Definition - Chronic auto-immune disorder of the post-synaptic membrane at the neuromuscular junction (NMJ) in skeletal muscle
- Circulating antibodies against the nicotinic acetylcholine receptor (AchR) and associated proteins impair neuromuscular transmission
- Patients present with muscle weakness which typically worsens with continued activity (fatigue) and improves on rest
- Severity varies from isolated eye muscle weakness to generalised muscle weakness and respiratory failure requiring mechanical ventilation
Risk Factors - Female gender
- Ages 20 – 40
- Familial myasthenia gravis
- D-penicillamine ingestion (drug-induced myasthenia)
- Having other autoimmune diseases
Differential diagnosis - Lambert-Eaton myasthenic syndrome (LEMS)
- Prominent proximal leg and arm weakness accompanied by diminished muscle stretch reflexes that improve with brief exercise.
- Autonomic symptoms such as dry mouth, constipation and impotence are present in some patients.
- Eye muscles are occasionally involved at presentation.
- Respiratory failure is uncommon.
- Associated with small-cell lung cancer in up to 70% of patients.
- Botulism
- Symptoms similar to myasthenia gravis (MG) but there may be hypotension, bradycardia, diarrhoea followed by constipation, and urinary retention.
- Penicillamine-induced myasthenia gravis
- Symptoms similar to MG can occur after weeks or months of treatment
- They may remit on withdrawal of the drug; recovery may be slow or incomplete
- Primary myopathies
- Gradually progressive muscle weakness which is not fatigable.
- These include auto-immune inflammatory myopathies or heritable myopathies as in mitochondrial diseases, such as progressive external ophthalmoplegia, or oculopharyngeal muscular dystrophy (OPMD).
- Positive family history
Epidemiology - Uncommon disease with an estimated worldwide prevalence of 100 to 200 per million population. [5]
- While MG reportedly occurs in all ethnic groups, relative differences in disease prevalence are yet to be determined.
- The disease is manifest from infancy to old age and can occur in both genders although more women than men are affected. [4]
- Women usually present during childbearing age.
- Men typically develop symptoms at a later age with a median age of onset in the seventh decade.
- It appears that the prevalence of MG is on the increase, particularly in developed countries.
- This may be, in part, due to an ageing population, improved longevity of MG patients and availability of more accurate diagnostic tools.
- The subset of MG with antibodies directed against muscle tyrosine kinase (MuSK) predominantly affects women (between 80% to 90% of patients)
- The incidence is significantly higher in black women, particularly in the US, and the average age at symptom onset is in the mid-30s; earlier than that in non-MuSK MG. [2]
Aetiology - Several lines of evidence suggest that myasthenia gravis (MG) is an organ-specific, antibody-mediated auto-immune disease.
- Antibodies are present at the neuromuscular junction (NMJ), the site of pathology. [6]
- About 80% to 90% of patients have detectable antibodies against the nicotinic acetylcholine receptor (AchR) on the post-synaptic muscle membrane at the NMJ.
- Another 3% to 7% of patients have antibodies directed against muscle tyrosine kinase (MuSK), another NMJ protein.
- Passive transfer of AchR antibodies from experimental rodents or immunoglobulins from patients with MG causes symptoms similar to MG in rodents. [7]
- Furthermore, immunisation with AchR reproduces MG in experimental animals. [8]
- In addition, removal of antibodies by plasma exchange or immunosuppression ameliorates symptoms in patients with MG. [9] [10]
- The aetiology for the synthesis of auto-immune antibodies remains unclear
- Certain genotypes, particularly linked to the HLA complex, may be more susceptible. [11]
- Also, the thymus may be involved.
- MG is associated with thymic follicular hyperplasia or thymoma in 70% and 10% patients, respectively. [12]
- Thymic myoid cells express AchR and may possibly trigger auto-antibody synthesis.
- In contrast in MuSK MG, thymus gland histology is usually normal and thymoma is rare.
Clinical features - Muscle fatigability
- The weakness worsens with activity (fatigue) and improves on rest and the fluctuations show diurnal variation (better in morning than in the evening)
- Ptosis
- Drooping eyelids and double vision occur early in the majority of patients. [3]
- The pupils are spared.
- Cooling of eyelid for at least 2 minutes with an ice pack (ice test) improves ptosis in more than 95% of patients with myasthenia gravis (MG).
- It does not improve severe ptosis
- Diplopia
- Double vision occurs early in the majority of patients. [3]
- Dysphagia
- Difficulties in chewing or swallowing occur when the facial and oropharyngeal muscles are affected
- Dysarthria
- Changes in speech occur when the oropharyngeal muscles are affected and there may be a characteristic nasal speech
- Facial paresis
- Changes in expression occur when the facial muscles are affected and there may be a characteristic flattened smile
- Proximal limb weakness
- Difficulty in getting out of chairs or climbing stairs.
- There is no evident muscle wasting.
- Reflexes are normal.
- Sensations are intact
- Shortness of breath
- If shortness of breath becomes severe enough to require mechanical ventilation, the patient is said to be in MG crisis
Pathophysiology - In myasthenia gravis (MG), an auto-immune attack against acetylcholine receptors (AchRs) results in destruction of the post-synaptic membrane. [4]
- The reduced number of available binding sites for acetylcholine leads to inconsistent generation of muscle fibre action potentials which manifest as skeletal muscle weakness.
- Muscle tyrosine kinase (MuSK) is an agrin dependent protein on muscle membrane with an essential role in anchoring AchR at the tips of the postsynaptic folds
Investigations- Serum anti-acetylcholine receptor (anti-AchR) antibody analysis
- Antibodies are detectable in 80% to 90% of patients with generalised myasthenia gravis (MG) and up to 50% of patients with ocular MG. [17]
- Sensitivity: greater than 90% in generalised MG; 40% to 60% in ocular MG.
- Specificity: 99%.
- If the result is negative or equivocal proceed to antimuscle tyrosine kinase (MuSK) antibody assay
- Antimuscle tyrosine kinase (MuSK) antibodies
- Positive test in up to 70% of AchR seronegative generalised MG. [14] [2]
- Serial pulmonary function tests
- Indicated if shortness of breath and suspected MG crisis.
- Serial measurements of FVC and negative inspiratory force (NIF) are taken.
- Indication for mechanical ventilation includes FVC 15 mL/kg or less (normal ≥60 mL/kg) and NIF 20 cm H2O or less (normal ≥70 cm H2O).
- Physicians should not wait for abnormal ABG as it occurs late in the course after clinical decompensation
- Antistriational antibodies
- This test is not done routinely in all patients
- These antibodies are rare in patients without thymoma.
- Detected in 75% to 95% of patients with thymoma and MG
- Repetitive nerve stimulation
- Sensitivity, 79% in generalised MG, 50% in ocular MG.
- Specificity, 97%. [17]
- Brief exercise of a muscle prior to the test may enhance decrement response.
- If the result is negative and clinical suspicion is high, proceed to single fibre EMG.
- Positive decrement also seen in Lambert-Eaton myasthenic syndrome (LEMS) and amyotrophic lateral sclerosis (ALS).
- In MuSK MG, generally the yield of abnormal result is high in proximal muscles, for example the trapezius, deltoid and facial muscles.
- For patients with neck and respiratory weakness, it is important to evaluate clinically affected muscles as the test may be normal in limb and face muscles. [2]
- Greater than 10% decline in compound muscle action potential (CMAP) amplitude between the first and fourth potential in a train of 10 stimulations of the motor nerve at 2 to 3 Hz is considered a positive response
- Single-fibre EMG
- Sensitivity, 86% to 92% and specificity, 70% to 96% in facial muscles in ocular MG;
- Sensitivity and specificity, 98% in generalised MG. [17]
- Abnormal test may be seen in LEMS and ALS, inflammatory myopathies, or patients injected with botulinum toxin.
- Increase variability in motor latencies (jitter) or complete failure of neuromuscular transmission (block) in some muscle fibres
- CT of chest
- Should be performed in all newly diagnosed patients to detect thymoma (which occurs in about 15% of patients with MG) or thymic hyperplasia (which occurs in 75% of MG patients)
Managementa) conservative- Supportive care
- Includes DVT prophylaxis; ulcer prophylaxis; adequate nutrition and hydration; and avoidance of infections and drugs that may worsen myasthenia symptoms.
b) medical - Plasma exchange or intravenous immunoglobulin
- Acute therapy for the recovery of transmission across neuromuscular junction
- Plasma exchange has rapid response with onset usually after 2 to 3 sessions.
- Effects are temporary, lasting weeks.
- Therapy is expensive and requires hospitalisation.
- Intravenous immunoglobulin (IVIG) is easy to administer but expensive
- When patients respond, the onset is rapid within 4 to 5 days with maximal response apparent within 1 to 2 weeks
- In patients with muscle tyrosine kinase (MuSK) MG, plasma exchange and immunoglobulin are used during acute exacerbations and crises.
- Observational studies indicate plasma exchange to be more effective than immunoglobulin. [2]
- Pyridostigmine
- Patients with frequent symptoms should be treated with a cholinesterase inhibitor.
- In patients with muscle tyrosine kinase (MuSK) MG, clinical response to cholinesterase inhibitor therapy is generally less favourable
- Frequent muscarinic and nicotinic side effects, and sometimes even worsening of symptoms.
- Despite this poor response, most patients receive pyridostigmine due to its low side effect profile and low cost
- Corticosteroids
- Corticosteroids are used in older men with ocular myasthenia gravis (MG) and those with mild disease who fail pyridostigmine monotherapy
- Immunosuppressant
- Several options are available and include low-dose corticosteroids, azathioprine, mycophenolate mofetil, ciclosporin and tacrolimus
- Patients with generalised myasthenia gravis (MG) with moderate symptoms usually require chronic corticosteroid maintenance therapy. [1] [25]
- It is prudent to begin therapy with low dose and gradually titrate up towards maximum dose
- High doses can induce worsening of MG symptoms, including precipitating a myasthenic crisis.
- Immunotherapy is tailored for each patient, including time to onset of response, adverse effect profile, availability and cost
- Tacrolimus is generally better tolerated than ciclosporin. [31]
c) surgical- Intubation and mechanical ventilation
- Indication for mechanical ventilation includes FVC 15 mL/kg or less (normal ≥60 mL/kg) and negative inspiratory force (NIF) 20 cm H2O or less (normal ≥70 cm H2O)
- Some patients may require a tracheostomy and percutaneous endoscopic gastrostomy (PEG) tube. [4]
- Thymectomy
- Performed in patients with thymoma (any age) or without thymoma (15 to 55 years old). [27]
- Approaches available include robotic thoracotomy, transcervical or full sternotomy.
- It is generally accepted that more complete the removal of thymus, higher is the rate of remission in MG symptoms.
- Onset of benefit is delayed, rarely seen within 6 months and requires follow-up of up to 2 to 5 years for demonstrated efficacy.
- The role of thymectomy for patients with muscle tyrosine kinase (MuSK) MG remains uncertain in the absence of a controlled trial.
-
Prognosis- Symptomatic improvement and clinical remission are the goals of therapy.
- However, the onset of improvement varies greatly from days to months.
- Typically, older men with ocular complaints respond promptly to corticosteroid monotherapy whereas generalised symptoms are slower to respond and require more aggressive therapy.
- Chronic maintenance drug therapy is often required.
- Disease exacerbations can occur due to infections, surgery, medicine exposures, malignancy, pregnancy or other stressors.
- Myasthenic crisis can sometimes be averted with aggressive early intervention during an exacerbation.
- Most patients enjoy good quality of life and normal lifespan due to advances in diagnosis and immunosuppressive treatment.
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