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Myasthenia gravis

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)
Management

a) 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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