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Epilepsy & Behavior 5 (2004) 894–902

Effects of oxcarbazepine and phenytoin on the EEG and cognitionin healthy volunteers

M.C. Salinsky*, D.C. Spencer, B.S. Oken, D. Storzbach

Department of Neurology, Oregon Health and Science University, Portland, OR 97201, USA

Received 8 June 2004; revised 14 July 2004; accepted 19 July 2004

Available online 15 September 2004

Abstract

We studied the EEG and cognitive effects of oxcarbazepine (OXC) and phenytoin (PHT) using a double-blind, randomized, par-

allel-group design. Thirty-two healthy volunteers received a maximum of 1200 mg of OXC or 360 mg of PHT. EEG and cognitive

testing were performed at baseline and after 12 weeks of treatment. For each subject and measure, test–retest Z scores were calcu-

lated from regression equations derived from 73 healthy controls. Twenty-six subjects completed the study. Both the OXC and PHT

groups had significant slowing of the EEG peak frequency and increased relative theta and delta power. Differences between AEDs

(antiepileptic drugs) were not significant. Significant cognitive effects were seen on 5 of 20 measures, primarily measures of motor

speed and reaction time. Again, there were no significant differences between AEDs. The only significant difference between AEDs

was for the POMS–Vigor scale, favoring OXC. The small sample size may have contributed to the lack of significant differences

between AEDs.

� 2004 Elsevier Inc. All rights reserved.

Keywords: Oxcarbazepine; Phenytoin; Cognition; EEG; Neurotoxicity

1. Introduction

Antiepileptic drugs (AEDs) are used in the treatment

of nearly all persons with epilepsy and are also com-

monly prescribed for other neurological and psychiatric

disorders. The selection of an AED is based on a bal-

ance of expected efficacy and tolerability. Comparisonstudies have shown relatively small differences in efficacy

among several of the AEDs used to treat partial seizures

[1–7]. Tolerability, rather than efficacy, has been the ma-

jor factor in determining which AEDs have the highest

retention rates during initial therapy. Neurotoxic side ef-

fects of AEDs are the most common and are a major

component of overall tolerability. Subjective neurotox-

icity is highly correlated with overall quality of life [8].

1525-5050/$ - see front matter � 2004 Elsevier Inc. All rights reserved.

doi:10.1016/j.yebeh.2004.07.011

* Corresponding author. Fax: +1 503 494 6658.

E-mail address: Salinsky@ohsu.edu (M.C. Salinsky).

Comparative studies of AED neurotoxicity are therefore

of clinical relevance.

Controlled studies have demonstrated that AEDs can

have measurable effects on standardized cognitive and

mood measures and on subjective measures of neurotox-

icity [9–14]. In general, the effects on objective cognitive

measures have been mild, whereas subjective complaintshave been of greater magnitude. The sensitivity of stan-

dardized cognitive test measures to detect AED cogni-

tive effects has been questioned [15,16]. We have

suggested that changes in EEG background rhythms

add additional information regarding the CNS impact

of AED therapy. In prior studies, treatment with several

of the older AEDs resulted in substantial slowing of

EEG background rhythms, and this slowing correlatedwith changes in cognitive test measures and subjective

complaints [14,17]. There are limited data on the effects

of newer AEDs on the EEG background and on cogni-

tive tests.

M.C. Salinsky et al. / Epilepsy & Behavior 5 (2004) 894–902 895

Oxcarbazepine (OXC) is a novel AED that is chemi-

cally related to carbamazepine and is approved for ini-

tial or add-on treatment of partial seizures in adults

and children. Studies have suggested that oxcarbazepine

is at least as effective as carbamazepine and that it may

be better tolerated [4,18,19]. It also has significant phar-macological advantages over carbamazepine [20]. Phe-

nytoin (PHT) remains the most commonly prescribed

AED for the treatment of partial seizures in the United

States. A comparison of the neurotoxic effects of these

two AEDs is therefore of clinical relevance. We studied

the effects of oxcarbazepine and phenytoin on psycho-

metric measures, alertness, and EEG background mea-

sures in healthy volunteers treated at therapeutic dosesfor 12 weeks.

Fig. 1. Study design.

2. Methods

2.1. Subjects

Thirty-two healthy volunteers were studied. To be eli-gible subjects had to be between the ages of 18 and 55, in

good health, and not using any centrally acting medica-

tions. Candidates were screened with a health question-

naire and interview. Exclusion criteria included (1)

history of present or past neurologic or major psychiat-

ric disorder(s) (minor disorders such as nonmigraine

headache were allowed); (2) history of alcohol or drug

abuse (within the past 10 years); (3) chronic medical ill-ness; (4) ongoing use of any medications (except minor

analgesics); (5) head injury with loss of consciousness

of greater than 10 min; (6) skull defect; (7) previous neu-

ropsychological testing involving any of the study tests;

(8) previous exposure to any marketed or research anti-

epileptic drug; (9) abnormality on baseline CBC or ser-

um chemistry panel; (10) positive baseline urine drug

screen; (11) total body mass index >31.25 (age <35) or33.75 (age P35); (12) estimated IQ <80. Subjects had

not used any centrally acting medications for a mini-

mum of 30 days prior to entry and were not allowed

to use any such medications during the study. Nonsedat-

ing minor analgesics were allowed on a PRN basis,

including medications such as aspirin, ibuprofen, na-

proxen, and acetaminophen. A urine drug screen was

performed at study entry and repeated at the end ofthe study to assure compliance.

Candidate subjects were also prescreened with a brief

EEG (posterior leads only). Subjects in whom a count-

able posterior (alpha) rhythm could not be recorded

were excluded (15% of candidates).

The control group (Nco) consisted of 73 healthy sub-

jects, ages 18–57 (median 35), who otherwise met inclu-

sion/exclusion criteria as above. These subjects werecollected separately and did not receive a treatment or

a placebo. All subjects were paid for their participation.

All subjects reviewed and signed an informed consent

consistent with the policies of the institutional review

board of the Oregon Health and Science University.

2.2. Study design

The study design is diagrammed in Fig. 1. This was a

12-week, longitudinal, parallel group, double-blinded

trial of oxcarbazepine vs phenytoin in healthy volun-

teers. Subjects underwent neuropsychological testing,

EEG recording for quantitative analysis, and the Awake

Maintenance Task (AMT) prior to initiating AED ther-

apy (baseline) and again 12 weeks after the initiation of

therapy (retest), at least 4 weeks after achieving plateaudosing. The subjects, principal investigator, examining

physician, EEG personnel, and psychometrist were

blind to treatment assignment. Subjects were random-

ized in blocks of four using a computer-generated ran-

domization code prepared by the project statistician.

A flexible dosing protocol was used. Each AED was

titrated in a series of five steps (10-day intervals) over

a period of 8 weeks, followed by 4 weeks of plateau dos-ing. The maximum allowable dose of PHT was 360 mg/

day, and the maximum allowable dose of OXC was

1200 mg/day. These doses were chosen as average daily

dosing for adult monotherapy. The initial dose of

PHT was 100 mg/day. PHT was increased by 100 mg/

day for the next two steps and by 30 mg/day for the final

two steps. The initial dose of OXC was 300 mg/day.

OXC was increased by 300 mg/day for steps two andthree and by 150 mg/day for the final two steps. Subjects

were seen for outpatient visits every 2 weeks. At these

visits a blinded examining physician decided whether

to advance the dose by one step, hold the dose constant,

or reduce the dose by one step. The decision was based

on a discussion with the subject and a neurological

examination. The examiner was instructed to manage

the subjects much as a patient with some residual seizureactivity, increasing the dose as tolerated, but not to the

point of clinical toxicity. Between-visit dose adjustments

were also allowed. CBC, serum chemistry, and AED lev-

els were checked monthly. PHT and OXC were admin-

istered as identically appearing capsules, packaged in

896 M.C. Salinsky et al. / Epilepsy & Behavior 5 (2004) 894–902

visit- and dose-specific blistercards. Dilantin Kapseals

were used as the PHT formulation, and Trileptal as

the OXC formulation.

2.3. Research measures

2.3.1. Cognitive/mood measures

All tests were conducted in a temperature-controlled,

sound-insulated room. The test battery was always

administered in the morning and the 12-week retest bat-

tery was always started within 1 h of the time of day of

the baseline battery. Caffeine and food intake were re-

corded at the baseline testing and duplicated for the

12-week repeat testing. Sleep history was taken. Subjectswere only tested if they had received a normal night�ssleep (±20%) based on a 1-week history. Retest was only

performed if baseline sleep was duplicated. Cognitive

tests were administered in a set order. A single psychom-

etrist administered all tests.

The test battery included:

Finger Tapping: From the Halstead–Reitan test bat-

tery [21].Digit Symbol: From the WAIS-R [22].

Stroop Color–Word Test: This version of the test

used a single-color plate with four words (orange, red,

blue, green) printed in incongruous colors. The subject

first read the words, ignoring the color of print, and then

the color of print, ignoring the words [23].

Selective Reminding Test: A verbal memory test.

Measures include consistent long-term retrieval(CLTR), total long-term storage (TLTS), total recall

(TREC), and 30-min delayed recall. A six-trial version

was used [12,24,25].

Story Recall: This version (MCG paragraphs) tested

immediate and delayed recall of details from a brief

story read to the subject by the examiner [11,12].

Digit Cancellation: This 4-min version required the

subject to cancel as many of two single-digit targets aspossible from a full-page list of random single digits.

The number of correct items was scored [26].

Visual Reaction Time: A computer-based measure

including tests of simple reaction time (RT), choice

RT, complex RT (specific sequence of targets), and

word RT (animal names). This was taken from the Cal-

ifornia Computerized Assessment Package [27].

Auditory Reaction Time: Obtained during the EEGacquisition (described below).

Name Learning Task: Subjects are shown 12 black

and white slides of faces and are asked to memorize

the associated first names. A recall trial with random or-

der of presentation follows. Three learning and three re-

call trials are given. Latency to correct response and

total number of correct responses are recorded [28].

Profile ofMood States (POMS): A validated symptomchecklist yielding six scale scores (vigor, fatigue, tension,

depression, anger, confusion/bewilderment) [29].

Portland Neurotoxicity Scale (PNS): A validated, pa-

tient-based, subjective rating of common neurotoxicity

symptoms. Fifteen items were endorsed on a scale of

1–9. Two subscales were calculated: one for cognitive

toxicity and one for somatomotor toxicity. The form

was labeled ‘‘Epilepsy Patient Questionnaire’’ in orderto not prejudice the reporting [14,17].

For Selective Reminding, Digit Cancellation, Name

Learning, and Story Recall, alternate forms were used

in a fixed order.

2.3.2. EEG measures

Methods for EEG testing and quantification have

been presented elsewhere [14,17]. Gold electrodes wereplaced at F3, F4, F7, F8, T3, T4, T5, T6, C3, C4, Cz,

P3, P4, O1, and O2 of the international 10–20 system.

Four additional electrodes monitored eye movements.

The reference electrode was passively linked ears, loaded

through 12-kX resistors (to minimize small impedance

inequalities). A Grass Instruments Model 8 EEG was

used for amplification and printout. Band pass was

0.3–70 Hz (6 dB/octave). Amplified signals were low-pass filtered (45 Hz Butterworth filter; 24 dB/octave),

digitized at 205 samples/channel/s on a 12-bit A to D

converter, and written to disk. Gains (all channel) were

adjusted for each subject to optimize the range of the

analog-to-digital converter. The system was calibrated

prior to each recording session, using a 50-lV, 10 Hz

sine wave.

2.3.2.1. EEG task. Subjects were seated in a quiet, dimly

lit room. All equipment was housed in a separate studio.

During EEG recording subjects performed a dual-choice

auditory reaction-time task. Tones of 70 dBa (SPL), of

250 ms, and of either 375 or 500 Hz were presented in

random order via loudspeaker, against a 40-dB white

noise background. Interstimulus intervals averaged

10 s (5–15 s). Subjects were instructed to respond bypressing the appropriate soft-contact switch on the left

or right arm of the chair. Speed and accuracy were

emphasized during 5 min of prerecording training.

After instruction and training, a 12-min structured

EEG recording was obtained. The first 6 min consisted

of 40-s periods of eyes-closed RT testing followed by a

20-s eyes-open rest. During the rest subjects were given

scripted alerting instructions. The cycle was then re-peated for a total of 6 min. After the initial 6 min the

tones were stopped and subjects were asked to sit quietly

with eyes closed for an additional 6 min while remaining

fully awake (AMT) [30]. No interactions were allowed

during the AMT.

2.3.2.2. Processing/analysis. Twenty-four 2.5-s epochs of

relatively artifact-free EEG were selected from the eyes-closed EEG (initial 6 min) using a structured editing

protocol [31]. The editor was blind to subject and order.

M.C. Salinsky et al. / Epilepsy & Behavior 5 (2004) 894–902 897

Selected epochs (512 points) were passed through a 10%

cosine window, zero padded to 2048 points, and ana-

lyzed using the fast Fourier transform. The frequency

resolution was 0.1 Hz. Four target ‘‘features’’ were cal-

culated [14,17,32]. These included (a) ‘‘peak frequency’’

(based on power) within the 7–14-Hz frequency band;(b) ‘‘median frequency’’ (based on power) within the

1.6–29.2-Hz frequency band; (c) relative power within

the delta frequency band [(power at 1.6–3.9 Hz/power

at 1.6–29.2 Hz) · 100]; and (d) relative power within

the theta frequency band [(power at 4.0–7.9 Hz/power

at 1.6–29.2 Hz) ·100]. Results were averaged across all

24 epochs. Analysis was limited to the O1 and O2 elec-

trodes (averaged) to minimize the number of variables.The AMT was analyzed for the total number of

drowsy 10-s epochs (total drowsiness) [30]. Each 10-s

page of EEG was assigned a ‘‘state,’’ either awake,

drowsy [fragmentation and/or slowing of the alpha

rhythm (>1 Hz), alpha anteriorization, slow rolling eye

movements, increased theta], or sleep (vertex sharp

waves, sleep spindles, and K-complexes) [33]. Drowsy

and sleep epochs were combined for this analysis.

2.4. Statistical analysis

The 73 healthy control subjects completed a neuro-

psychological test battery identical to the one used in

this study, including retest after an interval of 12 weeks.

The test–retest results for each cognitive/mood measure

were subjected to linear regression analysis using thescore at baseline testing (T1) as the primary regressor,

with age and education as additional regressors when

significant. Details for this procedure are presented else-

where [34].

For each cognitive and mood measure, the research

subject�s score was compared to the regression distribu-

tion obtained from the healthy controls. Subject scores

were transformed to standard Z scores [number of stan-dard deviations from the mean expected score at T2 (ret-

est), based on performance at T1 and the individual

confidence interval, derived from the control regression

analysis]. These Z scores provided a common metric for

the comparison of different tests. The regression-based

scoring approach helps to correct for practice effects

and regression to the mean effects in test–retest data

[34–36].To reduce statistical problems associated with the use

of multiple tests, we chose specific cognitive/mood mea-

sures for analysis (pre hoc). These were designated as

‘‘target’’ test measures and were selected based on re-

sults from our previous studies [14,17]. Other tests were

analyzed for supportive data. Primary measures for this

study included Digit Symbol, Stroop–Interference Trial,

Selective Reminding-CLTR, Visual Reaction Time–Words, Story Recall–Delayed, and the Wonderlic Per-

sonnel Test. Primary subjective measures included

POMS–Fatigue, POMS–Confusion, PNS–Cognitive

Scale, and PNS–Somatomotor Scale.

The primary outcome measure was a comparison of

the test–retest Z scores from the PHT and OXC groups

using the Wilcoxon rank-sum test. Secondary analyses

included a comparison of test–retest Z scores from theOXC and PHT groups (together and separately) vs the

Nco group. The significance level was set at P 6 0.05.

The quantitative EEG measures were evaluated in the

same manner as the cognitive tests. Test–retest regres-

sions were calculated from Nco subjects. Test–retest Z

scores were then calculated for each experimental sub-

ject. Wilcoxon tests were used to compare the test–retest

Z scores of OXC and PHT subjects and each AEDgroup to the Nco subjects. The effects of OXC and

PHT on the AMT were analyzed using Wilcoxon tests

comparing the two AED groups and each AED group

vs controls.

2.4.1. Definition of an evaluable subject

Evaluable subjects (pre hoc criteria) included all

those completing a minimum of 11 weeks on AED withat least 4 weeks at a stable dose prior to retest and a

PHT serum level P6 lg/ml or an OXC [monohydroxy

derivative (MHD)] serum level P5 lg/ml at the time

of final testing. The serum-level criterion was used to re-

duce the chance of negative results due to the inclusion

of subjects who were markedly subtherapeutic (due to

noncompliance or underdosing of the AED).

3. Results

Twenty-nine of 32 subjects completed the protocol.

Three subjects discontinued prior to completion (2

OXC, 1 PHT), one due to nausea thought possibly to

be related to the study medication, another due to a

back injury that led to use of chronic narcotics for paincontrol, and the third due to noncompliance. One addi-

tional subject (PHT) was disqualified at completion due

to a positive drug screen (marijuana). Two other sub-

jects (PHT) failed to achieve the minimum AED serum

level for inclusion. Therefore, the final group for analy-

sis consisted of 14 OXC subjects (median age, 26 years)

and 12 PHT subjects (median age, 26.5 years). There

were no significant differences in age, years of education,or male/female ratio between the OXC, PHT, and Nco

groups. There was no evidence of neurotoxicity on phys-

ical examination for any subject, and no significant lab-

oratory abnormalities were encountered on CBC or

serum chemistry. Twelve of the 14 OXC patients toler-

ated the maximum allowable dose (1200 mg/day). All

PHT subjects tolerated the maximum allowable dose

(360 mg/day). The mean OXC (MHD) serum level atthe time of completion was 19.9 lg/ml (range 11.5–

30.5), and the mean PHT level was 11.6 lg/ml (range

Table

1

Baselineandretest

values

fortheEEG

measures

Nco

OXC

PHT

Statisticaltests(P)

Base

Retest

Base

Retest

Base

Retest

OXC

vsPHT

OXC

vsNco

PHTvsNco

Peakfrequency

(Hz)

10.14(0.63)

10.12(0.66)

10.34(0.65)

9.67(0.96)

10.07(0.44)

9.78(0.50)

NS

<0.001

<0.001

Medianfrequency

(Hz)

10.04(0.60)

9.99(0.62)

10.18(0.55)

9.43(1.00)

10.00(0.44)

9.48(0.97)

NS

<0.001

<0.001

Relativethetapower

(%)

9.27(5.60)

9.32(5.28)

9.13(3.34)

15.64(7.44)

8.49(4.55)

10.47(5.11)

NS

<0.001

<0.001

Relativedelta

power

(%)

8.40(4.34)

7.90(3.88)

13.34(6.37)

20.82(6.37)

9.44(6.81)

11.23(9.11)

NS

<0.001

<0.01

AwakeMaintenance

Task

(s)*

0(36.9)

0(65.2)

15(95.0)

70(125)

0(94.3)

75(116)

NS

<0.05

<0.05

Note.Allvalues

are

mean(SD)except*,themedian(SD).Statisticaltestsare

Wilcoxonrank-sum

testsontest–retest

Zscores.EEG

measuresare

foraveraged

occipitalelectrodes.Nco,healthy

controls;OXC,oxcarbazepinesubjects;PHT,phenytoin

subjects.

898 M.C. Salinsky et al. / Epilepsy & Behavior 5 (2004) 894–902

of 6.4–27.5). Five PHT subjects had a serum level of less

than 10 lg/ml.

3.1. EEG test results (EEG, AMT)

The EEG analysis is based on 23 subjects (12 OXC,11 PHT). Three subjects (2 OXC, 1 PHT) were excluded

due to insufficient relatively artifact-free EEG for analy-

sis. Our results are summarized in Table 1. The peak fre-

quency of the posterior rhythm was essentially

unchanged (baseline to 12-week retest) in the Nco

group. However, there was a decrease in peak frequency

for subjects receiving either OXC or PHT (Fig. 2). A

comparison of test–retest Z scores for this measure inthe OXC or PHT groups vs the Nco group was highly

significant (P < 0.001; Wilcoxon tests). However, there

was no significant difference between the OXC and

PHT groups. Results for the other EEG measures were

similar. There was a significant decrease in median fre-

quency and an increase in the percentage of theta and

delta activity with use of either OXC or PHT compared

to controls (Table 1). All test–retest comparisons be-tween the PHT and OXC groups were not significant

(NS).

The effects on EEG peak frequency were also signifi-

cant for individual subjects. In Fig. 3 the test–retest re-

sults for the OXC and PHT subjects are overlaid on

the regression line and the 95% confidence interval

(CI) for individuals obtained from the Nco subjects.

Twelve of the 23 OXC and PHT subjects fell outsideof the 95% CI for individual test–retest change. The pro-

portion of OXC and PHT subjects falling outside of the

95% CI was similar (Fisher�s exact test, NS).

The AMT results are also shown in Table 1. Both

OXC and PHT led to an increase in objectively mea-

sured drowsiness, which was statistically significant

compared to Nco subjects. The OXC and PHT groups

did not differ one from another.

3.2. Cognitive test results

Table 2 provides the results of Wilcoxon tests com-

paring the test–retest Z scores for the OXC, PHT, and

Nco groups. Two of the six target cognitive measures

and five of 20 cognitive measures overall (Finger Tap-

ping; Selective Reminding–CLTR; Visual RT–Words,Visual RT–Extended, Auditory RT) evidenced signifi-

cant test–retest change in subjects receiving AEDs (com-

bined OXC and PHT groups) compared to controls.

These differences always indicated poorer performance

at retest in the AED group. However, the test–retest Z

scores for the OXC and PHT groups were not signifi-

cantly different for any measure. In contrast to the

EEG results, few individuals fell outside of the 95% CIfor any of the cognitive tests (maximum of three subjects

on any test; Visual RT–Words). For both the OXC and

Fig. 3. Individual subject test–retest values for the EEG peak

frequency measure. The center (bold) and parallel lines are the

regression line and 95% confidence interval (for individuals) from

control subjects tested at baseline (x axis) and again after 12 weeks (y

axis). Superimposed are the test–retest values for the oxcarbazepine

and phenytoin subjects. Solid stars, oxcarbazepine; open stars,

phenytoin.

Fig. 2. Median values for the EEG measure ‘‘peak frequency of the

posterior rhythm’’ at the baseline evaluation and 12 weeks later

(retest). Nco, healthy controls; PHT, phenytoin subjects; OXC,

oxcarbazepine subjects. ***P < 0.001 (for the comparison of test–

retest Z scores for each AED group vs controls).

M.C. Salinsky et al. / Epilepsy & Behavior 5 (2004) 894–902 899

PHT groups, all tests averaged less than �1 SD of test–

retest change. Baseline and retest values for each of the

cognitive and subjective measures are provided in the

Supplementary Table in the online publication of thisarticle.

Significant test–retest changes on subjective mood

measures were more common in subjects taking PHT.

Four POMS scales (Depression, Vigor, Fatigue, Confu-

sion) and the POMS total score were negatively affected

in the PHT group, whereas only Confusion was signifi-

cantly affected in the OXC group. Test–retest Z score

differences between PHT and OXC were statistically

significant only for POMS–Vigor (favoring OXC). A

similar pattern was seen on the PNS. The magnitude

of test–retest changes seen on the subjective measures

was generally larger than that of the objective measures,averaging more than �1 SD for the POMS–Vigor

(PHT), –Fatigue (PHT), and –Confusion (OXC) scales

and for all PNS scales (both AEDs).

4. Discussion

The principal findings of this study are that (1) bothPHT and OXC produce significant changes in quantita-

tive measures derived from the posterior EEG back-

ground. These changes occur at doses commonly used

in clinical practice and with serum levels in or near the

usual therapeutic range. The EEG effects (slowing of

the dominant frequency, increase in relative theta and

delta power) varied between subjects. However, more

than 50% of individual subjects fell outside of the 95%CI for no-drug individual test–retest change. There were

no substantive differences between PHT and OXC on

these EEG measures. (2) Cognitive effects of these AEDs

(using standard psychometric measures) are relatively

mild. Significant AED effects were demonstrated for

two of the six primary cognitive test measures. Measures

sensitive to motor speed were particularly affected.

These effects averaged less than �0.5 SD and never ex-ceeded an average of �1 SD for test–retest change. In

contrast to EEG measures, cognitive tests were relatively

insensitive to individual change, and few individuals fell

outside the 95% CI for test–retest change in an individ-

ual. There were no significant differences between PHT

and OXC on these tests. (3) Subjective measures

(POMS, PNS) showed considerably larger AED effects

than did the objective psychometric measures. Mediantest–retest changes greater than �1 SD were common.

For most mood measures, and for the total score on

the PNS, subjects receiving PHT registered greater com-

plaints than subjects receiving OXC. However, this

reached statistical significance only for the POMS–Vigor

scale.

The effects of PHT and OXC on quantitative EEG

background measures are consistent with observationswe have previously made in epileptic patients treated

for 12–16 weeks with conventional AEDs and in healthy

subjects treated for 12 weeks with either gabapentin or

carbamazepine [14,17]. In both cases the EEG effects

were seen without signs of clinical toxicity on neurolog-

ical examination, as was the case in the present study.

Also in both studies, subjective complaints were more

pronounced than were objective findings on psychomet-ric tests, again as in the present study. The EEG back-

ground is known to be sensitive to the metabolic

Table 2

Wilcoxon test results for comparisons of test–retest Z scores

OXC vs PHT AED vs Nco OXC vs Nco PHT vs Nco

(OXC n = 14) (PHT n = 12)

Digit symbol UDigit cancellation

Finger tapping *** ** *

Stroop

Reading words *

Interference UWonderlic USelective reminding

TREC

TLTS

CLTR U ** *

30-min recall

Visual RT

Simple *

Extended *** *** *

Choice

Complex

Words U *** * ***

Auditory RT *** ** **

Name learning

Correct RT

Number correct

Story recall

Immediate

Delayed U *

POMS

Tension

Anger

Depression *

Vigor * **

Fatigue U * **

Confusion U *** *** *

Total *** **

PNS

Cognitive *** * ***

Somatic *** ** ***

Total *** ** ***

Note. U, pre hoc target test measure. OXC, oxcarbazepine; PHT, phenytoin; Nco, control group; TREC, total recall; TLTS, total long-term storage;

CLTR, consistent long-term retrieval; RT, reaction time; POMS, Profile of Mood States; PNS, Portland Neurotoxicity Scale.* P 6 0.05.** P 6 0.01.

*** P 6 0.001.

900 M.C. Salinsky et al. / Epilepsy & Behavior 5 (2004) 894–902

environment of the brain, and slowing is a consistent

finding in all toxic/metabolic encephalopathies [37–39].

This also applies to AED toxicity. Rosemann and others

demonstrated that during intoxication with PHT there isgross slowing of the EEG, which resolves as the intoxi-

cation clears [40,41]. Intoxication with other AEDs pro-

duces similar effects. In the absence of clinically

apparent toxicity, EEG background slowing may reflect

milder degrees of CNS dysfunction [14,42,43]. In the

present study, and in previous studies, quantitative

EEG slowing was considerably more sensitive to AED

effects than were any cognitive measures, with >50%of individual subjects falling outside the 95% CI for

test–retest change on the EEG peak frequency measure

[14,17]. This physiological test appears to validate pa-

tient/subject complaints in the absence of substantial

cognitive test changes.

Test–retest changes for the EEG peak frequency mea-sure were statistically significant (P < 0.001) for both

PHT and OXC compared to untreated controls. How-

ever, the average change was less than �0.5 Hz and

could easily be missed on routine EEG interpretation.

For this and other practical reasons it is unlikely that

routine EEG examination would be a useful tool for

evaluating AED-related neurotoxicity. The EEG

changes seen in our subjects demonstrate that thereare significant negative effects of PHT and OXC on a

physiologic measure of brain function and that EEG

M.C. Salinsky et al. / Epilepsy & Behavior 5 (2004) 894–902 901

measures are generally more sensitive to AED effects

than are cognitive test measures.

One previous study directly compared the cognitive

effects of OXC and PHT. Aikia et al. [44] performed a

randomized, double-blind trial in 29 patients with new-

onset seizures. Cognitive testing was performed atbaseline, at 6 months, and at 12 months on therapy.

The cognitive battery included the Stroop test, Tap-

ping Speed, and Word-List Recall, all similar to tests

used in the present study. No significant differences

between AED group effects were seen. There was no

control group, so the effect of each drug vs expected

test–retest change could not be estimated. Meador et

al. [12] compared PHT and carbamazepine in a dou-ble-blind crossover trial in healthy volunteers. Three

of 12 cognitive measures (Stroop, Grooved Pegboard,

Reaction Time) were significantly affected by AEDs.

There was no clear advantage of one AED over the

other. Our results are consistent with these reports.

OXC and PHT use were associated with mild average

negative effects on some cognitive measures, compared

to untreated controls. Given these mild effects, differ-ences between the two AEDs could not be demon-

strated. The observed effects were largely in tests of

motor speed/reaction time, consistent with observa-

tions by Dodrill and Tempkin [15,45]. In their compar-

ison of PHT patients with high (mean, 43 lg/ml) vs

lower (mean, 17 lg/ml) serum levels, all significant cog-

nitive test differences disappeared when the results

were corrected for simple tapping speed. These obser-vations suggest that our standard cognitive tests do

not measure AED effects adequately, which is also sug-

gested by the gap between subjective complaints and

objectively measured cognitive changes.

Although double-blind and randomized, this study

has significant limitations. The results are based on a rel-

atively small number of subjects in each AED group,

limiting the statistical power. It is possible that a largerstudy would have demonstrated statistically significant

differences between AEDs. Also, the PHT serum levels

were mostly in the low therapeutic or subtherapeutic

range, whereas OXC subjects averaged mid to high ther-

apeutic levels of MHD. Even with elimination of 2 PHT

subjects with levels <6.0 lg/ml (pre hoc threshold for an

evaluable subject), five of 12 PHT subjects had blood

levels less than 10.0 lg/ml, commonly used as the lowerend of the therapeutic range. The AED comparison may

therefore have favored PHT. The lack of a placebo con-

trol group may have also influenced the results. Expec-

tations of AED side effects potentially bias the

subjective measures and may also influence objective

cognitive measures. It is unlikely that the EEG back-

ground measures were affected.

In conclusion, this double-blind, randomized, con-trolled trial of PHT and OXC in healthy volunteers re-

vealed significant effects of each AED on quantitative

measures derived from the EEG, with relatively mild ef-

fects on cognitive tests. There was little difference be-

tween the two AEDs on these objective measures of

brain function.

Acknowledgments

The authors thank Renee Hohimer for psychometric

testing, Debbie Johnstone, R.N., for study coordina-

tion, and James Cereghino, M.D., for valuable com-

ments on the manuscript. This article was presented in

part at the 2003 meeting of the American Epilepsy Soci-

ety in Boston, MA, USA. This work was supported byan independent investigator-initiated research grant

from Novartis Pharmaceuticals.

Appendix. Supplementary material

Supplementary data associated with this article can

be found, in the online version, at doi:10.1016/j.yebeh.2004.07.011.

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