The Effect of AED’s upon Cognition: What we Know

1. The Effect of AED’s upon Cognition: What we Know Cynthia Smith, PhD Program Director, Division of Neuropsychology The Brain & Spine Institute

2. AED’s suppress seizures and do not “cure” them • AED success rate 50% to 70%

3. Academic Performance & Epilepsy • Contributing Factors • Idiopathic vs sympathic • Age at first seizure • Presence of >1 Status Epilepticus • Frequency of seizures • Single versus polytherapy • Mood state • Family organization and quality of function

4. Aggression and hyperactivity more common in children than depression in adults • Children with epilepsy 5 times more likely to have behavior or other mental health problems than adults with epilepsy • Children w/ epilepsy 2.5 more likely than other children to have psychiatric difficulties • Cumulative effect of learning interference • Majority of childhood seizures are nocturnal. Poor sleep quality effect upon cognition?

5. The most prevalent of the CNS adverse effects observed during AED therapy are sedation, somnolence, distractibility, insomnia and dizziness. Sedation, in particular, is associated with most of the commonly used AED therapies. CNS Drugs 2009; 23 (2): 121-137

6. Testing Models • Vast majority of studies on adult men • Vast majority of animal studies on adult males

7. Seizure type, clinical and electroencephalographic phenotype, syndrome, and etiology are often quite different in children with epilepsy than in adults. Despite these age-related unique features, drugs used in children are generally the same as those in adults. • Holmes GL, Zhao Q. Choosing the correct antiepileptic drugs: From animal studies to the clinic. Pediatr Neurol 2008; 38:151-162

8. Adult studies suggest improvement of cognitive dysfunction with cessation of AED and seizures.

9. Excitation Inhibition glutamate, aspartate GABA NormalCNS Function Modified from White, IGES, 2001

10. glutamate, aspartate Abnormal excitation Inhibition Excitation GABA Modified from White, IGES, 2001

11. AEDs Act By Restoring Balance Excitation Inhibition Reduce excitation PHT, CBZ, VPA, FBM, LTG, TPM, OCBZ, ZNS, Increase inhibition PB, BDZ’s, VPA, FBM, TPM, ZNS, TGB, VGB Modified from White, IGES, 2001

12. Brivaracetam Lacosamide, Retigabine, Rufinamide Pregabalin Zonisamide Oxcarbamazepine & Levetriacetam Tiagabine Topiramate Gabapentin Felbamate Lamotrigine Vigabatrin Valproate Carbamazepine Ethosuximide Phenytoin Phenobarbitol Bromides 1857 1912 1938 1960 1965 ‘76‘89 ‘91 ‘93 ‘96 ‘97 ‘99 ’00 ‘05 ‘09 ‘10

13. AEDs Spectrum of Activity Partial Onset Generalized Onset Atonic Tonic Tonic-Clonic Complex Absence Myoclonic Simple Ethosuximide Benzodiazepines Carbamazepine Phenytoin Gabapentin Oxcarbazepine Pregabalin Phenobarbital Valproate Lamotrigine Levetiracetam Topiramate Zonisamide

14. FDA-ApprovedIndications Partial Gen. LGS Status Seizure Seizure Epilepticus Phenobarbital X X X X Phenytoin X X X X Carbamazepine X X X Valproic acid X X X Felbamate X X Gabapentin X Lamotrigine X X X Levetiracetam X X Oxcarbazepine X Pregabalin X Topiramate X X X Zonisamide X

15. AAN guidelines for new AEDs in newly diagnosed epilepsy French et al, Epilepsia 45, 2006

16. AAN guidelines for new AEDs in refractory epilepsy French et al, Epilepsia 45, 2006

17. High Topiramate Zonisamide Phenobarbital AED: Cognitive Side Effects • Low • Gabapentin • Lamotrigine • Levetiracetam • Pregabalin • Intermediate • Carbamazepine • Oxcarbazepine • Phenytoin • Valproic acid • Zonisamide

18. Carbamazepine • Benign Rolandic Seizure (J Child Neurol 1999;14:716-723). • Slow processing • Impaired verbal memory • Partial or Generalized TC(Epilepsy & Behavior 14 (2009) 522–528) • Overall decline from baseline • Information processing speed and Attention

19. Remacemide • Partial or Generalized TC(Epilepsy & Behavior 14 (2009) 522–528) • Overall decline from baseline • Information processing speed and Attention

20. Valproate • Mild to Moderate slowing in psychomotor speed and mental speed • Decreased verbal memory retrieval • Decreased visuospatial skills

21. Vigabatrim • Visual field restriction • Behavioral problems • Conflictual findings

22. Oxcarbazepine • No changes six and twelve months post

23. Lamotrigine • Contrasted with topiramate • Less impairment with phonemic fluency • Less impairment with coding

24. Gabapentin • No known cognitive side effects • Tiagabine • No known cognitive side effects • As an add on therapy, can improve motor speed, reading speed, attention and verbal fluency

25. Topiramate • Decline in verbal fluency and verbal working memory • Levetiracetam • Improved reaction time and motor speed

26. Zonisamide • Initial impaired memory and verbal learning in dose/concentration manner. Recovery to baseline after 12 weeks

27. ADHD and Epilepsy • 20% of children with epilepsy have ADHD • 3% to 7% typical children have ADHD • The overall ADHD population has a greater incidence of electroencephalography abnormalities (5.6-30.1% vs. 3.5%) • Methylphenidate treatment is equally efficient in children with isolated attention-deficit hyperactivity disorder and in children with attention-deficit hyperactivity disorder and epilepsy (70%-77%). (Kaufmann, Journal of Child Neurology, Volume 24 Number 6, June 2009 727-733)

28. ADHD and Epilepsy • Significantly impacts quality of life • Executive system dysfunction predictor of poor quality of life • Use of Psychostimulants • no concern for children with controlled seizures • Some concern for children with uncontrolled seizures. Seizure frequency can increase

29. BECTS: Longitudinal Study • Six children with Benign Epilepsy with Central-Temporal Spikes (BECTS) were evaluated for longitudinal neuropsychological abilities (memory, attention, visuospatial skills, receptive and expressive language, and executive system) using a within-patient repeated measures design.

31. BECTS: Longitudinal Study • The children (ages 7-11 yrs) previously diagnosed with BECTS underwent repeated neuropsychological assessment following EEG recordings for 2-3 sessions at 1-2 month intervals. All patients demonstrated impaired performance (at least one standard deviation below the normative mean) on four or more of the cognitive measures.

34. BECTS: Longitudinal Study • Impaired performance was not associated with spike frequency rates or focus. All patients demonstrated some variability of performance (greater than one standard deviation of change) between sessions. Five of the six patients’ performance on the Test of Variables of Attention was consistent with the presence of Attention Deficit/Hyperactivity Disorder.

35. BECTS: Longitudinal Study • In particular, fluctuation was observed on measures of visual and auditory attention, executive system abilities, visual and verbal memory, and visuospatial organization.

36. BECTS: Longitudinal Study • EEG recordings revealed spike activity that was not correlated with cognitive performance. EEG recordings differed from session to session.

38. BECTS: Longitudinal Study • Children with BECTS experience fluctuating EEG recordings and cognitive abilities on repeated measures over a two to three month period of time (1SD or greater difference) in attention, memory, visuospatial skills and executive system abilities, that can adversely affect their development and education