Dravet Syndrome: Diagnosis History Seizure Evolution

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-TermCognitive 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. General characteristics seizures in Dravet syndrome2. 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