Cognition in Epilepsy: Issues, Challenges, Clinical Trials to Date, Next Steps Kimford Meador, MD Department of Neurology & Neurosciences Stanford University Palo Alto, California kmeador@stanford.edu
Financial Disclosures Grants: • NIH/NINDS 2U01-NS038455-11A1. Meador (Multi- PI). “Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs.” * • NIH/NINDS R01NS088748- 01. Drane (PI). “Dissecting the Cognitive Roles of Hippocampus & Other Temporal Lobe Structures.” Role: Co -I. •Medtronics. Halpern (PI). “Stereotactic Laser Ablation for Temporal Lobe Epilepsy (SLATE).” Role: Co -I. •Eisai Inc. Razavi (PI). “Multicenter, Open -Label Study to Evaluate the Efficacy and Safety of Perampanel as Monotherapy or First Adjunctive Therapy in Subjects With Partial Onset Seizures With or Without Secondarily Generalized Seizures or With Primary Generalized Tonic- Clonic Seizures.” Role: Co -I. •Sunovion Pharma. Meador (PI). “Cognitive and Behavioral Effects of Eslicarbazepine Acetate and Carbamazepine in Healthy Adults.” Consultant (Note direct no personal income) : • Epilepsy Consortium (funds paid to my university)* for Eisai, GW Pharmaceuticals, Medtronics, NeuroPace, Novartis, Supernus, Upsher Smith Labs, UCB Pharma, and Vivus Pharm. Other: Clinical income: EEG procedures and patient care* *Items with asterisk involve income > $10,000 for recent years.
International Bureau for Epilepsy: 2004 Cognitive Function Survey • 44% Difficulty learning • 45% Felt that they were slow thinkers • 59% Felt sleepy or tired • 63% ASM effects prevented them from achieving activities or goals N = 425 Europeans with epilepsy ASMs= http://www.ibe- anti-seizure epilepsy.org/downloads/IBE%20Epilepsy%20and%20CognitiveFunctionResults.pdf medications
Factors Affecting Cognition and Behavior in Epilepsy Seizure- Treatment- Related Related Variables Variables Non – Seizure- Related Variables
Relationship of Subtle ASM Toxicity to Quality of Life 100 QOLIE-89 Total Score QOLIE-89 Total Score 80 60 40 20 0 15 30 45 60 75 Adverse Events Profile Average Monthly Summary Score Seizure Rate ASMs= N = 200 r = -0.76, anti-seizure Gilliam, et al. Neurology 2004;62:23-27 P <0.0001 medications
Perception of Cognitive Function is More Related to Mood than Function Subjective Mood Best All Perception Objective Objective Test Tests Memory 17.2% 4.3% 7.9% Language 14.6% 4.9% 12.7% Attention 28.7% 3.6% 9.3% QOLIE-89 total 46.7% 5.2% 13.3% % Variance explained by each factor N = 257 epilepsy patients Perrine et al, Arch Neurol 1995;52:997-1003
Cognitive Effects Wine ASMs • Higher Dose/ABL • Polytherapy • Rapid Titration • Habituation • AED differences • Individual differences ASMs= anti-seizure medications
Challenges to Interpreting Studies • Generalization Methodological • Measures: choice & To what extent will results with this sample administration generalize to my patients? – Appropriate measures administered by properly trained personnel Statistical • Dosing regimen • Failure to correct for – Consistent current guidelines – Are comparators being dosed multiple comparisons (Type I error) equivalently? – Length of exposure • Over correction • Subject selection bias (Type II error) – Why did these patients receive the • Low power due to different drugs in the first place? small sample sizes • Confounding factors • Statistical vs. Clinical – seizures, etiology, depression Significance
Trial Design Issues • Randomized double-blind crossover or parallel group with matched control group & repeated measures design. • Placebo vs. Head-to-head drug comparisons • Anti-seizure vs Disease Modifying Treatments (eg, truly antiepileptic, everolimus for tuberous sclerosis, immune therapies for autoimmune epilepsy) • Future Goal: Cognitive enhancing treatments
Trial Design Issues • Need to consider test-retest effects (practice effects) and variability across repeat testing. • Need to control for habituation & titration effects. – (CNS side effects most marked early) • Cognitive studies in patients need to control for effects of seizures. • Difficult to combine efficacy and cognition studies. • Early cognitive assessment in treatment has potential to compensate for dropouts, thus allowing imputations for missing later assessments. But only to a degree.
Cognitive Domains Most Likely to Be Affected by Anti-seizure Meds • Processing Speed (e.g., reaction time) • Complex or Sustained Attention • Dual Processing • Memory: Verbal learning – Paragraphs more sensitive than word lists • Verbal fluency • Executive function • Mood (FDA requires only a measure of Suicidality)
Assessment Tools • NIH Toolbox http://www.healthmeasures.net/explore-measurement- systems/nih-toolbox • Epitrack Lutz MT, Helmstaedter C. Epilepsy Behav. 2005;7(4):708-14 • Computerized Tests e.g., CNS-Vitals, Cogstate, Cognitive Drug Research (CDR) System • Standard Paper & Pencil Neuropsych Tests e.g., SDMT, Stroop, COWA • Subjective Measures e.g., POMS, AEP, BDI
Newer ASMs vs Placebo ASM % placebo > ASM 0 – 19% gabapentin 1 – 17% lamotrigine *all healthy levetiracetam 11% volunteer studies perampanel* 30% except perampanel oxcarbazepine 46% patient 29 – 88% topiramate study tiagabine 0% ASMs= Kalviainen et al, Epi Res 1996;25:291-7. Dodrill et al, Neurology 1997;48:1025-31. Leach et al, JNNP 1997;62:372-6. Meador et al., Epilepsia 1999;40(9):1279-1285. Meador et al., Neurology 2001;56:1177-82. Salinsky et al., Epilepsy & Behavior 2004;5:894- anti-seizure 902. Aldenkamp et al., Epilepsia 2000;41:1167-7. Meador et al., Neurology 2003;13;60:1483-8. Salinsky et al., Neurology 2005;64:792-8. Meador et al., Neurology 2005;64(12):2108-2115. Blum et al., Neurology 2006;67:400-406. Meador et al. medications Epilepsia 2016;57(2):243-51.
Healthy Adult Volunteer Studies: Newer ASMs vs Older ASMs LESS impact on cognition MORE impact on cognition % tests Gabapentin Carbamazepine 26% Gabapentin Topiramate 50% Eslicarbazepine Carbamazepine 43% Lacosamide Carbamazepine 75% Lamotrigine Carbamazepine 48% Lamotrigine Topiramate 80% Levetiracetam Carbamazepine 42% Oxcarbazepine Phenytoin 0% ASMs= Meador et al., Epilepsia 1999;40(9):1279-1285. Meador et al., Neurology 2001;56:1177-82. Salinsky et al., Epilepsy & anti-seizure Behavior 2004;5:894-902. Meador et al., Neurology 2003;13;60:1483-8. Salinsky et al., Neurology 2005;64:792-8. Meador et al., Neurology 2005;64(12):2108-2115. Meador et al. Epi & Beh 2019;94:151-157. medications
Cognitive Effects of ASMs at Age Extremes are Less Studied
Fetal Exposure to Valproate Associated with Cognitive Deficits at Age 6 Years Old (VPA 7-10 IQ points lower) NEAD CBZ LTG PHT STUDY VPA Mean IQ 105 * 108 * 108 * 97 Verbal IQ 104 * 105 * 106 * 97 Non-Verbal IQ 104 T 106 T 108 * 101 Memory Index 104 * 106 * 101 * 92 Exec Index 105 107 * 103 101 * Significantly better than VPA. T = trend. CBZ=carbamazepine, LTG=lamotrigine, PHT=phenytoin, Meador et al. Lancet Neurology 2013: 12(3):244-52. VPA=valproate
Fetal Levetiracetam & Topiramate: Cognition at 5-9 years old No ASM TPM LEV VPA N 55 27 42 47 FSIQ* 100 100 99 96 (SD) (14) (13) (14) (14) VIQ 102 99 101 94 (SD) (13) (11) (11) (15) *Man Full Scale IQ (standard deviation) ASMs= anti-seizure Bromley et al, Neurology 2016;87:1-11 medications
ASMs with Reasonable* Data on Neuropsychological Neurodevelopment • • • Acetazolamide Lamotrigine Primidone • • • Retigabine Breviracetam Levetiracetam • • • Rufinamide Carbamazepine Lorazepam • • • Stiripentol Clobazam Nitrazepam • Tiagabine • • Clonazepam Oxcarbazepine • Topiramate • • Eslicarbazepine Perampanel • Valproate • • Ethosuximide Piracetam • Vigabatrin • • Felbamate Phenobarbital • Zonisamide • • Gabapentin Phenytoin • • Lacosamide Pregabalin ASMs= * Note that “reasonable” does not imply “adequate.” anti-seizure medications
ASMs and Apoptosis in Developing Brain • Widespread neural apoptosis in rats aged 3-30 days. Apoptosis associated with impaired synaptogenesis for surviving neurons – Apoptosis present for clonazepam, diazepam, phenobarb, phenytoin, valproate, & vigabatrin 1,2 • Apoptosis absent for carbamazepine, lamotrigine, levetiracetam, & topiramate monotherapy 3-8 1. Bittigau et al. Proc Natl Acad Sci U S A. 2002. 2. Bittigau et al. Ann N Y Acad Sci. ASMs= 2003. Glier et al. Exp Neurology. 2004. 4. Manthey et al. Exp Neurol 2005. 5. Kim et anti-seizure al. JPET 2007. 6. Katz et al, JPEG 2007. 7. Forcelli et al, JPEG 2012. 8. Forcelli et al, Ann Neurol 2012. medications
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