What is the appropriate evaluation and management for a 35‑year‑old who develops marked fatigue, generalized muscle aches, lower‑leg weakness, and drooping eyelids after intense exercise lasting 2–3 days?

Myasthenia Gravis Evaluation and Management

This patient requires urgent neurologic evaluation for myasthenia gravis, given the combination of exercise-induced fatigue, muscle weakness, and drooping eyelids—a classic triad that demands immediate diagnostic workup to prevent potentially life-threatening respiratory compromise.

Clinical Reasoning

The presentation is highly suspicious for myasthenia gravis based on several key features:

• Drooping eyelids (ptosis) after exertion is often the first symptom of myasthenia gravis and is characteristic of ocular involvement 1
• Muscle aches and lower leg weakness lasting 2-3 days after intense workouts represents the hallmark fatigable weakness that worsens with activity 1, 2
• Extreme fatigue following exercise aligns with the neuromuscular junction dysfunction where symptoms worsen with continued muscle use 1
• The 35-year-old age fits the typical demographic, as adult-onset myasthenia gravis commonly occurs in the third to fourth decade in women and slightly later in men 1

Critical distinction: While the American Heart Association guidelines flag chronic fatigue after exercise as a sign of over-exercising 3, the addition of drooping eyelids and the specific pattern of lower extremity weakness point away from simple overtraining toward neuromuscular pathology 1, 4.

Immediate Diagnostic Workup

Bedside Clinical Tests (Perform Today)

Ice pack test – This is your most immediate diagnostic tool:

• Apply an ice pack over closed eyelids for 2 minutes to assess ptosis 5, 2
• A positive test shows improvement of ptosis by ≥2 mm and is highly specific for myasthenia gravis 5
• The physiologic basis is that cooling slows acetylcholine breakdown, temporarily improving neuromuscular transmission 5

Sustained upgaze test:

• Have the patient look upward continuously for 30-60 seconds 2
• Progressive worsening of ptosis or development of diplopia indicates fatigable weakness characteristic of myasthenia gravis 2

Sustained arm abduction test:

• Patient holds arms extended at 90 degrees for 1-2 minutes 2
• Observe for progressive weakness, which would support the diagnosis 2

Essential Laboratory Studies

Serologic panel (order immediately):

• Anti-acetylcholine receptor (AChR) antibodies – present in 80% of generalized myasthenia gravis but only 50% of ocular cases 2
• If AChR antibodies are negative, order anti-muscle-specific kinase (MuSK) antibodies, as one-third of seronegative patients are MuSK-positive 5, 2
• Anti-lipoprotein-related protein 4 (LRP4) antibodies should also be considered in seronegative cases 1, 5
• Anti-striated muscle antibodies to identify higher risk for thymoma 5, 2

Screening for concurrent conditions:

• Creatine kinase (CPK), aldolase, ESR, and CRP to evaluate for concurrent myositis 1, 2
• Troponin T and ECG to rule out myocarditis, especially if respiratory symptoms develop 1, 2
• Thyroid-stimulating hormone to exclude thyroid disease, which frequently coexists with myasthenia gravis 1

Respiratory Assessment (Critical)

Pulmonary function testing with negative inspiratory force (NIF) and vital capacity:

• This is essential because dysphagia and bulbar weakness precede myasthenic crisis in more than 50% of cases 5, 2
• The patient's extreme fatigue after exertion raises concern for potential respiratory muscle involvement 2
• Early respiratory compromise can be fatal if missed 1

Electrodiagnostic Studies

Repetitive nerve stimulation:

• Slow-frequency (2-3 Hz) stimulation showing >10% decrement in compound muscle action potential amplitude supports myasthenia gravis 2

Single-fiber electromyography (SFEMG):

• Gold standard with >90% sensitivity for ocular myasthenia gravis 5, 2
• Measures increased "jitter" (variability in neuromuscular transmission) 2

Imaging

Chest CT with contrast:

• Mandatory after diagnosis confirmation to evaluate for thymoma, present in 10-20% of AChR-positive patients 2
• Thymoma is a risk factor for myasthenia gravis and requires different management 1

Management Algorithm

If Diagnosis Confirmed

Discontinue exercise immediately until symptoms are controlled – the American Heart Association guidelines correctly identify chronic fatigue and inability to finish workouts as signs of over-exercising 3, but in the context of myasthenia gravis, continued intense exercise could precipitate crisis 1.

Medication review:

• Avoid beta-blockers, IV magnesium, fluoroquinolones, aminoglycosides, and macrolide antibiotics, which can precipitate myasthenic crisis 1, 5

Initiate treatment under neurology guidance:

• First-line: Pyridostigmine 30 mg orally three times daily, gradually increasing to maximum 120 mg four times daily as tolerated 5, 2
• However, approximately 50% of patients with ocular myasthenia show minimal response to pyridostigmine alone 5
• Second-line: Corticosteroids (prednisone 1-1.5 mg/kg daily) if symptoms persist, with 66-85% showing positive response 1, 5
• Third-line: Immunosuppressive therapy with azathioprine for moderate to severe disease 5

Thymectomy consideration:

• Indicated if thymoma is identified on imaging 1, 5

Critical Prognostic Information

50-80% of patients with initial ocular symptoms develop generalized myasthenia gravis within a few years, most commonly within the first two years 1, 5, 2. This makes early diagnosis and close monitoring essential to prevent life-threatening respiratory failure 1.

Common Pitfalls to Avoid

• Do not dismiss this as simple overtraining syndrome – the presence of ptosis is a red flag that distinguishes myasthenia gravis from exercise-related fatigue 1, 4
• Do not delay respiratory assessment – respiratory muscle weakness is the most life-threatening manifestation and can progress rapidly 1, 2
• Do not initiate treatment in primary care – definitive management must be overseen by a neurologist experienced in myasthenia gravis 5
• Do not assume negative AChR antibodies exclude the diagnosis – 50% of ocular myasthenia cases are seronegative 5

Urgent Neurology Referral

Refer immediately – all grades of myasthenia gravis warrant thorough workup and intervention given the potential for progressive disease leading to respiratory compromise 1, 5. Early recognition allows for appropriate treatment and prevention of potentially fatal complications 1.