Myasthenia gravis

A 35-year-old woman presents with progressive, fluctuating muscle weakness. She initially develops ptosis and diplopia, particularly later in the day, followed by dysphagia, dysarthria, and proximal limb weakness. Symptoms worsen with repeated activity and improve with rest. Examination shows fatigable weakness with spared pupils, preserved deep tendon reflexes, and intact sensation. Anti-acetylcholine receptor antibodies are positive. Repetitive nerve stimulation shows a decremental response. Chest imaging demonstrates a thymoma. Diagnosis?

Diagnosis is Generalized AChR antibody-positive myasthenia gravis associated with thymoma.

1. Definition

Myasthenia gravis (MG) is an autoimmune disorder of the postsynaptic neuromuscular junction characterized by fluctuating, fatigable skeletal muscle weakness that typically worsens with activity and improves with rest.

2. Pathophysiology

1.      Autoantibodies target postsynaptic proteins, most commonly the acetylcholine receptor (AChR).

2.      Less commonly, antibodies target MuSK or LRP4.

3.      In AChR-positive MG, antibodies cause complement-mediated postsynaptic membrane injury and loss of functional AChRs.

4.      MuSK antibodies disrupt MuSK signaling and AChR clustering.

5.      Reduced neuromuscular transmission decreases the safety factor, producing fatigable weakness.

3. Clinical Features

3.1 Characteristic Pattern

1.      Fluctuating, fatigable weakness

2.      Worse with repeated activity

3.      Improves with rest

4.      Often worse later in the day

3.2 Ocular Features

1.      Ptosis

2.      Diplopia

3.      Ocular symptoms are commonly the initial manifestation.

4.      Pupils are spared.

3.3 Bulbar Features

1.      Dysarthria

2.      Dysphagia

3.      Weakness of mastication

4.      Nasal or weak speech

3.4 Generalized Features

1.      Proximal limb weakness

2.      Neck weakness

3.      Respiratory muscle weakness in severe disease

3.5 Examination Findings

1.      Fatigable weakness

2.      Preserved sensation

3.      Preserved deep tendon reflexes

4.      Spared pupils

4. Thymic Association

1.      MG is associated with thymic follicular hyperplasia and thymoma.

2.      Approximately 10 to 15% of patients with MG have a thymoma.

3.      Patients with MG should undergo chest CT or MRI to evaluate for thymoma.

4.      Thymectomy is indicated for thymoma when surgical resection is appropriate.

5. Diagnosis

1.      AChR antibodies

o    Present in approximately 80 to 85% of generalized MG

o    Highly specific in the appropriate clinical setting

2.      MuSK antibodies

o    Consider when AChR antibodies are negative

o    Often associated with prominent bulbar, facial, neck, or respiratory weakness

3.      Repetitive nerve stimulation

o    Shows a decremental compound muscle action potential response

4.      Single-fiber EMG

o    Shows increased jitter and blocking

o    The most sensitive electrophysiologic test for impaired neuromuscular transmission, but not specific for MG

5.      Ice-pack test

o    May transiently improve myasthenic ptosis

6.      Chest CT or MRI

o    Used to evaluate for thymoma

6. Factors That May Exacerbate MG

1.      Infection

2.      Surgery or physiologic stress

3.      Drugs that may worsen MG include:

o    Aminoglycosides

o    Fluoroquinolones

o    Macrolides

o    Beta blockers

o    Magnesium

o    Neuromuscular blocking agents

7. Management

7.1 Symptomatic Therapy

Pyridostigmine, an acetylcholinesterase inhibitor, is commonly used for symptomatic improvement.

7.2 Immunotherapy

Generalized MG often requires immunotherapy.

1.      Corticosteroids

2.      Azathioprine as a commonly used steroid-sparing agent

3.      Other options include mycophenolate mofetil and tacrolimus

7.3 Rapid Immunomodulatory Therapy

IVIG or plasma exchange is used when rapid improvement is required, particularly in:

1.      Myasthenic crisis

2.      Severe exacerbation

3.      Significant bulbar or respiratory weakness

4.      Selected patients requiring stabilization before surgery

7.4 Thymectomy

1.      Thymoma

o    Surgical resection is indicated when appropriate.

o    The primary purpose is treatment of the tumor.

o    Thymectomy does not guarantee remission of MG.

2.      Nonthymomatous generalized MG

o    Thymectomy should be considered early in AChR antibody-positive generalized MG, particularly in younger adults.

o    Routine thymectomy is not recommended for MuSK-positive MG without thymoma.

8. Complications

1.      Myasthenic crisis

o    Life-threatening respiratory or severe bulbar weakness that may require ventilatory support

o    Requires urgent respiratory assessment and treatment with IVIG or plasma exchange

2.      Aspiration pneumonia

3.      Complications of long-term immunosuppressive therapy

9. Key Clinical Insight

Fluctuating fatigable weakness + ptosis/diplopia + bulbar weakness + spared pupils + preserved reflexes + intact sensation + positive AChR antibodies + decrement on repetitive nerve stimulation = Myasthenia gravis.

In this patient, bulbar and limb involvement establishes generalized MG, while positive AChR antibodies and thymoma further characterize the disease.

References

1.      Narayanaswami P, Sanders DB, Wolfe G, et al. International Consensus Guidance for Management of Myasthenia Gravis: 2020 Update. Neurology. 2021;96(3):114-122. doi:10.1212/WNL.0000000000011124.

2.      Wiendl H, Abicht A, Chan A, et al. Guideline for the management of myasthenic syndromes. Ther Adv Neurol Disord. 2023;16:17562864231213240. doi:10.1177/17562864231213240.

3.      Wolfe GI, Kaminski HJ, Aban IB, et al. Randomized Trial of Thymectomy in Myasthenia Gravis. N Engl J Med. 2016;375(6):511-522. doi:10.1056/NEJMoa1602489.