1. Dravet Syndrome: Diagnosis History Seizure Evolution
Linda Laux, MD
Pediatric Epileptologist
Lurie Children’s Epilepsy Center
Northwestern University Feinberg
School of Medicine

2. DISCLOSURES
Salary support from Dravet Syndrome Foundation for Predictive Factors for Long-Term Cognitive Outcome in Dravet Syndrome

3. Dravet Syndrome (DS)
Epilepsy syndrome with intractable seizures and cognitive/motor/behavior concerns that is highly associated with a sodium channel receptor mutation
Clinical diagnosis of DS:
Seizure onset < 12 months of age
Prior to seizure onset: unremarkable PMHx, normal development, normal neuroimaging
Seizures
Pleomorphic seizure types
Generalized (GTC, myoclonic, atypical absence)
Focal (alternating unilateral hemiconvulsions, other)
Developmental issues (slowing/plateau/regression)
Co-morbidity: Ataxia/gait abnormalities, behavioral issues

4. Historical Overview
Charlotte Dravet: recognized the clinical constellation of this epilepsy syndrome [Dravet, Vie Medicale 1978]
Studying children with Lennox-Gastaut syndrome
Group of children were different
Initial normal development, history
Seizure onset in the first year of life, often as febrile convulsions
Primarily clonic and myoclonic seizures
Seizures treatment resistant
Cognitive, behavior problems
No brain lesions
New syndrome: Severe Myoclonic Epilepsy of Infancy (SMEI)
Publications
1978: “Les epilepsies graves de l’enfant”
1982: “Advances in Epileptology: the XIIIth Epilepsy International Symposium

5. Historical Overview Severe Myoclonic Epilepsy in Infancy: Variants
Severe Myoclonic Epilepsy Borderline (borderland) [SMEB]
Intractable Childhood Epilepsy with GTC seizures [ICE-GTC]
Identification of high association with SCN1A mutation
Identification of SCN1A mutation with epilepsy (GEFS+) [Escayg, Nat Genet. 2000]
Association of SCN1A mutation with Dravet syndrome [Claes, Am J Hum Genetic 2001]
Seven patients with de novo SCN1A mutations (no mutations in 184 control chromosomes
“SMEI” not the best name
Children not “severe” in infancy
Not all the children have myoclonic seizures.
Dravet syndrome
Dravet Syndrome Spectrum

6. Dravet Syndrome: The First Seizure
Seizure onset:
Less than one year of age: mean 6 month
Seizure semiology (description):
Convulsive seizure (clonic >> tonic clonic)
Generalized, unilateral (hemiconvulsions)
Less likely: complex partial, myoclonic
May be prolonged (status epilepticus)
Seizure Trigger: fever, vaccinations
Normal development, examination
Normal MRI and EEG
Typical initial diagnosis: (Complex) febrile seizures
No medication begun (+/- Diastat)

7. Dravet Syndrome: The First Year
Seizures:
Semiology:
Convulsive seizure (clonic >> tonic clonic)
Generalized
Alternating unilateral clonic seizures (hemiconvulsions)
Less frequent: complex partial, myoclonic
Duration: prolonged
Frequency: Not frequent
Triggers: fever (low), vaccinations, hyperthermia, abrupt change in temperature
Normal development (majority)

8. Dravet Syndrome: Childhood
Very active seizure phase
Seizures more varied
Seizure frequency markedly increases
Multiple medication/treatment trials
Seizures initially still prolonged
Less prolonged seizures (status epilepticus) over time
With active seizure phase, developmental, cognitive, motor, behavioral concerns develop (1-5 years)
EEG becomes abnormal:
Background slowing
Generalized and multifocal interictal spikes/sharps

9. Interictal EEG

10. Dravet Syndrome: Varied Seizure Types
Convulsive and focal seizures
Convulsive (clonic >> tonic clonic)
Generalized, unilateral
May have preserved consciousness with unilateral
Focal seizures
From any brain region
Atypical convulsive seizures with both generalized and focal components
Any variation: stiffness (body turning), clonic jerks
Asymmetric, asynchronous, focal
EEG with generalized and focal features during the seizures
In some literature: “falsely generalized”, “unstable seizures”
Triggers: Fever, vaccinations, hyperthermia, abrupt change in temperature, excitement

11. Dravet Syndrome

12. Dravet Syndrome

13. Dravet Syndrome

14. DS: Varied Seizure Types
Nonconvulsive Seizures:
Atypical absence
5-20 seconds (but may be prolonged)
Often with myoclonic jerks (head nods, eye blinks)
Myoclonic seizures
Quick muscle jerks
Whole body, head drops, extremities
Eyelid flutters: +/- EEG correlate
“Obtundation State”
Prolonged nonconvulsive seizure (atypical absence, myoclonic)
Triggers: photic stimulation, visual patterns, concentration, fine motor skills, tired, excitement

15. Eyelid flutter

16. Myoclonic seizure

17. Myoclonic Seizure

18. Myoclonic seizure

19. Atypical absence seizure

20. Dravet Syndrome: Adolescent, Adults
“Stabilize”
Less frequent (although seizure control can worsen pre- teens/teenagers)
Decreased incidence of prolonged seizures
However, limited literature
Adults
Brief nocturnal “convulsions” most common seizure type [Jansen, Neurology 2006, Akiyama, Epilepsia 2010]
Refractory to medications/treatment
Adults: 16% seizure free > 1 year (5/31 patients) [Akiyama, Epilepsia 2010]
Adults: 8% seizure free > 1 year (5/64 patients) [Tayayama, Epilepsia, 2014] 20

21. General characteristics seizures in Dravet syndrome
1. Mixed seizure types
Both generalized and focal seizures
Generalized: convulsions, myoclonic atypical absence
Focal: hemiconvulsions, other
Seizures with both generalized and focal features
Treatment:
Broad spectrum medication useful for generalized and focal seizures
Although a child may have many different seizure types, may have a specific seizure type of concern to focus treatment. 21

22. Fewest seizures possible Limited adverse side effects
General characteristics seizures in Dravet syndrome 2. Seizures are treatment resistant
Seizure Control
Fewest seizures possible
No status epilepticus
Medications
Limited adverse side effects
Maximize Cognitive Potential
Maximize Quality of Life

23. General characteristics seizures in Dravet Syndrome
3. Seizures prolonged especially when young
Need specific acute seizure plan
Convulsive versus nonconvulsive status epilepticus
May be different for seizure clusters
Acute seizure Plan:
Home
Paramedics
Emergency room
Revisions to plan over time 23

24. General characteristics seizures in Dravet syndrome
4. Specific seizure triggers (avoidance):
Vaccinations
Do not recommend avoiding
Fever
Antipyretics, benzodiazepines
Hyperthermia
Use of cooling vest
Abrupt change in temperature
Excitement
Visual: Photic stimuli, visual patterns
Sunglasses (Zeiss Z1F133)
Unilateral eye patching 24

25. Vaccinations in Dravet Syndrome
De-Novo mutations of the sodium channel gene SCN1A in alleged vaccine encephalopathy: a retrospective study [Berkovic , Lancet 2006]
14 patients with alleged vaccine encephalopathy
SMEI: 8/8 patients + SCN1A mutations
SMEB: 3/4 patients + SCN1A mutations
Lennox-Gastaut: 0/2 patients + SCN1A mutations
Effect of vaccination on onset and outcome of Dravet syndrome: a retrospective study [McIntosh, Lancet Neurology, 2010]
40 patients with DS: Vaccine proximate (n=12), vaccine distant (n=28)
No difference in intellectual outcome, subsequent seizure type, or SCN1A mutation
Early seizure onset in vaccine proximate group (7.8 weeks) 25

26. Overview: History, Diagnosis, Seizure Evolution in Dravet Syndrome
Friday:
Morning: SCN1A mutation, genetics
Afternoon: Treatment
Saturday:
Track 1: Research
Clinical, SUDEP, Basic Science
Track 2: Family Program
Sunday: Co-morbidities
Cognitive, behavior, gait, sleep

27. WELCOME!!

28. Lurie Children’s Epilepsy Center