Basics
Description
- A neuromuscular (NM) 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 within first 2 years of life; caused by inherited disorder in NM transmission; classified by mutation site (presynaptic, postsynaptic) or by molecular genetics
- Juvenile myasthenia: autoimmune disorder similar to adult-onset, autoimmune myasthenia gravis; mostly due to production of antibodies against the acetylcholine receptor (AChR). Relatively rare: 1 new diagnosis per million per year; average age of onset 10 " 13 years, with a female predominance of 2:1 or 4:1
Epidemiology
- Rare: incidence 4 " 6 per million per year
- Prevalence: 40 " 80 per million
- Children account for 10 " 15% of cases of myasthenia gravis annually.
Risk Factors
Genetics
- Congenital type: generally autosomal recessive (check consanguinity)
- Occasional family history
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 AChR.
- Normally, when stimulated, the motor nerve terminal releases acetylcholine that binds receptors, causing muscle contraction. The cleft contains acetylcholinesterase (AChE), an enzyme that breaks down acetylcholine and helps terminate muscle contractions.
- Autoimmune form (juvenile or JMG)
- Autoantibody blocks AChR activity ’ increased rate of receptor breakdown ’ fewer receptors are present ’ leads to decreased muscle contraction
- AChR antibody accounts for ’ Ό85% of JMG.
- Thymic pathology is believed to be central to pathogenesis of autoimmune myasthenia; however, thymic pathology (e.g., hyperplasia) is present in less than 1/3 of children who undergo thymectomy.
- Of JMG patients without elevated AChR antibody, some are positive for antibodies to muscle-specific kinase (MuSK).
- A small percentage of autoimmune JMG patients do not have an identified antibody.
- Neonatal (transient) myasthenia: Infants are born with weakness and hypotonia.
- Due to maternal " fetal transmission of antibodies against AChR
- Severity of maternal symptoms does NOT predict likelihood that infant will be affected. Occasional arthrogryposis (joint contractures) reflects decreased fetal movement in utero.
- High levels of maternal antibodies against fetal form of AChR pose an increased risk of disease.
- Previous pregnancy with affected infant places future child at much higher risk.
- In rare cases, mother is asymptomatic despite placentally transmitted antibody.
- Congenital myasthenic syndromes: group of genetic disorders of NM junction; classified by site of NM transmission defect and more recently by molecular genetics
- Includes presynaptic defects, synaptic defect (due to end plate AChE deficiency), postsynaptic defects (primary AChR deficiency, primary AChR kinetic abnormality, or perijunctional skeletal muscle sodium channel mutation)
Commonly Associated Conditions
- In juvenile myasthenia, other autoimmune disorders may occur:
- Hyperthyroidism in 3 " 9% of patients
- Small increase in incidence of juvenile idiopathic arthritis and diabetes
- Some reports suggest increased incidence of seizures in autoimmune myasthenia
- Screening for thymoma at initial diagnosis by chest CT or MRI scan is appropriate:
- Children appear to have lower incidence of thymic tumor or pathology than adults with autoimmune myasthenia.
Diagnosis
Most patients present with ptosis and diplopia alone or in combination with swallowing difficulties, dysphonia, and generalized weakness.
History
- Neonatal transient: mother with known autoimmune myasthenia or history of weakness, ptosis, or dysphagia
- Congenital myasthenia
- Usually presents in first 1 " 2 years 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 fatigable 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.
- Ocular myasthenia gravis: a subset of 10 " 15% of patients with myasthenia who have isolated ptosis and ophthalmoplegia (weakness in extraocular muscles) in absence of systemic or bulbar symptoms
Physical Exam
- Neonatal transient: from birth, hypotonic infant with weak suck, weak cry, and ptosis
- Congenital and juvenile myasthenia
- Weakness of neck flexion
- Reflexes often preserved
- Ptosis, ophthalmoplegia, and variable feeding problems often are earliest findings.
- Generalized weakness in limbs may be asymmetric. Weakness is more pronounced with endurance tasks.
- Shallow, rapid respirations and/or vital capacity <50% predicted (in older children) suggest impending respiratory failure.
- Check for scoliosis.
Diagnostic Tests & Interpretation
- Juvenile myasthenia
- Nerve conduction and electromyography studies: Repetitive stimulation of nerve shows diagnostic decremental response due to decreased AChR. May be normal in some patients; normal study doesn 't exclude diagnosis.
- Single-fiber electromyography measures variability in firing rates of 2 muscle fibers innervated by different branches of the same motor neuron. Large variability suggests higher threshold for activation. This test is more sensitive than repetitive nerve stimulation but is technically more challenging and often requires sedation.
- Edrophonium chloride (Tensilon) is a fast-acting AChE-blocking agent (no longer widely available in the United States).
- Patients with myasthenia often show immediate, transient improvement in muscle strength after IV infusion.
- Measurable weakness should be present prior to testing, and a placebo dose of saline should be given initially.
- Although risk of hyperreactive cholinergic response with muscle weakness and bradycardia is low, atropine should always be available, and vital signs should be closely monitored during test; contraindicated in patients with heart disease
- Measurable cranial nerve dysfunction, such as ptosis, is often responsive to edrophonium.
- Children receive 20% of 0.2 mg/kg dose (0.04 mg/kg) of Tensilon over 1 minute; if no response after 45 seconds, the rest of the dose (0.16 mg/kg) is given, up to a maximum of 10 mg. Have atropine and epinephrine readily available.
Lab
- AChR antibody levels (most specific): elevated in ’ Ό80% of patients with generalized myasthenia and ’ Ό50% of patients with isolated ocular myasthenia
- Second most common antibody is to muscle-specific receptor tyrosine kinase (MuSK-Ab). Antibodies to striated muscle protein and low-density lipoprotein receptor " related protein are also described but are rare.
Differential Diagnosis
- Generalized botulism
- In endemic areas, may cause generalized weakness in infants; caused by Clostridium toxin that blocks release of acetylcholine from nerve terminal
- Guillain-Barre syndrome or acute inflammatory demyelinating polyneuropathy
- Frequent cause of rapidly progressive generalized weakness
- Unlike myasthenia, patients often have sensory symptoms, and areflexia occurs even with minimal weakness.
- Acute spinal cord compression
- Can present as generalized (but not variable) weakness of extremities
- Look for sparing of facial and extraocular muscles, a sensory level, bowel or bladder dysfunction, and hyperactive reflexes.
- Organophosphate ingestion: pyridostigmine bromide (Mestinon)
- Can cause profound weakness
- Symptoms of parasympathetic hyperactivity are usually present: hypersalivation, miosis, diarrhea, and bradycardia.
- Penicillamine used to treat autoimmune disorders can induce autoantibodies that bind AChR, causing myasthenia gravis.
Treatment
Initial Stabilization
Treat respiratory failure, a rare but serious complication of juvenile myasthenia gravis.
General Measures
- Neonatal myasthenia
- Severity of disability should be used to guide aggressiveness of therapy.
- Respiratory or swallowing impairment: Pyridostigmine syrup, 60 mg/5 mL, 1 mg/kg/dose q4h up to a daily maximum of 7 mg/kg/24 h divided 5 " 6 doses; 1 mg IM = 30 mg PO dose
- Juvenile myasthenia
- Most patients benefit from pyridostigmine bromide (Mestinon) given 3 " 4 times/day. A long-acting formulation prior to bedtime may alleviate obstructive hypoventilation during sleep.
- Pyridostigmine blocks AChE activity and results in increased acetylcholine.
- Usual starting dosage is ’ Ό1 mg/kg/24 h. Dosage is slowly titrated upward, following symptoms, at several-day intervals to a maximum dose of ’ Ό7 " 8 mg/kg/24 h. Absolute maximum daily dose is 300 mg/day for older children. Common side effects: 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, and taper toward 1.5 mg/kg/24 h on alternate-day schedule for 4 months. Taper slowly thereafter by 5 mg/week.
- Monitor for side effects, including growth stunting.
- Calcium every-other-day dosing may limit bone loss from chronic steroids.
- Rituximab
- MuSK Ab " positive patients are often refractory to other treatments (Mestinon, steroids, IVIG) with incomplete or short-lived benefit.
- Rituximab has induced sustained benefit in patients with refractory disease via B-cell depletion in MuSK Ab " positive patients; however, large controlled studies in this population have not been performed.
- Azathioprine
- Induces remission in 30%; significant improvement in another 25 " 60%
- Useful adjunct to steroids and thymectomy; however, requires 3 " 12 months for benefits to occur
- Juvenile myasthenics with profound weakness and respiratory failure (myasthenic crisis) should undergo immediate therapy to decrease the number of circulating antibodies:
- Plasmapheresis or IV immunoglobulin can help within days by decreasing AChR antibodies
- Steroids diminish antibody production over weeks to months.
Surgery/Other Procedures
Thymectomy
- In adults, 20 " 60% remission; another 15 " 30% show marked improvement (somewhat less in pediatric patients)
- Thymectomy earlier in the course of illness appears to produce a higher rate of remission.
Ongoing Care
- The following medications can exacerbate myasthenia gravis:
- Corticosteroids may worsen symptoms.
- Aminoglycosides
- Ciprofloxacin
- ²-Adrenergic blocking agents, including eye drops
- Lithium
- Procainamide
- Quinidine
- Phenytoin
- Prolonged recovery after exposure to nondepolarizing NM blocking agents
- Always start new medications cautiously.
Prognosis
- Neonatal transient
- Self-limited disorder that resolves spontaneously over weeks or months of life as maternal antibodies disappear
- Infant may require ventilator and nutritional support during first few months of life.
- Infants with arthrogryposis multiplex congenita (born to mothers with antibodies against the fetal form of AChR) may gain some mobility over time and with passive range-of-motion therapy.
- Congenital myasthenia
- Prognosis depends on specific defect.
- Autosomal recessive disorders tend to be more severe than 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 rate of spontaneous remission ’ Ό2% per year.
- Patients with generalized weakness slightly less likely to experience remission.
- Mortality rate from myasthenia is near that of the general population in patients <50 years old.
Patient Monitoring
- Watch for transient worsening of symptoms.
- Monitor for side effects of corticosteroids, including growth stunting.
- Medication effects: GI upset due to AChE inhibitors
Complications
Respiratory failure, nocturnal hypoventilation, visual disturbance, thymic cancer (more common in adults, rare in pediatrics), other autoimmune disorders
Additional Reading
- Castro D, Derisavifard S, Anderson M, et al. Juvenile myasthenia gravis: a twenty year experience. J Clin Neuromusc Dis. 2013;14(3):95 " 102. [View Abstract]
- Harper CM. Congenital myasthenic syndromes. Semin Neurol. 2004;24(1):111 " 123. [View Abstract]
- Liew W, Kang PB. Update on juvenile myasthenia gravis. Curr Opin Pediatr. 2013;25(6):694 " 700. [View Abstract]
- Lindner A, Schalke B, Toyka VK. Outcome in juvenile-onset myasthenia gravis: a retrospective study with long-term follow up. J Neurol. 1997;244(8):515 " 520. [View Abstract]
- Newsom-Davis J. Therapy in myasthenia gravis and Lambert-Eaton myasthenic syndrome. Semin Neurol. 2003;23(2):191 " 198. [View Abstract]
- Parent internet information: Myasthenia Gravis Foundation of America, Inc. Living with MG. http://www.myasthenia.org/LivingwithMG.aspx. Accessed March 16, 2015.
- Pineles SL, Avery RA, Moss HE, et al. Visual and systematic outcomes in pediatric ocular myasthenia gravis. Am J Ophthalmol. 2010;150(4):453.e3 " 459.e3. [View Abstract]
Codes
ICD09
- 358.00 Myasthenia gravis without (acute) exacerbation
- 775.2 Neonatal myasthenia gravis
- 358.01 Myasthenia gravis with (acute) exacerbation
ICD10
- G70.00 Myasthenia gravis without (acute) exacerbation
- P94.0 Transient neonatal myasthenia gravis
- G70.01 Myasthenia gravis with (acute) exacerbation
SNOMED
- 91637004 myasthenia gravis (disorder)
- 82178003 Neonatal myasthenia gravis
- 193216006 Congenital and developmental myasthenia
- 193207007 Juvenile or adult myasthenia gravis (disorder)