Myasthenia Gravis

Myasthenia Gravis: Causes, Symptoms, Diagnosis, and Management

~Introduction

Myasthenia Gravis (MG) is a chronic autoimmune neuromuscular disorder characterized by weakness and rapid fatigue of voluntary muscles. The condition interferes with the communication between nerves and muscles, making it difficult for the body to perform even basic movements such as walking, talking, chewing, or breathing. The name itself—derived from the Greek and Latin words meaning "grave muscle weakness"—reflects the potentially serious nature of the disease.

While it is considered rare, with an estimated prevalence of about 14–40 cases per 100,000 people worldwide, MG significantly impacts the quality of life for those affected. Advances in diagnosis and treatment have transformed MG from a life-threatening disease to a manageable condition for most patients, but it still poses unique medical challenges.

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~Historical Background

The first descriptions of MG date back to the late 17th century, when physicians documented patients with fluctuating muscle weakness. In the 19th century, British physician Samuel Wilks and German neurologist Hermann Oppenheim provided more detailed clinical descriptions. In 1895, German physician Wilhelm Erb formally identified MG as a distinct neuromuscular disease. The autoimmune nature of the disorder was not recognized until the mid-20th century, when researchers discovered antibodies targeting components of the neuromuscular junction.

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~Understanding the Neuromuscular Junction

To understand MG, it is important to know how normal muscle activation works.

1. Nerve signal initiation – A motor neuron sends an electrical signal (action potential) down its axon toward a muscle fiber.

2. Acetylcholine release – At the neuromuscular junction, the nerve ending releases acetylcholine (ACh), a neurotransmitter.

3. Receptor activation – ACh binds to acetylcholine receptors (AChRs) on the muscle cell membrane.

4. Muscle contraction – Binding triggers muscle fiber depolarization, leading to contraction.

5. Signal termination – Acetylcholinesterase breaks down ACh, stopping the signal and allowing relaxation.

In MG, autoantibodies interfere with this process—either by blocking, altering, or destroying the AChRs, or by affecting related proteins such as muscle-specific kinase (MuSK). This results in weak or absent muscle contractions.

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~Causes and Pathophysiology

Myasthenia Gravis is primarily an autoimmune disorder. The immune system mistakenly produces antibodies that target proteins in the neuromuscular junction.

Types of Autoantibodies

• Anti-AChR antibodies – Found in ~80% of generalized MG cases; these block or destroy acetylcholine receptors.

• Anti-MuSK antibodies – Present in 5–8% of cases; these affect muscle-specific kinase, a protein essential for receptor clustering.

• Anti-LRP4 antibodies – Found in a smaller percentage; these interfere with neuromuscular junction development.

• Seronegative MG – About 10–15% of patients have no detectable antibodies with standard tests, though more sensitive methods may identify them.

Role of the Thymus Gland

The thymus gland, located behind the breastbone, is involved in immune cell maturation. In MG:

• About 65% of patients have thymic hyperplasia (enlarged thymus with active immune cells).

• 10–15% have thymomas (benign or malignant tumors).
  The thymus may produce abnormal immune cells that mistakenly attack muscle receptors.

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~Types of Myasthenia Gravis

MG is classified based on symptom distribution, severity, and antibody profile:

1. Ocular Myasthenia Gravis

   • Weakness confined to the eye muscles.

   • Symptoms: drooping eyelids (ptosis), double vision (diplopia).

   • May progress to generalized MG in ~50% of cases within 2 years.

2. Generalized Myasthenia Gravis

   • Involves multiple muscle groups: eyes, face, neck, limbs, respiratory muscles.

   • Symptoms are more disabling and variable.

3. Congenital Myasthenic Syndromes

   • Rare, inherited conditions due to genetic mutations affecting neuromuscular transmission.

   • Not autoimmune in nature.

4. Juvenile Myasthenia Gravis

   • Onset before age 18.

   • More common in certain ethnic groups, such as Asians.

5. MuSK-Antibody MG

   • Often more severe bulbar symptoms (speech, swallowing, breathing difficulties).

   • May respond differently to certain treatments.

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~Symptoms and Clinical Features

MG symptoms vary in severity, timing, and muscle groups affected, but they share a hallmark feature: fluctuating weakness that worsens with activity and improves with rest.

Common Symptoms

• Ocular Symptoms:

  • Ptosis (drooping eyelids), often asymmetric.

  • Diplopia (double vision) due to impaired eye muscle control.

• Facial and Bulbar Weakness:

  • Slurred speech (dysarthria).

  • Difficulty swallowing (dysphagia).

  • Trouble chewing, especially toward the end of meals.

• Limb Weakness:

  • Difficulty climbing stairs, lifting objects, or holding arms above the head.

• Neck and Respiratory Muscle Weakness:

  • Dropped head due to weak neck muscles.

  • Shortness of breath.

• Myasthenic Crisis:

  • Life-threatening worsening of muscle weakness, leading to respiratory failure.

  • Requires immediate hospitalization and mechanical ventilation.

Patterns of Fatigue

• Symptoms typically worsen late in the day or after prolonged activity.

• Periods of improvement may occur, especially after rest.

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~Diagnosis

Diagnosing MG involves a combination of medical history, clinical examination, and specialized tests.

Medical History and Physical Examination

• Fluctuating weakness pattern is a key clue.

• Eye movement and eyelid fatigue tests can reveal ocular involvement.

Diagnostic Tests

1. Blood Tests

   • Detect anti-AChR, anti-MuSK, or anti-LRP4 antibodies.

2. Electrophysiological Studies

   • Repetitive Nerve Stimulation (RNS): Shows a decremental response in muscle action potentials.

   • Single-Fiber Electromyography (SFEMG): Highly sensitive; detects transmission delays.

3. Edrophonium Test (less common now):

   • Temporary improvement in muscle strength after administration of edrophonium chloride.

   • Rarely used due to side effects and availability of better tests.

4. Imaging

   • Chest CT or MRI to detect thymoma or thymic hyperplasia.

5. Pulmonary Function Tests

   • Measure respiratory strength, important for crisis risk assessment.

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~Treatment and Management

While MG has no permanent cure, treatments aim to improve muscle function, reduce autoimmune attack, and manage symptoms.

1. Symptomatic Treatment

• Acetylcholinesterase Inhibitors (e.g., pyridostigmine)

  • Prolong action of acetylcholine at the neuromuscular junction.

  • Improve strength temporarily.

  • Side effects: diarrhea, cramps, sweating, salivation.

2. Immunosuppressive Therapy

• Corticosteroids (e.g., prednisone)

  • Reduce antibody production but have long-term side effects (weight gain, osteoporosis, diabetes).

• Non-steroidal Immunosuppressants (e.g., azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus)

  • Slower onset of action but useful for long-term control.

3. Rapid Immunomodulating Treatments

• Plasmapheresis (Plasma Exchange)

  • Removes circulating antibodies; works quickly but temporarily.

• Intravenous Immunoglobulin (IVIG)

  • Modulates immune system; effective in crisis or severe flares.

4. Surgical Treatment

• Thymectomy

  • Removal of the thymus gland can improve symptoms and may induce remission, especially in AChR-positive generalized MG.

  • Recommended for thymoma patients and sometimes for non-thymoma cases.

5. Emerging Therapies

• Monoclonal Antibodies (e.g., eculizumab, ravulizumab)

  • Target specific components of the immune response.

• FcRn Inhibitors (e.g., efgartigimod)

  • Reduce antibody levels rapidly.

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~Complications

• Myasthenic Crisis

  • Medical emergency; may be triggered by infection, surgery, certain drugs.

• Side Effects of Long-Term Immunosuppression

  • Increased infection risk, organ toxicity.

• Coexisting Autoimmune Disorders

  • Thyroid disease, rheumatoid arthritis, lupus.

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~Prognosis

• Before modern treatments, MG had a high mortality rate.

• With current therapies, most patients lead near-normal lives, though some have persistent weakness.

• About 10–20% achieve remission.

• Lifelong monitoring is needed, especially for those at risk of crisis.

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~Lifestyle and Self-Management

Patients benefit from:

• Energy conservation – Planning activities and resting between tasks.

• Avoiding triggers – Heat, stress, infections, certain medications (e.g., some antibiotics, beta-blockers).

• Nutrition – Soft foods for swallowing difficulty.

• Support systems – Physical therapy, counseling, patient support groups.

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~Ongoing Research

Research in MG is focused on:

• More targeted immunotherapies to minimize side effects.

• Better biomarkers for predicting disease progression.

• Genetic studies in congenital syndromes.

• Cell-based therapies aiming for long-term immune tolerance.

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~Conclusion

Myasthenia Gravis, though rare, profoundly affects the lives of those who live with it. Early diagnosis, careful symptom monitoring, and an individualized treatment plan are essential to improve outcomes. Advances in immunotherapy, surgical techniques, and supportive care have transformed MG from a potentially fatal disease into a manageable chronic condition. Continued research offers hope for more precise treatments and possibly a cure in the future.