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 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

Types: Autoimmune MG (Juvenile): (JMG)

Congenital MG (CMG)

Neonatal (transient) MG: 10%

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 ??

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.

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.

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)

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.

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.

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)

JMG (diagnosis): Fluctuating weakness Positive edrophonium (tensilon) test: negative in 8% of children.

Non-specific. Electrophysiological test is age limited: RNS SFEMG AChR antibodies

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.

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.

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 .

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.

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.

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

positive patients.

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

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

JMG (therapeutic options):

Anticholinesterase medications

Short-term immunomodulation (PE or IVIG)

Long-term immunosuppression

Thymectomy

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)

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

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.

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.

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.

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

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?????

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.

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.

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.

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.

Rx (Thymectomy): Patients with elevated MuSK Ab respond poorly to

thymectomy (Avoid surgery here).

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.

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.

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.

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).

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

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.

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.

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.

Rx:(Long-term immunosuppressants: others):

Mycophenolate: Newest immunosuppressant. Mild side effects Rapid onset of therapeutic benefit. Long term efficacy and safety???

Questions????