Myasthenia Gravis
Myasthenia Gravis: Excerpt from The 5-Minute Pediatric Consult
Brenda E. Porter, MDGrant T. Liu, MD
Myasthenia Gravis - BASICS
Myasthenia Gravis - description
A neuromuscular disease presenting with varying weakness that worsens with exercise and improves with rest.
3 types of myasthenia gravis seen in childhood:
- Neonatal transient:
- 10–20% of infants born to mothers with autoimmune myasthenia
- Congenital myasthenia:
- Rare: <10% of all childhood myasthenia
- Weakness usually starts in the 1st year of life and is caused by an inherited disorder in neuromuscular transmission.
- Mutations have been described in the presynaptic nerve terminal, acetylcholinesterase, acetylcholine receptors, and postsynaptic proteins.
- Juvenile myasthenia:
- Autoimmune disorder similar to adult onset, autoimmune myasthenia gravis
- Caused by aberrant production of antibodies against the acetylcholine receptor
- Relatively rare: 1 new diagnosis per million per year
- The average age of onset is 10–13 years, with a female predominance of 2:1 or 4:1.
Myasthenia Gravis - risk factors
Myasthenia Gravis - genetics
- Congenital type: Generally autosomal-recessive (check consanguinity)
- Occasional family history
Myasthenia Gravis - pathophysiology
- Caused by a disruption in signal transmission from the motor neuron to the muscle. Sensory or cognitive symptoms are absent:
- The motor nerve terminal lies in close proximity to the end plate, a region of the muscle cell membrane with a high concentration of acetylcholine receptors.
- When stimulated, the motor nerve terminal releases acetylcholine that binds receptors, causing contraction of the muscle. The cleft contains acetylcholinesterase, an enzyme that breaks down acetylcholine and helps terminate the muscle contractions.
- In the autoimmune form of myasthenia, an autoantibody blocks acetylcholine receptor activity. The rate of receptor breakdown increases and fewer receptors are present, resulting in decreased muscle contraction.
- Thymic pathology is believed to be central to the pathogenesis of autoimmune myasthenia; hyperplasia is present in most children who undergo thymectomy.
- In neonatal myasthenia, infants are born with weakness and hypotonia due to maternal-fetal transmission of antibodies against the acetylcholine receptor:
- The severity of maternal symptoms does not predict the likelihood that the infant will be affected. Occasional arthrogryposis (joint contractures) reflects in utero paralysis.
- High levels of maternal antibodies against the fetal form of the acetylcholine receptor pose an increased risk of disease.
- A previous pregnancy with an affected infant places future pregnancies at much higher risk. In rare cases, the mother is asymptomatic, despite presence of a (placentally transmitted) antibody.
Myasthenia Gravis - associated conditions
- In juvenile myasthenia, other autoimmune disorders may occur:
- Hyperthyroidism is present in 3–9% of patients.
- Small increase in the incidence of rheumatoid arthritis and diabetes
- Some reports suggest an increased incidence of seizures in autoimmune myasthenia.
- Screening for thymoma at initial diagnosis is appropriate (by chest CT scan):
- Children appear to have a lower incidence of thymic tumor than adults with autoimmune myasthenia.
Myasthenia Gravis - DIAGNOSIS
Myasthenia Gravis - signs & symptoms
Most patients present with ptosis and diplopia alone or in combination with swallowing difficulties, dysphonia, and generalized weakness.
Myasthenia Gravis - history
- Transient neonatal: Mother with known autoimmune myasthenia or a history of weakness, ptosis, or dysphagia
- Congenital myasthenia:
- Usually presents in the first year of life (rarely later) with hypotonia, poor feeding, ptosis, and delayed motor milestones
- Possible family history of similar weakness
- No response to thymectomy or immunosuppressant medications
- Juvenile myasthenia:
- Gradual onset of weakness over weeks, months, or even years
- Symptoms are worse after prolonged activity or late in the day.
- Intermittent ptosis, diplopia, dysphagia, and dysphonia are common.
Myasthenia Gravis - physical exam
- Neonatal: From birth, the infant is hypotonic, with a weak suck, a weak cry, and ptosis.
- Congenital and juvenile myasthenia:
- Weakness of neck flexion
- Ptosis, ophthalmoplegia, and variable-feeding problems are often the earliest findings.
- Generalized weakness may be asymmetric in the limbs. The weakness is more pronounced with endurance tasks.
- Shallow, rapid respirations suggest impending ventilatory failure. Vital capacity of <50% of predicted (in older children) suggests impending respiratory failure.
Myasthenia Gravis - tests
Juvenile myasthenia:
- Nerve conduction and electromyography studies: Repetitive stimulation of a nerve shows a diagnostic decremental response owing to decreased acetylcholine receptors. Single-fiber electromyography measures the variability in firing rates of 2 muscle fibers innervated by different branches of the same motor neuron. A large variability, suggests a higher threshold for activation.
- Edrophonium chloride is a fast-acting acetylcholinesterase-blocking agent. Patients with myasthenia often show an immediate, transient improvement in muscle strength after IV infusion of this drug. A measurable weakness should be present prior to testing, and a placebo dose of saline should be given initially. Although the risk of a hyperreactive cholinergic response with muscle weakness and bradycardia is low, atropine should always be available, and the patient’s vital signs should be closely monitored during the test, which is contraindicated in patients with heart disease. Measurable cranial nerve dysfunction, such as ptosis, is often responsive to edrophonium. Children receive 20% of a 0.2-mg/kg dose of Tensilon over 1 minute; if there is no response after 45 seconds, the rest of the dose is then given, up to a maximum of 10 mg. Have atropine and epinephrine readily available.
Myasthenia Gravis - lab
Acetylcholine receptor antibody levels (most specific):
- Elevated in ~80% of patients with generalized myasthenia
- Only 50% of patients with isolated ocular myasthenia have an elevated level.
Myasthenia Gravis - differencial diagnosis
- Generalized botulism:
- In specific endemic areas, may cause generalized weakness in infants. It is caused by a Clostridium toxin that blocks the release of acetylcholine from the nerve terminal.
- Guillain-Barré syndrome, or acute inflammatory demyelinating polyneuropathy:
- A frequent cause of rapidly progressive generalized weakness
- Unlike myasthenia, there are often sensory symptoms, and areflexia occurs even with minimal weakness.
- Acute spinal cord compression:
- Can present as generalized (but not variable) weakness of the extremities
- Look for sparing of facial and extraocular muscles; a sensory level, bowel, or bladder dysfunction; and hyperactive reflexes.
- Organophosphate ingestion: Mestinon (pyridostigmine bromide):
- Can cause profound weakness
- Symptoms of parasympathetic hyperactivity, such as hypersalivation, miosis, diarrhea, and bradycardia, will usually be present.
- Penicillamine used for the treatment of autoimmune disorders can induce autoantibodies that bind the acetylcholine receptor, causing myasthenia gravis.
Myasthenia Gravis - TREATMENT
Myasthenia Gravis - initial stabilization
Treat respiratory failure, a rare but serious complication of juvenile myasthenia gravis:
- Shallow breathing, a vital capacity of <50% predicted, or a rapidly worsening vital capacity suggests impending respiratory failure.
Myasthenia Gravis - general measures
- Neonatal myasthenia:
- Severity of disability should be used to guide the aggressiveness of therapy.
- Respiratory or swallowing impairment: Pyridostigmine syrup, 60 mg/5 mL, 7 mg/kg, 30 minutes before feeds; 1 mg IM = 30 mg PO dose.
- Juvenile myasthenia:
- Most patients benefit from pyridostigmine bromide (Mestinon) given 3–4 times per day. A long-acting formulation prior to bedtime may alleviate obstructive hypoventilation during sleep.
- Pyridostigmine increases acetyl choline by blocking acetylcholinesterase activity. A normal starting dosage is approximately 7 mg/kg/d. The dosage is slowly titered upward, following symptoms, at several-day intervals. Common side effects are hypersalivation, blurry vision, and diarrhea. Glycopyrrolate, 1 mg PO, may decrease diarrhea.
- Prednisone:
- Consider in patients with disabling symptoms and inadequate response to pyridostigmine.
- Watch for transient worsening within weeks in up to 50% of patients.
- Start daily dose at 2 mg/kg, watch for improvement in 3–6 weeks, taper toward 1.5 mg/kg/d on alternate-day schedule for 4 months. Taper slowly thereafter by 5 mg/wk.
- Monitor for side effects, including growth stunting.
- Calcium and every-other-day dosing may limit the bone deterioration from chronic steroids.
- Azathioprine:
- Induces remission in 30% of patients and significant improvement in another 25–60%
- Useful adjunctive to steroids and thymectomy; however, it takes 3–12 months for benefits to occur.
- Juvenile myasthenics with profound weakness and respiratory failure should undergo immediate therapy to decrease the number of circulating antibodies:
- Plasmapheresis or IV immunoglobulin can help within days by decreasing acetylcholine receptor antibodies.
- Steroids diminish antibody production over weeks to months.
- Newer immunosuppressants have been reported to be effective in small case series for refractory myasthenia gravis, including mycophenolate mofetil, and anti-CD20.
Myasthenia Gravis - surgery
Thymectomy:
- Generally results in a 20–60% remission, and another 15–30% of patients show a marked improvement after surgery.
- Thymectomy earlier in the course of illness appears to produce a higher rate of remission.
Myasthenia Gravis - FOLLOW UP
- The following medications can exacerbate myasthenia gravis:
- Corticosteroids may worsen symptoms.
- Aminoglycosides
- Ciprofloxacin
- β-Adrenergic blocking agents, including eye drops
- Lithium
- Procainamid
- Quinidin
- Phenytoin
- Prolonged recovery after exposure to nondepolarizing neuromuscular blocking agents
- Always start new medications cautiously.
Myasthenia Gravis - prognosis
- Neonatal transient:
- A self-limited disorder that resolves spontaneously over weeks or months of life as maternal antibodies disappear
- The infant may require ventilatory and nutritional support during the 1st few months of life.
- Infants with arthrogryposis multiplex congenita (born to mothers with antibodies against the fetal form of acetylcholine receptors) may gain mobility over time and with passive range-of-motion therapy.
- Congenital myasthenia:
- Prognosis varies, depending on the specific defect.
- Autosomal-recessive disorders tend to be more severe than the dominant disorders. Weakness shows variable response to cholinesterase inhibitors.
- Immunosuppressants are not helpful. In general, these are indolent disorders.
- Ptosis and fatigability resemble the juvenile type, but are more stable over time.
- Juvenile myasthenia:
- Most patients do extremely well with treatment; patient selection for early surgery requires experience and may improve outcome.
- Longitudinal studies suggest that the rate of spontaneous remission is ~2% per year.
- Patients with generalized weakness are slightly less likely to experience remission.
- The mortality rate from myasthenia is near that of the general population in patients younger than 50 years.
Myasthenia Gravis - complications
Respiratory failure, visual disturbance, thymic cancer, other autoimmune disorders
Myasthenia Gravis - patient monitoring
- Watch for transient worsening of symptoms.
- Monitor for side effects of corticosteroids, including growth stunting.
- Medication effects: GI upset due to acetyl cholinesterase inhibitors
Myasthenia Gravis - bibliography
- Lindner A, Schalke B, Toyka VK. Outcome in juvenile-onset myasthenia gravis: A retrospective study with long-term follow up. J Neurol. 1997;244:515–520.
- Newsom-Davis J. Therapy in myasthenia gravis and Lambert-Eaton myasthenic syndrome. Semin Neurol. 2003;23:191–198.
Parent internet information: http://www.myasthenia.org
Myasthenia Gravis - CODES
Myasthenia Gravis - icd9
- 358.0 Myasthenia gravis
- 775.2 Juvenile myasthenia gravis
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Book Source Details
- Book Title: The 5-Minute Pediatric Consult
- Author(s): M. William Schwartz MD; et al.
- Year of Publication: 2008
- Copyright Details: The 5-Minute Pediatric Consult, Copyright © 2008 Lippincott Williams & Wilkins.
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Copyright notice for book excerpts: Copyright © 2008 Lippincott Williams & Wilkins. All rights reserved.
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More About This Book:
Title: The 5-Minute Pediatric Consult
Authors: M. William Schwartz MD; et al.
Publisher: Lippincott Williams & Wilkins
Copyright: 2008
ISBN: 0-7817-7577-9
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