Neurobehavioral Problems in the Childhood Epilepsies

1. 47th Annual Meeting of the International Neuropsychological Society Marriott Marquis Times Square February 20, 2019 New York City, NY Bruce P. Hermann, PhD, ABPP-CN Charles Matthews Neuropsychology Section Department of Neurology University of Wisconsin School of Medicine & Public Health Madison, Wisconsin Neurobehavioral Problems in the Childhood Epilepsies

2. Overview • Lifespan presentation. • Development and course of neurobehavioral comorbidities (e.g., cognition, academics, behavior). • Relationships to neuroimaging markers. • Brain and cognitive development and subsequent aging. • Model for understanding.

3. Overview (cont.) • Try to stay out of the weeds. • Give a broad picture of where the field is at—including its strengths and limitations. • Stress clinical utility as well as a few research ideas. • Orient presentation around 3 core questions

4. 3 Core Questions 1) What is the nature and extent of cognitive and behavioral problems in children with established epilepsy? 2) How do we parse the impact of epilepsy, repeated seizures, and AEDs on cognition and behavior in children? 3) What are the persisting effects of childhood epilepsy into youth and adulthood?

5. Learning Objectives • Understand the prevalence of cognitive and behavioral comorbidities in children with epilepsy and relevant clinical presentations. • Understand the timingof cognitive and behavioral comorbidities in children with epilepsy and provide a useful model. • Understand the course of cognitive and behavioral comorbidities in children with epilepsy. • Identify the long term consequences of neurobehavioral comorbidities on life outcomes.

6. Definitions • Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate seizures and by neurobiological, cognitive, psychological and social consequences of this condition (Fischer, 2014). • Neurobehavioral comorbiditiesare the collective cognitive, behavioral, and social complications associated with the epilepsies—a major source of disability for youth and adults with epilepsy (Wilson & Baxendale, 2014).

7. Definitions • Epilepsyis a disorder of the brain characterized by an enduring predisposition to generate seizures and by neurobiological, cognitive, psychological and social consequences of this condition (Fischer, 2014). • Neurobehavioral comorbiditiesare the collective cognitive, behavioral, and social complications associated with the epilepsies—a major source of disability for youth and adults with epilepsy (Wilson & Baxendale, 2014).

8. Definitions and Classifications • What is a seizure? • A sudden and episodic occurrence of motor, sensory, autonomic, psychic, or behavioral phenomenon secondary to abnormal (excessive) neuronal discharge. • What is epilepsy? • Old definition--two or more unprovoked seizures. • New definition— 2014

9. Epilepsy • Epilepsy exists when someone has an epileptic seizure and their brain demonstrates an enduring tendency to have recurrent seizures. a) 2 unprovoked reflex seizures > 24 hrs apart b) 1 unprovoked or reflex seizure and the probably of a second and the probability of a second seizure is high. c) An epilepsy syndrome Fisher et al. (2014)

10. Epilepsy • 4th most common neurological disorder in the US after migraine, stroke and Alzheimer’s disease. • Not a single disorder but a family of over 40 syndromes that impact 3.4 million people in the US (CDC Fast Facts) and 50 million worldwide (WHO, 2019). • Epilepsy strikes most often in the very young and the old, although anyone can develop epilepsy at any age.

11. Epilepsy consequences • Epilepsy imposes an annual economic burden of $15.5 billion on the nation in associated health care costs and losses in employment, wages and productivity. • The mortality rate among people with epilepsy is 2-3 times higher than the general population and the risk of sudden death is 24 times greater.

14. https://www.epilepsydiagnosis.org

17. Definitions • Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate seizures and by neurobiological, cognitive, psychological and social consequences of this condition (Fischer, 2014). • Neurobehavioral comorbiditiesare the collective cognitive, behavioral, and social complications associated with the epilepsies—a major source of disability for youth and adults with epilepsy (Wilson & Baxendale, 2014).

18. Definitions • A comorbidity refers to one or more diseases or conditions that occur along with another condition in the same patient at the same time. • Conditions considered comorbidities are often but not always long-term or chronic conditions.

19. Comorbidity “Pathways” Keezer et al. (2016 Lancet Neurology, 15, 106-115)

20. Comorbidity “Pathways” Keezer et al. (2016 Lancet Neurology, 15, 106-115)

21. Comorbidity “Pathways” Keezer et al., 2016 Lancet Neurology, 15, 106-115

22. Lin et al., 2014

23. 3 Core Questions 1) What is the nature and extent of cognitive and behavioral problems in children with established epilepsy? 2) How do we best characterize the impact of epilepsy, seizures and AEDs on cognition and behavior in children? 3) What are the persisting effects of childhood epilepsy into adulthood?

24. 3 Core Questions 1) What is the nature and extent of cognitive and behavioral problems in children with established epilepsy? Epidemiological and clinical studies 2) How do we best characterize the impact of epilepsy, seizures and AEDs on cognition and behavior in children? 3) What are the persisting effects of childhood epilepsy into adulthood?

26. 2007 National Survey of Children’s Health 91,605 children—birth-17 • Lifetime epilepsy (Y/N) • Mental Health/Development • Function Health Indicators • Service Use & Access Indicators

27. Distribution of intelligence shifted to the left • IQ < 80 in 57% of children • Earlier age at onset of epilepsy—strongest predictor of IQ • Neuropsychological deficits in areas other than memory 70 children with unilateral TLE Presented for surgical consideration Mean age= 11.7

28. 69 children with childhood absence epilepsy (mean age=9.6) • 103 age and gender matched controls (mean age=9.9) • Cognitive and linguistic testing and psychiatric assessment • 25% with subtle cognitive deficits (vs 6% in HC) • 43% linguistic abnormalities (vs. 15% in HC) • 61% psychiatric diagnosis (vs. 15% in HC)

31. (DMCN, 2003) • 1999 British Child and Adolescent Mental Health Survey • N=10,483 children age 5-15 • Structured interviews, teacher and clinician ratings • Epilepsy in 67 (42 uncomplicated, 25 complicated)

32. Psychiatric Epidemiology Percent with Psychiatric Cormorbidity

34. Psychiatric Complications—Clinical Meta-analysis of 46 studies involving 2,434 CWE. CWE vs. healthy controls (medium to large effect sizes) CWE to illness controls (small to medium effect sizes) CWE to siblings (family factors play a role) Increased behavioral problems in CWE due to combined effects of epilepsy, chronic illness and family factors.

35. In established epilepsy, CWE exhibit elevated rates of cognitive and behavioral/psychiatric complications compared to healthy controls. Question 1: Summary

36. In established epilepsy, CWE exhibit elevated rates of cognitive and behavioral/psychiatric complications compared to healthy and illness controls. This elevated risk in CWE has been documented in epidemiological investigations and characterized in detail in clinical investigations. Question 1: Summary

37. In established epilepsy, CWE exhibit elevated rates of cognitive and behavioral/psychiatric complications compared to healthy and illness controls. This elevated risk in CWE has been documented in epidemiological investigations and characterized in detail in clinical investigations. How and when do these complications develop? Question 1: Summary

38. In established epilepsy, CWE exhibit elevated rates of cognitive and behavioral/psychiatric complications compared to healthy and illness controls. This elevated risk in CWE has been documented in epidemiological investigations and characterized in detail in clinical investigations. How and when do these complications develop? How are these complications influenced by epilepsy, seizures, AEDs, and other factors? Question 1: Summary

39. 3 Core Questions 1) What is the nature and extent of cognitive and behavioral problems in children with established epilepsy? 2) How do we determine the impact of epilepsy, repeated seizures and AEDs on cognition and behavior in children? 3) What are the persisting effects of childhood epilepsy into adulthood?

41. ↑ “Starting at the beginning”—early in the course of epilepsy, prior to effects of years of recurrent seizures and, possibly, prior to AED initiation.

42. 51 children with newly diagnosed uncomplicated epilepsy • no known lesion/cause identified • mainstream education • outpatient care • “epilepsy only” • 48 sex matched controls • Tested within 48 hours of diagnosis (drug naïve) • Cognition, behavior, teacher and parent interview • Audit of school career

44. Needed special school assistance 51% epilepsy 27% controls “School career already at risk”

46. Controls=first degree cousins Age 8-18 (mean age = 12, mean grade= 6) Diagnosed within the past 12 months Normal neurological examination Normal clinical MRI No other developmental disabilities No other neurological disorder Inclusion criteria

47. New Onset “Epilepsy Only”

48. Protocol • Neuropsychological assessment • IQ assessment of mother • Neurodevelopmental history (questionnaire) • Structured clinical interview (epilepsy, academics, other) • Structured psychiatric interview (K-SADS) • Neuroimaging (MR, DTI, rs-fMRI) • Seen at baseline and then 2, 5, and 10 years later

50. Baseline cognition