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. Normal CNS Function Excitation Inhibition glutamate, aspartate GABA Modified from White, IGES, 2001

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

11. Excitation Inhibition AEDs Act By Restoring Balance 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. Bromides Phenobarbitol Phenytoin Ethosuximide Carbamazepine Valproate Vigabatrin Lamotrigine Gabapentin Topiramate Oxcarbamazepine & Levetriacetam 18571912 1938 1960 1965 ‘76 ‘89 ‘91 ‘93 ‘96 ‘97 ‘99 ’00 ‘05 ‘09 ‘10 Tiagabine Zonisamide Pregabalin Lacosamide, Retigabine, Rufinamide Brivaracetam Felbamate

13. AEDs Spectrum of Activity Generalized Onset AbsenceMyoclonic AtonicTonicTonic-Clonic EthosuximideBenzodiazepines Partial Onset Simple Complex Carbamazepine Phenytoin Gabapentin Oxcarbazepine Pregabalin Phenobarbital Valproate Lamotrigine Levetiracetam Topiramate Zonisamide

14. FDA-Approved Indications Partial Seizure Gen. Seizure LGSStatus Epilepticus Phenobarbital XXXX Phenytoin XXXX Carbamazepine XXX Valproic acid XXX Felbamate XX Gabapentin X LamotrigineXXX Levetiracetam XX Oxcarbazepine X Pregabalin X Topiramate XXX Zonisamide X

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

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

17. Potential Worsening of Seizure Types Carbamazepine Gabapentin Phenytoin Lamotrigine Carbamazepine Phenytoin Carbamazepine Gabapentin Phenytoin AtonicMyoclonicAtypical Absence/ Lennox- Gastaut Typical Absence Perucca et al., Epilepsia 1998

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

19. 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

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

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

22. Vigabatrim Visual field restriction Behavioral problems Conflictual findings

23. Oxcarbazepine No changes six and twelve months post

24. Lamotrigine Contrasted with topiramate Less impairment with phonemic fluency Less impairment with coding

25. 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

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

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

28. 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)

29. 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

30. 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. Subject No.GenderAge Duration of Epilepsy FSIQMedication 1M10297CBZ 2F112109CBZ 3M112105VPA 4F71116None 5F113107CBZ 6M93137CBZ 7M11595Unk

32. 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.

35. 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.

36. 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.

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

38. Sub ject EEG #1EEG #2EEG #3Consistency Spik e Cou nt Asyn c Foci Slow Wav e Focu s Spik e Cou nt Asyn c Foci Slow Wav e Focu s Spik e Cou nt Asyn c Foci Slow Wav e Focu s ≥5 vs. ≤6/min ≥10 vs. <10/ Asyn c Foci Slow Wav e Focu s 1NA 11.5NY0NYNNYN 2NA 0NN0NYYYYN 30NN4.2NNNA YYYY 42.3NY0NN4.8NYYYNN 50.8YN3.8YN0.8NNYYYY 60.7NY0.2NY0.8NYYYYY 78.5YY28.6YYNA YNYY

39. 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