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

From febrile seizures to epileptic encephalopathy

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.

CLIDEP YEAR 1

June 2008 to June 2009

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

Geographic repartitionGeographic repartition

Press a key to continue …

Nippes

Rural area=71(16%)

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

MARCH 2010

• New EEG machine portable

• Tegretol- Valproic acid and Keppra given

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