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Childhood Myasthenia Gravis (MG)

Childhood Myasthenia Gravis (MG). Roula al-Dahhak, M.D. Assistant Professor of Pediatrics and Neurology Columbus Children’s Research Institute Neuromuscular Program. Introduction. MG is a neuromuscular disorder that affects skeletal muscles

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Childhood Myasthenia Gravis (MG)

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  1. Childhood Myasthenia Gravis (MG) Roula al-Dahhak, M.D. Assistant Professor of Pediatrics and Neurology Columbus Children’s Research Institute Neuromuscular Program

  2. Introduction • MG is a neuromuscular disorder that affects skeletal muscles • MG was first described in the year1672 • Onset in childhood was recognized by Erb in 1879 • MG in childhood comprises 10-20% of all myasthenic patients

  3. Types: • Autoimmune MG (Juvenile): (JMG) • Congenital MG (CMG) • Neonatal (transient) MG: 10%

  4. Juvenile MG (JMG): • Autoimmune • Antibodies directed against AChR in skeletal muscle • Cell and complement mediated process • This leads to a reduced number and function of AChRs • The severity of the symptoms parallels the reduction in AChRs. • Factors that starts the process ??

  5. JMG (epidemiology): • Almost never occurs before 1 year of age. • It is more common in Oriental than Caucasian: In North America: 10-15% (1.1 per million total population/ year) In China and Japan: 43% • Pre-puberty: Incidence is higher in black as compared to white • Pre- puberty: white patients show an equal sex ratio; female are more affected among black population. • Post-puberty: Females are more commonly affected than males. • Possible genetic and environmental trigger factors.

  6. JMG (pathology): • Pathogenic mechanisms are similar to adult. • Age, sex hormones influence the incidence of JMG. • Female sex hormones enhance while the male sex hormones inhibit the thymus function. • Certain HLA types are linked to earlier age of onset.

  7. JMG ( Presentation): • Similar to adult. • Fluctuating and fatigable weakness • Symptoms are worse through the day. • Worsening of symptoms may occur after febrile illness or insect bites or certain medications. • Extraocular, bulbar and limb weakness. • Ocular symptoms occur in 90% of cases. • MG remains ocular in only 10-15% of cases (usually with prepubertal onset)

  8. JMG ( Presentation): • The maximal disease severity is within 2 years of onset. • 50% of cases with ocular MG will become generalized within 2 years and 75% within 4 years.

  9. JMG (presentation): • Bulbar symptoms affect 75% of patients: dysphagia, dysarthria, facial weakness. • Limb weakness (proximal), fluctuating. • Systemic weakness may affect the diaphragm and other muscles of respiration.

  10. JMG (presentation): • Thymoma is rare • Other autoimmune disease are common: diabetes, thyroid dx and JRA. • Spontaneous remission is more common among young patients (up to 30% of cases within 15 years of disease onset in one study)

  11. JMG (diagnosis): • Fluctuating weakness • Positive edrophonium (tensilon) test: negative in 8% of children. Non-specific. • Electrophysiological test is age limited: • RNS • SFEMG • AChR antibodies

  12. JMG (diagnosis): RNS • Studies on pediatric population are limited: • One study of 12 children with all forms of MG showed: RNS is positive in: 75% of neonatal MG 88% of JMG • Sensitivity increases with proximal muscle evaluation.

  13. JMG (diagnosis): RNS • Decrement>10% indicates a NMJ disorder. • RNS does not discriminate between CMG and JMG. • SF-EMG: most sensitive methode • Absence of jitter on SFEMG of a weak muscle r/o NMJ d/o. • SFEMG can’t discriminate between CMG and JMG.

  14. JMG (Diagnosis): AChR antibodies: • A Higher percentage of young childrens are sero-negative as compared with adults (adults are positive is 70-90%). • Age related: Pre-puberty: 36-50% are sero-negative peri-puberty: 25-30% post puberty: 0-9% • Most common AChR Ab are binding Ab. • Modulating antibodies are positive in 6% of sero-negative adults. • Seroconversion may occur within 12 months of onset in 15% of cases .

  15. JMG (diagnosis): MuSK antibodies • MuSK Ab is positive in 40% of seronegative adult pts, but it is less positive in children. • MuSK is negative in pure ocular cases and in patients with thymoma, and in seropositive pts. • Mechanism of action of Musk?? • Are mainly Ig G4 subclass • The disruption of NMJ may not be mediated by complement.

  16. JMG (diagnosis): MuSK antibodies • Among MuSK ab positive pts, bulbar and facial weakness and atrophy are prominent in white women. • In black women who have positive MuSK ab, neck, shoulder, respiratory weakness with less marked or absent ocular weakness predominate. • Both seronegative and positive pts respond similarly to PE and IS therapy.

  17. JMG (diagnosis): MuSK antibodies • Thymus role with MuSK is ?? • The role of cell mediated immunity is ?? • Thymic hyperplasia is absent among MuSK positive patients.

  18. JMG (DDx): • Congenital MG • CN palsies • GBS • Myopathies (with ptosis and EOM abnormalities) • Botulism • LEMS • Venoms, toxins, drugs • Brain stem lesions. • hysteria

  19. JMG (DDx): • DDx between JMG and CMG: JMGCMG Age of onset >12 months since birth Weakness fluctuating stable Spontaneous remession possible no AChR Ab varies normal FH - + Response to IS effective non-effective Thymectomy possibly effective non-effective Response to AChEI±62% ± 40% MG crisis yes no

  20. JMG (therapeutic options): • Anticholinesterase medications • Short-term immunomodulation (PE or IVIG) • Long-term immunosuppression • Thymectomy

  21. Rx:(AChEI): • Are usually the first treatment for JMG. • Pyridostigmine: 1 mg/kg q 4-6 hours • AChEIs do not influence the autoimmune process and do not control all symptoms. • Response may diminish with time • A drug holiday is recommended to reestablish efficacy. • SE: n/v, abdominal pain, diarrhea, sweating, cholinergic crisis (worsening weakness)

  22. Rx:(Short-term immunomodulation): PE • PE removes antibodies and other protein from circulation. • Improvement within days and may last~4-10 weeks. • Equally effective in seronegative and seropositive patients. • It is effective in pediatric population • A course of 5-6 treatment over 2 weeks. Volume is replaced with saline, and close monitoring of fluid and electrolytes balance is recommended. • Needs to be repeated frequently

  23. Rx:(Short-term immunomodulation):PE • Indication of PE: 1) Preoperative period 2) Acute care of very weak patients 3) At initiation of immunosupressive therapy • It requires double lumen venous catheter under general anesthesia in children younger than 7 years.

  24. Rx:(Short-term immunomodulation):IVIG • IVIG use in pediatrics population is not very well documented. • Up to 70% of pts improve with IVIG, usually within 5 days of onset of treatment. • Easier to use for acute therapy in young pts. • However, improvement is less than with PE.

  25. Rx:(Short-term immunomodulation):IVIG • The standard dose is 2 gm/kg giving slowly at 400 mg/kg/ day X 5days. • Another approach: dose of 1 g/kg daily for 2 days. • Improvement lasts for 3-6 weeks and up to 17 weeks for pts on long-term immunosuppressants.

  26. Rx:(Short-term immunomodulation):IVIG • Indications for IVIG: 1) Preoperative period 2) Pts with severe weakness 3) At the initiation of immunosuppressants • IVIG can be repeated as needed. • SE: headache, aseptic meningitis (in migraineurs), flu-like symptoms, hyperactivity, (CHF, DVT, ARF in adults) • Beware of IgA deficiency

  27. Rx:(Thymectomy): • No controlled studies available. • Several studies address thymectomy in children with generalized and/or bulbar weakness: It produces complete remission in 10-75% and improvement in 57-95%. • It is more effective within 12 months of disease onset. • Helpful for pts with bulbar or generalized weakness. • Ocular MG?????

  28. Rx:(Thymectomy): • Complete excision of the thymus is recommended. • It may help in reducing the dose of medications. • It is relatively safe. • Preoperative prep that includes AChEI, PE, IVIG, or steroids minimizes the complications. • Consider surgery in seropositive (AChR Ab) patients.

  29. Rx (Thymectomy): Timing of surgery: • Pre-pubertal: • The incidence of JMG is low. • Difficult to differentiate from CMG. • Spontaneous remission is more common (better in white than black) than among older pts. • Spontaneous remission (w/o thymectomy) is better in younger children with onset before 11 years.

  30. Rx (Thymectomy): • Among children with onset less than 11 years, thymectomy did not influence the remission rate. • ?? Risk for T cell depletion after the thymectomy (in pre-pubertal pts). • Conclusion: Among pts with prepubertal onset, spontaneous remission is common and thymectomy may make little difference to the rate of remission.

  31. Rx (Thymectomy): • Peri-puberty: • Response is excellent among white pts who have the surgery within 12 months of onset. • The only response in black was when the surgery occurred within 1 year of disease onset. • General consensus: thymectomy is recommended early for all peripubertal pts with bulbar or generalized weakness.

  32. Rx (Thymectomy): • Patients with elevated MuSK Ab respond poorly to thymectomy (Avoid surgery here).

  33. Rx(Long-term immunosuppressants: steroids): • Steroids suppress multiple aspects of the humoral, cell-mediated, and other arms of the immune system. • Steroids are helpful in 80% of adults pts with ocular, bulbar, or generalized weakness. • In children: improvement occurs in only 10-61% of pts treated with steroids. • Steroids do not influence the chance for remission after thymectomy.

  34. Rx(Long-term immunosuppressants: steroids): • Always start slow. • Starting at higher (therapeutic dose: 1-2 mg/kg/day) will produce weakness in 8% of pts within the first 3 weeks of treatment. • Improvement begins w/i 4 weeks and maximal by 3-9months. • Preparatory PE or IVIG is helpful. • Long term treatment: lowest effective dose given on alternate days.

  35. Rx(Long-term immunosuppressants: steroids): • SE of chronic steroid use may be serious. • 60% of adults experience side effects. • SE are more in children due to the effect of steroids on development: growth retardation, bone mineralization and development abnormalities.

  36. Rx(Long-term immunosuppressants: steroids): High dose IVMP: • Limited use, limited data. • SE can be serious: sudden death, atrial fib, peptic bleeding, transient psychosis. • Remember that severe muscle weakness may occur with IVMP. • Typical dose: 1gm/day given slowly (1/6th hourly) for 5 days. • Watch for fluid balance, electrolytes, blood pressure, hematuria, ECG, and use ranitidine prophylaxis. • It is used in less severe cases (ocular MG).

  37. Rx:(Long-term immunosuppressants: others): • Azathiprine: • It metabolizes to a cytotoxic 6-MP. • It inhibits DNA and RNA synthesis and interfers with T cell function. • It is used to limit steroid use for long duration. • Dose: 2mg/kg/day with weekly increments of 0.5 mg/kg/day

  38. Rx:(Long-term immunosuppressants: others): • Azathiprine (cont): • Onset of action is slow. • Maximum benefit is delayed for 3-12 months. • Improvement occurs in 30-90% of adult and pediatric pts. • SE: flu-like symptoms, abnormal LFTs, leukopenia, pancytopenia, immunosuppression, late development of malignancy.

  39. Rx:(Long-term immunosuppressants: others): • Cyclosporin A: • A fungal metabolite. • It inhibits T helper function and T cell-dependent antibody responses and activates T suppressor functions. • In adults, improvement occurs in 40%, it also lowered AChR Ab levels, and leads to reduction of steroid dose. • Improvement occurs within 2 months. • Dose: 5 mg/kg/day divided in two doses. • SE: nephrotoxicity, HTN, headache, and cost.

  40. Rx:(Long-term immunosuppressants: others): • Cyclophosphamide: • It inhibits B cell proliferation and IG synthesis. • Faster action than Azathioprine. • Worse side effects: immunosuppression, sterility, teratogenesis, and malignancy.

  41. Rx:(Long-term immunosuppressants: others): • Mycophenolate: • Newest immunosuppressant. • Mild side effects • Rapid onset of therapeutic benefit. • Long term efficacy and safety???

  42. Questions????

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