Cognitive Issues in the Cognitive Issues in the Treatment of EpilepsyTreatment of Epilepsy

Kimford Meador, MD

Departments of Neurology & Pediatrics

Emory University

Atlanta, Georgiakimford.meador@emory.edu

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

Factors Affecting Cognition and Behavior in Epilepsy

Seizure-Related

Variables

Treatment-Related

Variables

Non–Seizure-Related

Variables

Patient with Complex Partial Seizure from Left Mesial Temporal Sclerosis

Lee KH et al, Neurology 2002;24:59(6):841-6

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 (2.5-5.2yrs)• Progressive hippocampal atrophy occurred

only in patients with continuing seizures• Mean 10% loss of hippocampal volume in

patients with continued seizuresTLE = temporal lobe epilepsy

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 Neurol Neurosurg Psychiatry 1999;67:44-50

Cognitive EffectsWine AEDs

• Higher Dose/ABL• Polytherapy• Rapid Titration• Habituation• AED differences• Individual

differencesAEDs = antiepileptic drugs

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

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.

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., Epilepsia 1999;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.

AED % tests with placebo

better than AED

gabapentin 0 – 19%

lamotrigine 1 – 17%

levetiracetam 11%

oxcarbazepine 46%

topiramate 29 – 88%

tiagabine 0%

Healthy Volunteers: Newer AEDs vs Other AEDs

Meador et al., Epilepsia 1999;40(9):1279-1285. Meador et al., Neurology 2001;56:1177-82. Salinsky et al., Epilepsy & Behavior 2004;5:894-902. 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.

LESS impact on cognition

MORE impact on cognition

% tests

gabapentin carbamazepine 26%

gabapentin topiramate 50%

lamotrigine carbamazepine 48%

lamotrigine topiramate 80%

levetiracetam carbamazepine 42%

oxcarbazepine phenytoin 0%

Incidence of Unprovoked Seizures in Incidence of Unprovoked Seizures in Developed CountriesDeveloped Countries

Cloyd et al. Epilepsy Res 2006;68 (Suppl 1): 39-48

Cognitive Effects ofAEDs in the Elderly

• Phenytoin = ValproateCraig & Tallis, Epilepsia 1994;35:381-390

• Elderly more sensitive to cognitive effects of AEDs:Carbamazepine, Phenobarb, Phenytoin, PrimidoneVA Cooperative Study

VA Coop Geriatric Epilepsy Study

Rowan et al, Neurology 2005;64:1868-73.

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

CBZ=carbamazepine, GBP=gabapentin, LTG=lamotrigine

GBP

LTG

CBZ

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.

Children AED Cognition StudiesVining et al, 1987 PB < VPA

Farwell et al, 1990 PB < Placebo

Forsythe et al, 1991 CBZ = PHT = VPA

Chen et al, 1996, 2001 PB < CBZ = VPA

Aldenkamp et al, 1998 CBZ = PHT = VPA

Pressler et al, 2006 LTG = Placebo

Donati et al, 2006 CBZ = OXC = VPA

Kang et al, 2007 TPM < CBZ

Levisohn et al, 2009 LEV = Placebo

CBZ=carbamazepine, GBP=gabapentin, LEV=levetiracetam, LTG=lamotrigine, OXC=oxcarbazepine, PB=phenobarb, PHT=phenytoin, TPM=topiramate

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.

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.

Neurodevelopment in Children of Women with Epilepsy

• Maternal seizure type

• # of seizures during pregnancy

• IQ & education of parents

• AEDs & other drugs

• Other environmental factors

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

Cognitive Effects of In Utero AEDs• PHENOBARBITALPHENOBARBITAL

– 2 retrospective Danish cohorts without maternal IQ (n=114 PB total): PB vs. general population: -7 VIQ1

• PHENYTOINPHENYTOIN– 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.

Cognitive Effects of In Utero AEDs:

• VALPROATEVALPROATE– 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.

25 sites: USA &

UK

http://www.neadstudy.comFunded by NIH/NINDS #2RO1 NS 38455

NEAD StudyNeurodevelopmental Effects of Antiepileptic Drugs

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

Fetal valproate exposure related with lower IQ. Carbamazepine Lamotrigine Phenytoin Valproate

Mean IQ 98 101 99 92Difference 6 9 7(CIs) (0.6:12.0) (3.1:14.6) (0.2:14.0)

Neurodevelopmental Effects Neurodevelopmental Effects of Antiepileptic Drugsof 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

Child IQ vs. Maternal IQ

60 80 100 120 140

4060

8010

012

014

0

Maternal IQ

Ag

e 3

IQ

Carbamazepine

60 80 100 120 140

4060

8010

012

014

0

Maternal IQ

Ag

e 3

IQ

Lamotrigine

60 80 100 120 140

4060

8010

012

014

0

Maternal IQ

Ag

e 3

IQ

Phenytoin

60 80 100 120 140

4060

8010

012

014

0

Maternal IQ

Ag

e 3

IQ

Valproate

r = .54 p<.001

r = .49p<.001

r = .23p<.04

r = .09 NS

Pearson correlations (p values) by AED Group from multiple imputation analyses for Child IQ vs. Maternal IQ

Means (95% CIs) for Child IQ as Function of Dose and AED Group

High Dose Carbamazepine Lamotrigine Phenytoin Valproate

Low Dose Carbamazepine Lamotrigine Phenytoin Valproate

N47522822

N46482739

MeanIQ

97100 98 87

MeanIQ

100102 98 97

80 85 90 95 100 105

Age 3 IQ Mean: 95% CI

Median dosages: CBZ = 750 mg/day, LTG = 433 mg/day, PHT = 398 mg/day, and VPA = 1000 mg/day

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

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

Success with Antiepileptic Drugs

Kwan P, Brodie MJ. N Engl J Med. 2000;342(5):314-319

Previously Untreated Epilepsy Patients (N=470)Previously Untreated Epilepsy Patients (N=470)

Sz Free

Not Sz

Free

Anterior Temporal Lobectomy (ATL)

• 60-75% Seizure Free• <5% Morbidity• <1% Mortality• Average duration epilepsy 20

years prior to surgery

Henry Gustav MolaisonPatient HM

Born: February 26, 1926Surgery: 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.

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;43:1800-1805Hermann BP et al. Behav Neurosci 1994;108:3-10Helmstaedter C. Epilepsy & Behavior 2004;5:S45-S55.

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

Other Predictors of Post-ATL Cognitive Outcomes

• Wada test• fMRI• MRS• PET• Evoked Potentials from

implanted electrodes

ATL= anterior temporal lobectomy

Other Types of Epilepsy Surgery & Cognitive Risks

• Frontal• Parietal• Occipital• Multiple Subpial Transections• Callosotomy• Hemispherectomy

Vagal Nerve StimulatorVagal 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

Comparison of Quality of Life With Seizures, HTN, Comparison of Quality of Life With Seizures, HTN, Diabetes, & Heart DiseaseDiabetes, & Heart Disease

Vickrey BG. Epilepsia. 1994;35:597-607

46

49

52

55

58

61

Seizure-freeAurasSeizuresHypertension/ DiabetesHeart Disease

OverallQualityof Life

EmotionalWell-Being

SocialFunction

Role–Emotional

Energy/Fatigue

Pain Role–Physical

PhysicalFunction

HealthPerception

T-S

CO

RE

N = 166

Gilliam, et al. Neurology 2004;62:23-27

Relationship of Subtle AED Toxicity Relationship of Subtle AED Toxicity to Quality of Lifeto Quality of Life

Adverse Events Profile Summary Score

QO

LIE

-89

To

tal S

co

re

N = 200r = -0.76,P<0.0001

Average Monthly Seizure Rate

QO

LIE-

89 T

otal

Sco

re

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;52:997-1003

% Variance explained by each factor; N = 257 epilepsy patients

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.

Prevalence of Psychiatric Disorders Prevalence of Psychiatric Disorders in Epilepsyin 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

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.