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Myasthenia Gravis

- 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

para>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 receptor-associated 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%)

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 musclesClass 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 musclesClass 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 musclesClass IVb: predominantly bulbar and/or respiratory muscles (can also include feeding tube without intubation)
  • Class V: intubation needed to maintain airway

HISTORY

The hallmark of MG is fatigability.

  • Fluctuating weakness, often subtle, that worsens during the day and after prolonged use of affected muscles, may improve with rest
  • Early symptoms are transient with asymptomatic periods lasting days or weeks.
  • With progression, asymptomatic periods shorten, and symptoms fluctuate from mild to severe.
  • >50% of patients present with ocular symptoms (ptosis and/or diplopia). Eventually, 90% of patients with MG develop ocular symptoms.
  • Ptosis might be unilateral, bilateral, or shifting from eye to eye.
  • 15% present with bulbar symptoms.
  • <5% present with proximal limb weakness alone.

ALERT

Myasthenic crisis: respiratory muscle weakness producing respiratory insufficiency and pending respiratory failure

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 seronegativeStrong 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 ageCan 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 mgA positive test shows improvement of strength within 30 seconds of administration.Sensitivity 80 " 90% (3)[C]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 usedModerately 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 specificTechnically 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

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 tabletStarting dose of 30 mg PO TID with foodMaximum dose: 120 mg q3 " 4hLong-acting available, but effect not consistent
  • Neostigmine methylsulfate (Prostigmin):Starting dose of 0.5 mg SC or IM q3hTitrate 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 alternate-day 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 BIDAzathioprine: 100 to 200 mg/day PO (5)[B]Most frequently used for long-term immunomodulation, similar efficacy to steroids and IVIGBenefit 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 per week, repeated until rate of improvement plateaus (6)[B]Improves weakness in nearly all and can last up to 3 monthsImmunoglobulin: 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 actionUsed 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:TacrolimusRituximab:Seronegative MuSK-antibody positive MG patients may have better response to rituximab than conventional therapies.

ALERT

Use caution with drugs that can precipitate weakness: aminoglycosides, fluoroquinolones, ²-blockers, calcium channel blockers, neuromuscular blockers, statins, diuretics, oral contraceptives, gabapentin, phenytoin, lithium, among others.

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 ³-globulin

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.

COMPLICATIONS

Acute respiratory arrest; chronic respiratory insufficiency

REFERENCES

11 Berrih-Aknin S, Frenkian-Cuvelier M, Eymard B. Diagnostic and clinical classification of autoimmune myasthenia gravis. J Autoimmun. 2014;48 " 49:143 " 148.22 Jaretzki AIII, 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 " 23.33 Meriggioli MN, Sanders DB. Myasthenia gravis: diagnosis. Semin Neurol. 2004;24(1):31 " 39.44 Schneider-Gold C, Gajdos P, Toyka KV, et al. Corticosteroids for myasthenia gravis. Cochrane Database Syst Rev. 2005;(2):CD002828.55 Hart IK, Sathasivam S, Sharshar T. Immunosuppressive agents for myasthenia gravis. Cochrane Database Syst Rev. 2007;(4):CD005224.66 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

  • 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

ICD10

  • G70.00 Myasthenia gravis without (acute) exacerbation
  • G70.01 Myasthenia gravis with (acute) exacerbation
  • P94.0 Transient neonatal myasthenia gravis

ICD9

  • 358.00 Myasthenia gravis without (acute) exacerbation
  • 358.01 Myasthenia gravis with (acute) exacerbation
  • 775.2 Neonatal myasthenia gravis

SNOMED

  • 91637004 myasthenia gravis (disorder)
  • 230684008 Ocular myasthenia (disorder)
  • 82178003 Neonatal myasthenia gravis
  • 230686005 Generalized myasthenia (disorder)

CLINICAL PEARLS

  • 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.