK MG is frequently an exception).
  • Pyridostigmine should be started at 30–60 mg PO tid–qid and titrated for symptom relief.

Second Line

  • Immunosuppressive drugs are typically used when additional benefit is needed beyond cholinesterase inhibitors.
  • High doses of prednisone (usually 50 mg daily) can be used to achieve rapid improvement. However, up to 50% of patients experience a transient worsening of weakness on initiation of prednisone therapy. Hence, it is important to start low and increase slow (see above), especially if the patient has not been or is not being treated with PLEX or IVIG.
  • Azathioprine, mycophenolate mofetil, cyclosporine A, tacrolimus, and cyclophosphamide are steroid-sparing immunomodulatory agents that have all been used to treat MG with varying degrees of evidence to support their efficacy.
  • There is strong evidence that rituximab (anti-CD20 chimeric monoclonal antibody) has great efficacy in treating anti-MuSK MG.4
  • Eculizumab (Soliris), a humanized monoclonal antibody that binds with high affinity to human terminal complement protein C5, is approved for use in treatment-refractory anti-AChR MG.

Surgical Management

  • Thymectomy is indicated in all patients with thymoma, regardless of age, and in patients with generalized MG who are aged 65 years or younger.5
  • Thymectomy in ocular MG patients and generalized MG patients older than 65 years is considered on a case-by-case basis.

References

  1. Alshekhlee A, Miles JD, Katirji B, et al. Incidence and mortality rates of myasthenia gravis and myasthenic crisis in US hospitals. Neurology. 2009;72(18):1548-1554.  [PMID:19414721]
  2. Barth D, Nabavi Nouri M, Ng E, et al. Comparison of IVIg and PLEX in patients with myasthenia gravis. Neurology. 2011;76(23):2017-2023.  [PMID:21562253]
  3. Sanders DB, Wolfe GI, Narayanaswami P; MGFA Task Force on MG Treatment Guidance. Developing treatment guidelines for myasthenia gravis. Ann N Y Acad Sci. 2018 1412(1):95-101.  [PMID:29381223]
  4. Hehir MK, Hobson-Webb LD, Benatar M, et al. Rituximab as treatment for anti-MuSK myasthenia gravis: multicenter blinded prospective review. Neurology. 2017;89(10):1069-1077.  [PMID:28801338]
  5. Wolfe GI, Kaminski HJ, Aban IB, et al. Randomized trial of thymectomy in myasthenia gravis. N Engl J Med. 2016;375(6):511-522.  [PMID:27509100]

Outline


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