Dravet Syndrome:DiagnosisHistorySeizure Evolution

1

Linda Laux, MDPediatric EpileptologistLurie Children’s Epilepsy CenterNorthwestern University Feinberg School of Medicine

DISCLOSURES• Salary support from Dravet Syndrome Foundation for

Predictive Factors for Long-TermCognitive Outcome in Dravet Syndrome

2

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

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

5

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)

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

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

Dravet Syndrome

Dravet Syndrome

Dravet Syndrome

DS: Varied Seizure TypesNonconvulsive 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

Eyelid flutter

15

Myoclonic seizure

16

Myoclonic Seizure

17

Myoclonic seizure

18

Atypical absence seizure

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.

General characteristics seizures in Dravet syndrome 2. Seizures are treatment resistant

22

Seizure ControlFewest seizures possible

No status epilepticus

MedicationsLimited adverse side

effects

Maximize Cognitive PotentialMaximize 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

24

General characteristics seizures in Dravet syndrome4. 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

• 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

Vaccinations in Dravet Syndrome

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

26

WELCOME!!

Lurie Children’s Epilepsy Center