American Epilepsy Society
Epilepsy in the Elderly:
Old Concepts and New Data
L. James Willmore, MD
Professor, Department of Neurology
Associate Dean
Saint Louis University School of Medicine
Symposium Overview
Introduction to Epilepsy and the Elderly
L. James Willmore, MD
Professor, Department of Neurology, Associate Dean, Saint Louis University School of Medicine, St. Louis, MO
Before (or after) the Fall: A Practical Rapid Approach
Joseph Flaherty, MD
Associate Professor, Saint Louis University & St. Louis VA GRECC, St. Louis, MO
Diagnosis and Epidemiology
Mark Spitz, MD
Anschutz Center for Advanced Medicine, Denver Veterans Administration Medical Center, Denver, CO
Pharmacokinetics and Drug Interactions
James Cloyd, PharmD
Professor and Director, Epilepsy Research and Education Program
University of Minnesota, Minneapolis, MN
Cognition and Behavior
John R. Gates, MD
President of the Association of Neurologists of Minnesota
Minnesota Epilepsy Group, PA® St. Paul, MN
Treatment Strategies
A. James Rowan, MD
Professor, Department of Neurology, Mount Sinai School of Medicine, Bronx VA Medical Center, New York, NY
Symposium Learning Objectives
• Review the importance of appropriate diagnosis of
seizures in the elderly
• Describe current trends in the epidemiology of epilepsy
in the elderly
• Discuss neurobehavioral and cognitive effects of
antiepileptic medications on elderly patients
• Examine the impact of drug interactions and
pharmacokinetic properties of antiepileptic medications
on the elderly epileptic patient
• Identify key issues and treatment strategies in the
management of epilepsy in the elderly
Epilepsy in the Elderly
• Important issues to consider:
• Proper identification and diagnosis
• Physiological changes of aging
• Drug interactions
• Treatment strategies
Before (or after) the Fall:
A Practical Rapid Approach
Joseph H. Flaherty, MD
Associate Professor
Internal Medicine Department
Geriatrics Division
Saint Louis University &
St. Louis VA GRECC
Overview
• Epidemiology (So what?)
• Case (Typical)
• Risk factors, causes and work up (in 15
minutes?)
Falls: Common and Consequential
• ~1/3 of community-dwellers >75 fall/year
• ~1/2 of fallers fall repeatedly
• ~1 in 20 community-dwelling fallers
fracture (~1/6 NH residents)
Rubenstein LZ. Josephson KR. The epidemiology of falls and syncope.
Clinics in Geriatric Medicine. 18(2):141-58, 2002 (½ women >85 fall/year)
Thapa PB, et al. Injurious falls in nonambulatory nursing home residents: a comparative study
of circumstances, incidence, and risk factors. J Am Geriatrics Soc. 44(3):273-8, 1996
Falls:
Common and Consequential
MORTALITY
• US: Injury = 6th leading cause of death (age >65)
(falls = 2/3 these injuries)
• US: Hip Fractures = 15% hospital mortality, 33%
one year mortality
• Australia: Accidental falls = 2% all deaths >65
Tinetti ME, et al. Prevention of falls among the elderly. NEJM 320:1055-9;1989
Thapa PB, et al. Injurious falls in nonambulatory nursing home residents: a comparative study
of circumstances, incidence, and risk factors. J Am Geriatrics Soc. 44(3):273-8, 1996
Percent Falling in One Year
Tinetti et al, 1998
100
80
60
%
40
20
0
0 1 2 3 4+
Number of risk factors
Identifying Risk Factors and
Causes of Falls
• Multi-factorial problem
• Evaluate multiple areas
• Multiple interventions
Case Study
An 84-year-old retired high school teacher with a
history of tonic-clonic seizures since age 70 (last
seizure was 4 years ago when she stopped all of her
meds), hypertension, OA (mainly hands, knees R>L)
and insomnia.
Her family is worried because she was admitted to
the hospital after being found down at home and
“they didn’t find anything except a urine infection.”
Since being home (2 weeks) she has fallen twice.
She says, “I just fall.” No LOC, but admits to
“dizziness…yes, well, kind of, but also I just feel
unsteady.”
Case Study
• phenytoin Exam: Frail appearing, having
• diltiazem lost 6 pounds since
• furosemide hospitalization
(ht 5’3”, wt 106#);
• lorazepam SBP drops 25 mmHg from a
• amitriptyline supine to a standing position,
• Tylenol-PM, pulse increases from 68 to 80.
• famotidine “Puffy” ankles. MMSE is 22/30
• calcium (she is a college graduate).
• colace
A
G Risk Factors
A & Causes
I’ of Falls
I F
V ….
N A
E in a 15 minute
L
L office visit
E
N
A
G
A
I’ Risk Factors
I F
V & Causes
N A
E of Falls
L
L find them
fix them
E or get rid of them
N
A = Again….If you fall once,…
G
A
I
N
I’
V
E
F
A
L
L
E
N
A
G = Gait & Balance
A
I
N Evaluation:
“Get up and go”
I’ 1-leg stand
V (RR 2.13 for injurious falls)
E Tandem or near-tandem
F
A
L
L Podsiadlo D, et al. “The Timed “Up & Go”: J Am Geriatr Soc 39:142-148, 1991
E Bohannon RW, et al. Decrease in time balance test scores with aging.
Phys Ther 64:1067-1070, 1984
N Lord SR, et al. Lateral stability, sensorimotor function and falls in older people.
J Am Geriatr Soc 47:1077-1081, 1999 Vellas B, et al. J Am Geriatr Soc 1997
A
G
A = ADL impairment (function)
I
N
I’
V
E
F
A
L
L
E Tinetti ME, et al. Risk factors for falls among elderly persons living in the
N community. NEJM 1988
Tinetti ME, et al. Fall risk index for elderly patients based on number of chronic
disabilities. Am J Med 1986
Change in ADL Function
during Hospitalization
Decline Same Improve Total
n=320 n=656 n=96 N=1072
31% 59% 10% 100%
1279 Community dwelling older persons (>70); 5 hospitals; Acute
medical illnesses OUTCOMES: Change in Function during
hospitalization & Function at 3 months after hospitalization Sager: Arch
Intern Med, Volume 156(6).March 25, 1996.645-652
Change in ADL Function
3 Months AFTER Hospitalization
Decline Same Improve Total
31% 59% 10% 100%
n=320 n=656 n=96 N=1072
3 months
Decline 130 (41%) 56 (9%) 22 (23%) 208 (19%)
Same 157 (49%) 573 (87%) 15 (16%) 745 (70%)
Improve 33 (10%) 27 (4%) 59 (61%) 119 (11%)
A
G
A
I = Illness (acute)
N
I’
Up to 1 out of 3 patients
V
E
Fall is a DELIRIUM equivalent
F
A
L
L
E
Bourdel-Marchasson I, et al. Delirium symptoms and low dietary intake in older inpatient
N are independent predictors of institutionalization. J Gerontol 2004.
Morley JE. http://www.cyberounds.com/conf/geriatrics/ 1999-08-05/
1 2
or
3 Combination
Causes
Drugs
Eyes, Ears
Low O2 States (MI,Stroke,PE)
Infection
Retention (Urine or Feces)
Ictal
Under hydration, Under nutrition
Metabolic
Subdural
Restraints?
• More harm than “protection”
-Neufeld RR, et al. JAGS 1999 -Capezuti E, et al. J Gerontol 1998
-Dunn KS. J Gerontol Nursing 2001 -Powell C, et al. Can Med Ass J 1989
A
G
A
I
N = Number & Type of Drug
I’
V
>4 of any type is a risk factor.
E
F
A
L
L
E
N
Leipzig RM, et al J Am Geriatr Soc 47:40-50, 1999
Type of Drug
Type Pooled odds ratio
(95% Confidence Interval)
Any psychotropic use 1.73 (1.52 – 1.97)
Neuroleptics (outpatient use) 1.66 (1.38 – 2.00)
Sedative/hypnotics 1.54 (1.40 – 1.70)
Any antidepressant 1.66 (1.4 – 1.95)
Benzodiazepines 1.48 (1.23 – 1.77)
Leipzig RM, et al. J Am Geriatr Soc 47:30-39, 1999
Notes: Psychotropic medication data from meta-analysis, 40 studies, none randomized.
-Groups: age 75, fallers 35% = did not affect pooled OR.
-Increased falls in patients on 2 or more psychotropic
-No difference between long and short acting benzodiazepines
Type of Drug
Type Pooled odds ratio (95% Confidence Interval)
Type Ia antiarrhythmics 1.59 (1.02 – 2.48)
Digoxin 1.22 (1.05 – 1.42)
Thiazide diuretic 1.06 (0.97 – 1.16)
Loop diuretic 0.90 (0.73 – 1.12)
B-blockers 0.93 (0.77 – 1.11)
Centrally acting antihypertensives 1.16 (0.87 – 1.55)
ACE inhibitors 1.20 (0.92 – 1.58)
Calcium channel blockers 0.94 (0.77 – 1.14)
Nitrates 1.13 (0.95 – 1.36)
Narcotics 0.97 (0.78 – 1.20)
Leipzig RM, et al J Am Geriatr Soc 47:40-50, 1999
Cardiac and analgesic medication data from meta-analysis, 29 studies, none randomized.
Type of Drug:
Risk for hip fracture
Type Pooled odds ratio
(95% Confidence Interval)
SSRIs 2.4 (2.0 – 2.7)
TCAs (secondary-amine) 2.2 (1.8 – 2.8)
TCAs (tertiary amines) 1.5 (1.3 – 1.7)
Case-control study, n=8239, age >65, admitted to hospital for hip fracture.
Liu B, et al. Use of SSRI’s and TCA’s and risk of hip fractures in elderly people. Lancet
351: 1303-7, 1998
With adjustment for potential confounding effects by concomitant drug use and
comorbidity, adjusted OR for hip fracture.
A
G In addition to Fall as a DELIRIUM
A Equivalent, Dementia is a risk factor
I for falls.
N
I’ = Impaired Cognition
V
E
Tinetti, Tinetti,
F 1986 1988
A n=79 N=272
L
L RR 2.0 2.3
E
N
A
G
A
I
N
I’
V = Vestibular dysfunction
E
Possible age related decline in balance due to
F accumulation of minute calciferous granules
A within the stratoconic membrane
L
L Meds leading to vest. Dysfunction (AGs,
E aspirin, furosemide, alcohol)
N
Tinetti ME, et al. NEJM 1989
A Age-related changes:
G visual acuity
A adaptation to dark
I peripheral vision
N contrast sensitivity
accommodation
I’
V Common disorders:
E = Eyes and Ears Cataracts
Macular Degeneration
F Glaucoma
A
L One of the most common
L reason for hearing deficit in
E NH Cerumen
N
A
G
A
I Calluses
N
Bunions
I’ Poor fitting shoes
V
Thick or long toe nails
E
F = Feet
A
L
L
E
N
A
G
A
I
N
I’
V
E
F
A = Alcohol
L
L
E
N
A One of the strongest RR for falls
G Tinetti, Robbins, Lipschitz, Tinetti,
A 1986 1989 1991 1988
I n=79 n=149 n=126 N=272
N RR 5.4 8.4 4.9 2.4
I’
V
E
F
A
L = Lower extremity weakness
L
E
N
A Lipsitz LA. Syncope in the elderly.
G Ann Intern Med 1983
A (Postprandial hypotension)
I
Tinetti, Lipschitz, Tinetti,
N
1986 1991 1988
n=79 n=126 N=272
I’
V RR 3.4 NS NS
E
F
A
L
L = Low blood pressure (or OH)
E
N
A
G
A
I
N
I’
V
E
F
A
L
L
E = Environment
N
A
G
A
I
N
I’
V
E
F
A
L
L
E
N = Neurological
A
Again
G
Gait & Balance
A
ADL impairment
I Impaired cognition
N Number and Type of Meds
I’ Illness (Acute)
V Vestibular function
E Eyes, Ears
F Feet
A Alcohol
L Lower extremity weakness
Low blood pressure (or OH)
L
Environment
E
Neurological
N
Case Study
An 84-year-old retired high school teacher with a
history of tonic-clonic seizures since age 70 (last
seizure was 4 years ago when she stopped all of
her meds), hypertension, OA (mainly hands,
knees R>L) and insomnia.
Her family is worried because she was admitted
to the hospital after being found down at home
and “they didn’t find anything except a urine
infection.” Since being home (2 weeks) she has
fallen twice. She says, “I just fall.” No LOC, but
admits to “dizziness…yes, well, kind of, but also I
just feel unsteady.”
Case Study
Medications Exam: Frail appearing,
having lost 6 pounds since
• phenytoin
hospitalization
• diltiazem (ht 5’3”, wt 106#);
• furosemide SBP drops 25 mmHg from a
• lorazepam supine to a standing
• amitriptyline position, pulse increases
• Tylenol-PM from 68 to 80. “Puffy”
• famotidine ankles. MMSE is 22/30 (she
• calcium is a college graduate).
• colace
Identifying Risk Factors and
Causes of Falls
• Can we prevent falls?
• Can we prevent fall-related injuries?
Gillespie LD, et al. Interventions for preventing falls in elderly people. The
Cochrane Library 2002;4
AGS, BGS, AAOS Panel on Falls Prevention. J Am Geriatr Soc 49:664-72, 2001
Intervention: MultiD, multifactorial,
health/environmental risk factor
screening/intervention programs
# Trials N Population RR (CI)
4 1,651 Unselected .73
(.63 – .85)
5 1,176 H/o falls or fall .86
risk factor (.76 – .98)
1 439 Residential .60
care facilities (.5 – .73)
Intervention: Muscle strengthening and
balance retraining*
# Trials N Population RR (CI)
3 566 Community .80
(.66 – .98)
*individually prescribed at home by trained professional
Intervention: Tai Chi (15 Weeks)
# Trials N Population RR (CI)
1 200 Community .51
(.36 – .73)
Intervention: Home Hazard assessment
and modification
# Trials N Population RR (CI)
3 374 H/o falls .66
(.54 – .81)
*individually prescribed at home by trained professional
Intervention: Withdrawal of
Psychotropic Medications
# Trials N Population RR (CI)
1 93 Community .34
(.16 – .74)
Interventions
A
Again Target
G
Gait & Balance PT/exercises if eval +
A OT
ADL impairment
I Impaired cognition Dementia w/u
N Number and Type of Meds Stop, furosemide,
lorazepam, amitriptylin,
Tyl-PM, famotidine, phenytoin
I’ Illness (Acute)
Consider acute illness
V Vestibular function (eg delirium)
E Eyes, Ears
F Feet
A Alcohol
L Lower extremity weakness Strengthening ex. If eval +
Low blood pressure (or OH) Stop meds as above
L
Environment Home OT eval
E Neurological
N
Thank you for your attention.
Epilepsy Beginning in the Elderly
Epidemiology and Diagnosis
Mark C. Spitz, MD
Anschutz Center for Advanced Medicine
Denver Veterans Administration Medical Center
Epilepsy Beginning in the Elderly
• Not rare
• Brain tumors are overrated
• Cerebrovascular cause underrated
• Demographics different than younger
people
• Often misdiagnosed
Incidence of Epilepsy
Elderly (>65 years)
• Incidence of Alzheimer's 123/100,000
• Incidence of Epilepsy 134/100,000
Olmsted County Data
Extended Care Facilities
• Important target population
• 6% of patients have epilepsy diagnosis
• Frequent comorbidities
• Multiple medications
Demographics
• Different for younger people with epilepsy
Etiology Of Epilepsy, Age 65 +
Idiopathic 51%
Stroke 38%
Degenerative 12 %
Tumor 5%
Trauma 2 %
Infection 2%
Hauser et. al.
Stroke As A Cause Of Epilepsy
• Annual Incidence of Stroke
(Williams, 2001)
• 750,000 in U.S. (1996)
• Seizures after Stroke Cooperative Study
(Bladin, 2000)
• Prospective, 9-month follow-up, n=2021
• Seizures in 8.9%
• 2.3% recurrent seizures
Seizures in Alzheimers
• Autopsy verified, n=81
• 10% had seizures
Hauser, 1986
Epilepsy in the Elderly:
Seizure Type
• Complex Partial 38%
• Generalized Tonic-Clonic 27%
• Simple Partial 14%
• Mixed 20%
VA Co-op 2003
n=593
Epilepsy in the Elderly:
Concurrent diseases
• Hypertension 64%
• Stroke 53%
• Cardiac Disease 49%
• Diabetes 27%
• History of Cancer 22%
VA Co-op 2003
n=593
Epilepsy in the Elderly:
Imaging
• Normal 18%
• CVA 44%
• Small vessel disease 40%
• Diffuse atrophy 35%
• Encephalomalacia 9%
VA Co-op 2003
n=593
Epilepsy in the Elderly:
EEG
• Normal 31%
• Epileptiform 39%
• Focal Slow 40%
• Generalized Slow 16%
VA Co-op 2003
n=593
Epilepsy in the Elderly
• Epilepsy in the elderly is often
misdiagnosed
Delay In Diagnosis
VA Co-op Subset
(n=167), 2003
• 9 months to seek medical attention
• 1.7 years to correct diagnosis
• GTC: immediate diagnosis in 67%
• Less dramatic seizures often ignored
• Concomitant cardiac or cerebrovascular
disease caused delays in diagnosis
Spitz, et al
Diagnosis of Epilepsy:
Elderly Compared to Younger People
• Higher percentage of partial seizures
• More extra-temporal onset complex partial
seizures (missing classic auras)
• More prominent post-ictal symptoms
• Weaker historians
• EEG less helpful
• More concomitant illnesses
Ocham’s Razor
• Explain all of the patient’s complaints by a
single diagnosis
Some Diagnostic Dilemmas
• GTC vs. syncope
• Complex partial seizure vs. TIA
• Transient Global Amnesia
GTC Compared to Syncope
GTC Syncope
•History of Cardiac Disease Common Common
•Positional Variable Orthostatic
•Warning Variable Pre-syncope
•Tongue biting Common Unlikely
•Complexion Normal Pale
•After Event Confused, sleepy Alert
•Movements Tonic-clonic Loss of tone,
brief clonic
movements
•Duration 1-2 minutes seconds to
then post-ictal minutes
•Incontinence varies varies
Complex Partial Seizures Compared to
TIA
CPS TIA
•Hx of CV Disease Common Common
•Anatomic distribution Not Vascular Vascular
•Confusion,
unresponsiveness Present Absent
(may be aphasic)
•Frequency Can be frequent Rarely frequent
•Amnesia Common Absent
•“Aura” Common Absent
•Automatisms Common Absent
Transient Global Amnesia
• Etiology is controversial
• Ischemic
• Venous Stasis
• Migrainous
• Transient epileptic amnesia
• Multiple etiologies are likely
• Epileptic cause is underdiagosed
Transient Epileptic Amnesia
• Classic literature considers it an
uncommon subset of Transient Global
Amnesia (5-10%)
• Features
• Recurrent Spells
• EEG
• Additional presence of obvious seizure
• Responsive to AED
Transient Global Amnesia
• Are many of these cases a one-time
expression of transient epileptic amnesia?
TGA Diagnostic Criteria
Proposed by Caplan, Hodges, and Warlow
• An attack must be witnessed by an observer who can
provide additional information
• Anterograde amnesia must be present
• No clouding of consciousness or loss of personal identity
• Cognitive impairment is limited to amnesia, no apraxia,
or aphasia
• No recent history of head trauma, no history of seizures
in the preceding 2 years
• There are no focal neurologic signs, and no epileptic
features
Transient Global Amnesia
• Annual incidence of 3.4 to 5.2 per 100,000
each year, 23.5 per 100,000 > 50 years
old
• Middle-aged or elderly, but otherwise
healthy
• Recurrent attacks 2 weeks - 1 year - 2 years 11 19%
Table 3: Infarct Types on CT in 38 Patients
With Epileptic Seizures After Symptomatic
Supratentorial Brain Infarction
Infarct Type Number of
Patients (%)
Cortical infarct(s) only* 28 (73.7)
Lacunar infarcts(s) only† 6 (15.8)
Cortical and lacunar infarct 2 (5.3)
Cortical and striatocapsular infarct 1 (2.6)
Cortical and watershed infarct 1 (2.6)
* Six had two infarcts
† Three had two infarcts, one had seven infarcts
Consequences of Brain Injury in the
Elderly
• Head injury and stroke
• Behavioral and cognitive consequences
• Epilepsy predisposes to further injury
Epilepsy Treatment in the Elderly
• Monotherapy not possible for 90%+ of patients.
• Typical nursing home patient is on 6-8 medications.
• Choose AEDs with minimal interactions
• e.g. levetiracetam and gabapentin
• Titrate slowly
• Avoid older AEDs with strong induction effects
(phenytoin, phenobarbital, and carbamazepine)
• Avoid newer AEDs with established adverse
cognitive effects (topiramate and zonisamide)
Topiramate and Zonisamide
• 94% of patients experienced cognitive
viscosity with either drug as an adjunctive
agent*
• 63% of the patients were unaware of the
effect*
Lee S, Sziklas V, Andermann, et al. The effects of adjunctive topiramate on cognitive function in patients with epilepsy. Epilepsia,
Vol 44, No 3, 2003: 339-347.
Older AEDs and the Elderly
• Inducing drugs: phenytoin, carbamazepine and
phenobarbital – result in consequences
• Behavioral
• Cognitive
• Valproate - weight gain, risk of encephalopathy. Can
be used, but carefully.
• Phenobarbitol can have significant cognitive
slowing, depression, or other behavioral
consequences
Epilepsy in the Elderly:
Treatment Strategies for
Seizures in the Elderly
A. James Rowan, MD
Professor, Department of Neurology
Mount Sinai School of Medicine
and Bronx VA Medical Center
New York, NY
VA Cooperative Studies Program (VA CSP #428)
Study Co-chairs: R. Eugene Ramsay, MD and A. James Rowan, MD
Treatment of Seizures in the Elderly
Objective:
To determine whether one or both of the
new AEDs (gabapentin and lamotrigine)
have significantly fewer side effects, while
providing equal or possibly better seizure
control, than the current worldwide choice
(carbamazepine) for treatment of seizures in
the elderly.
Admission Criteria
• Inclusion
• Age 60+ yrs (initially 65+ yrs)
• One or more seizures
• None or inadequate AED therapy
• Exclusion
• Allergic to one of the study AEDs
• Severe medical disorder (expected to survive less
than 12 mo)
• Progressive disorder that could affect the
outcome of the study
Target Doses
Carbamazepine (600 mg)
1+ seizure Gabapentin (1500 mg)
Lamotrigine (150 mg)
2-6 wks 1-2 year followup
Study Protocol
• Double-blind, double-dummy (RER and AJR)
• Medication
• Alpha: gabapentin or carbamazepine vs placebo
• Beta: lamotrigine vs placebo
• All patients receive treatment at onset of study
• Target pill count
• Alpha: either 3 or 5
• Beta: 6
• Patients titrated to target dose or maximal
tolerated dose
• Dose lowered if side effect encountered
• Dose increased if patient experienced seizure(s)
Patient Demographics
Screened 1358
Enrolled 593
Age, mean yrs 72.75
Range 59–93
Male/female 570/23
Race
White 418 (70.6%)
Black 143 (24.1%)
Hispanic 30 (5.1%)
American Indian 14 (2.4%)
Dosing Schedule
Number of capsules/tablets
7
6
LTG
5
GBP
4
CBZ
3
2
1
0
1 8 15 22 29 36
Days
Actual vs Target Dose
CBZ GBP LTG
Target dose 600 1500 150
Mean dose
achieved
3 mo 586 1428 145
12 mo 582 1614 152
Outcome Variables
• Primary
• Retention (tolerable side effects and no seizures)
• Seizure-free rate
• Secondary
• Time to nth seizure (1, 2, 5, and 10)
• Toxicity – systemic and neurotoxicity scores
• Cognitive function
• Mood
• Quality of life
Time to Early Termination
Time to Early Termination (cont’d)
1
LTG target dose
0.9
Patient survival
0.8
GBP target dose
0.7 Carbamazepine
CBZ target dose
Gabapentin
Lamotrigine
0.6
0 1 2 3 4 5 6 7 8
Weeks
Epilepsy in the Elderly
Outcome at 12 Months (Retention)
Carbamazepine Gabapentin Lamotrigine
12-Mo eligible 197 193 197
12-Month Retention
Completers 72 36.6 % 95 49.2 % 114 57.9 %
Early terminators 125 63.5 % 97 50.3 % 83 42.1 %
p-Values
Overall 0.00011 vs CBZ 0.01063
vs LTG 0.10443
vs CBZ 0.00003
Time to First Complex Partial Seizure
Percent Seizure-Free
3 mo 6 mo 12 mo
253 194 145
ALL
(62.9%) (58.7%) (52.7%)
Ignore sz
301 226 168
before 4
(74.9%) (67.9%) (61.1%)
wks
Ignore sz
322 235 174
before 6
(80.1%) (70.6%) (63.3%)
wks
VA CSP #428
Life Table Analysis
Time-to-First Seizure
Seizure type CBZ GBP LTG
Simple partial 82.7 % 79.2 % 73.1 %
Complex
78.1 % 62.9 % 67.1 %
partial
Generalized
88.1 % 82.2 % 85.9 %
TC
All seizures 59.4 % 41.2 % 46.4 %
p-values = 0.12 all; 0.054 CBZ/GBP; 0.08 CBZ/LTG; 0.78 GBP/LTG
Seizure-Free at 12 Months
Patients Completing 12 Months
Carbamazepine Gabapentin Lamotrigine
Total 70 94 111
Seizure-Free at 12 Mo (12 Mo Completers)
With seizure 25 35.7 % 50 53.2 % 55 49.6 %
Seizure-free 45 64.3 % 44 46.8 % 56 51.4 %
P-Value vs GBP 0.028
vs LTG 0.091
vs 0.674
LTG
Primary Reasons for Termination
n = 361
Adverse reaction to study drug 110 (30.5%)
Voluntary withdrawal 82 (22.7%)
Deceased 35 (9.7%)
Lost to follow-up 26 (7.2%)
Uncontrolled seizures 25 (6.9%)
Poor compliance 23 (6.4%)
Unable to continue medication 22 (6.1%)
Other 38 (10.5%)
Primary Reason for Termination
Carbamazepine Gabapentin Lamotrigine
(n = 198) (n = 195) (n = 200)
Uncontrolled 3 1.52 % 7 3.6 % 7 3.5 %
Side effect 54* 27.3 % 34 17.4 % 20 10.0 %
Noncompliant 7 3.54 % 4 2.1 % 7 3.5 %
Voluntary
12 14.1 % 22 11.3 % 24 12.0 %
w/drawal
Lost to F/U 4 2.0 % 5 2.6 % 6 3.0 %
Death 15 7.6 % 15 7.7 % 9 4.5 %
Other 17 8.6 % 16 8.2 % 14 7.0 %
Total 124* 62.6 % 96 49.3 % 84 42.0 %
* P 4 lb 88 51.5 % 120 67.8 % 87 47.5 %
> 18 lb 5 2.92 % 19 10.7 % 7 3.83 %
Weight loss
> 4 lb 44 25.7 % 37 20.9 % 66 36.1 %
> 18 lb 2 1.17 % 5 2.82 % 7 3.83 %
Causes of Death
Etiology Carbamazepine Gabapentin Lamotrigine
Cardiac 4 3 6
Unknown 3 3 3
Cancer 1 2
Pulmonary 2 2
Sepsis 4
Hepatic failure 1
Internal bleeding 1
Multiple system
1
failure
Stroke,
1
hemorrhagic
“Natural causes” 1
Head injury 1
Total 15 15 9
Effective AED Concentrations
Decrease with Age
Mean Plasma Concentration at Study
Termination
Age (yrs) CBZ (mg/L) VPA (mg/L)
<40 7.8 43.7
40–64 5.7 43.7
65 3.7 31.0
Ramsay 1994. (VA Cooperative Studies #118 and #264.)
Mean AED Plasma Levels
VA Co-op Study #428
Conclusions
• Retention in the study was significantly better for
gabapentin and lamotrigine than for carbamazepine
• Carbamazepine caused significantly more side effects
than lamotrigine or gabapentin, resulting in earlier
termination
• Optimal dose and/or serum levels of AEDs may be lower
in the elderly
• Lamotrigine and gabapentin should be considered as
possible first-line therapy for new onset-seizures in the
elderly
Questions &
Answers
American Epilepsy Society