Dravet Syndrome Disorders Evan Fertig Director of Research

Dravet Syndrome Disorders Evan Fertig Director of Research Director of NEREG Dravet Program Northeast Regional Epilepsy Group

Outline �What is Dravet? �How do we diagnosis it? �Dravet Genetics �How do we treat it?

A Brief History of Dravet Syndrome 1978 C. Dravet describes SMEI 1989 Dravet Syndrome 2001 SCN 1 A mutation discovered

Dravet Life Timeline Age 5+ Age 2+ Age 1+ Age 0 -1 • Febrile Seizures • EEG normal • Other seizure types appear • EEG abnormal • Cognitive/ Behavior problems develop • Seizures may become less frequent • Cognitive problems plateau

Dravet Seizure Types Focal Generalized �Simple and Complex �Myoclonic Partial seizures � Autonomic changes are prominent �Hemiclonic Seizures �Generalized Tonic Clonic �Myoclonic Absence Seizures � Triggered by flashing lights � Can be prolonged �Atonic

Conditions Associated with Dravet (Dravet. org) SUDEP Ortho Behavior and Development Autism/ASD ↓Sweating ↑ Infections Nutrition Sleep

How Do We Diagnosis Dravet? Get a History! EEG and MRI Genetic Testing positive in 7080% of cases • Mutation in SCN 1 a gene

Peas, Genes, and DNA 1953 1856

What is a Gene? http: //www. csiro. au

The Structure of the Genome Chromosome GENE A Mutation is a SPELLING ERROR here

Genes, Protein, and Disease Gene Cell Protein Mutation Neuron Nih. gov

Brain Communication http: //www. niaaa. nih. gov/NR/rdonlyres/9 E 5 D 5 B 9 F-C 28 E-49 F 2 -A 925 -33886 A 82 E 4 D 5/0/synapsebetween_neurons. gif

How do Neurons (Brain Cells) work? Ion Channel Sodium Channel: Excites! Potassium, Choride Channel: Rests!

SCN 1 A-related seizure disorders Febrile Seizures (FS) ICE-GTC SCN 1 A SMEI/Dr avet Syndrom e GEFS+

Treatment of Dravet Syndrome

How do we Treat Dravet: Teamwork PT/OT Developmental Specialist Orthopediatist Nutritonist Neurologist

Dravet Anti-Seizure Treatment Goals Seizure Freedom Development Safety

Avoid Seizure Triggers • Antipyrexics • Rescue Medication (benz 0) • Cooling vest for hot weather • Avoid big change in temp • Sunglasses: Zeiss Z 1 F 133. • Unilateral eye patching? Wrong Meds • Tegretol, Dilantin • Lamictal, Rufinamide

Should children with Dravet get Vaccines?

First Line Medicines for Dravet Syndrome in the United States Depakote *Broad spectrum *Behavior Clobazam Topamax *Broad Spectrum *Not typically Side Effects used under age 2 • Sedation • Drooling *Side effects Cognitive Side Effects

Ketogenic Diet for Dravet Syndrome 2 Sz free 16 continued 10 75 -99% decrease 4 50 -74% decrease 24 pt 8 stopped 5 not effective 3 vomiting Carabolla 2005

Stiripentol (Diacomnit) �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)

�Not FDA Approved �Orphan Drug Status �Medicaid Covered in some States

How Does Stiripentol Work? Blocks Clobazam “Metabolism” • Increases level of medication and important “metabolite” in blood Enhances “GABA” • SCN 1 A thought to effect GABA brain cells

Stiripentol Study � 71 % vs. 5 %; Responders �Almost half of the stiripentol recipients were seizure free during this period compared with none in the placebo group.

Side Effects and Interactions � 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 interactions � Clobazam � Depakote �Neutropenia

How Stiripentol is Taken

Stiripentol dosing �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

Possible Efficacy? �Keppra �Zonegran �Bromides �VNS �Felbamate �Steroids? �IVIG? �NOT effective: Resective Epilepsy Surgery

Treatment Approach “Convulsive Seizures” Myoclonic Absence • • Depakote Clobazam Stiripentol and Clobazam Topamax • Ketogenic Diet • Ethosuximide

Conclusion �No Magic Bullet for treatment �Intense Research Efforts are Ongoing �Dravet. org