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Médecine en mutation dans une société en mutation: Nouveautés en Épilepsie

Médecine en mutation dans une société en mutation: Nouveautés en Épilepsie. L 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

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Médecine en mutation dans une société en mutation: Nouveautés en Épilepsie

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  1. Médecine en mutation dans une société en mutation: Nouveautés en Épilepsie L CARMANT SAINTE-JUSTINE HOSPITAL UNIVERSITY OF MONTREAL

  2. LEARNING OBJECTIVES • New treatments in neurology • Tuberous sclerosis • Neonatal seizure • Febrile seizures and epilepsies • Epilepsy care in Haiti • Update on the EEG clinic

  3. TUBEROUS SCLEROSIS • Autosomal dominant • 35% have a positive family Hx • 1/6000 children • TSC1: hamartin- 9q34 • TSC2: tuberin- 16p13

  4. 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

  5. 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

  6. 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)

  7. TUBEROUS SCLEROSIS • Sirolimus /Rapamycin: Streptomyces hygroscopicus • Originally developed as an antifungal agent. • Sirolimus is a new immunosuppressant especially useful in kidney transplants.

  8. 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.

  9. TUBEROUS SCLEROSIS • Adverse events: • Aphtous ulcers • Acneiform rash • Diarrhea • Arthralgia • Increase in serum cholesterol and lipoproteins

  10. 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

  11. 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

  12. NEONATAL SEIZURES • Most neonatal sz are triggered by acute illness: • hypoxic-ischemic encephalopathy • stroke • infection • Epileptic syndromes • They are often repetitive sometimes prolonged

  13. 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

  14. NEONATAL SEIZURES • 40% birth asphyxia • 14% hypoglycemia • 12% hypocalcemia • 12% kernicterus • 10 % infection /neonatal sepsis • 5% intracranial hemorrhage • 4% malformations • Memon S, A Memon MM. Spectrum and immediate outcome of seizures in neonates. J Coll Physicians Surg Pak. 2006;16:717-20

  15. 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

  16. 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

  17. NEONATAL SEIZURES • There are also distinct neonatal epileptic syndromes: • benign neonatal familial convulsions • benign neonatal convulsions • early myoclonic encephalopathy • early infantile epileptic encephalopathy.

  18. 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

  19. NEONATAL SEIZURES • Benign neonatal convulsions: • Fifth day fits • No family history • Often status episodes • No damage or epilepsy • Children linked to KCNQ2

  20. NEONATAL SEIZURES • Depolarizing GABA: • NKCC1 • KCC2 • NMDA receptors: • NR2B, NR2D, NR3A • AMPA receptors: • GluR2 lacking receptors Dzhala VI et al. Nat Med 2005

  21. NEONATAL SEIZURES • Bumetanide: • Effective in model • Upcoming study • Fukada A.Diuretic soothes seizures in newborns. Nature Med. 2005;11:1153-4

  22. SCN1A mutations From febrile seizures to epileptic encephalopathy

  23. 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

  24. 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.

  25. SCN1A mutations • The diagnosis of SCN1A-related seizure disorders relies on molecular testing of SCN1A. • This testing are available on a clinical basis

  26. 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.

  27. 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

  28. 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).

  29. 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.

  30. 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.

  31. 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.

  32. CLIDEP YEAR 1 June 2008 to June 2009

  33. IMPACT ON EPILEPSY IN HAITI Number of patients evaluated in the first year : 442 This represents about 40 EEGs on average per month.

  34. Age/Gender • Age • Minimum : 4 days • Maximum : 83 years • Median : 14 years • Gender : • Males : 149 (45%) • Females: 243 (55%) 0-11 months :44, 1-5 years :77, >5-17 years :129, >18 years: 192

  35. Geographic repartition Rural area=71(16%) Nippes Press a key to continue …

  36. EEG changes per age group

  37. 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

  38. 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.

  39. LINEAR NEVUS • Started on CBZ • Seizures controlled for past 6 months • No improvement on cognition or gait

  40. 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

  41. 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

  42. 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

  43. MARCH 2010 • New EEG machine portable • Tegretol- Valproic acid and Keppra given

  44. FUTURE • Buy transportation to perform assessment in rural areas • Association with Yélé to get people to come and get tested • Make imaging accessible to all • Maintain drug availability • Help local Haitian physicians

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