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
All 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 Sclerosis
This 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 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
Fuerst 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

7. Cognitive Effects Wine AEDs
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): ; 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 placebo
better than AED
gabapentin
0 – 19%
lamotrigine
1 – 17%
levetiracetam
11%
oxcarbazepine
46%
topiramate
29 – 88%
tiagabine 0%
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 cognition
MORE impact on cognition
% tests
gabapentin
carbamazepine
26%
topiramate
50%
lamotrigine
48%
80%
levetiracetam
42%
oxcarbazepine
phenytoin 0%
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 = 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
N = 593
>65 y/o
New onset epilepsy
Mean Dose (mg/d) ABL (mcg/ml)
CBZ =
GBP =
LTG =
LTG
GBP
CBZ
Rowan et al, Neurology 2005;64:
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):
Donati et al, Neurology 2006;67:

16. Children AED Cognition Studies
Vining 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
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
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.
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 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: % 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
Two Class III for PB worse
One Class II and Two Class III for PHT worse
See next slide note for CBZ
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
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: 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
Two Class II for VPA worse
Two Class II for CBZ not worse
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. NEAD Study Neurodevelopmental Effects of Antiepileptic Drugs
25 sites: USA & UK
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
309 mother/child pairs from 25 centers in US & UK
Meador et al. NEJM 2009;360:
Funded by NIH/NINDS #2RO1 NS and #1 R
Multicenter 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 Valproate
Mean IQ
Difference
(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 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
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
Previously Untreated Epilepsy Patients (N=470)
Not
Sz Free
Sz Free
Kwan P, Brodie MJ. N Engl J Med. 2000;342(5):

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:
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. Vickrey BG. Epilepsia. 1994;35:597-607
Comparison of Quality of Life With Seizures, HTN, Diabetes, & Heart Disease
Seizure-free
Auras
Seizures
Hypertension/ Diabetes
Heart Disease
N = 166 61 58 55
T-SCORE 52
HRQOL 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. 49 46
Overall Quality of Life
Emotional Well-Being
Social Function
Role– Emotional
Energy/ Fatigue
Pain
Role– Physical
Physical Function
Health Perception
Vickrey BG. Epilepsia. 1994;35:

39. Relationship of Subtle AED Toxicity Adverse Events Profile
to Quality of Life
QOLIE-89 Total Score
QOLIE-89 Total Score
The 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 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:

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.