What is myasthenia gravis and how is it managed?

Myasthenia Gravis: Comprehensive Overview

What Is Myasthenia Gravis?

Myasthenia gravis is a B-cell mediated autoimmune disorder where antibodies attack the neuromuscular junction, causing fluctuating muscle weakness that worsens with activity and improves with rest, with potential progression to life-threatening respiratory failure. 1

The disease disrupts normal nerve-to-muscle signal transmission when antibodies target acetylcholine receptors (AChR), preventing acetylcholine from properly binding to muscle fibers. 1 This autoimmune attack reduces the number of functional receptors available at the motor endplate, resulting in lower amplitude muscle stimulations and progressive weakness with repeated use. 2

Disease Classification

Myasthenia gravis presents in two main forms: 1

• Ocular myasthenia gravis (MGFA Class I): Limited to levator, orbicularis oculi, and extraocular muscles 1, 3
• Generalized myasthenia gravis (MGFA Classes II-V): Affects larger muscle groups including bulbar, limb, and respiratory muscles 1, 3

The Myasthenia Gravis Foundation of America (MGFA) classification system grades severity from Class I (mildest, ocular only) through Class V (most severe, requiring intubation for myasthenic crisis). 3

Epidemiology and Risk Factors

• Incidence ranges from 0.04 to 5 per 100,000 people annually, with prevalence of 0.5 to 12.5 per 100,000 1
• Women typically develop symptoms in their third to fourth decade of life 1
• Men develop the disease later in life 1
• Thymoma (thymic tumor) is a significant risk factor, present in 10-20% of AChR-positive patients 3
• The disease affects all ages, races, and geographic regions 1

Pathophysiology

In healthy neuromuscular transmission, acetylcholine is released during an action potential and crosses the synapse to bind muscle fiber receptors. 1 In myasthenia gravis, this process is disrupted by pathogenic antibodies:

• AChR antibodies are found in nearly all patients with generalized MG and 40-77% with ocular MG 1, 4
• MuSK antibodies are detected in approximately 6% of patients 5
• LRP4 antibodies represent a third autoantigen target 5
• Extraocular muscles are particularly vulnerable due to their twitch fiber composition and fewer acetylcholine receptors 1, 4

Clinical Presentation

Ocular Manifestations (Often First to Appear)

• Ptosis (drooping eyelids): May be unilateral or bilateral 4, 3
• Diplopia (double vision): Results from extraocular muscle weakness 4
• Variable strabismus: Characteristic misalignment of eyes that changes during examination 1, 4
• Slow ocular saccades: Impaired rapid eye movements 1

Bulbar Manifestations

• Dysarthria: Slurred speech from facial and pharyngeal muscle weakness 4, 3
• Dysphagia: Difficulty swallowing 4, 3
• Facial weakness: Reduced facial expressions 4
• Neck weakness: Difficulty holding up the head 1, 4

Limb and Trunk Involvement

• Proximal muscle weakness: Affects proximal muscles more than distal ones 4, 3
• Bilateral but asymmetrical: Weakness is typically on both sides but may be uneven 4, 3
• Trunk muscle involvement: Affects posture 4

Respiratory Manifestations (Most Serious)

• Respiratory muscle weakness: Can progress to respiratory insufficiency or failure 1, 4
• Myasthenic crisis: Life-threatening complication requiring ventilatory support 1, 3

Hallmark Clinical Characteristics

• Fluctuating weakness: Symptoms worsen with continued activity and improve with rest 1, 4
• Fatiguability: Weakness worsens as the day progresses or with repetitive muscle use 1, 4
• Variable presentation: Pattern of weakness changes during examination 1, 4
• Temporary improvement with rest or ice: Ice pack test shows characteristic improvement 1, 4
• "Great masquerader": Can mimic many eye movement disorders 1

Natural History and Progression

• 50% of patients initially present with ocular symptoms only 4, 3
• 50-80% of those with ocular onset develop generalized MG within a few years 1, 4
• Progression typically follows: ocular → bulbar → limb → respiratory involvement 4
• Without treatment, the disease can lead to respiratory failure requiring mechanical ventilation 1

Diagnostic Approach

Clinical Diagnosis

Diagnosis is based on the characteristic pattern of fluctuating muscle weakness with specific findings: 1

• Variable strabismus and ptosis that worsen with fatigue 1
• Slow ocular saccades 1
• Positive ice pack test (temporary symptom improvement) 1, 4

Laboratory Testing

• AChR antibody assay: Positive in nearly all generalized MG and 40-77% of ocular MG 1, 4
• MuSK antibody testing: For AChR-negative patients 5
• LRP4 antibody testing: For seronegative patients 5

Electrodiagnostic Studies

• Repetitive nerve stimulation: Shows characteristic neuromuscular junction dysfunction 4, 2
• Single fiber electromyography: Highly sensitive diagnostic test 2

Pharmacological Testing

• Tensilon (edrophonium) test: Anticholinesterase agent that temporarily improves symptoms 2
• Critical for differentiating myasthenic crisis from cholinergic crisis 6

Pulmonary Function Assessment

• Negative inspiratory force (NIF) and vital capacity (VC): Essential for monitoring respiratory function 4
• Regular assessment is critical to prevent life-threatening complications 3

Imaging

• Chest CT or MRI: To evaluate for thymoma 3

Management Strategies

Symptomatic Treatment

Pyridostigmine (acetylcholinesterase inhibitor) is FDA-approved for treating myasthenia gravis and serves as first-line symptomatic therapy. 6

• Increases acetylcholine availability at the neuromuscular junction 2
• Critical warning: Overdosage can cause cholinergic crisis, characterized by increasing muscle weakness that may lead to respiratory failure and death 6
• Distinguishing crises: Myasthenic crisis (needs more medication) versus cholinergic crisis (needs drug withdrawal) requires edrophonium testing and clinical judgment 6
• Atropine can abolish gastrointestinal side effects but may mask overdosage signs, potentially leading to cholinergic crisis 6

Immunomodulatory Therapy

For MGFA Class 1-2 (mild symptoms interfering with daily activities): 3

• Pyridostigmine as initial therapy 3
• Add corticosteroids if symptoms persist 3

For MGFA Class 3-4 (moderate to severe generalized weakness): 3

• May require hospitalization 3
• IVIG or plasmapheresis for acute management 3, 2
• Higher doses of corticosteroids 3
• Consider additional immunosuppressants 2

Surgical Intervention

• Thymectomy: Surgical removal of the thymus gland, especially indicated when thymoma is present 1, 3

Novel Therapies

Recent advances include: 7

• Monoclonal antibodies targeting specific immune pathways 7
• B cell-depleting agents 7
• Complement inhibitors 7
• Fc receptor antagonists 7
• CAR T cell-based therapies 7

These molecular therapies offer promise for the approximately 15% of patients who exhibit inadequate responses to standard treatments. 7

Critical Pitfalls to Avoid

Medication-Induced Exacerbations

Avoid these medications that can worsen myasthenia: 4, 3

• Beta-blockers 4, 3
• IV magnesium 4, 3
• Fluoroquinolones 4, 3
• Aminoglycosides 4, 3
• Macrolide antibiotics 4, 3

Respiratory Monitoring

• Failure to recognize respiratory compromise can rapidly progress to life-threatening myasthenic crisis 4, 3
• Regular pulmonary function testing is mandatory 4
• Close monitoring is essential for all grades of disease 3

Crisis Differentiation

• Myasthenic crisis (disease worsening): Requires increased anticholinesterase therapy 6
• Cholinergic crisis (medication overdose): Requires immediate withdrawal of all anticholinesterase drugs and atropine administration 6
• Misidentification can have grave consequences 6

Essential Management Principles

• Early recognition is crucial for preventing complications and initiating appropriate treatment 1
• Neurologist referral is essential for proper disease management 1
• Treatment goals include: Preventing morbidity and mortality, reducing diplopia, improving eye alignment, and restoring normal function 1
• Subgroup stratification based on autoantibody profile (AChR, MuSK, LRP4) is important for tailoring therapy, as different subtypes respond differently to treatments 8

Pregnancy Considerations

The safety of pyridostigmine during pregnancy or lactation has not been established in humans, requiring careful weighing of potential benefits against possible hazards to mother and child. 6