Myasthenia Gravis

Pathophysiology

Neuromuscular Autoimmune Disease
Antibodies form to nicotinic acetylcholine receptors
1. Affects post-synaptic mambrane of the neuromuscular junction
Results in fluctuating and variable, progressive weakness and true fatigability
Associated with thymoma in up to 25% of cases

Epidemiology

Annual Incidence: 10-20 new cases per million
Prevalence: 150-200 cases per million
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

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
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
5. Seronegative in 10% of cases
Other forms
1. Thymoma-associated Myasthenia Gravis

Associated Conditions

Neuromyelitis optica
Autoimmune Thyroid disease
Systemic Lupus Erythematosus
Rheumatoid Arthritis

Risk Factors
Medication Triggers for Myasthenia Gravis and Myasthenia crisis

Magnesium
Beta Blockers
Class Ia Antiarrhythmics (e.g. Quinidine, Procainamide, Amiodarone)
High-dose Corticosteroids
Haloperidol
Prochlorperazine
Phenytoin
Antihistamines
IV Contrast (risk 3% with low osmolarity contrast, increased risk with older, higher osmolarity agents)
Antibiotics

Risk Factors
Other Triggers for Myasthenia Gravis and Myasthenia crisis

Infection
1. Infection triggering myasthenia is common
2. Consider empiric antibiotics (see safe antibiotics below)
Electrolyte abnormalities
Trauma
Surgery
Thyroid disease
Pregnancy

Presentations

Early course
1. Typically transient with symptom free intervals lasting days to weeks
Ocular Myasthenia Gravis (50%)
1. Ptosis (80% of cases)
2. Diplopia (vertical or horizontal)
Bulbar symptoms (15%)
1. Dysarthria
2. Dysphagia
3. Fatigable chewing
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

Symptoms

Muscle Weakness provoked by exertion
May be precipitated by infection, fever, stress and other acute factors
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
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
Facial Muscle Weakness
1. Loss of expression (especially loss of smile, or sneer appearance)
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
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
Respiratory Muscle Weakness
1. Respiratory insufficiency may progress to Respiratory Failure (myasthenia crisis)

Signs

See symptoms above
Muscle Weakness as above
Deep Tendon Reflexes normal
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

Labs
Specific Antibody

Seronegative Myasthenia Gravis occurs in 6-12% of cases (most frequently ocular Myasthenia Gravis)
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
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

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

Differential Diagnosis

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
Ocular Myasthenia Gravis mimics
1. Hyperthyroidism (including Thyroid ophthalmopathy)
2. Kearns-Sayre Syndrome
3. Brainstem lesions
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
Drug-induced Myasthenia
1. Penicillamine
2. Polymyxin
3. Tetracycline
4. Aminoglycosides
5. Procainamide
6. Propranolol
7. Phenothiazine
8. Lithium

Complications

Aspiration Pneumonia
Cholinergic crisis (excessive Acetylcholinesterase Inhibitor)
1. See Cholinergic Toxicity
Myasthenia Crisis (30% of cases)
1. Risk of Respiratory compromise
2. Signs of impending respiratory compromise
  1. Chest wall weakness
    1. Intercostal Muscle and diaphragm weakness
    2. Accessory Muscle use
    3. Intercostal retractions
    4. Abnormal lung sounds (e.g. Stridor)
  2. Bulbar weakness
    1. Unable to swallow secretions
    2. Difficulty holding head up
    3. Difficult phonation
3. Monitor respiratory effort
  1. Negative Inspiratory Force
  2. 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. Single breath test
    1. How high can a patient count on a single breath
    2. Normal patients are able to count >40 on one breath

Management
General

Eliminate triggers (esp. medications, see above)
Correct Electrolyte abnormalities
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)

Management
Medication

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
Immunosuppressive therapy
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)
Plasmapheresis (Plasma Exchange) and Intravenous Immunoglobulin
1. Indicated for emergent worsening/crisis
2. Response rate: 70%
3. Plasmapheresis onset of action is rapid
4. Intravenous Immunoglobulin has longer duration of action

Management
Thymectomy

Indications
1. Age <60 years
2. Inadequately controlled on Pyridostigmine
3. Thymoma discovered
Effect
1. Clinical improvement after thymectomy in 80%
2. Benefits may not be seen for 6 months
3. Transcervical thymectomy may be preferred
References
1. Calhoun (1999) Ann Surg 230:555-61 [PubMed]

Precautions

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
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)
References
1. Hayes in Herbert (2015) 15(9):14

References

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