Presentation on theme: "Cognitive Issues in the Treatment of Epilepsy"— Presentation transcript:
1 Cognitive Issues in the Treatment of Epilepsy Kimford Meador, MDDepartments of Neurology & PediatricsEmory UniversityAtlanta, Georgia
2 International Bureau for Epilepsy: 2004 Cognitive Function Survey 44% Difficulty learning45% Felt that they were slow thinkers59% Felt sleepy or tired63% AED effects prevented them from achieving activities or goalsN = 425 Europeans with epilepsy
3 Factors Affecting Cognition and Behavior in Epilepsy Seizure- Related VariablesTreatment- RelatedVariablesAll patients with epilepsy are at increased risk for cognitive and/or behavioral impairment, and the origin for this type of impairment appears to be multifactorial. These variables may be seizure- or non–seizure-related or related to treatment with certain AEDs. Clinician awareness of the factors that comprise these variables and their relationship with cognitive/behavioral impairment is vital within the context of managing epilepsy and choosing appropriate AED therapy.Non–Seizure- Related Variables
4 Lee KH et al, Neurology 2002;24:59(6):841-6 Patient with Complex Partial Seizure from Left Mesial Temporal SclerosisThis slide shows an example of CLOA group. Patient was a 17 year old male with complex partial seizure. MRI showed left mesial temporal sclerosis. Ipsilateral thalamic and midbrain hyperperfusion is demonstrated.Lee KH et al, Neurology 2002;24:59(6):841-6
5 Longitudinal Study of Hippocampal Atrophy 12 unilateral TLE patientsRepeat MRI: mean 3.4 yrs ( yrs)Progressive hippocampal atrophy occurred only in patients with continuing seizuresMean 10% loss of hippocampal volume in patients with continued seizuresTLE = temporal lobe epilepsyFuerst D et al. Ann Neurol. 2003;53:
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
8 Cognitive Abilities Most Likely to be Affected by AEDs Processing Speed (e.g., reaction time)Complex or Sustained AttentionDual ProcessingVerbal learningParagraphs more sensitive than word listsVerbal fluencyRate at which words beginning with a specific letter can be generatedAEDs = 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): ; Meador KJ et al. Epilepsia. 1993;34(1): ; Meador KJ et al. Neurology. 1995;45(8):
10 Healthy Volunteers: Newer AEDs vs Placebo % tests with placebobetter than AEDgabapentin0 – 19%lamotrigine1 – 17%levetiracetam11%oxcarbazepine46%topiramate29 – 88%tiagabine0%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:
11 Healthy Volunteers: Newer AEDs vs Other AEDs LESS impact on cognitionMORE impact on cognition% testsgabapentincarbamazepine26%topiramate50%lamotrigine48%80%levetiracetam42%oxcarbazepinephenytoin0%When comparing the newer AEDs to each other, performance while taking some medications are more affected than while taking other medications. This table demonstrates the impact of those differences. For instance, the first row demonstrates that patients taking gabapentin significantly outperformed patients taking carbamazepine on 26% of the tests taken by the groups.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):
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 = ValproateCraig & Tallis, Epilepsia 1994;35:Elderly more sensitive to cognitive effects of AEDs:Carbamazepine, Phenobarb, Phenytoin, PrimidoneVA Cooperative Study
14 VA Coop Geriatric Epilepsy Study N = 593>65 y/oNew onset epilepsyMean Dose (mg/d) ABL (mcg/ml)CBZ =GBP =LTG =LTGGBPCBZRowan et al, Neurology 2005;64:CBZ=carbamazepine, GBP=gabapentin, LTG=lamotrigine
15 Cognitive Effects of AEDs in Children Loring & Meador, Neurology 2004;62:872-7Pressler et al., Neurology 2006;66(10):Donati et al, Neurology 2006;67:
16 Children AED Cognition Studies Vining et al, 1987PB < VPAFarwell et al, 1990PB < PlaceboForsythe et al, 1991CBZ = PHT = VPAChen et al, 1996, 2001PB < CBZ = VPAAldenkamp et al, 1998Pressler et al, 2006LTG = PlaceboDonati et al, 2006CBZ = OXC = VPAKang et al, 2007TPM < CBZLevisohn et al, 2009LEV = PlaceboWhen comparing the newer AEDs to each other, performance while taking some medications are more affected than while taking other medications. This table demonstrates the impact of those differences. For instance, the first row demonstrates that patients taking gabapentin significantly outperformed patients taking carbamazepine on 26% of the tests taken by the groups.Vining et al, Pediatrics 1987;80: ; Farwell et al,,NEJM 1990;322: ; Forsythe et al, Dev Med Child Neurol 1991;33: ; Chen et al, Epilepsia 1996;37:81-86; Aldenkamp et al, Epilepsia 1998;39:1070-4; Pressler et al, Neurology 2006;66:1495-9; Donati et al, Neurology 2006; 67; ; Kang et al, Epilepsia 2007;48: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 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 pregnancyIQ & education of parentsAEDs & other drugsOther environmental factors
20 Factors Affecting Cognitive Neurodevelopment When maternal IQ is controlled, no other single environment factor has a large effect.Heritability: % of IQ varianceSattler JM, 1992
21 Cognitive Effects of In Utero AEDs PHENOBARBITAL2 retrospective Danish cohorts without maternal IQ (n=114 PB total): PB vs. general population: -7 VIQ1PHENYTOINProspective without maternal IQ (n=20 PHT):PHT vs. controls: -8 IQ2Prospective cohort (n=34 PHT, 36 CBZ):PHT not different when analyses using maternal IQ; also no effect for CBZ 3Swedish (?prospective) cohort without maternal IQ (n= 67 PHT): PHT vs. unexposed controls: -8 IQ4Two Class III for PB worseOne Class II and Two Class III for PHT worseSee next slide note for CBZ1. 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: VALPROATE2 retrospective cohorts from UK, which controlled for maternal IQ): VPA vs. other monotherapy or no AEDSpecial education: 30% vs. 3-6%1VPA group 6-16 years old: 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. unexposed3Two Class II for VPA worseTwo Class II for CBZ not worse1. 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 NEAD Study Neurodevelopmental Effects of Antiepileptic Drugs 25 sites: USA & UKFunded by NIH/NINDS #2RO1 NS 38455
24 STUDY DESIGNMulticenter 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/oPrimary outcome: IQ at 6 y/o
25 Neurodevelopmental Effects of Antiepileptic Drugs 309 mother/child pairs from 25 centers in US & UKMeador et al. NEJM 2009;360:Funded by NIH/NINDS #2RO1 NS and #1 RMulticenter prospective, parallel-group observational study with statistical control. Pregnant mothers with epilepsy enrolled from late 1999 to late Primary outcome IQ at 6 y/o.Fetal valproate exposure related with lower IQ.Carbamazepine Lamotrigine Phenytoin ValproateMean IQDifference(CIs) (0.6:12.0) (3.1:14.6) (0.2:14.0)
26 Child IQ vs. Maternal IQ r = .23 r = .54 p<.001 p<.04 r = .49 r = .09 NSPearson 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 IQ24.2% > 900 mg/day vs. 9.1% < 900 mg/dayNorth America Not significant1033 mg/day (+434) with malformations vs. 983 mg/day (+431) withoutAustralia Significant34.5% malformations > 1400 mg/day vs. 5.5% at < 1400 mg/dayFinland Significant23.8% for doses >1500mg/day vs. 9.5% for doses <1500mg/dayUK Not significant9.1% >1000 mg/day, 6.1% mg/day, 4.1% <600 mg/dayUK Liverpool SignificantReduce VIQ 15 points > 1500mg/d, 9.9 at mg/d, 2.2 < 800mg/dReduce VIQ 20 points > 1500mg/d, 16.6 at mg/d, 4.2 < 800mg/dSweden and GSK data Not analyzed for dose effect of VPA
29 Cognitive Effects of Levetiracetam Fetal Exposure Griffiths Mental Development Scale at age <24 mosDevelopmental Quotient in Children of:WWE on Levetiracetam (n=51): 100WWE on Valproate (n=44): 88Healthy women on drug (n=97): 99Weaknesses:Young age at assessmentRetrospective collection of seizures and alcohol & tobacco use during pregnancyCompleter Rate: 58% LEV and 37% VPAShallcross et al, Neurology 2011
30 Success with Antiepileptic Drugs Previously Untreated Epilepsy Patients (N=470)NotSz FreeSz FreeKwan P, Brodie MJ. N Engl J Med. 2000;342(5):
31 Anterior Temporal Lobectomy (ATL) 60-75% Seizure Free<5% Morbidity<1% MortalityAverage 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 disorderRetrograde memory disorder back 11 yearsIntact: immediate memory, procedural memory, priming, & release from proactive interferenceScoville 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 LEFTNaming DeficitsWorsening of Verbal Episodic MemoryRIGHTNon-Verbal Episodic Memory Deficits(less consistent & less clinically significance)Trenerry MR et al. Neurology 1993;43:Hermann BP et al. Behav Neurosci 1994;108:3-10Helmstaedter C. Epilepsy & Behavior 2004;5:S45-S55.
34 Predictors of Greater Risk for Post-ATL Cognitive Decline ATL on language dominant sideOlder age of seizure onsetOlder age at surgeryHigher pre-op cognitive performanceNo hippocampal atrophy/sclerosisPoor post-op seizure controlHelmstaedter C. Epilepsy & Behavior 2004;5:S45-S55.ATL= anterior temporal lobectomy
35 Other Predictors of Post-ATL Cognitive Outcomes Wada testfMRIMRSPETEvoked Potentials from implanted electrodesATL= anterior temporal lobectomy
36 Other Types of Epilepsy Surgery & Cognitive Risks FrontalParietalOccipitalMultiple Subpial TransectionsCallosotomyHemispherectomy
37 Vagal Nerve Stimulator No cognitive side effectsApparent improvements in some patients probably related to reduced seizures & Antiepileptic Drugs.Dodrill & Morris,Epilepsy Behav 2001;2:46-53
38 Vickrey BG. Epilepsia. 1994;35:597-607 Comparison of Quality of Life With Seizures, HTN, Diabetes, & Heart DiseaseSeizure-freeAurasSeizuresHypertension/ DiabetesHeart DiseaseN = 166615855T-SCORE52HRQOL of 166 adult patients who had previously undergone surgical treatment for intractable epilepsy was compared with that of outpatients with hypertension, diabetes, and heart disease. QOL scales were converted to T-scores (the Y-axis variable in this figure) by transforming raw scores linearly to produce a mean of 50 and SD of 10 in the combined sample of patients with chronic diseases (Medical Outcomes Study) and epilepsy patients. Results showed that 55 completely seizure-free patients scored higher than patients with hypertension in 6 of 9 HRQOL domains, higher than diabetic patients in 8 of 9 domains, and higher than those with heart disease in all 9 domains. Patients who continued to have seizures with altered consciousness postoperatively scored significantly worse than patients with hypertension, diabetes, or heart disease on overall QOL and emotional well-being, and worse than patients with hypertension or diabetes on social function. In contrast, patients with seizures scored significantly higher than patients with diabetes and heart disease on general health perceptions.From this study, it appears that epilepsy surgery patients who become seizure-free for at least 12 months report better HRQOL than patients with hypertension, diabetes, or heart disease on most HRQOL dimensions.4946Overall Quality of LifeEmotional Well-BeingSocial FunctionRole– EmotionalEnergy/ FatiguePainRole– PhysicalPhysical FunctionHealth PerceptionVickrey BG. Epilepsia. 1994;35:
39 Relationship of Subtle AED Toxicity Adverse Events Profile to Quality of LifeQOLIE-89 Total ScoreQOLIE-89 Total ScoreThe impact of adverse AED effects on quality of life was studied in 194 patients with refractory epilepsy considering evaluation for epilepsy surgery.This slide shows a scatterplot of the correlation of the Adverse Events Profile (AEP) Summary Score with QOLIE-89 scores. The AEP is a reliable and valid measurement of the burden of common AED side effects. The correlation of quality of life with AEP total scores was highly statistically significant (P<.0001).Adverse Events ProfileSummary ScoreAverage MonthlySeizure RateN = 200r = -0.76, P<0.0001Gilliam, 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 patientsPerrine et al, Arch Neurol 1995;52:
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: 240-2Weissman, et al. J Clin Psychopharm 1986; Suppl 6:11-17Kessler, 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 effectsCBZ, 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.