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Cognitive Issues in the Treatment of Epilepsy

Cognitive Issues in the Treatment of Epilepsy. Kimford Meador, MD Departments of Neurology & Pediatrics Emory University Atlanta, Georgia. kimford.meador@emory.edu. International Bureau for Epilepsy: 2004 Cognitive Function Survey. 44% Difficulty learning

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Cognitive Issues in the Treatment of Epilepsy

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  1. Cognitive Issues in the Treatment of Epilepsy Kimford Meador, MD Departments of Neurology & Pediatrics Emory University Atlanta, Georgia kimford.meador@emory.edu

  2. International Bureau for Epilepsy: 2004 Cognitive Function Survey • 44% Difficulty learning • 45% Felt that they were slow thinkers • 59% Felt sleepy or tired • 63% AED effects prevented them from achieving activities or goals N = 425 Europeans with epilepsy www.ibe-epilepsy.org/whatsnew_det.asp

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

  4. Patient with Complex Partial Seizure from Left Mesial Temporal Sclerosis Lee KH et al, Neurology 2002;24:59(6):841-6

  5. Longitudinal Study of Hippocampal Atrophy • 12 unilateral TLE patients • Repeat MRI: mean 3.4 yrs (2.5-5.2yrs) • 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 Fuerst D et al. Ann Neurol. 2003;53:413-416

  6. Cross-Sectional Cognition Study in Temporal Lobe Epilepsy (TLE) • FSIQ of WAIS-R in 209 patients with unilateral TLE. • 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. • Decline is in patients without seizure control. Jokeit H et al. J NeurolNeurosurg Psychiatry 1999;67:44-50

  7. Cognitive EffectsWineAEDs • Higher Dose/ABL • Polytherapy • Rapid Titration • Habituation • AED differences • Individual differences AEDs = antiepileptic drugs

  8. Cognitive Abilities Most Likely to be Affected by AEDs • 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 beginning with a specific letter can be generated AEDs = antiepileptic drugs

  9. Cognitive Effects of Older AEDs in Healthy Adults • Carbamazepine (CBZ), phenytoin (PHT), or valproate (VPA) rarely differ. • Phenobarbital significantly worse on about 1/3rd of tests than PHT or VPA. • Patients statistically better on placebo than older AEDs for about 50% of tests. Meador KJ et al. Neurology. 1991;41(10): 1537-1540; Meador KJ et al. Epilepsia. 1993;34(1):153-157; Meador KJ et al. Neurology. 1995;45(8):1494-1499.

  10. Healthy Volunteers: Newer AEDs vs Placebo 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., Epilepsia1999;40(9):1279-1285. Meador et al., Neurology 2001;56:1177-82. Salinsky et al., Epilepsy & Behavior 2004;5:894-902. 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.

  11. Healthy Volunteers: Newer AEDs vs Other AEDs Meador et al., Epilepsia1999;40(9):1279-1285. Meador et al., Neurology 2001;56:1177-82. Salinsky et al., Epilepsy & 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.

  12. Incidence of Unprovoked Seizures in Developed Countries Cloyd et al. Epilepsy Res 2006;68 (Suppl 1): 39-48

  13. Cognitive Effects ofAEDs in the Elderly • Phenytoin = Valproate Craig & Tallis, Epilepsia 1994;35:381-390 • Elderly more sensitive to cognitive effects of AEDs: Carbamazepine, Phenobarb, Phenytoin, Primidone VA Cooperative Study

  14. VA Coop Geriatric Epilepsy Study N = 593 >65 y/o New onset epilepsy Mean Dose (mg/d) ABL (mcg/ml) CBZ = 558 6.8 GBP = 1424 8.7 LTG = 152 3.5 LTG GBP CBZ Rowan et al, Neurology 2005;64:1868-73. CBZ=carbamazepine, GBP=gabapentin, LTG=lamotrigine

  15. Cognitive Effects of AEDs in Children • Loring & Meador, Neurology 2004;62:872-7 • Pressler et al., Neurology 2006;66(10):1495-9. • Donati et al, Neurology 2006;67:679-682.

  16. Children AED Cognition Studies CBZ=carbamazepine, GBP=gabapentin, LEV=levetiracetam, LTG=lamotrigine, OXC=oxcarbazepine, PB=phenobarb, PHT=phenytoin, TPM=topiramate

  17. MCG Stories: Delayed Recall % Compared to Non-Drug AverageHealthy Volunteer Studies CBZ=carbamazepine, GBP=gabapentin, LTG=lamotrigine, PHT=phenytoin, TPM=topiramate. Meador et al, 1991, 1993, 2000, 2001, 2005

  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.

  19. Neurodevelopment in Children of Women with Epilepsy • Maternal seizure type • # of seizures during pregnancy • IQ & education of parents • AEDs & other drugs • Other environmental factors

  20. Factors Affecting Cognitive Neurodevelopment • When maternal IQ is controlled, no other single environment factor has a large effect. • Heritability: 30-50% of IQ variance Sattler JM, 1992

  21. Cognitive Effects of In Utero AEDs • PHENOBARBITAL • 2 retrospective Danish cohorts without maternal IQ (n=114 PB total): PB vs. general population: -7 VIQ1 • PHENYTOIN • Prospective without maternal IQ (n=20 PHT): PHT vs. controls: -8 IQ2 • Prospective cohort (n=34 PHT, 36 CBZ): PHT not different when analyses using maternal IQ; also no effect for CBZ 3 • Swedish (?prospective) cohort without maternal IQ (n= 67 PHT): PHT vs. unexposed controls: -8 IQ4 1. Reinisch et al. JAMA 1995;274:1518-1525. 2. Vanderloop et al. Neurotox Terat 1992;14:196-92. 3. Scolnik et al, JAMA 1994;271:767-70. 4. Wide et al. Acta Paediatr 2002;409-14.

  22. Cognitive Effects of In Utero AEDs: • VALPROATE • 2 retrospective cohorts from UK, which controlled for maternal IQ): VPA vs. other monotherapy or no AED • Special education: 30% vs. 3-6%1 • VPA group 6-16 years old: -10-14 VIQ2 (n=41 VPA) • VPA group <6 years old: greater delay on SGS II (Schedule of Growing Skills II)1 (n=21 VPA) • Prospective Finnish cohort without maternal IQ): VPA vs. CBZ: -12 VIQ3 (n=13 VPA MonoTx) No difference for CBZ vs. unexposed3 1. Adab N, et al. J Neurol Neurosurg Psychiatry. 2001;70:15-21. 2. Adab N, et al. Neurol Neurosurg Psychiatry. 2004;75:1575-1583. 3. Gaily E, et al. Neurology. 2004;62:28-32.

  23. NEAD StudyNeurodevelopmental Effects of Antiepileptic Drugs 25 sites: USA & UK http://www.neadstudy.com Funded by NIH/NINDS #2RO1 NS 38455

  24. STUDY DESIGN • Multicenter prospective, parallel-group observational study with statistical control. • Pregnant mothers with epilepsy enrolled from late 1999 to early 2004. • AED monotherapy: • Carbamazepine (CBZ) • Lamotrigine (LTG) • Phenytoin (PHT) • Valproate (VPA) • Blinded cognitive assessments: 2, 3, 4.5, & 6 y/o • Primary outcome: IQ at 6 y/o

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

  26. Child IQ vs. Maternal IQ r = .23 p<.04 r = .54 p<.001 r = .49 p<.001 r = .09 NS Pearson correlations (p values) by AED Group from multiple imputation analyses for Child IQ vs. Maternal IQ

  27. Means (95% CIs) for Child IQ as Function of Dose and AED Group Median dosages: CBZ = 750 mg/day, LTG = 433 mg/day, PHT = 398 mg/day, and VPA = 1000 mg/day

  28. Valproate Dose Effects • NEAD Significant for both birth defects and IQ • 24.2% > 900 mg/day vs. 9.1% < 900 mg/day • North America Not significant • 1033 mg/day (+434) with malformations vs. 983 mg/day (+431) without • Australia Significant • 34.5% malformations > 1400 mg/day vs. 5.5% at < 1400 mg/day • Finland Significant • 23.8% for doses >1500mg/day vs. 9.5% for doses <1500mg/day • UK Not significant • 9.1% >1000 mg/day, 6.1% 600-1000 mg/day, 4.1% <600 mg/day • UK Liverpool Significant • Reduce VIQ 15 points > 1500mg/d, 9.9 at 801-1500mg/d, 2.2 < 800mg/d • Finland Significant • Reduce VIQ 20 points > 1500mg/d, 16.6 at 800-1500mg/d, 4.2 < 800mg/d • Sweden and GSK data Not analyzed for dose effect of VPA

  29. Cognitive Effects of Levetiracetam Fetal Exposure • Griffiths Mental Development Scale at age <24 mos • Developmental Quotient in Children of: • WWE on Levetiracetam (n=51): 100 • WWE on Valproate (n=44): 88 • Healthy women on drug (n=97): 99 • Weaknesses: • Young age at assessment • Retrospective collection of seizures and alcohol & tobacco use during pregnancy • Completer Rate: 58% LEV and 37% VPA Shallcrosset al, Neurology 2011

  30. Success with Antiepileptic Drugs Previously Untreated Epilepsy Patients (N=470) Not Sz Free Sz Free Kwan P, Brodie MJ. N Engl J Med. 2000;342(5):314-319

  31. Anterior Temporal Lobectomy (ATL) • 60-75% Seizure Free • <5% Morbidity • <1% Mortality • Average duration epilepsy 20 years prior to surgery

  32. Henry Gustav Molaison • Patient HM • Born: February 26, 1926 • Surgery: September 1, 1953 (age 27) • Died: December 2, 2008 (age 82) • Severe anterograde declarative memory disorder • Retrograde memory disorder back 11 years • Intact: immediate memory, procedural memory, priming, & release from proactive interference • Scoville WB, Milner B. Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatr 1957;20:11-21.

  33. Neuropsychological Effects of Anterior Temporal Lobectomy • LEFT • Naming Deficits • Worsening of Verbal Episodic Memory • RIGHT • Non-Verbal Episodic Memory Deficits (less consistent & less clinically significance) Trenerry MR et al. Neurology 1993;43:1800-1805 Hermann BP et al. BehavNeurosci 1994;108:3-10 Helmstaedter C. Epilepsy & Behavior 2004;5:S45-S55.

  34. Predictors of Greater Risk for Post-ATL Cognitive Decline • ATL on language dominant side • Older age of seizure onset • Older age at surgery • Higher pre-op cognitive performance • No hippocampal atrophy/sclerosis • Poor post-op seizure control Helmstaedter C. Epilepsy & Behavior 2004;5:S45-S55. ATL= anterior temporal lobectomy

  35. Other Predictors of Post-ATL Cognitive Outcomes • Wada test • fMRI • MRS • PET • Evoked Potentials from implanted electrodes ATL= anterior temporal lobectomy

  36. Other Types of Epilepsy Surgery & Cognitive Risks • Frontal • Parietal • Occipital • Multiple Subpial Transections • Callosotomy • Hemispherectomy

  37. Vagal Nerve Stimulator • No cognitive side effects • Apparent improvements in some patients probably related to reduced seizures & Antiepileptic Drugs. Dodrill & Morris, Epilepsy Behav 2001;2:46-53

  38. Seizure-free Auras Seizures Hypertension/ Diabetes Heart Disease Comparison of Quality of Life With Seizures, HTN, Diabetes, & Heart Disease N = 166 61 58 55 T-SCORE 52 49 46 OverallQualityof Life EmotionalWell-Being SocialFunction Role–Emotional Energy/Fatigue Pain Role–Physical PhysicalFunction HealthPerception Vickrey BG. Epilepsia. 1994;35:597-607

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

  40. Mood, Quality of Life, & Neuropsychological Function Subjective Mood Best All 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

  41. Summary: Cognition & Epilepsy • Cognitive impairment in epilepsy is multifactorial. • Least cognitive effects: GBP, LEV, TGB, LTG. • Intermediate effects: CBZ, PHT, OXC, VPA. • Most adverse effects: PB, TPM, Benzos. • AED susceptibility can vary across patient groups as well as across individual patients. • Subjective and objective measures of cognitive function can dissociate. Benzos=benzodiazepines, CBZ=carbamazepine, GBP=gabapentin, LEV=levetiracetam, LTG=lamotrigine, PB=phenobarbital, PHT=phenytoin, OXC=oxcarbazepine, TGB=tiagabine, TPM=topiramate, VPA=valproate.

  42. Prevalence of Psychiatric Disorders in Epilepsy • Depression 11%–60% • Anxiety 19%–45% • Psychosis 2%–8% Anthony, et al. Epidemiol Rev 1995;17: 240-2 Weissman, et al. J Clin Psychopharm 1986; Suppl 6:11-17 Kessler, et al. Arch Gen Psych 1994;51:8-19

  43. 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) CBZ=carbamazepine, GBP=gabapentin, LTG=lamotrigine, TPM=topiramate, VPA=valproate.

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