section name header

Info


A. Characteristicsnavigator

  1. Disease characterized initially by episodic muscle weakness
  2. Primarily involves muscles innervated by cranial nerves
  3. Improvement by acetylcholinesterase inhibiting drugs
  4. Affects ~20-25,000 patients in USA
  5. Associated with thymoma in ~25% of patients
  6. Congenital forms of MG exist which do not have anti-AChR Abs

B. Etiologynavigator

  1. Antibodies (Abs) Mediated Disease
    1. Abs against neuromuscular acetylcholine receptors (AChR) in 85-90% of patients [3]
    2. These Abs block action of ACh
    3. Ab with Complement mediated destruction of AChR occurs over time
    4. For individual patients, there is a fairly good correlation between Ab titer and symptoms
    5. Reduction in Ab titers of ~50% usually correlate with symptom reduction
    6. 10%-15 of patients with MG have no demonstrable anti-AChR Abs in radioassays
    7. Transfer of serum from these patients to mice leads to myasthenia and AChR loss
    8. About 5% of MG patients have auto-Abs to P/Q calcium channel
    9. About 40% of patients with MG are ANA positive
    10. Nearly 50% of patients with MG have autoantibodies to thyroid or gastric tissue [3]
  2. Role of the Thymus
    1. Removal of the thymus results in substantial improvement in ~75% of patients
    2. Germinal centers appear to be present in the thymus of some patients with MG
    3. When thymoma is present, removal has less significant impact on MG
    4. Suggests role of T cell development or autoantigen found in thymus in MG etiology
  3. Drug-Induced Myasthenia Gravis [4]
    1. Penicillamine
    2. Anticonvulsants (mainly phenytoin) may be associated
    3. Glucocorticoids may exacerbate disease and can inhibit neuromuscular junction function
    4. ß-adrenergic blockers, litherium, and procainamide should be avoided
  4. Bimodal Age Distribution
    1. Age 20-30 years predominantly affects women
    2. Age 50-60 years predominantly affects men
    3. Age over 80 years is being reported increasingly

C. Symptoms [2]navigator

  1. Presentation
    1. Speech becoming uninteliglbe during period of prolonged speaking
    2. Presence of peek sign: orbicularis oculi weakness due to inability to maintain lid closure
    3. Weakness in all muscle groups increase with activity, improve with rest
    4. Findings limited to motor system
  2. Ocular most common: 40% of cases initially, 85% eventually
    1. Diplopia - most pronounced on lateral gaze
    2. Ptosis
    3. Ophthalmoplegia
  3. Other muscles
    1. Dysphagia, Dysarthria
    2. Proximal (> distal) limb weakness
    3. Difficulty breathing is a rare presentation
  4. Symptoms are often worse during first several years, then improve over time
  5. Thymoma [6]
    1. Often asymptomatic chest mass detected on computerized tomographic (CT) scan
    2. May increase in size and obstruct trachea or other structures
    3. Thymoma is present in ~45% of men and ~20% of women with MG
  6. Myasthenic Crisis
    1. Medical and neurological emergency
    2. Occurs when a patient with MG suffers bulbar or respiratory muscle weakness severe enough to require mechanical assistance
    3. Mechanical assistance is usually ventilator support and/or feeding tubes
    4. This is a rare presentation of MG
  7. Grading
    1. Grade I: focal disease
    2. Grade II: generalized disease (mild IIa; moderate IIb)
    3. Grade III: severe generalized disease
    4. Grade IV: crisis, with severe respiratory compromise

D. Diagnosis [2]navigator

  1. Edrophonium (Tensilon®) test
    1. Administer 2mg IV (intravenous)
    2. Evaluate periorbital muscles for improvement
    3. If no improvement, give 8mg more IV and reassess
    4. Overshooting may cause weakness by cholinergic blockade
    5. Likelihood ratio (LR) of positive test 15
  2. Laboratory
    1. Presence of anti-AChR Abs
    2. Thyroid Function Tests
    3. Serum electrolytes including calcium and magnesium
  3. Electrophysiologic Tests
    1. Neuromuscular transmission (Nerve Conduction Velocity and EMG)
    2. Repetitive stimulation of affective muscle leads to increasing deficity
  4. Computed Tomography (CT)
    1. Neck and upper mediastinum
    2. 20% of patients have thymoma associated with myasthenia gravis
    3. Removal of thymoma can lead to improved clinical course (see below)
  5. Abnormal sleep test (LR 53; normal sleep test LR 0.01) is confirmatory

E. Differential Diagnosisnavigator

  1. Lambert-Eaton (Eaton-Lambert) Syndrome [1]
    1. Production of autoantibodies against pre-synaptic nerve terminals
    2. 60% are associated with small cell lung cancer
    3. Removal of tumors often leads to reduction in disease symptoms
    4. Symptoms similar to MG, but strength improves with repetatitve motion or stimulation
    5. Thus, EMG/NCV studies can clearly distinguish MG from Lambert-Eaton Syndrome
  2. Botulism
  3. Drug induced myasthenia: penicillamine, curare, procainamide, quinines
  4. Hyperthyroidism / Graves' Disease
  5. Progressive external ophthalmoplegia
  6. Intracranial mass compressing cranial nerves

E. Treatmentnavigator

  1. Overview
    1. Most patients will receive cholinesterase inhibitors, which rapidly improve symptoms
    2. Most patients will also need immunosuppression
    3. Intravenous immunoglobulin (IVIg) can provide a bridge to immunosuppression []
    4. Recent trials suggest that azathioprine added to prednisone is optimal therapy
    5. Azathioprine permits substantial reduction in prednisone dosage
    6. About 90% of patients with MG are well controlled (normal or near normal) on therapy
  2. Peripherally Acting Cholinesterase inhibitors
    1. Block acetylcholinesterase leading to increased ACh levels
    2. Physiostigmine (Mestinon®): maximum dose 120mg q3 hours (CNS specific action)
    3. Pyridostigmine and Neostigmine are no longer used (non-specific)
    4. Long acting newer agents
    5. Side Effects: abdominal cramps, diarrhea, mucosal hypersecretion, but not bradycardia
  3. Thymectomy
    1. 25% of young MG patients without thymoma remit after removal of thymic remnant
    2. 50% of all MG patients have substantial improvement after thymectomy
    3. Thymoma patients derive less significant MG symptom reduction from thymectomy
    4. Thymoma may also be treated with radiolabelled octreotide and prednisone [5]
  4. Plasmapheresis
    1. Five day plasmapheresis or plasma exchange (complete plasma volume)
    2. Useful to prepare patients for thymectomy (reduce MG symptoms prior to surgery)
    3. Especially effective during respiratory crisis
    4. Improvement is usually seen about 7 days after initial plasmapheresis
    5. Ab titers fall at 7 days, then rise rapidly in 3-4 weeks to pretreatment values
  5. Immune Globulin (IVIg)
    1. Immunomodulatory activity, probably by interfering with pathogenic autoantibodies
    2. Dose is 400mg/kg/d x 5 days
    3. Generally well tolerated but ~80% develop a headache with infusion
    4. Improvement usually seen within 4 days
    5. Can be effective in rapidly progressive or symptomatic MG
    6. Can provide a bridge while immunosuppressive agents begin to work
  6. Immunosuppressive
    1. Glucocorticoids: oral prednisone or intravenous methylprednisolone
    2. Azathioprine (Imuran®)
    3. Cyclosporin (Sandimmune®): 5mg/kg/d in two divided doses
    4. Cyclophosphamide (Cytoxan®) 150-250 mg po daily or high dose intravenously
    5. High dose IV cyclosphosphamide may "reset" immune system in refractory MG [7]
  7. Prednisone
    1. Care must be taken when beginning MG patients on corticosteroids
    2. Unexplained respiratory crisis ("crashing") may occur in patients begun on high doses of glucocorticoids (usually 7-10 days after beginning medication)
    3. May admit for inpatient evaluation, begin on 15mg qd x 3 days, increased dose ~5mg q3d
    4. Aim for 60-100mg qod. Effects begin 2-3 weeks after dosing
    5. Suggest baseline bone density and PTH testing to prevent steroid osteoporosis
    6. All patients should start extra calcium + vitamin D and consider bisphosphonates
    7. PPD (tuberculosis skin test) should be checked prior to beginning therapy
    8. Monitoring of blood pressure and glucose levels is critical
    9. Some patients will require blood pressure treatment and/or oral hypoglycemics
  8. Azathioprine (Imuran®)
    1. Acts as "steroid-sparing" agent, permitting substantial prednisone dose reduction
    2. Dose is oral 2-3 mg/kg/d in 1 or 2 divided doses
    3. Effects seen in 3-12 months; "steroid-sparing" effects in 18-24 months
  9. Supportive Therapy
    1. May require intubation
    2. Often requires enteral (or parenteral) nutrition

F. Myasthenic Crisisnavigator

  1. Causes
    1. Bacterial or other infection
    2. Stress / Anxiety
    3. Metabolic Disturbance - eg. hypokalemia
    4. Thymectomy - postoperative reaction
    5. Acetylcholinesterase Inhibitors - overdose in most cases ("cholinergic crisis")
    6. Other Medications: aminoglycosides, procainamide, glucocorticoids, depolarizing agents
    7. Idiopathic
  2. Stages
    1. Impending Crisis - restlessness, insomnia, tachycardia, dyspnea
    2. MG Exacerbation - increased weakness, not severe enough to require assistance
    3. Crisis - respiratory and/or bulbar weakness, mechanical assistance required
  3. Signs of Decompensation
    1. PaO2 <50mmHg and/or PaCO2 >45mmHg on room air
    2. Arterial pH <7.25 (respiratory)
    3. Respiratory Rate >30 per minute; Forced Vital Capacity < 1 Liter
  4. Treatment
    1. Identification of underlying cause and appropriate treatment
    2. Plasmapheresis (50ml plasma/kg removed, replace with albumin solution)
    3. Supportive care as needed
    4. Mechanical ventilation should be instituted early
    5. Anticholinesterase drugs are usually stopped for 2 days during crisis
    6. Intravenous gammaglobuline (IVIg) 400mg/kg may also be used for impending crisis
    7. IVIg cannot be used in IgA deficiency, requires ~7 days for efficacy; effects last weeks

References navigator

  1. Boonyapisit K, Kaminski HJ, Ruff RL. 1999. Am J Med. 106(1):97 abstract
  2. Scherer K, Bedlack RS, Simel DL. 2005. JAMA. 293(15):1906 abstract
  3. Lennon VA. 1997. Neurology. 48(S5):S23
  4. Wittbrodt ET. 1997. Arch Intern Med. 157(4):399 abstract
  5. Palmieri G, Lastoria S, Colao A, et al. 1997. NEJM. 336(4):263 abstract
  6. Siao P and Zukerberg LR. 2000. NEJM. 342(20):1508 (Case Record)
  7. Hampton T. 2007. JAMA. 298(2):163 abstract