Myasthenia Gravis

Aka: Myasthenia Gravis, Erb-Goldflam Gravis, Myasthenic Crisis, Generalized Myasthenia, Ocular Myasthenia Gravis

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II. Pathophysiology

  1. Neuromuscular Autoimmune Disease
  2. Antibodies form to Nicotinic Acetylcholine Receptors (as well as other Antigens, e.g. Muscle specific Tyrosine Kinase)
    1. Affects post-synaptic membrane of the Neuromuscular Junction
    2. Results in post-synaptic membrane receptor internalization and decreased skeletal Muscle response
  3. Results in fluctuating and variable, progressive weakness and true fatigability
  4. Associated with thymoma in up to 25% of cases

III. Epidemiology

  1. Annual Incidence: 10-20 new cases per million (60,000 cases in U.S.)
  2. Prevalence: 14 to 40 cases per 100,000 in U.S. (similar to worldwide Prevalence)
  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)

IV. 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 facial Muscle and extraocular Muscle Weakness as above AND
    2. Bulbar weakness (Dysarthria, Dysphonia, Dysphagia, fatigable chewing)
    3. Extremity weakness (proximal Muscle Weakness)
    4. Respiratory Muscle Weakness (includes Myasthenia Crisis, see below)
    5. Seronegative in 10% of cases
  3. Other forms
    1. Thymoma-associated Myasthenia Gravis

V. Associated Conditions

  1. Neuromyelitis optica
  2. Autoimmune Thyroid disease
  3. Systemic Lupus Erythematosus
  4. Rheumatoid Arthritis

VI. Risk Factors: Medication Triggers for Myasthenia Gravis and Myasthenia crisis

  1. Magnesium
  2. Beta Blockers
  3. Calcium Channel Blockers
  4. Statins
  5. Class Ia Antiarrhythmics (e.g. Quinidine, Procainamide, Amiodarone)
  6. High-dose Corticosteroids
  7. Haloperidol
  8. Prochlorperazine
  9. Phenytoin
  10. Antihistamines
  11. IV Contrast (risk 3% with low osmolarity contrast, increased risk with older, higher osmolarity agents)
  12. Antibiotics
    1. Fluoroquinolones (e.g. Ciprofloxacin)
    2. Aminoglycosides (e.g. Gentamicin)
    3. Macrolides (e.g. Azithromycin)

VII. Risk Factors: Other Triggers for Myasthenia Gravis and Myasthenia crisis

  1. Infection
    1. Infection triggering myasthenia is common
    2. Consider empiric Antibiotics (see safe Antibiotics below)
  2. Electrolyte abnormalities
  3. Trauma
  4. Surgery
  5. Thyroid disease
  6. Pregnancy

VIII. Presentations

  1. Early course
    1. Typically transient with symptom free intervals lasting days to weeks
  2. Ocular Myasthenia Gravis (50%)
    1. Ptosis (80% of cases)
    2. Diplopia (vertical or horizontal)
  3. Bulbar symptoms or Generalized Phase (15%)
    1. Dysarthria
    2. Dysphagia
    3. Fatigable chewing
  4. Isolated motor weakness (<5%)
    1. Proximal Muscle Weakness
    2. Other sites of isolated Muscle Weakness are less common presentations
      1. Neck weakness
      2. Distal limb weakness
      3. Respiratory Muscle Weakness

IX. 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
    4. Normal Deep Tendon Reflexes
    5. Normal Sensation
  8. Respiratory Muscle Weakness
    1. Respiratory insufficiency may progress to Respiratory Failure (myasthenia crisis)
    2. Patient initially compensates for decreased lung excursion (due to Muscle Weakness) with Tachypnea
    3. Orthopnea may be present (gravity when upright may aid diaphragm excursion)
    4. Progression from Dyspnea to Tachypnea to reaspiratory arrest may be rapid
      1. Close monitoring of respiratory status is critical (see myasthenia crisis below)

X. Signs

  1. See symptoms above
  2. Muscle Weakness as above
  3. Deep Tendon Reflexes normal
  4. Respiratory function (see below)
    1. Pulmonary Function Assessment of Respiratory Muscle Strength
      1. Single Breath Counting
      2. Forced Vital Capacity (FVC)
      3. Negative Inspiratory Flow (NIF) or Maximal Inspiratory Pressure (MIP)
    2. Respiratory Muscle Weakness
      1. Tachypnea
      2. Hypophonia
      3. Intercostal Muscle and diaphragm weakness
      4. Accessory Muscle use or paradoxical breathing
      5. Intercostal retractions
      6. Abnormal lung sounds (e.g. Stridor)
    3. Bulbar weakness
      1. Unable to swallow secretions
      2. Difficulty holding head up
      3. Difficult phonation
  5. Specific Tests
    1. Ice Pack Test
      1. Cold pack applied to eye with Ptosis for 2 minutes
      2. Myasthenia Gravis related Ptosis improves (at least 2 mm) with cold applied
      3. Test Sensitivity 90% for Myasthenia Gravis
    2. Tensilon Test (Edrophonium Test)
      1. Acetylcholinesterase Inhibitor given and Motor Strength improves in Myasthenia Gravis
      2. Rarely performed due to lack of edrophonium (FDA discontinued drug in 2018 for poor Specificity)

XI. Labs: Specific Antibody

  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

XII. Labs: Other testing

  1. Serum Electrolytes
  2. Thyroid Function Test
    1. Hyperthyroidism (3-8%)
  3. Electromyogram (EMG)
    1. Decremental response to repetitive nerve stimulation
  4. CT neck or MRI neck
    1. Thymoma evaluation
  5. Rheumatoid Factor (RF)
  6. Antinuclear Antibody (ANA)

XIII. Differential Diagnosis

  1. Contrast with unique features of Myasthenia Gravis
    1. Ptosis and weak extraocular Muscles (e.g. Diplopia)
    2. Bulbar weakness (Dysphonia, Dysarthria, Dysphagia)
    3. Proximal Muscle Weakness (chewing Fatigue, neck Muscles, proximal extremities)
    4. Preserved normal Sensation, pupil reaction, Deep Tendon Reflexes
    5. No increased secretions, Autonomic Dysfunction, or muscle Fasciculations
  2. Ocular Myasthenia Gravis mimics
    1. Hyperthyroidism (including Thyroid ophthalmopathy)
    2. Kearns-Sayre Syndrome
    3. Brainstem lesions
  3. 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
  4. Drug-induced Myasthenia (distinguish from medications that exacerbate mysathenia, see above)
    1. Penicillamine
    2. Polymyxin
    3. Tetracycline
    4. Aminoglycosides
    5. Procainamide
    6. Propranolol
    7. Phenothiazine
    8. Lithium

XIV. Complications

  1. Aspiration Pneumonia
  2. Cholinergic crisis (excessive Acetylcholinesterase Inhibitor)
    1. See Cholinergic Toxicity
  3. Myasthenia Crisis (30% of cases)
    1. See Below

XV. Management: General

  1. Eliminate triggers (esp. medications, see above)
    1. Many of the triggering medications may be used with caution, at lowest effective dose in stable patients
    2. Exercise caution with CNS Depressants (e.g. Opioids, Benzodiazepines)
      1. Risk of respiratory depression
  2. Correct Electrolyte abnormalities
  3. Support airway and respiratory status as needed
    1. See myasthenia crisis evaluation as above
    2. BiPAP may be used to support respirations before requiring Endotracheal Intubation in alert patient
    3. In RSI, avoid paralysis with depolarizing medications (Succinylcholine)
      1. Use nondepolarizing agents (but consider 50% of typical dose due to increased sensitivity)

XVI. Management: Medication

  1. First-Line: 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. Adverse Effects
      1. Risk of Cholinergic Toxicity
      2. Risk of worsening myasthenia crisis (due to mucous plugging, bronchorrhea)
    3. Pyridostigmine Bromide (Mestinon)
      1. Child: 0.5 to 1 mg/kg every 4-6 hours (maximum 7 mg/kg/day divided every 4 to 6 hours)
      2. Adult
        1. Starting Dose: 30 mg three times daily
        2. Typical Dose: 60 to 90 mg every 4 to 6 hours while awake
        3. Maximum Dose: 120 mg every 4 hours while awake
      3. Pharmacokinetics
        1. Onset: 15-30 minutes
        2. Peaks: 2 hours
        3. Duration: 3-4 hours
    4. Neostigmine
      1. Less commonly used
  2. Second-Line: Immunosuppressants
    1. Prednisone
      1. Risk of worsening decompensation in early management
      2. Start at 20 mg orally daily
      3. Increase gradually by 5 mg every 3 days to 60mg
      4. Continue for 3 months OR
        1. Until clinical improvement stops or declines
      5. 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. Mycophenolate Mofetil (Cellcept)
      1. Has been used for Myasthenia Gravis roughly since 2000, but evidence of benefit is lacking
      2. Heatwole (2008) Neuropsychiatr Dis Treat 4(6):1203-9 +PMID: 19337460 [PubMed]
  3. Third-Line: Immunosuppressants (refractory to second-line agents)
    1. Cyclophosphamide (Cytoxan)
    2. Rituximab (Rituxan)
    3. Efgartigimod (Vyvgart)
      1. Antibody fragment binds neonatal Fc receptor (FcRn) and prevents recycling of IgG
      2. Lowers IgG Levels (including AChR antibodies in Myasthenia Gravis)

XVII. Management: Myasthenia Crisis

  1. Rapidly progressive skeletal Muscle Weakness with risk of Acute Respiratory Failure (Bellows Failure)
    1. Be prepared for emergent Endotracheal Intubation and Mechanical Ventilation
    2. Pyridostigmine is not typically recommended in myasthenia crisis
      1. May exacerbate airway and respiratory complications due to Cholinergic Toxicity effects
      2. May increase bronchorrhea and muous plugging
    3. Monitor frequent Pulmonary Function Assessment of Respiratory Muscle Strength
      1. Negative Inspiratory Flow (NIF) or Maximal Inspiratory Pressure (MIP)
      2. Forced Vital Capacity (FVC)
      3. Single Breath Counting
  2. Signs of impending Acute Respiratory Failure (see exam above)
    1. See Pulmonary Function Assessment of Respiratory Muscle Strength
    2. Negative Inspiratory Flow (NIF) less negative than -20 to 30 cm H2O
    3. Single Breath Counting <10 to 15 (normally >40)
      1. Assess how high a patient can count after a single inspiration
    4. Forced Vital Capacity (FVC)
      1. Normal FVC > 60 cc/kg
      2. Abnormal FVC < 30 cc/kg
      3. Intubate for FVC < 10 cc/kg (or inability to control secretions, respiratory Fatigue)
  3. Respiratory Support in Acute Respiratory Failure
    1. Bilevel Positive Pressure Ventilation
      1. May be trialed before Mechanical Ventilation in alert and oriented patients
      2. Hypercapnia predicts failed BiPAP and need for Mechanical Ventilation
      3. Myasthenia Gravis are high risk for Aspiration Pneumonitis (monitor closely)
      4. Seneviratne (2008) Arch Neurol 65(1): 54-8 [PubMed]
    2. Endotracheal Intubation and Mechanical Ventilation
      1. Depolarizing agents (e.g. Succinylcholine) are less potent in Myasthenia Gravis
      2. Nondepolarizing agents (e.g. Rocuronium) are preferred for Rapid Sequence Intubation (RSI)
        1. Use lower doses in Myasthenia Gravis
  4. Plasmapheresis (Plasma Exchange, PLEX) and Intravenous Immunoglobulin
    1. Indicated for emergent worsening or myasthenia crisis
    2. Response rate: 70%
    3. Plasmapheresis onset of action is rapid
    4. Intravenous Immunoglobulin has longer duration of action

XVIII. 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]

XIX. Precautions

  1. Avoid Antibiotics that significantly exacerbate neuromuscular weakness
    1. Alternative safe Antibiotics include Penicillins, Cephalosporins, Carbapenems, Doxycycline, Clindamycin
    2. Aminoglycosides
    3. Fluoroquinolones
    4. Telithromycin (Ketek)
    5. 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

XX. References

  1. Bird (2013) Myasthenia Gravis, in Shefner and Targoff, UpToDate, Wolters Kluwer
  2. Long and Gottleib in Herbert (2021) EM:Rap 21(9): 7-10
  3. (2022) Presc Lett 29(4): 23
  4. Keesey (2004) Muscle Nerve 29:484 [PubMed]
  5. Roper (2017) J Emerg Med 53(6):843-53 +PMID: 28916122 [PubMed]

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