Myasthenia Gravis for the American Board of Psychiatry & Neurology (ABPN) Exam
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Pathophysiology
Autoimmune Mechanism
- Myasthenia Gravis (MG) is primarily an autoimmune disorder where the body produces antibodies against acetylcholine receptors (AChR) at the neuromuscular junction.
- These antibodies impair the function of the receptors, leading to reduced transmission of nerve impulses to muscles, which manifests as muscle weakness.
- Less common antibodies: Anti-MuSK (muscle-specific kinase) antibodies are present in some patients, particularly those who are AChR antibody-negative. Anti-LRP4 antibodies are also implicated in a minority of cases.
- The thymus plays a crucial role in the pathogenesis of MG. About 65% of patients with MG have thymic hyperplasia, and 10-15% have thymomas.
- The thymus is thought to be the site where the autoimmune response against AChR is initiated.
Clinical Presentation
Ocular Symptoms
- Ptosis (drooping of one or both eyelids) and diplopia (double vision) are the most common initial symptoms.
- Ocular symptoms can fluctuate during the day, often worsening with fatigue.
- Weakness typically follows a descending pattern, starting with the ocular muscles and progressing to bulbar muscles (affecting speech and swallowing), and finally to limb and respiratory muscles.
- Fatigability: Muscle weakness characteristically worsens with use and improves with rest.
- Dysarthria (slurred speech) and dysphagia (difficulty swallowing) are common in more advanced stages.
- Respiratory muscle weakness can lead to a life-threatening condition known as myasthenic crisis, which requires immediate medical attention.
Diagnosis
Serological Testing
- Anti-AChR antibodies: Present in approximately 85% of patients with generalized MG and 50-60% of those with purely ocular MG.
- Anti-MuSK antibodies: Found in 30-40% of patients who are AChR-negative. These patients often present with a more severe form of the disease, predominantly affecting bulbar and respiratory muscles.
- Repetitive Nerve Stimulation (RNS): Shows a decremental response (a progressive decline in the amplitude of the muscle action potential) with repetitive stimulation.
- Single-Fiber EMG: The most sensitive diagnostic test, showing increased jitter (variability in neuromuscular transmission) and blocking.
Imaging
- Chest CT or MRI: Performed to evaluate for the presence of a thymoma, which is associated with MG in a significant number of cases.
- Ice Pack Test: A non-invasive bedside test where the application of an ice pack to the eyelid improves ptosis, supporting the diagnosis of MG.
Treatment
Symptomatic Treatment
- Acetylcholinesterase Inhibitors:
- Pyridostigmine is the first-line treatment for symptomatic relief. It increases the concentration of acetylcholine at the neuromuscular junction, enhancing neuromuscular transmission.
Immunosuppressive Therapy
- Corticosteroids: Often the first immunosuppressive agent used, particularly in moderate to severe cases.
- Other Immunosuppressants: Azathioprine, mycophenolate mofetil, or cyclosporine may be used for long-term management, especially to reduce the need for corticosteroids.
- Rituximab: Increasingly used in refractory MG, particularly in MuSK-positive patients.
- Myasthenic Crisis: Requires immediate treatment in an intensive care unit with respiratory support and either plasmapheresis or intravenous immunoglobulin (IVIG).
- Cholinergic Crisis: Can occur due to overmedication with acetylcholinesterase inhibitors, leading to symptoms such as muscle twitching, sweating, and salivation. Differentiation from myasthenic crisis is critical as treatment strategies differ.
- Thymectomy: Indicated in patients with thymoma and recommended in generalized MG even in the absence of a thymoma, especially in younger patients. Thymectomy can lead to significant long-term improvement and even remission in some cases.
Prognosis and Long-Term Monitoring
Prognosis: With appropriate treatment, many patients achieve good control of symptoms and can lead relatively normal lives. However, the disease requires ongoing management and monitoring.
Long-Term Monitoring
- Regular follow-up is essential to monitor disease progression, assess treatment efficacy, and manage any complications such as myasthenic crisis or side effects from long-term immunosuppressive therapy.
- Monitoring for thymoma recurrence or development in those who have undergone thymectomy is also important.
Commonly Tested Items on the ABPN Exam
- Pathophysiology: The role of autoantibodies (AChR, MuSK) and the thymus in MG.
- Diagnosis: Interpretation of serological tests and electrophysiological studies (RNS, single-fiber EMG).
- Management: The use of acetylcholinesterase inhibitors, immunosuppressive therapy, and the management of myasthenic crisis.
- Thymectomy: Indications for thymectomy, particularly in relation to thymoma and generalized MG.