Motor

Myasthenia Gravis

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Myasthenia Gravis

  • Pathophysiology
  1. Neuromuscular Autoimmune Disease
  2. Antibodies form to nicotinic acetylcholine receptors
    1. Affects post-synaptic mambrane of the neuromuscular junction
  3. Results in fluctuating and variable, progressive weakness and true fatigability
  4. Associated with thymoma in up to 25% of cases
  • Epidemiology
  1. Annual Incidence: 10-20 new cases per million
  2. Prevalence: 150-200 cases per million
  3. Age of onset (multimodal)
    1. Neonatal Myasthenia Gravis (transient related to maternal antibodies)
    2. Ages 20-30 (predominantly female)
    3. Ages 50-80 (predominantly male)
  • Types
  1. Ocular Myasthenia Gravis
    1. Eyelid weakness (Ptosis)
    2. Extraocular Muscle Weakness (Diplopia)
    3. Seronegative in 50% of cases
    4. Progresses to generalized Myasthenia Gravis within 2 years in 50% of cases
  2. Generalized Myasthenia Gravis
    1. Includes ocular Muscle Weakness as above AND
    2. Bulbar weakness (Dysarthria, Dysphagia, fatigable chewing)
    3. Extremity weakness
    4. Respiratory Muscle Weakness
    5. Seronegative in 10% of cases
  3. Other forms
    1. Thymoma-associated Myasthenia Gravis
  • Associated Conditions
  1. Neuromyelitis optica
  2. Autoimmune Thyroid disease
  3. Systemic Lupus Erythematosus
  4. Rheumatoid Arthritis
  • Presentations
  1. Early course
    1. Typically transient with symptom free intervals lasting days to weeks
  2. Ocular Myasthenia Gravis (50%)
    1. Ptosis
    2. Diplopia (vertical or horizontal)
  3. Bulbar symptoms (15%)
    1. Dysarthria
    2. Dysphagia
    3. Fatigable chewing
  4. Isolated motor weakness (<5%)
    1. Proximal limb weakness
    2. Other sites of isolated Muscle Weakness are less common presentations (neck weakness, distal limb weakness, respiratory Muscle Weakness)
  • Symptoms
  1. Muscle Weakness provoked by exertion
  2. May be precipitated by infection, fever, stress and other acute factors
  3. Ocular weakness
    1. Eyelid Muscle Weakness resulting in Ptosis (unilateral or bilateral)
      1. May increase with sustained upward gaze
    2. Extraocular Muscle Weakness resulting in binocular Diplopia (vertical or horizontal)
      1. Resolves with covering one eye
    3. Pupil reaction is always spared in ocular myasthenia
  4. Bulbar weakness
    1. Fatigable chewing (often mid-way through a meal)
      1. Patient may need to use their fingers to lift the jaw, and close the mouth
    2. Dysarthria
      1. Nasal quality or low intensity voice
    3. Dysphagia
      1. Difficulty swallowing liquids and solids
      2. Aspiration may occur with myasthenia crisis
    4. Nasal regurgitation
      1. Occurs if Palate weak
  5. Facial Muscle Weakness
    1. Loss of expression (especially loss of smile, or sneer appearance)
  6. Neck Muscle Weakness
    1. Neck flexor Muscle Weakness
    2. Neck extensor Muscle Weakness
      1. May give "dropped head" appearance with head flexed over chest later in the day
  7. Extremity Muscle Weakness (asymmetric)
    1. Arms affected more than legs
    2. Proximal Muscle Weakness are typically more affected than distal muscles
    3. Distal wrist extensors and foot dorsiflexors are most often involved
  8. Respiratory Muscle Weakness
    1. Respiratory insufficiency may progress to Respiratory Failure (myasthenia crisis)
  • Signs
  1. See symptoms above
  2. Muscle Weakness as above
  3. Deep Tendon Reflexes normal
  4. Specific Tests
    1. Ice Pack Test
      1. Cold pack applied to eye with Ptosis for 2 minutes
      2. Myasthenia Gravis related Ptosis improves with cold applied
    2. Tensilon Test (Edrophonium Test)
      1. Cholinesterase Inhibitor given and Motor Strength improves in Myasthenia Gravis
  1. Seronegative Myasthenia Gravis occurs in 6-12% of cases (most frequently ocular Myasthenia Gravis)
  2. Acetylcholine Receptor Antibody (AChR-Ab)
    1. Binding AChR-Ab is typically used as it has best efficacy
      1. Blocking AChR-Ab may be indicated in some cases due to its high Specificity
      2. Modulating AChR-Ab may slightly increase Test Sensitivity but at the risk of False Positives
    2. Present in 50% of Ocular Myasthenia Gravis
    3. Present in 80-90% of generalized Myasthenia Gravis
  3. Muscle-Specific Receptor Tyrosine KinaseAntibody (MuSK-Ab)
    1. Absent in most cases of ocular Myasthenia Gravis
    2. Present in 38-50% of generalized Myasthenia Gravis patients who are AChR-Ab negative
  • Labs
  • Other testing
  1. Electromyogram (EMG)
    1. Decremental response to repetitive nerve stimulation
  2. CT neck or MRI neck
    1. Thymoma evaluation
  3. Thyroid Function Test
    1. Hyperthyroidism (3-8%)
  4. Rheumatoid Factor (RF)
  5. Antinuclear Antibody (ANA)
  • Differential Diagnosis
  1. Ocular Myasthenia Gravis mimics
    1. Hyperthyroidism (including Thyroid ophthalmopathy)
    2. Kearns-Sayre Syndrome
    3. Brainstem lesions
  2. Generalized Myasthenia Gravis mimics
    1. Amyotrophic Lateral Sclerosis (ALS)
    2. Lambert-Eaton Syndrome
      1. Associated with cancer, and typically affects proximal extremity Muscle Weakness
    3. Botulism
    4. Neurasthenia
    5. Intracranial Mass lesion with extraocular affect
  3. Drug-induced Myasthenia
    1. Penicillamine
    2. Polymyxin
    3. Tetracycline
    4. Aminoglycosides
    5. Procainamide
    6. Propranolol
    7. Phenothiazine
    8. Lithium
  • Complications
  1. Aspiration Pneumonia
  2. Myasthenia Crisis
    1. Respiratory compromise
  3. Cholinergic crisis (excessive Acetylcholinesterase Inhibitor)
    1. See Cholinergic Toxicity
  • Management
  • Medication
  1. Anticholinesterase (Cholinergic)
    1. Provides symptomatic relief
      1. Most effective on extremity weakness and bulbar symptoms
      2. Less effective on Ptosis
      3. Least effective on Diplopia
    2. Pyridostigmine Bromide (Mestinon)
      1. Child: 0.5 - 1 mg/kg every 4-6 hours up to 7 mg/kg/day
      2. Adult: 30 mg three times daily (may be increased to maximum of 120 mg every 4 hours while awake)
      3. Onset: 15-30 minutes
      4. Peaks: 2 hours
      5. Duration: 3-4 hours
    3. Neostigmine
      1. Less commonly used
  2. Immunosuppressive therapy
    1. Prednisone
      1. Start at 20 mg qd
      2. Increase gradually by 5 mg every 3 days to 60mg
      3. Continue for 3 months OR
        1. Until clinical improvement stops or declines
      4. Taper gradually to every other day
    2. Azathioprine (Imuran)
      1. Dosing
        1. 2 mg/kg/day
      2. Efficacy
        1. Effective when given with Prednisone
        2. Effect not seen for 6 months or more
      3. Monitoring
        1. Complete Blood Count (CBC)
        2. Liver Function Tests (LFT)
  3. Plasmapheresis (Plasma Exchange) and IVIg
    1. Indicated for emergent worsening/crisis
    2. Response rate: 70%
  • Management
  • Thymectomy
  1. Indications
    1. Age <60 years
    2. Inadequately controlled on Pyridostigmine
    3. Thymoma discovered
  2. Effect
    1. Clinical improvement after thymectomy in 80%
    2. Benefits may not be seen for 6 months
    3. Transcervical thymectomy may be preferred
  3. References
    1. Calhoun (1999) Ann Surg 230:555-61 [PubMed]
  • Precautions
  1. Avoid antibiotics that significantly exacerbate neuromuscular weakness
    1. Aminoglycosides
    2. Fluoroquinolones
    3. Telithromycin (Ketek)
    4. Macrolides (Erythromycin, Azithromycin) - less effect than other agents above
  2. Avoid miscellaneous agents that exacerbate neuromuscular weakness
    1. Magnesium
    2. Class Ia Antiarrhythmics (e.g. Quinidine, Procainamide, Amiodarone)
    3. High-dose Corticosteroids
    4. Iodinated Contrast Dye (seen primarily with older contrast dyes)
  3. References
    1. Hayes in Herbert (2015) 15(9):14
  • References
  1. Bird (2013) Myasthenia Gravis, in Shefner and Targoff, UpToDate, Wolters Kluwer
  2. Keesey (2004) Muscle Nerve 29:484 [PubMed]