Transcript MG in childhood - Scioto County Medical Society

Childhood Myasthenia Gravis
(MG)
Roula al-Dahhak, M.D.
Assistant Professor of Pediatrics and Neurology
Columbus Children’s Research Institute
Neuromuscular Program
Introduction
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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:
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Autoimmune MG (Juvenile): (JMG)
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Congenital MG (CMG)
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Neonatal (transient) MG: 10%
Juvenile MG (JMG):
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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):
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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%
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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):
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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):
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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):
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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):
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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):
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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):
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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
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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
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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:
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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
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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
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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
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Thymus role with MuSK is ??
The role of cell mediated immunity is ??
Thymic hyperplasia is absent among MuSK
positive patients.
JMG (DDx):
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Congenital MG
CN palsies
GBS
Myopathies (with ptosis and EOM abnormalities)
Botulism
LEMS
Venoms, toxins, drugs
Brain stem lesions.
hysteria
JMG (DDx):
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DDx between JMG and CMG:
Age of onset
Weakness
Spontaneous remession
AChR Ab
FH
Response to IS
Thymectomy
Response to AChEI
MG crisis
JMG
>12 months
fluctuating
possible
varies
effective
possibly effective
±62%
yes
CMG
since birth
stable
no
normal
+
non-effective
non-effective
± 40%
no
JMG (therapeutic options):
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Anticholinesterase medications
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Short-term immunomodulation (PE or IVIG)
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Long-term immunosuppression
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Thymectomy
Rx:(AChEI):
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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
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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
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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
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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
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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
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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):
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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):
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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:
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Pre-pubertal:
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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.
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Rx (Thymectomy):
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Among children with onset less than 11 years,
thymectomy did not influence the remission rate.
?? Risk for T cell depletion after the thymectomy (in prepubertal pts).
Conclusion: Among pts with prepubertal onset,
spontaneous remission is common and thymectomy may
make little difference to the rate of remission.
Rx (Thymectomy):
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Peri-puberty:
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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.
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General consensus: thymectomy is recommended early for
all peripubertal pts with bulbar or generalized weakness.
Rx (Thymectomy):
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Patients with elevated MuSK Ab respond poorly to
thymectomy (Avoid surgery here).
Rx(Long-term immunosuppressants: steroids):
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Steroids suppress multiple aspects of the humoral, cellmediated, 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):
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Always start slow.
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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 39months.
Preparatory PE or IVIG is helpful.
Long term treatment: lowest effective dose given on
alternate days.
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Rx(Long-term immunosuppressants: steroids):
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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:
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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):
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Azathiprine:
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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
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Rx:(Long-term immunosuppressants: others):
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Azathiprine (cont):
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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.
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Rx:(Long-term immunosuppressants: others):
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Cyclosporin A:
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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.
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Rx:(Long-term immunosuppressants: others):
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Cyclophosphamide:
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It inhibits B cell proliferation and IG synthesis.
Faster action than Azathioprine.
Worse side effects: immunosuppression, sterility,
teratogenesis, and malignancy.
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Rx:(Long-term immunosuppressants: others):
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Mycophenolate:
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Newest immunosuppressant.
Mild side effects
Rapid onset of therapeutic benefit.
Long term efficacy and safety???
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Questions????