Myasthenia Gravis

Detailed Overview

The hallmark of MG is muscle weakness that worsens with exertion and improves with rest. It commonly affects ocular, bulbar, respiratory, and limb muscles. The thymus gland plays a central role in the pathogenesis of AChR-antibody positive MG, with thymic hyperplasia or thymomas frequently present. Without treatment, MG can lead to life-threatening respiratory failure.

Epidemiology & Demographics

Prevalence is approximately 15 to 20 per 100,000. It shows a bimodal distribution: an early peak in the 2nd-3rd decades (female predominant) and a late peak in the 6th-8th decades (male predominant).

Etiological Mechanism

Caused by pathogenic autoantibodies. 85% of generalized MG patients have anti-AChR antibodies. The thymus is abnormal in 75% of AChR-positive patients (65% hyperplasia, 10% thymoma).

Primary Causes

Antibody-mediated blockade, cross-linking/internalization, and complement-mediated destruction of postsynaptic acetylcholine receptors at the neuromuscular junction.

• Thymoma: Presence of a thymoma is highly associated with the development of paraneoplastic MG.
• Other autoimmune diseases: Concurrent thyroid disease, rheumatoid arthritis, or lupus increases risk.
• Medication triggers: Certain drugs (fluoroquinolones, aminoglycosides, beta-blockers) can unmask or exacerbate MG.

In normal neuromuscular transmission, acetylcholine is released from the presynaptic nerve terminal and binds to AChRs on the muscle endplate, generating an endplate potential (EPP). In MG, autoantibodies bind to the AChR. This activates the classical complement pathway resulting in destruction of the junctional folds (MAC complex formation). It also increases AChR turnover and blocks the binding site. The reduced number of functional receptors decreases the EPP. During repeated muscle contraction, the normal physiologic decline in ACh release leads to a failure to reach the threshold for an action potential, resulting in clinical fatigue.

Characteristic Clinical Presentation

• Ptosis: Drooping of one or both eyelids, often worsening towards the evening.
• Diplopia: Double vision due to asymmetric extraocular muscle weakness.
• Bulbar weakness: Dysarthria (slurred speech), dysphagia (difficulty swallowing), and difficulty chewing tough foods.
• Fatigable limb weakness: Weakness typically proximal > distal, notably in the arms, worsening with repetitive activity.

Physical Examination Signs

• Enhancement of ptosis with sustained upward gaze (fatigability).
• Ice pack test positive: Ptosis improves by >= 2 mm after applying ice to the eyelid for 2 minutes.
• Normal pupillary responses and normal deep tendon reflexes (differentiates from Lambert-Eaton).

• Myasthenic Crisis: Life-threatening exacerbation causing respiratory muscle failure requiring intubation.
• Aspiration Pneumonia: Resulting from severe bulbar weakness and dysphagia.
• Cholinergic Crisis: Weakness from overtreatment with acetylcholinesterase inhibitors, characterized by excessive salivation, sweating, and bradycardia.

Diagnostic Criteria & Guidelines

Clinical presentation combined with positive serology (AChR or MuSK antibodies). If seronegative, diagnosis requires electrodiagnostic confirmation with Repetitive Nerve Stimulation (RNS) showing a >10% decremental response, or Single-Fiber EMG showing increased 'jitter'.

Differential Diagnosis

• Lambert-Eaton Myasthenic Syndrome (LEMS)
• Botulism
• ALS (Amyotrophic Lateral Sclerosis)
• Thyroid eye disease

Laboratory Tests & Biomarkers

• Anti-AChR Antibody: Elevated in 85% of generalized MG and 50% of ocular MG.
• Anti-MuSK Antibody: Positive in about 40% of AChR-negative generalized MG patients.
• Thyroid Function Tests (TSH/Free T4): Often checked as thyroid disorders are frequently comorbid.

Imaging Modalities & Findings

• CT or MRI of the Chest without contrast:

• Class I
  Any ocular muscle weakness; may have ptosis. All other muscle strength is normal.
• Class II
  Mild weakness affecting other than ocular muscles; may also have ocular muscle weakness of any severity.
• Class V
  Defined by the need for intubation, with or without mechanical ventilation (Myasthenic Crisis).

Second-Line & Adjunctive Therapy

Mycophenolate mofetil (1000 mg PO BID) or Tacrolimus. For refractory disease: Eculizumab (complement inhibitor) or Efgartigimod (FcRn antagonist).

Surgical & Procedural Management

Thymectomy via VATS or sternotomy is recommended for all patients with thymoma, and for AChR-positive, non-thymomatous patients aged 18-50 to improve clinical outcomes and reduce medication requirements.

Recommended Lifestyle Changes

• Plan energy-consuming activities for the morning when strength is typically best.
• Eat small, frequent meals with soft textures to minimize chewing fatigue and choking risk.
• Avoid high heat, which can exacerbate weakness.

Patient Counseling & Advice

Provide a list of contraindicated medications (e.g., ciprofloxacin, magnesium supplements, certain anesthetics). Emphasize going to the ER for shortness of breath or difficulty clearing secretions.

Follow-Up & Monitoring Schedule

Monitor forced vital capacity (FVC) and negative inspiratory force (NIF) during clinic visits if the patient has respiratory symptoms. Assess MG-ADL (Activities of Daily Living) score at every visit.

Preventive Strategies

Infection prevention (pneumococcal and influenza vaccines) is crucial, as infections are the most common trigger for myasthenic crisis.

With modern treatment, mortality is <5%. The life expectancy is typically normal. Maximum weakness usually occurs within the first 2-3 years of onset.