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 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
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 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]
- 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
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 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 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 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.
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.