dravet syndrome disorders

Evan FertigDirector of Research

Director of NEREG Dravet ProgramNortheast Regional Epilepsy Group

Dravet Syndrome Disorders

What is Dravet?

How do we diagnosis it?Dravet Genetics

How do we treat it?

Outline

1978C. Dravet

describes SMEI1989

Dravet Syndrome2001

SCN1A mutation discovered

A Brief History of Dravet Syndrome

Age 0-1• Febrile

Seizures

• EEG normal

Age 1+• Other

seizure types appear

• EEG abnormal

Age 2+• Cognitive

/ Behavior problems develop

Age 5+• Seizures

may become less frequent

• Cognitive problems plateau

Dravet Life Timeline

FocalSimple and Complex

Partial seizuresAutonomic changes

are prominent

Hemiclonic Seizures

MyoclonicGeneralized Tonic

ClonicMyoclonic Absence

SeizuresTriggered by

flashing lightsCan be prolonged

Atonic

Dravet Seizure TypesGeneralized

SUDEP Ortho Behavior and Development

Autism/ASD ↓Sweating ↑

Infections

Nutrition Sleep

Conditions Associated with Dravet(Dravet.org)

Get a History!

EEG and MRI

Genetic Testing positive in 70-80% of cases• M

utation in SCN1a gene

How Do We Diagnosis Dravet?

Peas, Genes, and DNA

18561953

What is a Gene?

http://www.csiro.au

The Structure of the Genome

GENEGenome

Chromosome

A Mutation is a SPELLING ERROR here

Genes, Protein, and Disease

Gene Protein

Neuron Nih.gov

Mutation

Cell

Brain Communication

http://www.niaaa.nih.gov/NR/rdonlyres/9E5D5B9F-C28E-49F2-A925-33886A82E4D5/0/synapsebetween_neurons.gif

How do Neurons (Brain Cells) work?

Ion Channel

Sodium Channel: Excites!

Potassium, Choride Channel: Rests!

SCN1A

Febrile Seizures

(FS)

GEFS+SMEI/Dravet

Syndrome

ICE-GTC

SCN1A-related seizure disorders

Treatment of Dravet Syndrome

PT/OT Developmental Specialist

Nutritonist

Orthopediatist

Neurologist

How do we Treat Dravet: Teamwork

Seizure Freedom

Development

Safety

Dravet Anti-Seizure Treatment Goals

•Antipyrexics•Rescue Medication (benz0)

•Cooling vest for hot weather•Avoid big change in temp

•Sunglasses: Zeiss Z1F133.•Unilateral eye patching?

•Tegretol, Dilantin•Lamictal, RufinamideWrong Meds

Avoid Seizure Triggers

Should children with Dravet get Vaccines?

Depakote

*Broad spectrum *Behavior

*Not typically

used under age 2 *Side

effects

Clobazam

*Broad Spectrum

Side Effects• Sedation• Drooling

Topamax

*Broad Spectrum

Cognitive Side

Effects

First Line Medicines for Dravet Syndrome in the United States

24 pt

16 continued

2 Sz free

10 75-99% decrease

4 50-74% decrease

8 stopped

5 not effective

3 vomiting

Ketogenic Diet for Dravet Syndrome

Carabolla 2005

Only med with placebo controlled evidence

Evidence of efficacy from 2 short-term and 1 long-term European studies

Prescribed with Clobazam (onfi) +/- VPA (depakote)

Stiripentol (Diacomnit)

Not FDA Approved

Orphan Drug Status

Medicaid Covered in some States

Blocks Clobazam “Metabolism”

• Increases level of medication and important “metabolite” in blood

Enhances “GABA”

• SCN1A thought to effect GABA brain cells

How Does Stiripentol Work?

 71 % vs. 5 %; Responders

Almost half of the stiripentol recipients were seizure free during this period compared with none in the placebo group.

Stiripentol Study

21 patients on stiripentol had moderate side-effects (drowsiness, loss of appetite) compared with eight on placebo, but side-effects disappeared when the dose of comedication was decreased in 12 of the 21 cases.

Drug interactionsClobazam

DepakoteNeutropenia

Side Effects and Interactions

How Stiripentol is Taken

Comes in 250 mg or 500 mg capsule, or sachet

Taken twice or three times a day

Lower Clobazam by 20% before dosing

No need to change depakote dose

Stiripentol dosing

KeppraZonegranBromidesVNSFelbamateSteroids?IVIG?

NOT effective: Resective Epilepsy Surgery

Possible Efficacy?

“Convulsive

Seizures”

•Depakote•Clobazam•Stiripentol and Clobazam•Topamax

Myoclonic Absence

•Ketogenic Diet•Ethosuximide

Treatment Approach

No Magic Bullet for treatment

Intense Research Efforts are Ongoing

Dravet.org

Conclusion