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Cognitive Issues in the Treatment of Epilepsy Kimford Meador, MD Departments of Neurology & Pediatrics Emory University Atlanta, Georgia

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Presentation on theme: "Cognitive Issues in the Treatment of Epilepsy Kimford Meador, MD Departments of Neurology & Pediatrics Emory University Atlanta, Georgia"— Presentation transcript:

1 Cognitive Issues in the Treatment of Epilepsy Kimford Meador, MD Departments of Neurology & Pediatrics Emory University Atlanta, Georgia

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

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

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

5 Fuerst D et al. Ann Neurol. 2003;53: Longitudinal Study of Hippocampal Atrophy 12 unilateral TLE patients Repeat MRI: mean 3.4 yrs ( 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

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 years and <15 years. IQ for years and <15 years seizure duration did not differ. Decline is in patients without seizure control. Jokeit H et al. J Neurol Neurosurg Psychiatry 1999;67:44-50

7 Cognitive Effects WineAEDs 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 1/3 rd 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): ; Meador KJ et al. Epilepsia. 1993;34(1): ; Meador KJ et al. Neurology. 1995;45(8):

10 Healthy Volunteers: Newer AEDs vs Placebo Kalviainen et al, Epi Res 1996;25: Dodrill et al, Neurology 1997;48: Leach et al, JNNP 1997;62: Meador et al., Epilepsia 1999;40(9): Meador et al., Neurology 2001;56: Salinsky et al., Epilepsy & Behavior 2004;5: Aldenkamp et al., Epilepsia 2000;41: Meador et al., Neurology 2003;13;60: Salinsky et al., Neurology 2005;64: Meador et al., Neurology 2005;64(12): Blum et al., Neurology 2006;67: AED% tests with placebo better than AED gabapentin0 – 19% lamotrigine1 – 17% levetiracetam11% oxcarbazepine46% topiramate29 – 88% tiagabine0%

11 Healthy Volunteers: Newer AEDs vs Other AEDs Meador et al., Epilepsia 1999;40(9): Meador et al., Neurology 2001;56: Salinsky et al., Epilepsy & Behavior 2004;5: Meador et al., Neurology 2003;13;60: Salinsky et al., Neurology 2005;64: Meador et al., Neurology 2005;64(12): LESS impact on cognition MORE impact on cognition % tests gabapentincarbamazepine26% gabapentintopiramate50% lamotriginecarbamazepine48% lamotriginetopiramate80% levetiracetamcarbamazepine42% oxcarbazepinephenytoin0%

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

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

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

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

16 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 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 Average Healthy Volunteer Studies Meador et al, 1991, 1993, 2000, 2001, 2005 CBZ=carbamazepine, GBP=gabapentin, LTG=lamotrigine, PHT=phenytoin, TPM=topiramate.

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 PHENOBARBITAL – 2 retrospective Danish cohorts without maternal IQ (n=114 PB total): PB vs. general population: -7 VIQ 1 PHENYTOIN PHENYTOIN – Prospective without maternal IQ (n=20 PHT): PHT vs. controls: -8 IQ 2 – 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 IQ 4 1. Reinisch et al. JAMA 1995;274: Vanderloop et al. Neurotox Terat 1992;14: Scolnik et al, JAMA 1994;271: Wide et al. Acta Paediatr 2002;

22 Cognitive Effects of In Utero AEDs: VALPROATE 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: VIQ 2 (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 VIQ 3 (n=13 VPA MonoTx) No difference for CBZ vs. unexposed 3 1. Adab N, et al. J Neurol Neurosurg Psychiatry. 2001;70: Adab N, et al. Neurol Neurosurg Psychiatry. 2004;75: Gaily E, et al. Neurology. 2004;62:28-32.

23 25 sites: USA & UK Funded by NIH/NINDS #2RO1 NS NEAD Study Neurodevelopmental Effects of Antiepileptic Drugs

24 STUDY DESIGN Multicenter prospective, parallel-group observational study with statistical control. Pregnant mothers with epilepsy enrolled from late 1999 to early 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 Fetal valproate exposure related with lower IQ. CarbamazepineLamotriginePhenytoin Valproate Mean IQ Difference (CIs)(0.6:12.0) (3.1:14.6) (0.2:14.0) Neurodevelopmental Effects of Antiepileptic Drugs Funded by NIH/NINDS #2RO1 NS and #1 R mother/child pairs from 25 centers in US & UK Meador et al. NEJM 2009;360:

26 Child IQ vs. Maternal IQ r =.54 p<.001 r =.49 p<.001 r =.23 p<.04 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% mg/day, 4.1% <600 mg/day UK Liverpool Significant Reduce VIQ 15 points > 1500mg/d, 9.9 at mg/d, 2.2 < 800mg/d Finland Significant Reduce VIQ 20 points > 1500mg/d, 16.6 at mg/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 Shallcross et al, Neurology 2011

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

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:

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: Hermann BP et al. Behav Neurosci 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 Comparison of Quality of Life With Seizures, HTN, Diabetes, & Heart Disease Vickrey BG. Epilepsia ; 35: Seizure-free Auras Seizures Hypertension/ Diabetes Heart Disease Overall Quality of Life Emotional Well-Being Social Function Role– Emotional Energy/ Fatigue PainRole– Physical Physical Function Health Perception T-SCORE N = 166

39 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< Average Monthly Seizure Rate QOLIE-89 Total Score

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% Perrine et al, Arch Neurol 1995;52: % Variance explained by each factor; N = 257 epilepsy patients

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: 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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