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Cognitive Issues in the Treatment of Epilepsy

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Title: Cognitive Issues in the Treatment of Epilepsy


1
Cognitive Issues in the Treatment of Epilepsy
Kimford Meador, MD Departments of Neurology
Pediatrics Emory University Atlanta, Georgia
kimford.meador_at_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- Related Variables
Treatment- Related Variables
NonSeizure- Related Variables
4
Patient with Complex Partial Seizure from Left
Mesial Temporal Sclerosis
Lee KH et al, Neurology 20022459(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. 200353413-416
6
Cross-Sectional Cognition Study in Temporal Lobe
Epilepsy (TLE)
  • FSIQ of WAIS-R in 209 patients with unilateral
    TLE.
  • IQ lower if gt30 year Seizure Duration than 15 -
    30 years and lt15 years.
  • IQ for 15 - 30 years and lt15 years seizure
    duration did not differ.
  • Decline is in patients without seizure control.

Jokeit H et al. J Neurol Neurosurg Psychiatry
19996744-50
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. 199141(10)
1537-1540 Meador KJ et al. Epilepsia.
199334(1)153-157 Meador KJ et al. Neurology.
199545(8)1494-1499.
10
Healthy Volunteers Newer AEDs vs Placebo
AED 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 199625291-7. Dodrill
et al, Neurology 1997481025-31. Leach et al,
JNNP 199762372-6. Meador et al., Epilepsia
199940(9)1279-1285. Meador et al., Neurology
2001561177-82. Salinsky et al., Epilepsy
Behavior 20045894-902. Aldenkamp et al.,
Epilepsia 2000411167-7. Meador et al.,
Neurology 200313601483-8. Salinsky et al.,
Neurology 200564792-8. Meador et al., Neurology
200564(12)2108-2115. Blum et al., Neurology
200667400-406.
11
Healthy Volunteers Newer AEDs vs Other AEDs
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
Meador et al., Epilepsia 199940(9)1279-1285.
Meador et al., Neurology 2001561177-82.
Salinsky et al., Epilepsy Behavior
20045894-902. Meador et al., Neurology
200313601483-8. Salinsky et al., Neurology
200564792-8. Meador et al., Neurology
200564(12)2108-2115.
12
Incidence of Unprovoked Seizures in Developed
Countries
Cloyd et al. Epilepsy Res 200668 (Suppl 1) 39-48
13
Cognitive Effects of AEDs in the Elderly
  • Phenytoin Valproate
  • Craig Tallis, Epilepsia 199435381-390
  • Elderly more sensitive to cognitive effects of
    AEDs
  • Carbamazepine, Phenobarb, Phenytoin, Primidone
  • VA Cooperative Study

14
VA Coop Geriatric Epilepsy Study
N 593 gt65 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 2005641868-73.
CBZcarbamazepine, GBPgabapentin, LTGlamotrigine
15
Cognitive Effects of AEDs in Children
  • Loring Meador, Neurology 200462872-7
  • Pressler et al., Neurology 200666(10)1495-9.
  • Donati et al, Neurology 200667679-682.

16
Children AED Cognition Studies
Vining et al, 1987 PB lt VPA
Farwell et al, 1990 PB lt Placebo
Forsythe et al, 1991 CBZ PHT VPA
Chen et al, 1996, 2001 PB lt 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 lt CBZ
Levisohn et al, 2009 LEV Placebo
CBZcarbamazepine, GBPgabapentin,
LEVlevetiracetam, LTGlamotrigine,
OXCoxcarbazepine, PBphenobarb, PHTphenytoin,
TPMtopiramate
17
MCG Stories Delayed Recall Compared to
Non-Drug Average Healthy Volunteer Studies
CBZcarbamazepine, GBPgabapentin,
LTGlamotrigine, PHTphenytoin, TPMtopiramate.
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 (n114 PB total) PB vs. general population
    -7 VIQ1
  • PHENYTOIN
  • Prospective without maternal IQ (n20 PHT)
  • PHT vs. controls -8 IQ2
  • Prospective cohort (n34 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 19952741518-1525. 2.
Vanderloop et al. Neurotox Terat 199214196-92.
3. Scolnik et al, JAMA 1994271767-70. 4. Wide
et al. Acta Paediatr 2002409-14.
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. 3-61
  • VPA group 6-16 years old -10-14 VIQ2
  • (n41 VPA)
  • VPA group lt6 years old greater delay on SGS II
    (Schedule of Growing Skills II)1 (n21 VPA)
  • Prospective Finnish cohort without maternal IQ)
  • VPA vs. CBZ -12 VIQ3 (n13 VPA MonoTx)
  • No difference for CBZ vs. unexposed3

1. Adab N, et al. J Neurol Neurosurg Psychiatry.
20017015-21. 2. Adab N, et al. Neurol Neurosurg
Psychiatry. 2004751575-1583. 3. Gaily E, et al.
Neurology. 20046228-32.
23
NEAD Study Neurodevelopmental 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
309 mother/child pairs from 25 centers in US UK
Meador et al. NEJM 20093601597-605
Funded by NIH/NINDS 2RO1 NS 38455 and 1
R01050659
  • Fetal valproate exposure related with lower IQ.
  • Carbamazepine Lamotrigine Phenytoin
    Valproate
  • Mean IQ 98 101 99
    92
  • Difference 6 9 7
  • (CIs) (0.612.0) (3.114.6) (0.214.0)

26
Child IQ vs. Maternal IQ
r .23 plt.04
r .54 plt.001
r .49 plt.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 gt 900 mg/day vs. 9.1 lt 900 mg/day
  • North America Not significant
  • 1033 mg/day (434) with malformations vs. 983
    mg/day (431) without
  • Australia Significant
  • 34.5 malformations gt 1400 mg/day vs. 5.5 at lt
    1400 mg/day
  • Finland Significant
  • 23.8 for doses gt1500mg/day vs. 9.5 for doses
    lt1500mg/day
  • UK Not significant
  • 9.1 gt1000 mg/day, 6.1 600-1000 mg/day, 4.1
    lt600 mg/day
  • UK Liverpool Significant
  • Reduce VIQ 15 points gt 1500mg/d, 9.9 at
    801-1500mg/d, 2.2 lt 800mg/d
  • Finland Significant
  • Reduce VIQ 20 points gt 1500mg/d, 16.6 at
    800-1500mg/d, 4.2 lt 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 lt24 mos
  • Developmental Quotient in Children of
  • WWE on Levetiracetam (n51) 100
  • WWE on Valproate (n44) 88
  • Healthy women on drug (n97) 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 (N470)
Not Sz Free
Sz Free
Kwan P, Brodie MJ. N Engl J Med.
2000342(5)314-319
31
Anterior Temporal Lobectomy (ATL)
  • 60-75 Seizure Free
  • lt5 Morbidity
  • lt1 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 19572011-21.

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
    1993431800-1805
  • Hermann BP et al. Behav Neurosci
    19941083-10
  • Helmstaedter C. Epilepsy Behavior
    20045S45-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
    20045S45-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 2001246-53
38
Comparison of Quality of Life With Seizures, HTN,
Diabetes, Heart Disease
N 166
61
58
55
T-SCORE
52
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. 199435597-607
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, Plt0.0001
Gilliam, et al. Neurology 20046223-27
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 199552997-1003
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.

Benzosbenzodiazepines, CBZcarbamazepine,
GBPgabapentin, LEVlevetiracetam,
LTGlamotrigine, PBphenobarbital, PHTphenytoin,
OXCoxcarbazepine, TGBtiagabine, TPMtopiramate,
VPAvalproate.
42
  • Prevalence of Psychiatric Disorders in Epilepsy
  • Depression 1160
  • Anxiety 1945
  • Psychosis 28

Anthony, et al. Epidemiol Rev 199517 240-2
Weissman, et al. J Clin Psychopharm 1986 Suppl
611-17 Kessler, et al. Arch Gen Psych
1994518-19
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)

CBZcarbamazepine, GBPgabapentin,
LTGlamotrigine, TPMtopiramate, VPAvalproate.
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