What are the typical presentation, diagnostic work‑up, and management options for myasthenia gravis?

Myasthenia Gravis: Clinical Presentation, Diagnosis, and Management

Clinical Presentation

Myasthenia gravis presents with fluctuating, fatigable muscle weakness that worsens with repetitive use and improves with rest, most commonly beginning with ocular symptoms (ptosis and diplopia) in approximately 50% of patients. 1, 2

Ocular Manifestations

• Ptosis that worsens with sustained upward gaze and improves after rest 3, 2
• Diplopia from asymmetric, variable extraocular muscle weakness 3, 2
• Pupils are characteristically spared—this is a critical distinguishing feature that differentiates myasthenia gravis from third nerve palsy 1, 4, 2
• Cogan lid-twitch sign (brief eyelid overshoot when returning from downgaze to primary position) 2
• The disease can mimic many types of incomitant strabismus with or without ptosis 1

Bulbar and Generalized Manifestations

• Dysarthria that worsens with prolonged speech 3, 2
• Dysphagia—a red flag requiring urgent evaluation 3, 2
• Facial muscle weakness and hoarseness indicating bulbar involvement 4, 2
• Proximal muscle weakness greater than distal weakness 3, 4
• Difficulty climbing stairs (proximal lower limb weakness) 3, 2
• Neck weakness that can progress to respiratory involvement 3, 2

Critical Warning Signs Requiring Urgent Evaluation

• Respiratory symptoms or difficulty breathing with light activity 3, 4
• Progressive or new-onset dysphagia 3, 4
• Neck or respiratory muscle weakness—can lead to myasthenic crisis with life-threatening respiratory failure requiring intubation 1, 3, 2

Key Clinical Characteristics

• Variability: symptoms fluctuate throughout the day and can present with completely different patterns depending on fatigue level 1, 2
• Fatigability: weakness worsens with sustained or repeated muscle use 2, 5
• 50-80% of patients with initial ocular symptoms will progress to generalized myasthenia within a few years, most commonly within the first two years 1, 4, 2

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Diagnostic Work-Up

Bedside Clinical Tests (Perform First)

The ice pack test is highly specific for myasthenia gravis and should be performed immediately in suspected cases. 4, 2

• Ice pack test: Apply ice pack over closed eyes for 2 minutes (for ptosis) or 5 minutes (for strabismus); a positive test shows reduction of ptosis by approximately 2 mm or improvement in ocular alignment 4, 2
• Rest test: Temporary improvement in weakness after resting the affected muscles 4, 2

Serologic Testing (Essential for Diagnosis)

• Anti-acetylcholine receptor (AChR) antibodies: Present in nearly all patients with generalized myasthenia but only 40-77% of patients with ocular myasthenia 1, 4
• Anti-muscle-specific kinase (MuSK) antibodies: Should be ordered if AChR antibodies are negative, as approximately one-third of seronegative cases are MuSK-positive 4, 5
• Anti-lipoprotein-related protein 4 (LRP4) antibodies: Associated with both generalized and ocular myasthenia 4, 5
• About 50% of individuals with purely ocular myasthenia are seronegative for AChR antibodies; therefore a negative result does not exclude the diagnosis 4

Electrodiagnostic Studies

• Single-fiber electromyography (SFEMG): Has sensitivity >90% for ocular myasthenia and is the gold-standard test 4, 6
• Repetitive nerve stimulation (RNS): Demonstrates significant decrement in compound muscle action potential 5, 6
• Standard EMG and nerve conduction studies may be normal early in the disease course 4

Pharmacologic Testing (Use with Caution)

• Edrophonium (Tensilon) test: Demonstrates 86% sensitivity for ocular myasthenia but must be performed in a monitored setting with atropine (0.4-0.5 mg IV) readily available to treat potential muscarinic side effects (excessive tearing, salivation, sweating, bradycardia, bronchospasm, hypotension, syncope) 4, 6
• Empiric trial of pyridostigmine (starting at 30 mg orally three times daily) can serve both diagnostic and therapeutic purposes, though approximately 50% of ocular myasthenia patients exhibit minimal response 4

Imaging and Additional Studies

• Chest CT or MRI: Essential to evaluate for thymoma, as 10-15% of myasthenia gravis patients have thymoma, and thymectomy is indicated in the presence of thymoma 1, 2
• Thyroid function tests: Increased risk for autoimmune thyroid disease 1, 2
• Pulmonary function testing: Regular assessment is crucial in patients with generalized myasthenia to monitor for respiratory compromise 4

Important Diagnostic Pitfalls

• If pupils are abnormal, immediately consider other etiologies, particularly third nerve palsy, as pupillary involvement should not occur in myasthenia gravis 1, 4, 2
• A negative SFEMG result is atypical and warrants careful reconsideration of the differential diagnosis 4
• Electrodiagnostic studies are operator-dependent and require specialized equipment and expertise 4

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Management Options

Disease Classification (Guides Treatment Decisions)

The Myasthenia Gravis Foundation of America (MGFA) classification system: 4, 2

• Class I: Ocular myasthenia only
• Class II: Mild generalized weakness
• Class III: Moderate generalized weakness
• Class IV: Severe generalized weakness
• Class V: Myasthenic crisis requiring intubation

Treatment Algorithm

For MGFA Class I-II (Ocular or Mild Generalized Disease)

First-line treatment is pyridostigmine, starting at 30 mg orally three times daily and gradually increasing to a maximum of 120 mg orally four times daily as tolerated. 4

• Approximately 50% of ocular myasthenia patients may show minimal response to pyridostigmine alone 4
• Second-line treatment: Add corticosteroids (prednisone 1-1.5 mg/kg orally daily) if symptoms persist despite pyridostigmine 4
• Approximately 66-85% of patients show a positive response to corticosteroids 4

For MGFA Class III-V (Moderate to Severe or Crisis)

Immediate actions required: 4

• Admit patient with ICU-level monitoring capability
• Obtain urgent neurology consultation
• Permanently discontinue any causative immune checkpoint inhibitors

Acute treatment options: 4

• Corticosteroids (prednisone 1-1.5 mg/kg orally daily)
• IVIG (2 g/kg over 5 days)
• Plasmapheresis
• Combination therapy with pyridostigmine and prednisone for moderate to severe disease

Third-Line Immunosuppressive Therapy

• Azathioprine: Can be used for patients with moderate to severe disease who require steroid-sparing agents 4, 6
• Other options include cyclosporine and mycophenolate mofetil 6

Thymectomy

Thymectomy is indicated in the presence of thymoma and should be considered for specific age-based and immune-based characteristics, as it may substantially reduce clinical symptoms. 1, 4

• All patients suspected of having thymomas should have serum anti-AChR antibody levels measured before any surgical procedure 4
• Approximately 30-50% of thymoma patients have myasthenia gravis 4, 2

Medications to Avoid

The following medications should be avoided in patients with myasthenia gravis due to potential exacerbation of symptoms: 4

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

Surgical Management of Ocular Manifestations

For patients with stable, chronic ocular myasthenia: 1

• Prism correction may be used for diplopia management
• Strabismus surgery may be considered after disease stabilization
• Ptosis surgery should be tempered if Bell's response is extremely impaired (risk of exposure keratopathy)
• Postoperative prism correction may be required to allow for fusion in primary or reading position

Monitoring and Follow-Up

• Regular pulmonary function assessment is crucial given the risk of progression to respiratory involvement 4
• Monitor for progression from ocular to generalized disease, particularly within the first two years 4, 2
• Collaboration between ophthalmology and neurology is necessary for comprehensive management 4

Prognosis

• With improved diagnostic testing, immunotherapy, and intensive care, contemporary prognosis is favorable with less than 5% mortality and nearly normal life expectancy 6
• Myasthenic crisis (Class V) is life-threatening and requires immediate ventilatory support and aggressive immunotherapy 4