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Myasthenia Gravis
Melody A. Jordahl-Iafrato, MD
image BASICS
DESCRIPTION
Primary disorder of neuromuscular transmission characterized by fluctuating muscle weakness:
  • Ocular myasthenia gravis (MG) (15%): weakness limited to eyelids and extraocular muscles
  • Generalized MG (85%): commonly affects ocular as well as a variable combination of bulbar, proximal limb, and respiratory muscles
  • 50% of patients who present with ocular symptoms develop generalized MG within 2 years.
  • Onset may be sudden and severe, but it is typically mild and intermittent over many years, maximum severity reached within 3 years for 85%.
  • System(s) affected: neurologic; hematologic; lymphatic; immunologic; musculoskeletal
EPIDEMIOLOGY
Occurs at any age but a bimodal distribution to the age of onset:
  • Female predominance: 20 to 40 years
  • Male predominance: 60 to 80 years
Incidence
Estimated annual incidence 2 to 21/1 million
Prevalence
In the United States, 200/1 million; increasing over the past 5 decades
Pediatric Considerations
A transient form of neonatal MG seen in 10-20% of infants born to mothers with MG. It occurs as a result of the transplacental passage of maternal antibodies that interfere with function of the neuromuscular junction; resolves in weeks to months.
ETIOLOGY AND PATHOPHYSIOLOGY
  • Reduction in the function of acetylcholine receptors (AChR) at muscle endplates, resulting in insufficient neuromuscular transmission
  • Antibody-mediated autoimmune disorder
  • Antibodies are present in most cases of MG.
    • Seropositive/antiacetylcholine receptor (anti-AChR): a humoral, antibody-mediated, T-cell-dependent attack of the AChRs or receptorassociated proteins at the postsynaptic membrane of the neuromuscular junction. Found in 85% of generalized MG and 50% of ocular MG. Thymic abnormalities common (1)
    • Muscle-specific kinase (MuSK). 5% of generalized MG patients. Typically females. Is a severe form, respiratory and bulbar muscles involved. Thymic abnormalities are rare (1).
    • In remainder of seronegative, 12-50% with anti-LRP4, a molecule that forms a complex with MuSK, clinical phenotype not well defined (1)
    • Seronegative MG (SNMG): 5%; may have anti-AChR detectable by cell-based assay. Clinically similar to anti-AChR, thymic hyperplasia may be present (1).
  • Also documented immediately after viral infections (measles, Epstein-Barr virus [EBV], HIV, and human T-lymphotropic virus [HTLV])
Genetics
  • Congenital MG syndrome describes a collection of rare hereditary disorders. This condition is not immune-mediated but instead, results from the mutation of a component of the neuromuscular junction (autosomal recessive).
  • Familial predisposition is seen in 5% of cases.
RISK FACTORS
  • Familial MG
  • D-penicillamine (drug-induced MG)
  • Other autoimmune diseases
COMMONLY ASSOCIATED CONDITIONS
  • Thymic hyperplasia (60-70%)
  • Thymoma (10-15%)
  • Autoimmune thyroid disease (3-8%)
image DIAGNOSIS
Myasthenia Gravis Foundation of America Clinical Classification (2)[C]:
  • Class I: any eye muscle weakness, possible ptosis, no other evidence of muscle weakness elsewhere
  • Class II: eye muscle weakness of any severity; mild weakness of other muscles:
    • Class IIa: predominantly limb or axial muscles
    • Class IIb: predominantly bulbar and/or respiratory muscles
  • Class III: eye muscle weakness of any severity; moderate weakness of other muscles:
    • Class IIIa: predominantly limb or axial muscles
    • Class IIIb: predominantly bulbar and/or respiratory muscles
  • Class IV: eye muscle weakness of any severity; severe weakness of other muscles:
    • Class IVa: predominantly limb/axial muscles
    • Class IVb: predominantly bulbar and/or respiratory muscles (can also include feeding tube without intubation)
  • Class V: intubation needed to maintain airway
PHYSICAL EXAM
  • Ptosis may worsen with propping of opposite eyelid (curtain sign) or sustained upward gaze.
  • “Myasthenic sneer,” in which the midlip rises but corners of mouth do not move.
  • Muscle weakness is usually proximal and symmetric.
  • Test for muscle fatigability by repetitive or prolonged use of individual muscles.
  • Important to test and monitor respiratory function.
DIFFERENTIAL DIAGNOSIS
  • Thyroid ophthalmopathy
  • Oculopharyngeal muscular dystrophy
  • Myotonic dystrophy
  • Kearns-Sayre syndrome
  • Chronic progressive external ophthalmoplegia
  • Brainstem and motor cranial nerve lesions
  • Botulism
  • Motor neuron disease (e.g., amyotrophic lateral sclerosis [ALS])
  • Lambert-Eaton myasthenic syndrome
  • Drug-induced myasthenia
  • Congenital myasthenic syndrome
  • Dermatomyositis/polymyositis
  • Neurosarcoidosis
  • Tolosa-Hunt syndrome
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • Anti-AChR antibody (74-85% are seropositive):
    • Generalized myasthenia: 75-85%
    • Ocular myasthenia: 50%
    • MG and thymoma: 98-100%
    • Poor correlation between antibody titer and disease severity (1)[C]
    • False-positive results in thymoma without MG, Lambert-Eaton myasthenic syndrome, small cell lung cancer, and rheumatoid arthritis treated with penicillamine
  • Anti-MuSK antibody:
    • Used if MG is suspected, patient seronegative
    • Strong correlation between titer and disease severity (1)[C]
  • LRP4 and clustered anti-AChR:
    • Used if MG suspected, patient seronegative
  • Thyroid and other autoimmune testing antistriated muscle (anti-SM) antibody:
    • Present in 84% of patients with thymoma who are <40 years of age
    • Can be present without thymoma in patients >40 years of age
  • Chest radiographs or CT scans may identify a thymoma.
  • MRI of brain and orbits to rule out other causes of cranial nerve deficit
Diagnostic Procedures/Other
  • Tensilon (Edrophonium) test:
    • Initial 2-mg IV dose, followed by another 2 mg every 60 seconds up to a maximum dose of 10 mg
    • A positive test shows improvement of strength within 30 seconds of administration.
    • Sensitivity 80-90% (3)[C]
    • P.697

    • Cardiac disease and bronchial asthma are relative contraindications, especially in elderly.
    • Atropine: 0.4 to 0.6 mg IV may rarely be required as antidote; must be available.
    • Can also do trial of other cholinesterase inhibitors (neostigmine or oral) and monitor response
  • Ice pack test:
    • Ice pack applied to closed eyelid for 60 seconds, then removed; extent of ptosis immediately assessed.
    • Ice will decrease the ptosis induced by MG.
    • Sensitivity 80% in patients with prominent ptosis
  • Electrophysiology testing:
    • Repetitive nerve stimulation (RNS):
      • Widely available, most frequently used
      • Moderately sensitive for both generalized MG (75%) and ocular MG (50%) (3)[C]
    • Single-fiber electromyogram (SFEMG):
      • Assesses temporal variability between two muscle fibers within same motor unit (jitter)
      • Sensitive (90-95%) but less specific
      • Technically difficult to perform; limited availability, use if suspected and negative RNS (3)[C]
Test Interpretation
  • Lymphofollicular hyperplasia of thymic medulla occurs in 65% of patients with MG, thymoma in 15%.
  • Immunofluorescence: IgG antibodies and complement on receptor membranes in seropositive patients
image TREATMENT
GENERAL MEASURES
  • Treatment based on age, gender, and disease severity and progression
  • Three basic approaches: symptomatic, immunosuppressive, and supportive. Few should receive a single therapeutic modality.
MEDICATION
First Line
Symptomatic treatments (anticholinesterase agents)
  • Pyridostigmine bromide (Mestinon):
    • Most commonly prescribed because available in oral tablet
    • Starting dose of 30 mg PO TID with food
    • Maximum dose: 120 mg q3-4h
    • Long-acting available, but effect not consistent
  • Neostigmine methylsulfate (Prostigmin):
    • Starting dose of 0.5 mg SC or IM q3h
    • Titrate dosage to clinical need.
  • Patients with anti-MuSK may not respond well to these meds.
Second Line
  • Immunosuppressants: Oral corticosteroids are the first choice of drugs when immunosuppression is necessary.
    • Prednisone: Start as inpatient with a 60 mg/day PO; taper the dosage every 3 days; switch to alternateday regimen within 2 weeks. Taper very slowly to establish the minimum dosage necessary to maintain remission (4)[B].
    • Cyclophosphamide: adults: 1 to 5 mg/kg/day PO; children: 2 to 8 mg/kg/day PO (5)[B]
    • Cyclosporine: adults: 5 mg/kg/day PO (nephrotoxicity and drug interactions) (5)[B]
    • Mycophenolate: 1 g PO or IV BID
    • Azathioprine: 100 to 200 mg/day PO (5)[B]
      • Most frequently used for long-term immunomodulation, similar efficacy to steroids and IVIG
      • Benefit may not be apparent for up to 18 months after initiation of therapy.
      • Prednisolone + azathioprine may be effective when used as a corticosteroid-sparing agent.
  • Acute immunomodulating treatments:
    • Plasmapheresis: bulk removal of 2 to 3 L of plasma 3 times per week, repeated until rate of improvement plateaus (6)[B]
      • Improves weakness in nearly all and can last up to 3 months
    • Immunoglobulin: 2 g/kg IV over 2 to 5 days (5)[B]
    • Plasmapheresis and immunoglobulin have comparable efficacy in treating moderate to severe MG (6)[C].
    • Rapid onset of effect but short duration of action
    • Used for acute worsening of MG to improve strength prior to surgery, prevent acute exacerbations induced by corticosteroids, and as a chronic intermittent treatment to provide relief in refractory MG.
  • Other immunosuppressant therapies:
    • Tacrolimus
    • Rituximab:
      • Seronegative MuSK-antibody positive MG patients may have better response to rituximab than conventional therapies.
SURGERY/OTHER PROCEDURES
  • Thymectomy recommended for patients with thymic abnormalities
  • May be beneficial for patients without thymic abnormalities in those <60 years of age
Pediatric Considerations
  • Infants with severe weakness from transient neonatal myasthenia may be treated with oral pyridostigmine; general support is necessary until the condition clears.
  • Corticosteroids limited only to severe disease
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
  • Management of pulmonary infections
  • Myasthenic/cholinergic crises
  • Plasmapheresis
  • IV &ggr;-globulin
image ONGOING CARE
PATIENT EDUCATION
MG Foundation of America (MGFA): http://www.myasthenia.org/
PROGNOSIS
  • Overall good but highly variable
  • Myasthenic crisis associated with substantial morbidity and 4% mortality
  • Seronegative patients are more likely to have purely ocular disease, and those with generalized SNMG have a better outcome after treatment.
REFERENCES
1. Berrih-Aknin S, Frenkian-Cuvelier M, Eymard B. Diagnostic and clinical classification of autoimmune myasthenia gravis. J Autoimmun. 2014;48-49:143-148.
2. Jaretzki A III, Barohn RJ, Ernstoff RM, et al. Myasthenia gravis: recommendations for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Neurology. 2000;55(1):16-23.
3. Meriggioli MN, Sanders DB. Myasthenia gravis: diagnosis. Semin Neurol. 2004;24(1):31-39.
4. Schneider-Gold C, Gajdos P, Toyka KV, et al. Corticosteroids for myasthenia gravis. Cochrane Database Syst Rev. 2005;(2):CD002828.
5. Hart IK, Sathasivam S, Sharshar T. Immunosuppressive agents for myasthenia gravis. Cochrane Database Syst Rev. 2007;(4):CD005224.
6. 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.
Additional Reading
&NA;
  • Angelini C. Diagnosis and management of autoimmune myasthenia gravis. Clin Drug Investig. 2011;31(1):1-14.
  • Meriggioli MN. Myasthenia gravis: immunopathogenesis, diagnosis, and management. Continuum Lifelong Learn Neurol. 2009;15(1):35-62.
Codes
&NA;
ICD10
  • G70.00 Myasthenia gravis without (acute) exacerbation
  • G70.01 Myasthenia gravis with (acute) exacerbation
  • P94.0 Transient neonatal myasthenia gravis
Clinical Pearls
&NA;
  • An autoimmune disease, marked by abnormal fatigability and weakness of selected muscles, which is relieved by rest
  • Anticholinesterase medication and a thymectomy lessen symptom severity.
  • Steroid therapy, plasma exchange, or immunoglobulin can be used in severely affected patients.