What are the clinical and diagnostic features and tests used to diagnose myasthenia gravis?

Clinical and Diagnostic Features of Myasthenia Gravis

Myasthenia gravis (MG) is an autoimmune disorder affecting the neuromuscular junction, characterized by fluctuating skeletal muscle weakness and fatigability that worsens with exertion and improves with rest, with diagnosis confirmed through a combination of clinical features, antibody testing, and electrophysiological studies. 1

Clinical Presentation

Characteristic Symptoms

• Muscle weakness and fatigability that worsens with repeated or sustained activity and improves with rest
• Ocular symptoms (present in 50% of patients initially):
  • Ptosis (drooping eyelids) that worsens with fatigue and may show Cogan lid-twitch sign
  • Variable strabismus causing diplopia (double vision)
  • Slow ocular saccades 2
• Bulbar symptoms:
  • Dysarthria (slurred speech)
  • Dysphagia (difficulty swallowing)
  • Facial muscle weakness 1
• Limb weakness (typically proximal more than distal)
• Respiratory muscle weakness in severe cases 1

Clinical Patterns

• Ocular MG: Limited to eye muscles (ptosis and diplopia)
• Generalized MG: Affects multiple muscle groups beyond ocular muscles
• Bulbar MG: Predominant involvement of speech and swallowing muscles
• Respiratory MG: Significant involvement of respiratory muscles requiring ventilatory support

Disease Course

• 50-80% of patients with initial ocular symptoms develop generalized MG within a few years 1
• Disease severity may fluctuate with periods of exacerbation and remission
• Myasthenic crisis may occur with rapid worsening of symptoms and respiratory compromise

Diagnostic Evaluation

Laboratory Tests

1. Antibody testing:
   • Acetylcholine receptor (AChR) antibodies: positive in 80-85% of patients 3
   • Muscle-specific kinase (MuSK) antibodies: positive in 5-8% of patients 3
   • Lipoprotein-related protein 4 (LRP4) antibodies: positive in <1% of patients 3
   • Anti-striated muscle antibodies: often associated with thymoma 1
   • Approximately 10% of patients are seronegative for all known antibodies 3

Electrophysiological Tests

1. Repetitive nerve stimulation: Shows decremental response in affected muscles (positive in only one-third of patients with ocular MG) 2
2. Single-fiber electromyography (SFEMG): Shows increased jitter; considered the gold standard for diagnosis with >90% sensitivity for ocular MG 2
3. Nerve conduction studies: To exclude neuropathy 1

Pharmacological Tests

1. Edrophonium (Tensilon) test:

   • Intravenous administration: 2 mg initially, followed by 8 mg if no response after 45 seconds
   • Positive test shows temporary improvement in muscle strength
   • 95% sensitive for generalized MG and 86% sensitive for ocular MG 2, 4
   • Must be performed in a monitored setting with atropine available for potential cholinergic side effects 2

2. Ice pack test:

   • Application of ice pack over closed eyes for 2 minutes (ptosis) or 5 minutes (strabismus)
   • Positive test shows reduction of ptosis by about 2 mm or reduction of misalignment
   • Highly specific for MG 2

Imaging Studies

1. Chest CT or MRI: To evaluate for thymoma (present in 10-20% of AChR-positive MG patients) 1
2. Brain/spine MRI: To rule out other neurological conditions that may mimic MG 1

Pulmonary Function Tests

• Negative inspiratory force (NIF) and vital capacity (VC) to assess respiratory function 1

Common Diagnostic Pitfalls

1. Misdiagnosis as psychiatric disorder: Fluctuating symptoms may be mistaken for conversion disorder
2. Incomplete antibody testing: Testing only for AChR antibodies may miss MuSK or LRP4 antibody-positive cases
3. False-negative electrophysiological tests: Single tests may be negative, especially in ocular MG
4. Medication-induced exacerbation: Certain medications can unmask or worsen MG symptoms
5. Failure to recognize thymoma: Present in 10-20% of patients with AChR antibodies

Differential Diagnosis

• Lambert-Eaton myasthenic syndrome
• Botulism
• Guillain-Barré syndrome and its variants
• Brainstem stroke or inflammation
• Multiple sclerosis
• Thyroid ophthalmopathy
• Mitochondrial myopathies
• Drug-induced myasthenic syndromes
• Congenital myasthenic syndromes 2

Diagnostic Algorithm

1. Clinical suspicion based on characteristic fluctuating muscle weakness
2. Antibody testing for AChR, MuSK, and LRP4 antibodies
3. Pharmacological testing with edrophonium or ice pack test
4. Electrophysiological testing with repetitive nerve stimulation and SFEMG
5. Chest imaging to evaluate for thymoma
6. Pulmonary function tests to assess respiratory status

By following this systematic approach to diagnosis, clinicians can accurately identify myasthenia gravis and initiate appropriate management to improve morbidity, mortality, and quality of life outcomes for patients with this challenging autoimmune disorder.