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Epilepsy & Behavior 9 (2006) 469–477

The effects of duration of intractable epilepsy on memory function

Glenn P. Kent a, Bruce K. Schefft a,b,*, Steven R. Howe a, Jerzy P. Szaflarski b,c,Hwa-Shain Yeh d, Michael D. Privitera c

a Department of Psychology, University of Cincinnati, Cincinnati, OH, USAb Department of Neurology, University of Cincinnati, Cincinnati, OH, USA

c Cincinnati Epilepsy Center, The Neuroscience Institute, and Department of Neurology, University of Cincinnati Medical Center, Cincinnati, OH, USAd Department of Neurosurgery, University of Cincinnati Medical Center, Cincinnati, OH, USA

Received 27 March 2006; revised 10 July 2006; accepted 11 July 2006Available online 23 August 2006

Abstract

We assessed whether duration (time since diagnosis) of intractable epilepsy is associated with progressive memory loss in 250 individ-uals with left or right temporal lobe epilepsy and those diagnosed with psychogenic nonepileptic seizures. Verbal and nonverbal memoryfunction was assessed using several memory assessment measures administered to all individuals as part of a larger neuropsychologicalassessment. Multivariate multiple regression analyses demonstrated that duration of temporal lobe epilepsy and age of seizure onset aresignificantly related to verbal memory deficits in patients with epilepsy. The interaction between duration of epilepsy and diagnosticgroup was nonsignificant, as was the interaction between age at spell onset and diagnostic group. As measured by several neuropsycho-logical memory tests, duration of disease adversely affects verbal memory performance in patients diagnosed with temporal lobe epilepsy.Our study also supports the notion that age at seizure onset significantly affects verbal memory performance in this population. Theseresults have implications for the strategy of treatment and counseling of patients with intractable temporal lobe epilepsy.� 2006 Elsevier Inc. All rights reserved.

Keywords: Epilepsy; Seizure; Memory; Temporal lobe epilepsy; Psychogenic nonepileptic seizures

1. Introduction

Epilepsy, a chronic neurological condition characterizedby recurrent seizures, affects approximately 1% of the U.S.population [1]. It is also the second most common cause ofmental health disability, and it accounts for a worldwideburden of illness similar to that of breast cancer in womenand lung cancer in men [2]. Of the epilepsies, medial tempo-ral lobe epilepsy (MTLE) is the most frequently encoun-tered and the most difficult to treat pharmacologically[3,4]. In most cases, the diagnosis of pharmacoresistantMTLE is made based on typical history, description ofthe ictal behavior, and the results of electroencephalograph-ic and neuroimaging studies [5,6]. MTLE is commonly

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doi:10.1016/j.yebeh.2006.07.005

* Corresponding author. Fax: +1 513 556 1904.E-mail address: scheffbk@email.uc.edu (B.K. Schefft).

associated with impairment of memory and, in the case ofdominant hemisphere involvement, also impairment oflanguage.

Recurrent seizures may affect cognitive functioning inpatients with MTLE in areas involving intelligence, aca-demic achievement, language function, learning, and prob-lem solving [7,8]. However, the most prominent long-termdeficit associated with recurrent seizures in patients withMTLE is memory impairment [7,9].

Neuropsychological studies of memory disturbance inMTLE have focused on the differences in the results of sei-zures generated from the left versus the right temporallobe. When evidence indicates that seizures are of primarilyleft temporal lobe origin, verbal memory deficits are mostoften reported [8,10,11]. In contrast, in patients with righttemporal lobe epilepsy, nonverbal or visuospatial memorydeficits are frequently reported [12,13].

470 G.P. Kent et al. / Epilepsy & Behavior 9 (2006) 469–477

Past research has yielded contradictory evidence regard-ing the potential detrimental nature of epileptic seizures onmemory. This may be partially related to methodologicalshortcomings that may limit their generalizability. Forexample, although surgical resection of structures responsi-ble for seizure activity introduces the influence of uncon-trolled variables, postsurgical patients are often includedin these research protocols [10,14]. Other research hasincorporated neuroimaging techniques while excludingneuropsychological measures [15–17]. Still others haveassessed only one type of memory (verbal) [10,18,19], usedsmall sample sizes [20,21], or studied patients with limited-duration epilepsy [22,23].

A definitive experiment investigating the minimal seizureevent that produces sustained neuronal dysfunction has notyet been performed. However, a review of the literaturefocusing on hippocampal changes in the seizure-inducedexperimental models suggests repeated seizures as a causa-tive mechanism for long-term effects on neural circuitry[24,25].

Studies addressing the progressive effects of seizure activ-ity on memory functions use magnetic resonance imaging(MRI) or positron emission tomography (PET) to draw aconnection between neuronal loss, atrophy of the hippocam-pus, and repeated seizure activity [15–17,26]. Other imagingresearch supports the notion of hippocampal atrophy and/orneuronal loss with recurrent seizure activity and lendsfurther support to the potential detrimental effect of seizureson the anatomical structures responsible for memory func-tion [20,27–30].

Although there is good evidence to suggest that repeatedseizures damage the structures implicated in memory, fur-ther neuropsychological studies exploring this cognitivedomain in patients with seizures will help support acause-and-effect relationship between seizures and memorydecline. For example, a recent investigation suggests wide-spread neuropsychological morbidity in chronic temporallobe epilepsy despite a focal epileptic process. Further-more, the authors conclude that increasing duration of epi-lepsy is associated with worsening mental status [31]. Otherneuropsychological studies support these findings [7,8,32].Research focused on the effect of seizure activity on intelli-gence [33] and verbal and/or nonverbal memory perfor-mance [10,11,34,35] also supports the detrimental effect ofseizures, as do longitudinal investigations [23,36].

Although there is a substantial body of evidence thatrepeated seizures affect memory performance, some studieshave challenged this notion [37,38]. Further, a limited num-ber of longitudinal studies support the presence of mild

relationships between seizures and cognitive decline [39].Some experimental [40,41], histological [42–44], imaging[45,46], pre- and postoperative [47,48], cross-sectional[26], and longitudinal [22,49] studies cast doubt on thepotential detrimental effects of seizure activity on the ana-tomical structures responsible for memory function.

The effects of repeated seizures on memory performanceremain elusive. Therefore, in the cross-sectional study

described here, we sought to assess whether the duration(time since diagnosis) of intractable MTLE is associatedwith progressive memory loss. Although the effect of dura-tion on memory functions in patients with epilepsy hasbeen examined previously [37,45], there do not appear tobe neuropsychological investigations focused specificallyon duration of epilepsy that have also included the follow-ing characteristics: (1) a relatively large sample size(N > 200), (2) patients with confirmed temporal lobe epi-lepsy (left and/or right) who have not undergone resectivesurgery, (3) assessment of verbal and nonverbal memory,and (4) a wide range of patients with confirmed epilepticseizures in terms of duration of seizures. Further, in thisstudy we aimed to examine whether age at seizure onsetis significantly related to verbal and nonverbal memorydeficits. Individuals diagnosed with psychogenic nonepilep-tic seizures (PNES) were used as our comparison group.Further, we evaluated the relationship between durationand age at spell onset and verbal/nonverbal memory per-formance in these patients. Individuals with PNES wereselected as a comparison group for several reasons. Notonly did they serve as a comparison for the effects of epilep-tic seizures (ES), but they served as an interesting compar-ison group from a neuropsychological perspective. Forinstance, studies by our research group have demonstratedequal levels of neuropsychological impairment in PNEScompared with ES [50]. We have also shown that patientswith PNES have greater psychological distress than dopatients with ES [51]. Consequently, with our choice ofpatients with PNES as a comparison group, we hoped toprovide further understanding of the nature and courseof cognitive dysfunction in these patients.

2. Methods

2.1. Participants

This retrospective cross-sectional study involved data from a conve-nience sample of 626 patients selected from a research database ofpatients with medication-resistant seizures who were evaluated in the epi-lepsy monitoring unit (EMU) at the University Hospital in Cincinnati,OH, USA. The convenience sample of 626 patients was selected froma larger database of approximately 1000 patients. The basis for theirselection was that the nature of their seizures had been confirmed aseither epileptic or psychogenic nonepileptic. Consequently, approximate-ly 374 patients did not meet the criterion of confirmed seizure nature andwere thus not included in the sample of 626. The final sample of 250individuals (59 with left temporal lobe epilepsy (LTLE), 48 with righttemporal lobe epilepsy (RTLE), and 143 with PNES) remained afterinstitution of the inclusion and exclusion criteria. Participants wereincluded in the study if they demonstrated an absence of mental handi-cap (WAIS-R/Third Edition Full Scale IQ > 70), absence of neurologicaldisorders other than epilepsy, and completion of all verbal and nonver-bal memory assessment measures. Individuals with incomplete neuropsy-chological assessment data (n = 130), confirmed focal extratemporalseizures (n = 114), WAIS-R/Third Edition Full Scale IQ < 70 (n = 49),confirmed idiopathic generalized epilepsies (n = 26), abnormal EEG (inpatients with PNES, n = 18), duplicate test results (n = 17), prior surgeryfor seizures (n = 15), and other significant neurological and/or psychiat-ric problems (n = 7) were excluded from this study. Neuropsychologicalprofiles representing insufficient or questionable effort were not included

G.P. Kent et al. / Epilepsy & Behavior 9 (2006) 469–477 471

in the convenience sample of 626 patients. Racial profiles included 229who identified as Caucasian, 19 who identified as African-American,and 2 who identified as Asian.

Diagnoses of all participants were based on neurologists’ impressionsfrom prolonged 24-hour video/EEG recordings, the characteristics ofthe recorded events, and the results of neuroimaging. Patient diagnoseswere confirmed on the basis of concordance between EEG findings, semi-ology, and imaging results. The decision was made by at least two epilep-tologists, and was typically the outcome of a weekly conference discussion.Approximately half of study participants were found to have mesial tem-poral sclerosis on MRI. Seventeen participants (nine with LTLE, eightwith RTLE) underwent resective surgery subsequent to the study’s com-pletion and attained a seizure-free rate of 71% (three subjects had an80% reduction in seizures, one subject had a 50% reduction, and one sub-ject had less than 50% reduction in seizure activity). Two groups ofpatients were based on confirmed seizure focus, (1) left temporal lobeand (2) right temporal lobe, and a third group consisted of individualswith normal EEG recordings with confirmed PNES. The diagnosis ofPNES is based on recording of habitual spells in the setting of normalEEGs; PNES have been attributed to both psychological disorders andorganic brain dysfunction [50–53].

2.2. Procedure

Demographic information and medical history were collected throughchart review and self-report during patient interview. Verbal and nonver-bal memory function was assessed using several memory assessment mea-sures administered to all individuals as part of a larger neuropsychologicalassessment. All neuropsychological test measures were administeredaccording to standardized procedure protocols prior to establishment ofthe clinical diagnosis and recording of any events. This study wasapproved by the University of Cincinnati Institutional Review Board,and all participants signed an informed written consent form prior toparticipation.

2.3. Materials

Verbal memory was assessed with two subtests of the President’s Test[54]: (1) Verbal Naming (VN) and (2) Verbal Sequencing (VS). In addition,several subtests of the Wechsler Memory Scale Third Edition [55] wereused, including: (3) Logical Memory Immediate Recall (LMI), (4) LogicalMemory Delayed Recall (LMD), (5) Verbal Paired Associates ImmediateRecall (VPAI), (6) Verbal Paired Associates Delayed Recall (VPAD), (7)Word Lists Immediate Recall (WLI), (8) Word Lists Learning Slope(WLLS), (9) Word Lists Interference Score (WLIS), (10) Word ListsDelayed Recall (WLD), and (11) Word Lists Delayed Recognition test(WLR).

Five indicators of nonverbal memory performance were used in thisinvestigation including two subtests of the President’s Test, (1) PhotoNaming (PN) and (2) Photo Sequencing (PS), (3) the Warrington Recog-nition Memory Test for Faces (WAR) [56], the (4) Benton Visual Reten-tion Test Fifth Edition Administration A [57] number of correctreproductions (BVRC) and (5) number of errors (BVRE).

2.4. Statistical analyses

Each memory assessment measure was categorized as measuring eitherverbal memory (11 variables: VN, VS, LMI, LMD, VPAI, VPAD, WLI,WLLS, WLIS, WLD, WLR) or nonverbal memory (5 variables: PN,PS, WAR, BVRC, BVRE). Data screening was completed to addressthe accuracy of the data, missing data, and effects of extreme/influentialvalues, and to test assumptions necessary for parametric statistics. Evi-dence of nonnormality in the outcome variable data was remedied byapplying suitable transformations. A one-way analysis of variance(ANOVA) was used to assess between-group differences on select demo-graphic and seizure characteristics; v2 tests were used to evaluate discretevariables.

Multivariate multiple regression (MMR) analyses were conducted toassess the relationship between each dependent variable (score on thememory test) and the following independent predictor variables: sex(SEX), education (EDUC), age at seizure onset (AGEONSET), durationof TLE/PNES (DURATION), and diagnostic group (DXGROUP).Raw scores from the memory tests were used in each multiple linearregression equation. Duration of epilepsy and age at seizure onset weretested to see if they demonstrated a significant effect on the dependent vari-ables. If the multivariate null hypothesis could be rejected, univariate mul-tiple regressions were examined, one for each memory measure.

Pearson correlation coefficients were computed among the predictorvariables and the verbal and nonverbal memory measure models. Regres-sion diagnostics were completed to address potential outlying/influentialdata points. Although each might have been interesting to examine, itwas not possible to include AGE, AGEONSET, and DURATION in aregression solution, as there is a linear dependency (i.e., any two of thesevariables accounts for the third). Only AGEONSET and DURATIONwere included in the model. For example, someone’s age equals the sumof age at seizure onset and duration. In addition, one can subtract ageat seizure onset from a person’s age to derive duration of the disorder.Support for this phenomenon was confirmed by examination of the simplecorrelations among the three predictors from the correlation matrix (allr > 0.51) and the use of variance inflation factors (all >100). Two interac-tions, (1) DURATION · DXGROUP and (2) AGEONSET ·DXGROUP, were included to assess the relationship between durationand age at spell onset and verbal/nonverbal memory performance inpatients with PNES. Finally, contrasts were run between the PNES groupand the two seizure groups (LTLE and RTLE) and between the LTLE andRTLE groups.

3. Results

Demographic and seizure characteristics are summa-rized in Table 1. As expected, among the final sample,between-group comparisons demonstrated that the PNESgroup were older at spell onset and had a shorter durationof disease, and they were treated with fewer antiepilepticmedications [51]. Correlation analysis reveals a strong neg-ative relationship between age at onset and duration(r = �0.688), suggesting that as age at seizure onsetincreases, duration of disorder decreases. To examine thepossible influence of other demographic characteristics(including gender, race, and occupational status), we rancorrelations between expected IQ and duration (r = 0.03)and between expected IQ and age at onset (r = �0.04)and observed no significant relationships.

MMR analysis of the 11 verbal dependent variablesyielded unexpected nonuniform results for the variousdependent variables. A common factor analysis was per-formed to test the construct validity of verbal memory.Factor analysis was used to assess whether the two nonsig-nificant univariate findings (Word Lists Learning Slopeand Word Lists Interference Score) in the MMR analysiscontributed to this construct. Table 2 lists the prior com-munality estimates for the 11 verbal memory tests used inthis analysis. Four measures (Verbal Naming, VerbalSequencing, Word Lists Learning Slope, and Word ListsInterference Score) had communality estimates markedlylower than those of the other measures (the mean for thefour measures was 0.246, whereas the mean for the sevenmeasures was 0.677). The four tests were set aside from

Table 1Demographic and seizure characteristics by diagnostic group: ANOVA and v2 test

Diagnostic group F P

LTLE (n = 59) RTLE (n = 48) PNES (n = 143)

Age 37.9 (10.2) 36.7 (11.2) 37.3 (10.9) 0.17 0.85[43]a [40] [56]

Education 12.9 (2.3) 12.7 (1.8) 12.6 (1.9) 0.95 0.39[10] [8] [12]

Sexb 25 M; 34 F 23 M; 25 F 34 M; 109 F 65.10 0.00FSIQ 90.9 (12.0) 94.5 (12.6) 91.2 (11.4) 1.62 0.20

[45] [54] [53]Age at onsetc 19.3f (12.3) 18.8f (15.4) 30.3g (12.9) 21.94 0.00

[49] [51] [72]Durationd 18.6f (14.1) 17.7f (14.0) 7.0g (9.1) 29.38 0.00

[52] [49] [40]Number of AEDse 1.9h (0.9) 1.7h (0.77) 1.3i (0.87) 11.25 0.00

[4] [4] [4]

Note. LTLE, left temporal lobe epilepsy; RTLE, right temporal lobe epilepsy; PNES, psychogenic nonepileptic seizures; FSIQ, Full Scale IQ; n, number ofpatients.

a Mean (SD) [Range].b v2 test.c Age when diagnosed with condition.d Length of time since diagnosis with condition.e Number of antiepileptic drugs taken at time of assessment.f,g Group means that do not share subscripts differ at P < 0.001 in the Tukey HSD comparison.h,i Group means that do not share subscripts differ at P < 0.05 in the Tukey HSD comparison.

Table 2Prior communality estimates (SMC) for the 11- and 7-dependent-variable(verbal memory) models and the 5-dependent-variable (nonverbalmemory) model

Variable PCE (SMC)a

11-Variable model 7-Variable model 5-Variable model

VN 0.190 —VS 0.224 —LMI 0.773 0.769LMD 0.798 0.794VPAI 0.660 0.647VPAD 0.662 0.650WLI 0.623 0.596WLLS 0.262 —WLIS 0.308 —WLD 0.701 0.629WLR 0.519 0.492PN 0.138PS 0.151WAR 0.145BVRC 0.839BVRE 0.843

a PCE, prior communality estimate; SMC, squared multiple correlation.

472 G.P. Kent et al. / Epilepsy & Behavior 9 (2006) 469–477

further analysis based on statistical and/or clinicalreasoning. The relatively low communality estimates sug-gest that these tests were contributing too much uniquevariance to be good members of the universe of verbalmemory measures. In addition, the Verbal Naming andVerbal Sequencing tests have questionable utility as verbalmemory measures in patients with temporal lobe epilepsy[58,59].

Data analysis was conducted on the remaining seven-de-pendent-variable model. Regression diagnostics failed to

identify any observations whose inclusion or exclusionresulted in substantial changes in the fitted model. Theomnibus test was significant, Wilk’s = 0.67, F(42,1115) = 2.33, P < 0.0001, for the remaining seven-depen-dent-variable, five-independent-variable model. All sevenfollow-up univariate equations were significant(P < 0.001). Each predictor variable demonstrated signifi-cant effects on the group of dependent variables (allP < 0.05). The proportion of generalized variance in thedependent variables accounted for by the predictors was33%. Contrasts were run between the PNES group andthe two ES groups combined and between the PNES groupand the LTLE and RTLE groups separately. These resultsdemonstrated group differences between the ES groups, butnone between the PNES and ES groups. Finally, two inter-actions were examined to assess whether diagnostic groupinteracts with either duration or age at onset. No signifi-cant results were obtained for either interaction, DURA-TION · DXGROUP, Wilk’s = 0.97, F(14, 460) = 0.46,P = 0.9514 and AGEONSET · DXGROUP, Wilk’s =0.95, F(14,460) = 0.87, P = 0.589. Comparisons for select-ed verbal memory tests are presented graphically in Fig. 1.

Regression equations used to predict verbal memoryperformance are given in Table 3.

Similar analyses were conducted with the five nonverbalmemory measures. Again, MMR analysis of the nonverbaldependent variables yielded unexpected nonuniformresults, and a factor analysis was subsequently performedto test the construct validity of these memory measures.After a review of the five nonverbal variables, it was deter-mined that one test (WAR) would be retained for furtheranalysis because prior epilepsy research favors its use

Logical Memory Immediate Recall

0

10

20

30

40

50

Duration (yrs)

Duration (yrs)

Sco

reS

core

ES

PNES

Verbal Paired Associates Immediate Recall

0

5

10

15

20

25

5

ES

PNES

20

5 20

Fig. 1. Memory scores associated with duration of seizures/spells forparticipants with epileptic seizures (ES) and psychogenic nonepilepticseizures (PNES).

G.P. Kent et al. / Epilepsy & Behavior 9 (2006) 469–477 473

[60,61]. Data analysis was then conducted on the one-de-pendent-variable model setting aside AGE as previouslymentioned. The results of this evaluation identified themultiple regression equation as significant (F = 2.96,P = 0.0083). The predictor variables AGEONSET,R2 = 0.02, F(1, 243) = 4.13, P = 0.0433, and DXGROUP,R2 = 0.03, F(2, 243) = 3.35, P = 0.0367, demonstrated sig-nificant effects on the dependent variable (WAR). Contraststatistics yielded differences only between the LTLE andRTLE groups, R2 = 0.03, F(1,243) = 6.49, P = 0.0115.The regression equation used to predict nonverbal memoryperformance is given in Table 3.

Table 3Equations used to predict verbal and nonverbal memory performance based o

Verbal memory

LMI = 32.09 � 2.49(SEX) + 1.18(EDUC) � 0.15(AGEONSET) � 0.23(DURALMD = 15.87 � 1.16(SEX) + 0.91(EDUC) � 0.11(AGEONSET) � 0.15(DURVPAI = 4.13 + 0.23(SEX) � 0.12(EDUC) + 0.02(AGEONSET) + 0.02(DURAVPAD = 5.04 � 0.36(SEX) + 0.23(EDUC) � 0.04(AGEONSET) � 0.05(DURWLI = 3.39 + 0.38(SEX) � 0.07(EDUC) + 0.02(AGEONSET) + 0.02(DURATWLD = 2.22 + 0.22(SEX) � 0.03(EDUC) + 0.01(AGEONSET) + 0.01(DURAWLR = 5,559,973 � 706,793(SEX) + 166,018(EDUC) � 22,434(AGEONSET)

Nonverbal memory

WAR = 33.10 � 0.10(SEX) + 0.20(EDUC) + 0.07(AGEONSET) + 0.01(DUR

4. Discussion

The purpose of this cross-sectional study was to assesswhether the duration (time since diagnosis) of intractabletemporal lobe epilepsy is associated with progressive mem-ory loss in patients with left and right temporal lobe epilep-sy. We were also concerned with the effect of age at seizureonset on memory function in the same groups. Finally, wecompared the effects of these variables on subjects with ESand those with PNES. Our analysis indicated that durationof MTLE and age at seizure onset are significantly relatedto verbal memory performance in patients with ES. Theanalysis also suggested that in patients with PNES, verbalmemory performance is impaired with increased durationof spells and earlier age at onset.

These findings pose an important question: What are thecumulative cognitive effects of recurring brief seizures inpatients with confirmed temporal lobe epilepsy? Sutulaand Pitkanen suggested three reasons the answer has beenelusive [26]. First, individual variability and susceptibilityto seizure activity may cloud outcome. Second, a broadrange of underlying pathologies in patients with the disor-der may mask the effect of seizures. Finally, the stigmaassociated with epilepsy prevents clinicians and researchersfrom working with representative populations. The currentstudy may lead to a better understanding of the potentialadverse effects of seizure activity on memory function inpatients with temporal lobe epilepsy by investigating theadverse effects associated with prolonged duration of thedisorder. Such knowledge may benefit these patients withrespect to treatment options and the possible consequencesassociated with treatment decisions. In addition, cliniciansmay offer such information to their patients to more fullyaddress the risks of persistent, unremitting seizure activity.For example, the risk-to-benefit profile of antiepilepticdrugs that have more severe adverse effects or the risks ofepilepsy surgery must be weighed in an individual patientagainst the risk of progressive memory impairment causedby recurrent seizures. The more we understand about thenature, causes, and time course of memory impairment inepilepsy, the better clinicians can counsel patients andmake accurate risk–benefit assessments.

n demographics and other variables

R2 (adj.R2)

TION) � 2.30(LTLE) + 0.75(PNESs) 0.11 (0.09)ATION) � 2.15(LTLE) + 1.78(PNESs) 0.11 (0.09)TION) + 0.56(LTLE) + 0.02(PNESs) 0.15 (0.13)

ATION) � 1.52(LTLE) � 0.29(PNESs) 0.13 (0.11)ION) + 0.54(LTLE) + 0.16(PNESs) 0.15 (0.12)TION) + 0.40(LTLE) + 0.07(PNESs) 0.12 (0.09)� 14,736(DURATION) � 1,318,003(LTLE) � 63765(PNESs) 0.12 (0.12)

ATION) + 2.60(LTLE) + 1.82(PNESs) 0.07 (0.05)

474 G.P. Kent et al. / Epilepsy & Behavior 9 (2006) 469–477

Our findings support the theory that duration of seizureshas a negative effect on verbal memory performance amongindividuals with confirmed ES and those diagnosed withPNES. Although there was no effect of duration of diseaseon the nonverbal memory measure used in this study(WAR), age at seizure onset demonstrated a significanteffect on this measure.

Verbal memory performance appears to worsen withincreased duration and earlier age at seizure onset in per-sons diagnosed with ES and among those with PNESs. Pre-vious work in patients with ES [35] has suggested thatverbal memory functions decline with longer duration ofepilepsy and increased number of seizures. The currentstudy supports these findings. No mechanism to explainthese results can be known for certain as this investigationdid not address the neuropathological consequences of sei-zure activity on brain tissue. One possible explanation isthat temporal lobe seizures may disturb the processes ofmemory consolidation residing in this region [19]. If true,then preventing seizures may contribute to preservingpatients’ memory function, suggesting that cliniciansshould aggressively treat to eliminate seizures. One implica-tion of the current findings is the importance of early sei-zure relief to preserve memory function. The importanceof early seizure prevention is consistent with the notionthat earlier cessation of seizure activity may amelioratethe negative effects of temporal lobe seizures.

Memory function may also decline in persons diagnosedwith MTLE as a result of neuroanatomical changes in thehippocampus and associated mesial temporal lobe struc-tures. Among persons with MTLE, quantitative magneticresonance (MR) volumetric abnormalities are evident inthe hippocampus [17,62], amygdala [63,64], fornix [63,65],and entorhinal cortex [29]. In addition, atrophy has beenreported in extrahippocampal temporal lobe regions [66].The results of these studies lend support to the potentialdetrimental effect of seizures on the structures responsiblefor memory function. Other investigations have demon-strated a relationship between hippocampal neuron lossand verbal memory impairment [67] or have linked verbalmemory impairment specifically to hippocampal damage[10]. These results may further explain the decline in verbalmemory performance exhibited by the ES sample used inthe current study.

The results of this study also suggest that duration ofnonepileptic seizures in participants diagnosed with PNEShas a detrimental impact on memory function. The impli-cations of these results may increase our understandingof the effects of this condition on memory function. Indi-viduals diagnosed with PNES have been shown to have his-tories of early trauma and dissociation [68]. Furthermore,Vermetten et al. found smaller hippocampal and amygda-lar volumes in patients with dissociative identity disorders,compared with healthy subjects [69]. From a neurologicalstandpoint, poor memory outcomes among individualsdiagnosed with PNES may be explained by atrophy ofstructures implicated in memory. Further investigations

that explore the relationship between trauma, neurophysi-ology, and PNES are needed to clarify the nature of thesephenomena.

Our findings did not support the hypothesis that dura-tion plays a significant role in nonverbal memory perfor-mance; however, age at seizure onset was shown to havean effect. A factor analysis of the five nonverbal memorytests did not identify a general factor, unlike the resultsobtained for verbal memory. One explanation is that cur-rent neuropsychological measures may not demonstrateadequate sensitivity or specificity to detect nonverbal mem-ory problems. This notion is supported by a recent study [8]noting that ‘‘the relationship between lateralized hippo-campal pathology and adequacy of memory function ismore reliable for verbal memory among LTLE patientsthan for visual memory among RTLE patients’’ (p. 374).The authors concluded that standard clinical measures ofnonverbal memory sensitivity remain to be classified. How-ever, Testa et al. [60], from our institution, demonstratedthe diagnostic utility of one nonverbal memory measure,the Warrington Recognition Memory Test for Faces, inpatients with TLE. Two other groups found similar utilityfrom nonverbal memory measures [13,61], whereas othershave reported no differences in performance in patientsdiagnosed with TLE [70,71].

We were surprised to find that the duration of PNES wasassociated with worse verbal memory function. The lack of asignificant interaction between duration and PNES and ageat disease onset and PNES suggests that verbal memoryfunction of individuals with this condition may also deterio-rate over time. One explanation is that memory loss is a nor-mal part of the aging process and would be expected in allpatient groups, PNES included [53]. Although memorychanges have been linked to aging [72,73], significant chang-es tend to manifest themselves during midlife (fifties) andbeyond. In the present study, only 12% of participants diag-nosed with PNES were 50 years or older, whereas 3% wereolder than 60. Given these facts, it seems unlikely that agingalone would explain verbal memory performance in thisgroup. Another explanation is that PNES have been attrib-uted to both psychological disorders and organic brain dys-function [9,50] and that these biological conditionssignificantly impact the course of memory change and thedegree to which these individuals experience memory prob-lems. Health has an important effect on memory function[74], and individuals with PNES present with a significantdegree of cognitive impairment [75]. Other research findingsevaluating health-related quality of life (HRQOL) suggestthat individuals with PNES report poorer quality of life ascompared with patients with ES [76] and often rate them-selves as significantly more impaired than those with ES onsubjective measures of neuropsychological functioning(i.e., memory) [77]. The findings of these related studies sug-gests that significant psychological stress can adverselyimpact cognitive functioning in individuals with PNES andmay help explain verbal memory decline among participantswith this condition [69].

G.P. Kent et al. / Epilepsy & Behavior 9 (2006) 469–477 475

Both gender and education were significant predictors ofverbal and nonverbal memory outcome, and these resultswere expected. A review of normative data for the memorymeasures used in this investigation highlights the depen-dence of performance level on gender and education level.It is generally accepted that a host of demographic vari-ables affect neuropsychological performance, includingboth gender and education [78–81], and the results of ourinvestigation support this notion.

As with any study, there are limitations of the designand analytic strategy of this study. The cross-sectionaldesign of this investigation necessarily limits the robustnessof our findings. Longitudinal monitoring of patients withmedication-resistant MTLE who do not undergo surgicaltreatment and examinations of other factors that may con-tribute to deterioration of neurological and neuropsycho-logical functioning are needed [82,83]. Additionally,cross-sectional data, relative to longitudinal data, are notas sensitive to small-magnitude changes and can misrepre-sent processes of organization that occur within the indi-vidual [84].

Because of the retrospective cross-sectional nature ofthis study, healthy controls were not available for compar-ative purposes. The use of patients with PNES as a com-parison group in the current study may have provided asuboptimal sample for memory changes as a result of non-epileptic seizure activity over time. Inspection of findingsby others [50,53] suggests that individuals with PNES doindeed have significant neurocognitive defects which aredifficult to distinguish from those seen in ES. Therefore,serial, long-term neuroimaging and neuropsychologicalstudies are needed to elucidate the effect of seizures in per-sons diagnosed with epilepsy, and these studies shouldinclude healthy volunteers so that additional normativedata are used as a basis of comparison.

Although there were significant differences between thePNES group and the two ES groups with respect to num-ber of antiepileptic drugs, this study did not address possi-ble fluctuations in medication levels or effects ofpolypharmacy on memory, which may have an effect onattention and encoding during neuropsychological testing.Prior research findings strongly suggest a significant effectof antiepileptic drugs on cognition [84–86]. Other factors,such as type (partial vs generalized) and frequency of sei-zures, were not addressed in the current investigation, butthese variables may have an effect on memory functionsin patients with epilepsy and need to be examined in thefuture [39]. Finally, this study did not control for partici-pant age. The decision to exclude this variable was basedon statistical reasoning (above); however, from a clinicalviewpoint, it is well understood that memory functionsdecrease with age independent of the seizure variable.These may represent uncontrolled influences on memoryfunction.

The results of this study suggest that duration of leftMTLE adversely affects verbal memory performance inpatients with this diagnosis as measured by several neuro-

psychological memory tests. The results also support thenotion that age at seizure onset may significantly affect ver-bal memory performance in the same population. Theseresults have implications for quality of life, treatmentoptions, and awareness in research and clinical practice,as well as in the strategy of treatment and counseling ofpatients with intractable temporal lobe epilepsy.

Acknowledgments

This study was funded through a predoctoral researchfellowship from the Epilepsy Foundation of America andthe University Research Council of the University ofCincinnati.

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