1. The document discusses the classification and treatment of epilepsies, focusing on epileptic encephalopathies like KCNQ2E. 2. Epileptic encephalopathies are characterized by frequent seizures, abnormal EEG patterns, developmental impairment, and are often resistant to treatment. 3. Treatment aims to minimize seizures and side effects while optimizing quality of life, and may include medications, dietary therapies, devices, and early intervention.

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