1. The Problem of Cognitive Dysfunction/Decline in Epilepsy February 21,2014 Kimford J. Meador, MD Professor of Neurology & Neurological Sciences Stanford University American Society for Experimental NeuroTherapeutics | 16 th Annual Meeting

2. Disclosure Grants: GSK, Neuropace, Pfizer, & UCB. NIH/NINDS 2U01-NS038455-11A1. Meador (Multi-PI).* PCORI 527. Loring (PI); Role: Co-PI.* NIH 1 R01 NS076665-01A1. Marion (PI); Role: Consultant.* Consultant: Epilepsy Consortium (funds are paid to Emory or Stanford U)* for Eisai, NeuroPace, Novartis, UCB Pharma, Upsher Smith & Vivus. Other: Clinical income: EEG procedures and patient care* * Items with asterisk involve income > $10,000 for recent years. All industry related income goes to the university. American Society for Experimental NeuroTherapeutics | 16 th Annual Meeting

3. Learning Objectives Understand the effects of epilepsy on cognition. Understand the effects of treatments for epilepsy on cognition. American Society for Experimental NeuroTherapeutics | 16 th Annual Meeting

4. Factors Affecting Cognition and Behavior in Epilepsy Seizure- Related Variables Treatment- Related Variables Non–Seizure- Related Variables

5. Focal Seizure with dyscognitive state aka: complex partial seizure Blumenfeld et al, Cerebral Cortex 2004;14:892-902.

6. Temporal Lobe Seizures: Consciousness Blumenfeld H. Lancet Neurol. 2012;11(9):814-26.

7. Fuerst D et al. Ann Neurol. 2003;53:413-416 Longitudinal Study of Hippocampal Atrophy 12 unilateral TLE patients Repeat MRI: mean 3.4 yrs (2.5 - 5.2 yrs) Progressive hippocampal atrophy occurred only in patients with continuing seizures Mean 10% loss of hippocampal volume in patients with continued seizures TLE = temporal lobe epilepsy

8. Cross-Sectional Cognition Study in Temporal Lobe Epilepsy FSIQ of WAIS-R in 209 patients with unilateral Temporal Lobe Epilepsy Multiple regression Duration of epilepsy:  =-.195, P<.01 Education:  =.543, P<.01 IQ lower if >30 year Seizure Duration than 15 - 30 years and <15 years IQ for 15 - 30 years and <15 years seizure duration did not differ Jokeit H et al. J Neurol Neurosurg Psychiatry 1999;67:44-50

9. Longitudinal Cognition Study in Temporal Lobe Epilepsy 102 patients with nonsurgical TLE followed 2-10 yrs % of Patients With Loss or Gain * LossGain Memory function50%12% Executive function 28%22% *Losses primarily in patients who were not seizure-free. *Losses associated with seizure frequency and severity. Helmstaedter C et al. Ann Neurol. 2003;54:425-432

10. Cognitive Effects WineAEDs Higher Dose/blood levels Polytherapy Rapid Titration Habituation AED differences Individual differences AEDs = antiepileptic drugs

11. Cognitive Abilities Most Likely to be Affected by Antiepileptic Drugs Processing Speed (e.g., reaction time) Complex or Sustained Attention Dual Processing Verbal learning Paragraphs more sensitive than word lists Verbal fluency Rate at which words can be generated Mood

12. Cognition & AEDs in Adults Least cognitive effects: GBP, LEV, LTG, TGB. Intermediate effects: CBZ, PHT, OXC, VPA. Most adverse effects: PB, TPM, ZNG, Benzos. Many AEDs not formally assessed. AED susceptibility can vary across patient groups as well as across individual patients. Benzos=benzodiazepines, CBZ=carbamazepine, GBP=gabapentin, LEV=levetiracetam, LTG=lamotrigine, OXC=oxcarbazepine, PB=phenobarb, PHT=phenytoin, TGB=tiagabine, TPM=topiramate, VPA=valproate, ZNG=zonisamide

13. MCG Stories: Delayed Recall % Compared to Non-Drug Average Healthy Volunteer Studies CBZ LTG TPM PHT GB P

14. Gilliam, et al. Neurology 2004;62:23-27 Relationship of Subtle AED Toxicity to Quality of Life Adverse Events Profile Summary Score QOLIE-89 Total Score n = 200 r = -0.76, p<0.0001 Average Monthly Seizure Rate QOLIE-89 Total Score

15. Behavioral & Psychotropic Effects of Antiepileptic Drugs Most of the AEDs can produce untoward subjective side effects. CBZ, LTG, & VPA have proven efficacy in bipolar disorder. GBP & TPM used in add-on. AEDs are used in variety psych. disorders (eg, VPA in agitation & GBP in social phobia) AEDs=antiepileptic drugs, CBZ=carbamazepine, GBP=gabapentin, LTG=lamotrigine, TPM=topiramate, VPA=valproate.

16. Cognitive Effects of AEDs in the Elderly Phenytoin = Valproate Craig & Tallis, Epilepsia 1994;35:381-390 Elderly more sensitive to cognitive effects of AEDs 1st VA Cooperative Study More dropouts due to cognitive AEs for CBZ > GBP > LTG VA Cooperative Geriatric Epilepsy Study CBZ=carbamazepine, GBP=gabapentin, LTG=lamotrigine

17. Children AED Cognition Studies Vining et al, 1987PB < VPA Farwell et al, 1990PB < Placebo Forsythe et al, 1991CBZ = PHT = VPA Chen et al, 1996, 2001PB < CBZ = VPA Aldenkamp et al, 1998CBZ = PHT = VPA Pressler et al, 2006LTG = Placebo Donati et al, 2006CBZ = OXC = VPA Kang et al, 2007TPM < CBZ Levisohn et al, 2009LEV = Placebo Glauser et al, 2010ETX=LTG < VPA CBZ=carbamazepine, ETX=ethosuximide, GBP=gabapentin, LEV=levetiracetam, LTG=lamotrigine, OXC=oxcarbazepine, PB=phenobarb, PHT=phenytoin, TPM=topiramate, VPA=valproate

18. In Utero AEDs & Behavioral Neurodevelopment in Animals Phenobarb reduces brain weight & impairs behavior in mice. Phenytoin impairs coordination & learning in rats. Phenytoin can cause hyperactivity in monkeys. Neurobehavioral effects also found for valproate. Vorhees CV. Environ Health Perspect. 1994;102 Suppl 2:145-53. Review.

19. AEDs and Apoptosis in Developing Brain Widespread neural apoptosis in rats aged 3-30 days  Present for clonazepam, diazepam, phenobarb, phenytoin, valproate, & vigabatrin 1,2  Absent for carbamazepine, lamotrigine, levetiracetam, & topiramate monotherapy 3-6  Synergist effects with polytherapy. Reduced expression of neutrophins & extracellular signal proteins 1 Effects prevented by β-estradiol 1 1. Bittigau et al. Proc Natl Acad Sci U S A. 2002;189:15089-15094. 2. Bittigau et al. Ann N Y Acad Sci. 2003;993:103-114. 3. Glier et al. Exp Neurology. 2004;187:403-409. 4. Kim et al. JPET 2007;323:165–173). 5. Manthey et al. Exp Neurol 2005;193(2):497-503. 6. Katz et al. JPET 2007;322:494–500.

20. AEDs and Apoptosis in Developing Brain Widespread neural apoptosis in rats aged 3-30 days  Present for clonazepam, diazepam, phenobarb, phenytoin, valproate, & vigabatrin 1,2  Absent for carbamazepine, lamotrigine, levetiracetam, & topiramate monotherapy 3-6  Synergist effects with polytherapy. Reduced expression of neutrophins & extracellular signal proteins 1 Effects prevented by β-estradiol 1 1. Bittigau et al. Proc Natl Acad Sci U S A. 2002;189:15089-15094. 2. Bittigau et al. Ann N Y Acad Sci. 2003;993:103-114. 3. Glier et al. Exp Neurology. 2004;187:403-409. 4. Kim et al. JPET 2007;323:165– 173). 5. Manthey et al. Exp Neurol 2005;193(2):497-503. 6. Katz et al. JPET 2007;322:494–500.

21. Fetal valproate exposure related with lower IQ. CarbamazepineLamotriginePhenytoin Valproate Mean IQ 98 101 99 92 Difference 6 9 7 (CIs)(0.6:12.0) (3.1:14.6) (0.2:14.0) Neurodevelopmental Effects of Antiepileptic Drugs Funded by NIH/NINDS #2RO1 NS 38455 and #1 R01050659 309 mother/child pairs from 25 centers in US & UK Meador et al. NEJM 2009;360:1597-605

22. Mean IQs (95% Difference CIs from VPA) adjusted for maternal IQ, AED dose, gestational age & folate: CBZLTGPHTVPA Mean IQ 105 * 108 * 108 * 97 Difference 8 11 11 DCIs (3:12)(6:15)(5:16) # Children 93 100 56 62 * Significantly better than VPA. P values: CBZ =.0015, LTG =.0003, PHT =.0006 DCIs=Confidence Intervals for Difference from VPA Primary Analyses for Age 6 Years Meador et al., Lancet Neurol 2013; 12(3):244-52

23. CBZLTGPHTVPA IQ-.08.19-.11-.56* Verbal Index-.03.12.06-.40* Non-verbal Index-.17.10-.17 -.42* Memory (GMI)-.06.05-.20-.30* Nepsy Exec Index-.05.03-.10-.42* BRIEF**-.20.15.31.35* Dose Dependent Effects: Partial Correlations * Significant correlations ** Lower BRIEF scores better Meador et al., Lancet Neurol 2013; 12(3):244-52

24. ATL Epilepsy Surgery Deficits: verbal memory, naming, and facial recognition & naming. Predictors of Risk for Post-op Deficits: ATL on language dominant side Older age of seizure onset Older age at surgery No hippocampal atrophy/sclerosis Lack of ipsilateral dysfunction (PET, Wada, etc) Higher pre-op cognitive performance Poor post-op seizure control ATL=anterior temporal lobectomy

25. Laser Epilepsy Surgery Post-ablation T1 with Contrast Combined Irreversible Damage Estimate Pre-ablation T1 Ablation 1 Ablation 2

26. Neurostimulation Therapies VNSRNSSANTE No clear evidence of any negative or positive effects on cognition for these therapies. VNS=Vagal Nerve Stimulation, RNS=Responsive NeuroStimulation, SANTE=Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy

27. Perception of Cognitive Function is More Related to Mood than Function SubjectiveMoodBestAll PerceptionObjective Objective TestTests Memory17.2% 4.3% 7.9% Language14.6% 4.9%12.7% Attention28.7% 3.6% 9.3% QOLIE-8946.7% 5.2%13.3% total Perrine et al, Arch Neurol 1995;52:997-1003 % Variance explained by each factor n = 257 epilepsy patients

28. Impact on Clinical Care and Practice Cognitive impairment in epilepsy is common, clinically important, and multifactorial. AEDs have differential cognitive effects and susceptibility varies across dose, titration, age, and individual patients. Cognitive effects of epilepsy surgery are largely predictive. Stimulation therapies have no or minimal cognitive effects. Subjective and objective measures of cognitive function can dissociate.