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: JMG CMG 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 (1/6 th 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????