KCNQ2 Summit: Epileptic Encephalopathies

Kristen Park, M.D.Assistant Professor

Children’s Hospital of Colorado

OUTLINE• What‘s in a name?

– Classification and syndromes

• What is an epileptic encephalopathy?

• How many kids like mine are there?– Epidemiology of epilepsy in children

• What do we do about all this?– Treatment

WHAT’S IN A NAME?• Epilepsy - the occurrence of more

than one unprovoked seizure

• Questions regarding the diagnosis:– Why?

– What will happen (prognosis)?

– What is the best treatment?

• Enter: CLASSIFICATION

CLASSIFICATION• History

• Current themes– Seizure types

– Etiology

– Syndromes

New Term and Concept Examples Old Term and Concept

Genetic: Genetic defect directly contributes to the epilepsy and seizures are the core symptom of the disorder

Glut1 deficiency

KCNQ2

Idiopathic: presumed genetic

Structural-metabolic: caused by a structural or metabolic disorder of the brain

Cortical malformationsLeigh’s disease

Symptomatic: secondary to a known disorder of the brain

Infectious/Immune Rasmussen’sHerpes encephalitis

Unknown: the cause is unknown and might be genetic, structural, or metabolic

Cryptogenic: presumed symptomatic

1.Berg, AT et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005--‐2009. Epilepsia 2010;51:676--‐685.2.Berg AT, Cross JH. Lancet 2010:9;459--‐61.3.Blume WT et al. Glossary of descriptive terminology for ictal semiology: Report of the ILAE task force on classification and terminology. Epilepsia 2001:42;1212--‐1218.

What defines an epilepsy syndrome?

• Seizure type(s)

• Age of onset

• Etiology

• Anatomy

• Severity

• EEG – ictal and interictal

• Associated clinical features

• Duration of epilepsy

• Prognosis

The Story is Changing• Precise/Ultimate diagnosis

• Does this equal precise characterization?– SCN1A:

• Dravet syndrome

• Generalized epilepsy with febrile seizures

• Doose syndrome (myoclonic astatic epilepsy – MAE)

– KCNQ2

• BFNC

• Encephalopathy

• Genotype-Phenotype correlation– Specific mutation

– Clinical manifestations

What is an epileptic encephalopathy?

• Age dependent syndrome

• Unique types of frequent seizures

• Abnormal interictal EEG

• Heterogeneous causes

• Pharmacoresistant

• Frequently associated with developmental impairment and/or regression

0-3 mos

• Otahara Syndrome (EIEE)

• Tonic seizures

• Burst suppression EEG

• Early Myoclonic Encephalopathy (EME)

• Myoclonic seizures

• Burst suppression EEG

4m – 2y

• West Syndrome

• Epileptic spasms

• Hypsarrhythmia

1-8y

• Lennox-Gastaut Syndrome

• Multiple seizure types – tonic, atonic, convulsions, atypical absence

• Slow spike and wave (2Hz)

Etiology of Encephalopathy

• Seizures– Seizure themselves– Post-ictal periods

• Inter-ictal discharges• Episodes of status epilepticus• Medications

– Side effects– Rescue medications

• Underlying gene mutation?

Seizures: Example Dravet syndrome

• Largest study (n=26) failed to correlate seizure control with cognitive decline– Age of onset, seizure type, status

• But decline occurs during most active period of seizures

• In KCNQ2 developmental impairment persists after resolution of seizures

Interictal Abnormalities

Interictal Abnormalities• Faster treatment of infantile spasms and

resolution of hypsarrhythmia has been associated with better developmental outcomes

• Continuous spike wave discharges in sleep have been associated with impaired language; however, resolution of EEG abnormalities not always associated with recovery of skills

• Specific mechanisms may be unique to each syndrome

Medications• Poly-pharmacy has more side effects than

monotherapy

• All the medications cause mild general psychomotor slowing

– Medication class

– Age at administration?

• Some more effective than others at affecting the interictal EEG

• Medications vs seizures?

Genetics• Spectrum of severity

• Modifier genes

• SCN1A– Type of mutation not associated with cognitive

profile

– 2 children with truncation mutations followed and demonstrated progressive cognitive decline

• Specific profile?

How many kids like mine are there?Epidemiology of epilepsy in children

Epidemiology of Epilepsy• Prevalence: total number of new and

existing cases of a disease– 2.3-2.5 million people in the United States (1%)

• Incidence: number of newly diagnosed cases each year– 150,000-200,000 cases each year

– Mostly in young children and the elderly

Neonatal Seizures

• 2-3/1000 term infants and 10-15/1000 preterm infants

• 85% within the first 15 days with 65% between DOL 2-5

24%

17%

7%

52%

Developmental Brain

Abnormality

Acquired Insults

Metabolic

Unknown

Genetic Causes•KCNQ2

Epileptic Encephalopathies

• Otahara syndrome

– Incidence has been estimated at 1/100 000 births in Japan and 1/50,000 births in the U.K.

• Lennox Gastaut syndrome

– 1997 community-based retrospective study in Helsinki, the annual incidence of Lennox–Gastaut was 2 in 100,000 (0.002%) from 1975 to 1985

– 4% of children with epilepsy

• 0.026% of all children in the Atlanta, Georgia metropolitan area were estimated to have LGS in 1997

– More prevalent in males than females.

Specific Genetic Syndromes• Cohorts of patients with severe,

undiagnosed epilepsies– Targeted sequencing or candidate gene

testing

– 10-70% of patients with a probable genetic diagnosis in known or presumed pathogenic genes

What do we do about all this?

Treatment• Prevalence of refractory epilepsy

variably reported as 9-24%

• Predictors associated with intractability– Presence of multiple seizure types

– Persistence of seizures on treatment

– Developmental impairment

– High seizure frequency

– Onset <1y, history of neonatal seizures

– Slowing on EEG, especially focal

Treatment• Goal – minimize seizures and side effects,

optimize quality of life• Wholistic approach – not just seizures• Choose treatment based upon:

– Type of seizure or epilepsy syndrome• Specific agents – ACTH, Banzel, Onfi –

based on pathophysiology or clinical data– Side effect profile (cognitive)

• Consider adjunctive therapy early• Minimize polytherapy, if possible• Be cautious about treating EEG

Treatment• Adjunctive treatment

– Ketogenic diet

– VNS

– Corpus callosotomy

• Medications typically associated with significant cognitive side effects

– Topamax

– Zonegran

– Phenobarbital

• Medications thought to improve EEG

– Depakote

– Lamictal

– Keppra

Treatment• Early diagnosis and appropriate medications may reduce

overall seizure and medication burden

• Likely many factors contribute to the cognitive profile seen in KCNQ2E

• The best way to address the cognitive issues is to know what they are SO.....

• Get pscyhometric testing to identify your child’s strengths and facilitate communication with educators

• Early therapy

SUMMARY• Many epilepsies have traditionally been classified

into specific syndromes based on common features

• The utility of this scheme may be changing for genetically mediated epilepsies

• KCNQ2E fits into the epileptic encephalopathiesin many ways but is unique in others

• Treatment should be tailored towards seizure reduction and cognitive issues