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

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

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

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

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)

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

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 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

Eyelid flutter

Myoclonic seizure

Myoclonic Seizure

Myoclonic seizure

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

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

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

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

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

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

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

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