What is myasthenia gravis?

Myasthenia Gravis

Definition and Pathophysiology

Myasthenia gravis is a B-cell mediated autoimmune disorder that causes fluctuating skeletal muscle weakness and fatigue by disrupting neuromuscular junction transmission through pathogenic antibodies targeting acetylcholine receptors or related proteins. 1

The disease occurs when autoantibodies attack the postsynaptic neuromuscular junction, most commonly targeting:

• Acetylcholine receptors (AChR): Found in 80-85% of patients 2
• Muscle-specific kinase (MuSK): Present in 5-8% of patients 2
• Lipoprotein-related protein 4 (LRP4): Occurs in <1% of patients 2
• Seronegative: Approximately 10% have no detectable antibodies against known antigens 2

The antibodies reduce available acetylcholine receptors at the motor endplate, resulting in diminished muscle fiber activation and clinical weakness 3.

Epidemiology

• Incidence: 0.04 to 5 per 100,000 per year 1
• Prevalence: 0.5 to 12.5 per 100,000 per year 1
• Age of onset: Third to fourth decade in females; later onset in males 1
• Gender distribution: Equal prevalence, but earlier onset in females 2

Clinical Presentation

Ocular Manifestations

Fifty percent of patients present with purely ocular symptoms (ptosis and diplopia), and 50-80% of these will progress to generalized disease within a few years 1, 4. Key ocular findings include:

• Variable ptosis that worsens with prolonged upgaze
• Cogan lid-twitch sign: Quick upward twitch of eyelid when returning gaze from downgaze to primary position
• Fluctuating strabismus that changes pattern with fatigue or repeated examination
• Slow ocular saccades
• Contralateral ptosis worsening upon manual elevation of the more affected eyelid (Hering's law) 4

Generalized Manifestations

When generalized, the disease affects:

• Bulbar muscles: Dysphagia, dysarthria, difficulty chewing, facial weakness
• Limb muscles: Proximal more than distal weakness
• Neck muscles: Difficulty holding up head
• Respiratory muscles: Can lead to life-threatening respiratory failure 1, 4

Critical feature: Weakness is fatigable and fluctuating, worsening with repetitive activity and improving with rest 2, 5.

Risk Factors

• Autoimmune thyroid disease 1
• Thymoma: Present in 10-20% of AChR-positive patients 2

Diagnostic Workup

Clinical Testing

Ice pack test: Apply ice pack over closed eyes for 2 minutes (ptosis) or 5 minutes (strabismus). A reduction in ptosis of approximately 2mm or improvement in strabismus is highly specific for myasthenia gravis 4. This test relates to diminished anticholinesterase activity at cooler temperatures.

Rest test: Period of rest without ice pack can also demonstrate improvement 4.

Edrophonium (Tensilon) test: 95% sensitive for generalized MG, 86% sensitive for ocular MG. Must be performed in monitored setting with atropine available due to potential muscarinic side effects (bradycardia, bronchospasm, hypotension) 4.

Serologic Testing

All patients require antibody testing 6:

• First-line: AChR antibodies and antistriated muscle antibodies
• If AChR negative: Test for MuSK and LRP4 antibodies
• Note: 20% of generalized MG and 50% of ocular MG patients are AChR seronegative 4

Neurophysiological Studies

Single fiber electromyography (EMG): Gold standard for diagnosis, positive in >90% of ocular MG patients 4

Repetitive nerve stimulation: Positive in only one-third of ocular MG patients 4

Additional electrodiagnostic studies should include 6:

• Neuromuscular junction testing with repetitive stimulation and/or jitter studies
• Nerve conduction studies to exclude neuropathy
• Needle EMG to evaluate for concurrent myositis

Laboratory and Imaging

Essential workup 6:

• CPK, aldolase, ESR, CRP: To evaluate for concurrent myositis
• Pulmonary function tests: Negative inspiratory force and vital capacity (critical for assessing respiratory compromise risk)
• If respiratory insufficiency or elevated CPK: Troponin T, ECG, and transthoracic echocardiogram to rule out myocarditis
• MRI brain and/or spine: Consider based on symptoms to exclude CNS involvement or alternative diagnosis
• Chest CT or MRI: To evaluate for thymoma

Neurology consultation is mandatory 6.

Treatment Algorithm

Symptomatic Treatment

Pyridostigmine bromide is first-line symptomatic therapy 4:

• Start at 30 mg orally three times daily
• Gradually increase to maximum of 120 mg orally four times daily based on tolerance and symptom response
• Limitation: Only 50% of patients with strabismus-associated MG show meaningful response 4

Immunosuppressive Therapy

For patients inadequately controlled with pyridostigmine 5:

First-line immunosuppression:

• Corticosteroids: 66-85% of patients show positive response 4
  • Prednisone 1-1.5 mg/kg orally daily 6
  • Daily dosing is now standard practice (not alternate day) 7
  • Wean based on symptom improvement
• Azathioprine: Established efficacy as steroid-sparing agent 4
• Thymectomy: See below

Newer targeted therapies (for refractory disease) 7:

• Rituximab: Evidence supports early use within 1 year of generalized disease onset; less robust but still useful in established treatment-refractory MG
• Complement pathway inhibitors: Eculizumab, ravulizumab
• Neonatal Fc receptor antagonists: Efgartigimod, rozanolixizumab

Acute/Severe Disease Management

For Grade 3-4 toxicity or myasthenic crisis 6:

• Hospital admission with ICU-level monitoring capability
• Corticosteroids: Continue or initiate
• IVIG: 2 g/kg IV over 5 days (0.4 g/kg/day) OR
• Plasmapheresis: 5 days
• Frequent pulmonary function monitoring
• Daily neurologic evaluation

Thymectomy

Indications 1, 4:

• Always indicated in presence of thymoma
• Recommended for generalized AChR-positive MG, ideally within 2 years of disease onset 8
• Early thymectomy (within 2 years) shows clear beneficial effects 7
• May substantially reduce symptoms in specific age-based and immune-based subpopulations

Surgical Management of Strabismus

Timing: Consider only after 2-3 years of medical treatment when disease is stabilized or in remission 4

Approach:

• Adjustable sutures may be beneficial
• Multiple procedures may be necessary
• Critical precaution: Exercise extreme care with anesthetic agents if respiratory muscle weakness present
• Prism correction often insufficient due to variable deviation

Medications to Avoid

The following drugs can precipitate or worsen myasthenic weakness 6:

• β-blockers
• IV magnesium
• Fluoroquinolones
• Aminoglycosides
• Macrolides

Prognosis and Long-Term Management

With optimal treatment, prognosis is good 5. However:

• Remission or stabilization often possible after 2-3 years of treatment 4
• Long-term drug treatment essential for most patients 5
• Treatment must be tailored to specific MG subtype (based on antibody status)
• Mortality in many patients is not related to thymoma itself but to associated complications 9

Special Considerations

Immune checkpoint inhibitor-associated MG: May be monophasic; additional corticosteroid-sparing agents may not be required 6

Multidisciplinary care: Requires coordination between ophthalmology, neurology, and potentially thoracic surgery 4

Patient education and psychosocial support: Integral to effective management 8