1. KCNQ2 Summit: Epileptic
Encephalopathies
Kristen Park, M.D.
Assistant Professor
Children’s Hospital of Colorado

2. 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

3. 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

4. CLASSIFICATION
• History
• Current themes
– Seizure types
– Etiology
– Syndromes

6. 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 malformations
Leigh’s disease
Symptomatic: secondary
to a known disorder of
the brain
Infectious/Immune Rasmussen’s
Herpes 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.

7. 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

9. 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

10. 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

11. 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)

12. Etiology of
Encephalopathy
• Seizures
– Seizure themselves
– Post-ictal periods
• Inter-ictal discharges
• Episodes of status epilepticus
• Medications
– Side effects
– Rescue medications
• Underlying gene mutation?

13. 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

14. Interictal Abnormalities

15. 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

16. 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?

17. 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?

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

19. 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

20. 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

21. 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.

22. 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

23. What do we do about all
this?

24. 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

25. 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

26. 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

27. 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

28. 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 encephalopathies
in many ways but is unique in others
• Treatment should be tailored towards seizure
reduction and cognitive issues