Myasthenia gravis

A 35 year old woman presents to her primary care physician with progressive muscle weakness over the past few months. She initially noticed difficulty keeping her eyelids open, especially in the evening. She also reports diplopia, dysphagia, and dysarthria, which worsen with activity and improve with rest. She also reports weakness in her arms and legs, particularly after prolonged use. On examination, deep tendon reflexes are normal, pupils are normal, and there are no sensory deficits. Fatigability is present. Vital signs are normal. Laboratory studies show positive anti-acetylcholine receptor antibodies. Repetitive nerve stimulation shows a decremental response. MRI of the chest reveals a thymoma. Diagnosis?

Diagnosis is Myasthenia gravis.

1. Definition

Myasthenia gravis is an autoimmune disorder of the neuromuscular junction characterized by fluctuating muscle weakness due to antibodies against postsynaptic proteins, most commonly the acetylcholine receptor.

2. Pathophysiology

1. Autoantibodies against acetylcholine receptors (AChR), MuSK, or LRP4
2. In AChR MG, antibodies activate complement, causing destruction of the postsynaptic membrane
3. In MuSK MG, antibodies disrupt the Agrin–LRP4–MuSK complex without complement activation
4. Leads to reduced acetylcholine receptor density
5. Results in reduced safety factor of neuromuscular transmission
6. Weakness worsens with repeated use

3. Clinical Features

3.1 Core Features

1. Fluctuating weakness that worsens with activity and improves with rest
2. Symptoms are worse later in the day

3.2 Ocular Involvement

1. Ptosis
2. Diplopia
3. Present in approximately 85 percent of cases initially

3.3 Bulbar Involvement

1. Dysphagia
2. Dysarthria
3. Hoarseness

3.4 Limb Weakness

1. Proximal muscles more affected than distal
2. Upper limbs more affected than lower limbs

3.5 Examination Findings

1. Normal reflexes
2. No sensory deficits
3. Pupils are spared
4. Weakness demonstrated with repetitive use

4. Associated Conditions

1. Thymic hyperplasia
2. Thymoma present in approximately 10 percent of patients
3. Association with other autoimmune diseases

5. Diagnosis

1. Anti-acetylcholine receptor antibodies present in most generalized cases
2. Anti-MuSK antibodies in a subset
3. Electrophysiologic testing
• Repetitive nerve stimulation shows decremental response
• Single fiber electromyography is the most sensitive test
4. Edrophonium test
• May show transient improvement
• Rarely used now
5. Ice pack test improves ptosis
6. Chest imaging (CT or MRI) to evaluate for thymoma

6. Triggers and Exacerbating Factors

1. Infections
2. Surgery
3. Stress
4. Pregnancy
5. Drugs such as:
• Aminoglycosides
• Fluoroquinolones
• Beta blockers
• Neuromuscular blocking agents

7. Management

7.1 Symptomatic Treatment

1. Pyridostigmine is first line

7.2 Immunosuppressive Therapy

1. Corticosteroids
2. Azathioprine as first line steroid sparing agent
3. Other agents include mycophenolate, cyclosporine, tacrolimus, and methotrexate

7.3 Rapid Therapy

1. Intravenous immunoglobulin (IVIG)
2. Plasmapheresis
• Used in myasthenic crisis

7.4 Surgical

1. Thymectomy
• Indicated in thymoma
• Recommended in many AChR positive patients aged 15 to 50 years
• Not typically recommended in MuSK MG without thymoma

8. Complications

1. Myasthenic crisis causing respiratory failure
2. Aspiration pneumonia
3. Adverse effects of long term immunosuppression

9. Key Clinical Insight

Fluctuating weakness + ocular symptoms + fatigability + normal reflexes + spared pupils + positive AChR antibodies = Myasthenia gravis

10. Exam Level Pearls

1. Weakness worsens with use and improves with rest
2. Ocular symptoms are most common initial presentation
3. Reflexes and sensation are normal
4. Pupils are spared
5. Single fiber EMG is most sensitive
6. Pyridostigmine is first line therapy
7. Thymoma occurs in about 10 percent of patients
8. Myasthenic crisis is life threatening
9. Lambert Eaton improves with use, MG worsens with use