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Médecine en mutation dans une société en mutation: Nouveautés
en ÉpilepsieL CARMANT
SAINTE-JUSTINE HOSPITAL
UNIVERSITY OF MONTREAL
LEARNING OBJECTIVES
• New treatments in neurology– Tuberous sclerosis– Neonatal seizure– Febrile seizures and epilepsies
• Epilepsy care in Haiti– Update on the EEG clinic
TUBEROUS SCLEROSIS
• Autosomal dominant• 35% have a positive
family Hx• 1/6000 children• TSC1: hamartin- 9q34• TSC2: tuberin- 16p13
TUBEROUS SCLEROSIS
• Major criteria:– Hypomelanotic macules (three or
more)– Shagreen patch (connective tissue
nevus)– Facial angiofibromas or forehead
plaques– Periungual fibroma– Multiple retinal nodular hamartomas– Cortical tubers– Subependymal nodules– Subependymal giant cell astrocytoma– Cardiac rhabdomyoma, single or
multiple– Renal angiomyolipoma
– Lymphangiomyomatosis
TUBEROUS SCLEROSIS
• Minor criteria:– Multiple renal cysts– Non-renal hamartoma– Hamartomatous rectal polyps– Retinal achromic patch– Cerebral white matter radial
migration tracts– Bone cysts– Gingival fibromas– ‘Confetti' skin lesions– Multiple, randomly
distributed dental enamel pits
TUBEROUS SCLEROSIS
• Hamartin-tuberin complex inhibits the mTOR pathway
• Phosphorylation of TSC2 releases inhibition of mTOR through Rheb
• Loss of TSC1 or 2 will lead to the same phenomenon
• The Eker rat strain (TSC2)
TUBEROUS SCLEROSIS
• Sirolimus /Rapamycin: Streptomyces hygroscopicus
• Originally developed as an antifungal agent.
• Sirolimus is a new immunosuppressant especially useful in kidney transplants.
TUBEROUS SCLEROSIS
• DN Franz et al. report:– 5 patients with SEGA
– Previous Hx of Sx complication
– 1.5 mg/m2/day (level: 5-15 ng/ml)
– Significant response to rapamycin
Rapamycin causes regression of astrocytoma in tuberous sclerosis complex. Franz DN, Leonard J, Tudor C, Chuck G, Care M, Sethuraman G, Dinopoulos A, Thomas G, Crone KR. Ann Neurol. 2006;59(3):490-8.
TUBEROUS SCLEROSIS
• Adverse events:– Aphtous ulcers
– Acneiform rash
– Diarrhea
– Arthralgia
– Increase in serum cholesterol and lipoproteins
TUBEROUS SCLEROSIS
• Lesions resistant to radiation or chemotherapy
• Adequate length of rapamycin must be determined (6 mo.)
• Further confirmation in large scale studies
• Trials in glioblastome multiforme
• Combination g-interferon
NEONATAL SEIZURES
• The neonatal seizures are convulsive events in the first 28 days of life in term infants or for premature infants within 44 completed weeks CA.
• They are markers for time-specific etiologies– Antepartum
– Intrapartum
– Neonatal
NEONATAL SEIZURES
• Most neonatal sz are triggered by acute illness:– hypoxic-ischemic encephalopathy– stroke– infection
• Epileptic syndromes• They are often repetitive sometimes
prolonged
NEONATAL SEIZURES
• Single seizure type: 40%– Clonic 26%
– Tonic 12%– Subtle 2%
• Multiple seizure types: 60%– Clonic, tonic, subtle 19%
– Clonic + tonic 19%
– Clonic + subtle 17%
– Tonic + subtle 5%
Lanska et al 1995a
NEONATAL SEIZURES
• 40% birth asphyxia
• 14% hypoglycemia
• 12% hypocalcemia
• 12% kernicterus
• 10 % infection /neonatal sepsis
• 5% intracranial hemorrhage
• 4% malformationsMemon S, A Memon MM. Spectrum and immediate outcome of seizures in neonates. J Coll Physicians Surg Pak. 2006;16:717-20
NEONATAL SEIZURES
• Underlying etiology: metabolic disorders
• Glucose-hypothermia
• Phenobarbital (1914)– 20-40 mg/kg
• Phenytoin/fos- (1938)– 10-20 mg/kg
• Benzodiazepines– Diazepam-lorazepam-
midazolam
NEONATAL SEIZURES• Efficacy:
– 40-60% Pb + PHT (Painter 1999-NEMJ)– Midazolam controls majority of refractory patients (Castro-
Conde JR 2005-Neurology)– Prophylactic use decreases incidence of seizures but not
outcome (Singh D 2005-JMFNM vs Hall RT 1998- J Peds)– Cochrane review, no evidence of benefit for mortality or
disability (Evans and Levene). – Topiramate: 30-40 mg/kg
– AMPA receptor antagonist– Zonisamide: used in Japan for EIEE
NEONATAL SEIZURES
• There are also distinct neonatal epileptic syndromes:– benign neonatal familial convulsions – benign neonatal convulsions– early myoclonic encephalopathy– early infantile epileptic encephalopathy.
NEONATAL SEIZURES
• Benign familial neonatal convulsions:– Positive family history AD
– Chromosomes 20q13 (KCNQ2)- 8q24 (KCNQ3) (M-current)
– Up to a year
– Multiple seizure types, including apnea-tonic…
– Retigabine-diclofenac
– Na(V)1.2 Na+ channels
NEONATAL SEIZURES
• Benign neonatal convulsions:– Fifth day fits
– No family history
– Often status episodes
– No damage or epilepsy
– Children linked to KCNQ2
NEONATAL SEIZURES
• Depolarizing GABA:– NKCC1
– KCC2
• NMDA receptors:– NR2B, NR2D, NR3A
• AMPA receptors:– GluR2 lacking
receptors
Dzhala VI et al. Nat Med 2005
NEONATAL SEIZURES
• Bumetanide:– Effective in model
– Upcoming study
Fukada A. Diuretic soothes seizures in newborns. Nature Med. 2005;11:1153-4
SCN1A mutations
• Plays an essential role in nerve tissue conducting nerve impulse.
• A single gene on human chromosome 19 encodes the b-subunit expressed in the brain, heart, and skeletal muscle
SCN1A mutations• Clinical spectrum ranges from simple febrile
seizures (FS) or GEFS+ at the mild end to Dravet syndrome and intractable childhood epilepsy with generalized tonic-clonic seizures at the severe end.
• Less commonly observed:– myoclonic-astatic epilepsy (Doose syndrome),
Lennox-Gastaut syndrome (LGS), infantile spasms, and vaccine-related encephalopathy and seizures.
SCN1A mutations
• The diagnosis of SCN1A-related seizure disorders relies on molecular testing of SCN1A.
• This testing are available on a clinical basis
SCN1A mutations
• SCN1A-related seizure disorders are inherited as autosomal dominant.
• The proportion caused by de novo mutations varies with most SCN1A-related SMEI and ICE-GTC being a de novo heterozygous mutation.
SCN1A mutations
• The effectiveness of treatment may be improved by the observation that mutations affect GABA neurons
• ¸Seizures respond optimally to antiepileptic drugs (AEDs) that bind to the GABA receptor
SCN1A mutations
• Clobazam (0.2-1 mg mg/kg/day).
• Topiramate (5-10 mg/kg/day).
• Valproic acid (10-30 mg/kg/day).
• Phenobarbital (3-5 mg/kg/day).
SCN1A mutations
• Stiripentol (50-100 mg/kg/day). It is the only medication evaluated in a double-blind severe myoclonic epilepsy in infancy (SMEI) treatment study. They demonstrated efficacy of the drug when compared with placebo administration.
• only moderate side effects including drowsiness, loss of appetite, and occasional neutropenia.
SCN1A mutations
• Stiripentol acts directly on GABAA receptors, but also has the added benefit of increasing the serum concentration of other common AEDs, including valproic acid, clobazam, and its metabolite nor-clobazam.
• Children older than age 12 years may not tolerate stiripentol because of digestive tract side effects and nausea.
CONCLUSIONS
• Basic sciences, specially genetics, have provided neurologists with a better understanding of neurological disorders.
• This has in consequence led to better treatment of these disorders.
IMPACT ON EPILEPSY IN HAITI
• Number of patients evaluated in the first year : 442
• This represents about 40 EEGs on average per month.
Age/Gender
• Age– Minimum : 4 days
– Maximum : 83 years
– Median : 14 years
• Gender :– Males : 149 (45%)
– Females: 243 (55%)
0 -11 mois1 - 5 ans>5 -17 ans18 ans +
0-11 months :44, 1-5 years :77, >5-17 years :129, >18 years: 192
EEG changes per age group
0-11 months
1-5 years
>5-17 years
18 +
Epilepsy9 (20%) 7 (9%) 22 (17%)
20 (10%)
Slowing4 (9%) 7 (9%) 19 (15%)
21 (11%)
Both9 (20%)
12 (15%)
6 (5%) 10 (5%)
Normal 22(50%)/44
51(66%)/77
83(63%)/129
144(75%)/192
EEG changes
• 94% of children with witnessed seizures had an
abnormal EEG
• 16% of patients with headache had an abnormal
EEG with epileptiform discharges
• 76% of patients with seizures or headaches had an
epileptic EEG
Case history
• 5 years old, new onset seizures
• No family history
• New onset focal seizures with left hemiparesis with gait difficulties
• Seen in DR, no dx, MRI normal, started on phenobarbital.
LINEAR NEVUS
• Started on CBZ
• Seizures controlled for past 6 months
• No improvement on cognition or gait
CONCLUSION
• Education is key as a number of patients are not properly treated, however clear seizures are reliably diagnosed
• Need to reach a larger proportion of individuals in rural areas
• Imaging is a major problem for both availability and interpretation
JANUARY 2010• According to
governmental data 4000 new severe head injury cases
• Most assessed by foreign medical staff
• Impossible to do a funded study on post-traumatic epilepsy
JANUARY 2010
• Loss of pharmacies and capacity to produce generics
• Clinic spared, closed only for 12 days
• In 1 month, 600 patients seen with help of French emergency physicians and Dr Serge Pierre Louis
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