dr. kristen park kcnq2 summit parent track learn more at kcnq2summit.org
TRANSCRIPT
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
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• 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?
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
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