Epilepsy and cognition

CHAPTER 13

Epilepsy and cognition Rachel Friefeld Kesselmayer, Gloria M. Morel, Jessica M. Bordenave, Jana Jones, Bruce Hermann Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States

Contents 1. Introduction 2. The prospective epilepsy-neuropsychology literature: A quick synopsis 3. Child and adolescent studies 3.1 Summary of previously reviewed child and adolescent literature 3.2 Present review of child and adolescent literature 4. Adult studies 4.1 Summary of previously reviewed adolescent and adult literature 4.2 Present review of adult literature References

246 247 248 248 255 258 258 258 270

Abbreviations ABM AED ALF BECTS CWE DRS FSIQ GGE GTCS IQ JME LRE RCFT RE RMT SI SU TEA TLE

autobiographical memory antiepileptic drug accelerated long-term forgetting benign partial epilepsy of childhood with centrotemporal spikes children with epilepsy Dementia Rating Scale full scale intelligence quotient genetic generalized epilepsy generalized tonic-clonic seizure intelligence quotient juvenile myoclonic epilepsy localization-related epilepsy Rey Complex Figure Test rolandic epilepsy Warrington Recognition Memory Test seizures improved group seizures unimproved group transient epileptic amnesia temporal lobe epilepsy

The Comorbidities of Epilepsy https://doi.org/10.1016/B978-0-12-814877-8.00013-1

© 2019 Elsevier Inc. All rights reserved.

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T2 VIQ WAIS WAIS-R WAIS-III WISC WMS-III

time two verbal intelligence quotient Wechsler Adult Intelligence Scale Wechsler Adult Intelligence Scale—Revised Wechsler Adult Intelligence Scale—Third Edition Wechsler Intelligence Scale for Children Wechsler Memory Scale—Third Edition

1. Introduction According to the current definition of epilepsy put forth by the International League Against Epilepsy [1], “epilepsy is a disease characterized by an enduring predisposition to generate epileptic seizures and by the neurobiological, cognitive, psychological, and social consequences of this condition.” Researchers and clinicians have been concerned about the effects of epilepsy—to various degrees of medico-theoretical understanding— on cognition, mental status, and psychiatric status for several hundred years. Commentaries recognizing the impact of epilepsy on cognitive abilities can be found in the 18th-century literature, for example, by Tissot (1770), who recognized diminished memory and judgment, especially with severe and frequent seizures (as cited in Berrios [2]). More “modern” understanding and observation emerged in the early 19th century by Esquirol [3], who reported cognitive impairment (dementia with memory impairment) and mental disorder in a cohort of female child patients with epilepsy and remarked on the gradual decline in intelligence, perception, and memory, and Bouchet and Cazauvieilh [4], who reported on the development of dementia and insanity in epilepsy. Gowers [5] also postulated more frequent cooccurrence of dementia with epilepsy, “The mental state of epileptics, as is well known, frequently presents deterioration,” and inferred that dementia and epilepsy may represent a shared underlying etiology rather than one leading to the other. The advent of the field of neuropsychology and its psychometric measurement of cognition has allowed for objective quantification of discrete cognitive abilities and their change over time in epilepsy. It was not until 2004 that Carl Dodrill published the first review of the literature focusing specifically on longitudinal change in cognition in people with epilepsy [6]. In that review he examined publications in which formal objective psychological assessment was performed on at least two occasions and were not meant to assess treatment effects (e.g., drug, surgery). Dodrill [6] identified 22 papers that met his criteria (9 involving children and 13 with adolescents and adults), and the review concluded that there were “mild but definite relationships” between epilepsy and cognitive decline over time. This conclusion was tempered by the fact that multiple studies indicated mixed or uncertain results, as well as several studies demonstrating no relationship between seizures and deterioration of cognition. An updated review of the literature was published by Seidenberg et al. [7] using the same study inclusion criteria articulated by Dodrill [6], focusing on the longitudinal studies published in the interim, in order to extend Dodrill’s monitoring of studies examining prospective cognitive change. They reported ongoing evidence of cognitive progression in a subset of adults with epilepsy

Epilepsy and cognition

and a complicated pattern of prospective cognitive course in children. Further details regarding the specific findings contained in these reviews will be summarized in the respective pediatric and adult sections to follow. This review updates the prior reviews by Dodrill [6] and Seidenberg et al. [7], examining the totality of longitudinal research assessing cognitive change in adults and youth with epilepsy published to date. That said, it should be made clear that we take a fresh view and initially considered all published longitudinal cognitive investigations, including those contained in the prior reviews, plus others that we were able to locate in diverse sources, including book chapters. Consistent with Dodrill [6] and Seidenberg et al. [7], only studies that included objective measures of cognition on at least two evaluations were considered. Given the limitations of comparison and generalizability put forth by Seidenberg et al. when discussing studies without control subjects, this review includes only research that utilized a comparison group (healthy or other medical conditions). Additional inclusion criteria included formal neuropsychological assessments conducted with at least two time points, and in regard to the pediatric literature, only studies examining children who were school-aged were included for review. In essence, we take a fresh view and reexamine the prospective epilepsyneuropsychology literature, adding important additional selection criteria, finding new studies not previously included, and moving some papers reviewed in the Dodrill and Seidenberg et al. papers to uncontrolled status, which is not a primary focus here. While our focus is squarely on controlled prospective investigations, we have included tables that list and summarize findings from published uncontrolled pediatric and adult investigations, thereby compiling the prospective cognitive literature in a comprehensive manner. Cross-sectional investigations and analyses are neither considered nor tabled.

2. The prospective epilepsy-neuropsychology literature: A quick synopsis Table 1 provides an overall summary of core features of the published literature that is reflected in detail in Table 2 (controlled studies—children) and Table 3 (controlled studies—adults), which represent the focus of this chapter. Tables 4 and 5 provide additional information on uncontrolled pediatric (Table 4) and adult (Table 5) studies. These tables are not reviewed in this chapter and can be located in the Appendix. Taking a summary look at the prospective literature (Table 1), in terms of controlled studies it can be appreciated that this is a modestly sized literature, containing only 11 pediatric and 9 adult studies. Some of the published studies come from the same cohort, and when this is considered, the controlled literature is composed of seven independent pediatric and eight independent adult cohorts—the limited nature of this literature notable given the longstanding interest in this clinical issue. The total number of participants in the controlled pediatric and adult studies is modest as well, including less

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Table 1 Synopsis of prospective literature Pediatric

Adults

Controlled studies

Earliest study Most recent study Number of studies Number of independent cohorts Test-retest intervals Total epilepsy subjects Total control subjects

Bourgeois et al. [8] Rathouz et al. [10] 10 6 3 months–6 years 658 (652 at follow-up) 497 (503 at follow-up)

Dodrill and Wilensky [9] Savage et al. [11] 9 8 1–10 years 543 422

Fox [12] Reuner et al. [14] 14 14 1 month–9 years 1423

Barnes and Fetterman [13] Mamenisˇkien_e et al. [15] 16 14 1–13 years 1271

Studies without controls

Earliest study Most recent study Number of studies Number of independent cohorts Test-retest intervals Total epilepsy subjects

than 700 pediatric epilepsy patients and 550 adult patients in studies that began in 1983 and 1990, respectively. All but three studies involved only two test-retest sessions. The structure of the uncontrolled literature is interesting as well. It can be seen that interest in this topic is longstanding with the first pediatric and adult studies appearing in 1924 and 1938, respectively. The most recent uncontrolled studies appeared recently (2016), but again with a total number of epilepsy participants under 1500 in the pediatric and adult literature. In summary, the important clinical concern of the prospective course of cognition was addressed empirically for the first time in 1924, with both controlled and uncontrolled studies ongoing over the decades with publications appearing up to the present time. Despite this longstanding interest and the important clinical implications of this research, the degree of investigation (especially reflected in controlled studies) is modest in terms of the number of studies, number of participants, and number of controlled investigations. We now turn to a review of the controlled pediatric and adult studies (Tables 2 and 3) and begin with a brief summary provided in the prior reviews followed by critical examination of the target literature as described.

3. Child and adolescent studies 3.1 Summary of previously reviewed child and adolescent literature Dodrill [6] and Seidenberg et al. [7] provided discussions of controlled and uncontrolled prospective child and adolescent studies. Of the controlled studies, the earliest reviewed

Table 2 Controlled prospective pediatric studies Study

(N) Seizure type

Control group

45 siblings Bourgeois 72 generalized without et al. [8] motor, epilepsy generalized absence, mixed, simple febrile 23 siblings Bailet and 74 idiopathic epilepsy without Turk epilepsy [16]

Age

Mean retest interval

21 months– 4 years 15.9 years

Cognitive domains examined

IQ

8–13 years

 3 years

IQ, psychomotor speed, memory (verbal and visual), academic achievement

Oostrom et al. [17]

51 idiopathic or cryptogenic epilepsy

48 sexmatched classmates

7–16 years

3 and 12 months

General cognition, memory, sustained attention, academic achievement

Lindgren et al. [18]

32 initial, 26 follow-up rolandic epilepsy (RE)

25 healthy classmates

7–15 years

2.5–3 years

Memory (verbal and visual), executive function

Key results

Continued

Epilepsy and cognition

Baseline: cognitive domains not significantly different compared to controls. No prospective decline: across all cognitive domains Baseline: all cognitive domains significantly lower compared to controls. No prospective decline: across all cognitive domains Baseline: attention, reaction times, location learning, academic skills significantly lower compared to controls. Prospective decline: academic achievement. No prospective decline: general cognition, memory, sustained attention Baseline: memory and learning of auditory-visual material, delayed recall, measures of executive functioning and word comprehension significantly lower compared to controls. No prospective decline: across all cognitive domains

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Mean retest interval

Cognitive domains examined

7–16 years

3, 12, 42 months

48 healthy 52 idiopathic first-degree generalized, cousins localizationrelated epilepsy (LRE)

8–18 years

2 years

197 mixed epilepsy (generalized and LRE)

131 siblings (13 not at baseline, 7 not at follow-up)

6–14 years

36 months

50 focal and generalized

41 healthy first-degree cousins

8–18 years

2 and 5 years

Baseline: all cognitive IQ, attention, domains significantly memory, processing lower compared to speed, academic controls. No prospective linguistic skills decline: across all cognitive domains Baseline: cognitive domains IQ, academic of CWE with achievement, neurobehavioral comorbidities language, memory, significantly lower executive function, compared to controls. motor function Prospective decline: across all cognitive domains for CWE with neurobehavioral comorbidities Baseline: writing Academic significantly lower achievement compared to controls. (reading, writing, Prospective decline: math) across all cognitive domains Baseline: all cognitive Academic domains significantly achievement lower compared to (reading, spelling, controls for CWE with math) academic problems. Prospective decline: across all cognitive domains for CWE with academic problems across all domains

Study

(N) Seizure type

Control group

Age

Oostrom et al. [19]

42 idiopathic or cryptogenic epilepsy

30 gendermatched healthy classmates

Hermann et al. [20]

Dunn et al. [21]

Almane et al. [22]

Key results

The Comorbidities of Epilepsy

Table 2 Controlled prospective pediatric studies—cont’d

Lin et al. [23]

19 juvenile myoclonic epilepsy (JME)

57 healthy first-degree cousins

8–18 years

2 years

IQ, executive function, response inhibition, cognitive/ psychomotor processing speed

Rathouz et al. [10]

69 idiopathic and focal epilepsy

62 healthy first-degree cousins

8–18 years

2, 5, 6 years

Academic achievement (reading, spelling, math), IQ, language, executive function, motor function

Baseline: IQ, response inhibition and psychomotor speed significantly lower compared to controls. Prospective decline: IQ. No prospective decline: response inhibition, psychomotor speed, problem-solving abilities Baseline: arithmetic computation, response inhibition, attention, fine motor dexterity, and psychomotor speed significantly lower than controls. No prospective decline: across all cognitive domains

Epilepsy and cognition

251

Table 3 Controlled prospective adult studies Mean retest interval

Cognitive domains examined

Mean age 22 years

5 years

IQ

Mean age newly diagnosed: 5; chronic: 42; controls: 31

5 years

IQ, verbal memory

Study

(N) Seizure type Control group

Age

Dodrill and Wilensky [9]

105 without 143 chronic status unspecified epilepticus epilepsy syndrome 39 new-onset, 46 healthy controls previously untreated left temporal lobe epilepsy (TLE), 16 chronic left TLE

Aiki€a et al. [24]

Dodrill [25]

35 localization related epilepsy (LRE)

35 controls with no history of medical problems

10 years Mean age (6 months) 30 years at study onset

IQ, academic achievement, memory, motor function

Key results

Baseline: IQ insignificantly lower compared to controls. Prospective decline: IQ Baseline: among newly diagnosed LTLE total immediate recall, delayed recall, and % retained significantly lower than controls; among chronic LTLE total immediate recall, recency, delayed recall, % retained, and delayed recognition significantly lower than controls. No prospective decline: verbal memory Baseline: not provided. Prospective decline: visual memory loss noted across both groups; significance not indicated. *Notes greater improvement in control group on 3 of 20 variables; comparison to baseline or significance not provided

Hermann et al. [26]

46 LRE

65 controls

14–59 years

4 years

IQ, language, visuoperceptual/ spatial skills, memory, executive function, psychomotor processing, fine motor

Piazzini et al. [27]

50 LRE

50 healthy controls

18–60 years

Over 5 years

IQ, attention, psychomotor speed, language, memory (verbal and visual)

Andersson-Roswall et al. [28]

36 LRE, half with secondarily generalized tonic-clonic seizures

25 healthy controls

Mean age subjects: 33 years; controls: 36

4.8 years (epilepsy); 3.1 years (controls)

Verbal memory, verbal cognition, attention/ processing speed

Baseline: all cognitive domains significantly lower compared to controls. Prospective decline: indicated among a subset of LRE; 40% confrontation naming; 27% delayed visual memory; 38% delayed verbal memory; 64% bilateral motor speed Baseline: no significant differences across cognitive domains compared to controls. Prospective decline: attention; psychomotor speed. No prospective decline: IQ; language; memory (verbal and visual) Baseline: all cognitive domains significantly lower compared to controls. Prospective decline: 2 verbal memory variables; 3 attention/ processing speed variables. No prospective decline: verbal cognition Continued

Table 3 Controlled prospective adult studies—cont’d Mean retest interval

Cognitive domains examined

Mean age subjects: 65; controls: 64

2–3 years

Verbal memory, attention, visuospatial/ constructional, executive function, language

Mean age subjects: 40; controls: 29

12 months

Study

(N) Seizure type Control group

Age

Griffith et al. [29]

17 epilepsy older adults with LRE and generalized epilepsy

17 healthy older adults

Baker et al. [30]

147 newonset, unspecified epilepsy syndromes

69 healthy controls

Savage et al. [11]

14 patients with transient epileptic amnesia (TEA) in TLE

12 healthy age- Mean age at follow-up: matched 78; no controls baseline info

10 years

Key results

Baseline: overall cognitive and verbal memory significantly lower than controls. Prospective decline: executive control. No prospective decline: verbal memory, attention, visuospatial/constructional and language Memory, executive Baseline: psychomotor speed, memory, mental function, flexibility, information psychomotor processing significantly speed, lower than controls. information Prospective decline: processing, mood psychomotor speed, higher executive functioning, memory Baseline: no significant IQ, visuospatial/ differences across cognitive constructional, domains compared to memory (verbal controls. Prospective and visual), decline: memory. No executive prospective decline: visual function recall, object naming, visuoconstructional skills, executive functioning

Epilepsy and cognition

case-control prospective investigation compared the intelligence of children with active epilepsies and nonepileptic sibling controls to determine the stability of intelligence quotient (IQ) over time and found no significant differences between groups at baseline and follow-up [8]. Differences in intelligence were recognizable within groups; children with symptomatic epilepsy having a significantly lower IQ than children with idiopathic epilepsy. The authors noted a decrease in IQ in a minority of children with epilepsy (CWE, 11%) associated with a decrease of IQ by 10 or more points attributable to earlier age of onset of epilepsy, frequent seizures, and drug toxicity. Further drug toxicity, specifically phenobarbital, predicted decreases in IQ better than poor seizure control [8]. Lindgren et al. [18] found that general IQ did not differ between children with rolandic epilepsy (RE) and healthy classmate controls. Children with RE also did not differ from controls across measures of immediate memory, reading comprehension, reading speed, and spelling. At the initial evaluation, children with RE had greater difficulties with memory and learning of auditory-verbal material, delayed recall, measures of executive functioning, and word comprehension; however, these differences did not persist at follow-up leading investigators to conclude at nearly 5 years post-onset, that children with RE do not have major cognitive declines compared to controls. Also extending beyond a focus on only intelligence and aiming to understand educational predicaments of CWE, Oostrom et al. [17] compared CWE to healthy classmate controls across various components of cognition. CWE obtained significantly lower scores across measures of attention, reaction time, location learning, and academic skills at all follow-up time points (3 and 12 months). Contrary to findings by Bourgeois et al. [8], these findings could not be explained by epilepsy features within group.

3.2 Present review of child and adolescent literature The present primer reviews seven case-control longitudinal studies identified since reviews by Dodrill [6] and Seidenberg and colleagues [7]. Of these seven studies, four utilized the same cohort [10,20,22,23]. As such, the most recent and encompassing article from each will be included in this chapter as part of the review [10]. What proceeds is a discussion of domain-specific findings in five articles new to this literature. Significant findings were noted across a number of cognitive domains, including intelligence, academic achievement, executive function, and motor function. Full summation of these studies is presented in Table 3. Child and adolescent cognitive abilities were evaluated using a wide variety of domains and related tests including: intelligence (Wechsler Intelligence Scale for Children [WISC]—Revised, Coloured Progressive Matrices, Standard Progressive Matrices, WISC—Revised [Dutch edition], Wechsler Abbreviated Scale of Intelligence [vocabulary, matrix reasoning], Kaufman Brief Intelligence Test); academic achievement (Wide Range Achievement Test); executive function (Delis-Kaplan Executive Function System [Confirmed Correct Sorts, Color-Word Interference Test-Inhibition], Connors

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Continuous Performance Test-II, Colour Trails I and II, Balloon Piercing); memory (word span forward and backward, learning locations, Everyday Memory Questionnaire, WISC [Fourth Edition], Wide Range Assessment of Memory and Learning [Second Edition], Detroit Tests of Learning Aptitude-Revised, Benton Revised Visual Retention Test); motor function (WISC—Revised [coding subtest], Reaction Time [Vienna Test System], Grooved Pegboard, WISC [Third Edition, digit symbol-coding]). 3.2.1 Intelligence Three of the four newly reviewed studies included measures of intelligence across testretest intervals ranging from 3 months to 6 years 10,16,19]. Two of these studies found children with idiopathic and genetic generalized epilepsies to perform significantly worse than sibling and healthy children controls in direct case-control comparison [16] and stand in contrast to previously reviewed studies indicating no prospective differences between groups in IQ [8,18]. Bailet and Turk [16] assessed children across three test sessions with an unspecified amount of time between sessions. The epilepsy-control group effects on IQ were noted to be significantly lower than siblings for the first two sessions only. These comparisons, though concluded to indicate pervasive cognitive deficits, are not formal prospective changes. Investigations have found epilepsy severity, earlier age of onset and seizure type to be insignificant predictors poor performance across domains of intelligence [16]. Rathouz et al. [10] did not find significant differences or prospective changes in IQ across time. The remaining study did not explicitly report findings from intelligence measures [19]. 3.2.2 Academic achievement Across three testing sessions administered by Bailet and Turk [16], CWE performed worse than controls across all three sessions on measures of reading and spelling and only performed worse than controls at the third session on measures of arithmetic, suggesting variable group differences at individual time points, leading the authors to conclude persistent academic difficulties were present. Dunn et al. [21] found baseline reading and math scores to be comparable with follow-up at 36 months indicating deteriorating performance. Writing performance was significantly worse at baseline and follow-up with prospective decline. Consistent with Bourgeois et al. [8], earlier age of epilepsy onset and symptomatic/cryptogenic etiology were identified as risk factors for worse performance [21]. Rathouz et al. [10] found statistically significant differences only across measures of arithmetic computation while elemental academic skills, including word reading and spelling, were less affected. Further, these impairments, though present at baseline, remained stable with no progressive decline up to 6 years following baseline evaluation. General trends across these three studies measuring academic achievement indicate that CWE performed worse than control participants at the various time points but with no

Epilepsy and cognition

significant change over time. These findings are in the context of different populations of epilepsy examined and different measures of academic performance. 3.2.3 Executive function Recent studies continue to examine executive abilities of CWE. Though previously reviewed studies [18] suggest positive and comparable performance across executive functioning between CWE and controls, others find sustained attention and response inhibition to be vulnerable domains [10,19]. While Oostrom and colleagues [19] found CWE to maintain poor attentional abilities throughout follow-up, Rathouz et al. [10] only recognized differences in response inhibition and attention at baseline. The baseline impairments remained stable over time and did not appear to worsen or decline across subsequent evaluations. 3.2.4 Memory Two studies found CWE to have deficits compared to control participants across measures of verbal, visual, everyday, working, and short-term memory [16,19]. One of these studies recognized static group differences at two of three assessment points over the course of 3 or more years, finding CWE to have worse immediate verbal and visual recall [16]. Progressive decline was also found in memory span for words [19]. These findings occur in the context of test-retest intervals ranging from 3 months to 3.5 years and varying assessments across studies. Poorer performance at follow-up was associated with prediagnostic learning history [19]. 3.2.5 Motor function Additionally, findings suggest impairments in motor and psychomotor function among CWE that persist over time but are not progressive. Bailet and Turk [16] found CWE to have worse psychomotor speed than controls at test sessions one and two, but not at the third, indicating no progressive decline. Rathouz et al. [10] found fine motor dexterity and psychomotor speed to be vulnerable areas of cognitive development at baseline with abnormalities that persisted, but stable and not progressively worsening over time. In summary, across these investigations, CWE tended to perform worse than control participants at their initial assessments, sometimes but not always assessed near the onset of their epilepsy, across the areas of intelligence, academic achievement, executive function, memory, and motor function. These impairments are noted across varying retest intervals (3 months–6 years), assessment measures, and types of epilepsy. Frank declines were observed in intelligence [20,23], executive function [19], and academic achievement [17,20–22]. Otherwise, nonprogressive cognitive abnormalities predominated.

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4. Adult studies 4.1 Summary of previously reviewed adolescent and adult literature In Dodrill’s [6] initial review, he found that, compared to the pediatric literature, adult studies included and examined a more diverse group of cognitive domains and tests (8 of 13 studies examined other cognitive domains in addition to IQ) with longer test-retest intervals (1–10 years). Similar to studies assessing cognition in childhood epilepsy, the adult studies examined by Dodrill often did not provide specific details with regard to seizure type or frequency, with limited exceptions. Taken together, the findings were felt to be mixed, demonstrating a mild correlation between epilepsy and cognitive decline. For the studies reporting seizure frequency, seizures were related to adverse effects on verbal and visual memory, attention, executive function, and intellectual function (with gain in IQ associated with improved seizure control). In the Seidenberg et al. review [7] it was noted that, overall, the pattern of cognitive change exhibited by the epilepsy group could be described as “a lack of or less improvement compared to the controls [lack of practice effect from test-retest], rather than an absolute level of decline.” However, several studies reported objective decline in multiple cognitive domains, which were found to be most dramatic for verbal memory, attention, and psychomotor speed.

4.2 Present review of adult literature Results from nine longitudinal investigations with adults (Table 3) revealed progressive changes in verbal memory, attention, processing speed, and higher order executive functions. Five hundred twenty-seven individuals with epilepsy (e.g., partial, generalized, and mixed) and their controls (410) were followed and measured cognitive changes between 1- to 10-year periods. Cognitive abilities were evaluated using various assessments divided into specific cognitive domains including: IQ (Wechsler Adult Intelligence Scale [WAIS], WAIS-Revised, WAIS-III, Wechsler Abbreviated Scale of Intelligence, Wechsler Test of Adult Reading, Raven’s Progressive Matrices); achievement (Wide Range Achievement Test), global cognitive status (Dementia Rating Scale, DRS); attention/psychomotor speed (WAIS-R, Digit Span, Digit Symbol, Trail Making Test [Parts A and B], Binary Choice Reaction Time, and Computerized Visual Search Task); memory (Wechsler Memory Scale [WMS], WMS-III, Rey Auditory Verbal Learning Task, Claeson-Dahl Learning and Retention test, Cronholm-Molander Memory Test, Adult Memory and Information Processing Battery, Auditory Verbal Learning Test, Rey Complex Figure Test [RCFT] Delayed Recall, and the Warrington Recognition Memory Test [RMT]—Words and RMT-Faces); visuospatial/constructional abilities (RCFT); executive functions (Wisconsin Card Sorting Test, Stroop-Interference Test, WMS-III, Working Memory, and Executive Interview Test); language (Graded Naming Test, Graded Faces Test, Boston Naming Test, Controlled Oral Word Accentuation Test,

Epilepsy and cognition

FAS, animal fluency, and Token Test), and motor abilities (Grooved Pegboard). The Halsted-Reitan Neuropsychological Battery was utilized in only one study [25]. 4.2.1 Memory Five studies involving individuals with partial, generalized, and mixed epilepsy were followed for a period between 1 and 10 years demonstrating prospective declines in verbal memory [25,26,28–30]. Stable verbal memory performance was noted in four studies [11,24,27,29]. Andersson-Roswall [28] considered verbal memory declines to be the strongest association of epilepsy in a partial epilepsy cohort. Lower levels of verbal memory performance were also evident at baseline [28]. Worse verbal memory performance was associated with early onset in newly diagnosed and chronic left temporal lobe epilepsy individuals with secondary generalizations, but without noted decline over time [24]. Griffith et al. [29] found older adults with chronic partial epilepsy to perform lower on verbal memory measures than controls at baseline, but without evidence of a progressive verbal memory decline. Another cohort with transient epileptic amnesia demonstrated evidence of accelerated forgetting at baseline, with most individuals demonstrating improvements in recent autobiographical memory, but not in remote memory [11]. Two prospective studies (total of 81 subjects) with localization-related epilepsy were followed between 4 and 10 years demonstrating an association of status epilepticus with prospective changes in visual memory scores [25,26]. Two other cohorts demonstrated stability in visual memory performances [11,27]. 4.2.2 Intelligence Differences in IQ scores in individuals with status epilepticus have also been found in the literature. Two studies found changes in IQ scores over time [9,25]. One study found prospective changes in verbal IQ [9] and another in overall intelligence (e.g., WAIS FSIQ) [25]. 4.2.3 Attention/processing speed Attention and processing speed are domains particularly associated with progressive declines in individuals with epilepsy. Two studies demonstrated declines in attention [27,28], psychomotor speed [28,30], and processing speed [28]. Conversely, Griffith et al. [29] found no progressive changes in attentional measures (e.g., DRS) in a cohort of older adults over time. Attentional measures in this study were part of a cognitive screener, which may not be sensitive to more subtle cognitive changes. 4.2.4 Executive functions Declines in executive functions were evident in three longitudinal studies of epilepsy [26,29,30]. A study with older adults revealed lower performance in cognitive function at baseline, but these declines were not considered progressive. Declines were evident in executive control [29]. Baker et al. [30] found declines in mental flexibility.

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Hermann et al. [26] reported changes in aspects of executive functions over a 4-year interval. In this study, 12%–25% of individuals exhibited adverse cognitive outcomes, with declines associated with abnormalities in baseline quantitative magnetic resonance volumetrics, lower intellectual capacity, longer duration of epilepsy, and older chronological age [26]. Overall, results of these nine studies are indicative of longitudinal changes (1–10 years) in individuals with epilepsy, particularly in verbal memory, attention, processing speed, and higher order executive functions. 4.2.5 Limitations The current review focused on controlled prospective studies, which examined the cognitive trajectory of adults and adolescents with epilepsy. Though previous concerns regarding lack of control groups and, in turn, the ability to speak to conclusions about cognitive progression [7] were addressed, this compilation of studies is considered in the context of several methodological limitations identified the literature. First, the utilization of multiple and varied assessments to measure similar domains across studies serves to limit direct comparison of findings. While a standardized assessment battery across centers would certainly prove difficult to implement, it would certainly facilitate comparison of results across studies, particularly in long-term follow-up. Second, modest test-retest intervals continue to be seen in the reviewed articles. Several researchers [6,10,21,26] have acknowledged that perhaps longer durations of time must pass in order to fully characterize the possible extent of adverse effects of epilepsy on cognitive function. Third, with the exception of two studies [9,21], participant group sizes tend to be less than 100 individuals, perhaps limiting generalizability of findings outside the research context and across epilepsy types. Accounting for these limitations is essential in looking towards future directions of prospective studies on neuropsychological functioning of adults and CWE. We remain with the general view that cognitive decline does occur in some patients with epilepsy; this is the exception rather than the rule. More common are static abnormalities over time, lack of practice effects, or lack of normal development in pediatric patients. Compared to other fields of investigation (aging, preclinical Alzheimer’s disease, schizophrenia), controlled prospective neuropsychological research in epilepsy remains arguably rudimentary. Those fields show the importance of multiple assessments (>2) to rule out chance and transient declines of uncertain etiology, longer follow-up intervals, greater consideration of other important predictor variables (e.g., baseline health status, neuroimaging status), and use of advanced metrics to identify reliable change. Research of this type is complicated and expensive and requires the dedicated participation of persons with epilepsy. This is clearly an important clinical issue requiring substantial economic investment and collaboration across investigators and centers to undertake a big data approach to conclusively answer an empirical question first addressed in 1924 and of clinical concern far before that time.

Appendix Table 4 Uncontrolled prospective pediatric studies Cognitive domains examined

(N) Seizure type

Age

Mean retest interval

Fox [12]

130 unspecified epilepsy syndrome 128 unspecified epilepsy syndrome

5–17

IQ

Fetterman and Barnes [32]

46 unspecified epilepsy syndrome

Not provided

1 year (1922 vs. 1923) 98 cases (51 boys, 47 girls) were tested twice; 30 cases (12 boys, 18 girls) tested three times 21 months

Sullivan and Gahagan [33]

103 organic (definite or questionable), idiopathic (undifferentiated or psychogenic), or unspecified epilepsy syndrome 129 idiopathic epilepsy

1 month–4 years 11 months (average interval 14 months)

IQ

Varied from 3 months to 3 years Not provided

IQ

Patterson and Fonner [31]

Kugelmass et al. [34] Tenny [35]

284 unspecified epilepsy syndrome

Not provided

IQ

IQ

IQ

Key results

General tendency toward deterioration IQ variable over time (in either positive or negative direction)

No decided trend. Conjectured changes no different than those that would be found in healthy individuals IQ scores varied in positive or negative direction

Trend toward deterioration in unimproved group IQ scores varied in positive or negative direction. The negative change

261

Continued

Epilepsy and cognition

Study

262

Table 4 Uncontrolled prospective pediatric studies—cont’d (N) Seizure type

Age

Mean retest interval

Cognitive domains examined

Rodin et al. [36]

64 unspecified epilepsy syndrome

Initially between ages 5 and 16

At least 5 years (mean 9.6 years, range 5–33 years)

IQ

Aldenkamp et al. [37]

45 generalized epilepsy, partial (left or right), or multifocal epilepsy

Assessed at mean ages of 9.3, 10.5 (only 20), and 13.5 years

Mean follow-up 4.2 years (range from 2.1 to 9.8 years)

IQ

Key results

in IQ was somewhat more marked in pupils whose seizures were increased in frequency than for those whose seizures were unchanged, decreased, or controlled Verbal, performance, and FSIQ scores slightly lower but insignificant at follow-up. IQ insignificantly rose in children with controlled seizures, while IQ insignificantly fell in children with uncontrolled seizures Stable pattern of cognitive performance—mean full scale, verbal, and performance IQs did not yield significant increase or decrease. Following subtests consistently yielded lower scores: information, coding, digit span, vocabulary

The Comorbidities of Epilepsy

Study

Language, visuospatial/ constructional, memory, executive function IQ, memory, academic achievement, processing speed, language, executive function

44 rolandic epilepsy (RE)

Onset between 4 and 7 years

Twice yearly; WISC every 18 months

Northcott et al. [39]

42 RE

3–15 years

Varied: 17 between 12 and 18 months; 8 between 18 and 24 months; 3 at longer intervals (2 +, 3+, 5 + years)

Prevost et al. [40]

21 frontal lobe epilepsy

9.4 +/ 3.5 years

Not specified

Berg et al. [41]

198 West syndrome, benign partial epilepsy of childhood with centrotemporal spikes (BECTS), childhood absence epilepsy, myoclonic-atonic, nonsyndromic with focal features, generalized or mixed epilepsy, and unspecified epilepsy syndrome

Mean age of onset 6.7 (+/ 3.9) Onset <8

8–9 years

IQ

Atypical group had significantly lower FSIQ and verbal IQ than typical group. Slower reaction times Improvement in verbal memory, receptive language ability, and phonemic manipulation. No change in visual memory and aspects of phonologic awareness. Improvements were not related to the clinical variables No clear outcome data provided Pharmacoresistance associated with 11.4 point lower FSIQ. IQ correlated with age of onset in pharmacoresistant group

263

Continued

Epilepsy and cognition

Metz-Lutz and Filippini [38]

264

Cognitive domains examined

Study

(N) Seizure type

Age

Mean retest interval

van Iterson et al. [42]

113 generalized, focal, bilateral or multifocal, and unspecified epilepsy syndrome

4–15 years

Varied based on need for reassessment

IQ

Reuner et al. [14]

76 idiopathic epilepsy

6–17 years

3 months

Attention, executive function (EpiTrack Junior®)

Key results

Downward progression. Later age of onset associated with greater decline in verbal performance at follow-up Children with new onset epilepsy have prospective impaired performance compared to controls but better performance than children with chronic epilepsy. Unknown etiology or unclassified is predictor for prospective decline incognitive functions even before antiepileptic treatment

The Comorbidities of Epilepsy

Table 4 Uncontrolled prospective pediatric studies—cont’d

Table 5 Uncontrolled prospective adult studies Adult studies without controls (N) Seizure type

Age

Mean retest interval

Cognitive domains examined

Barnes and Fetterman [13]

35 idiopathic, organic, birth trauma, postencephalitic, alcoholic, glandular, hysterical epilepsy 100 unspecified epilepsy syndrome

15–52 years

1 year

IQ, verbal memory

3–58 years

1 year

IQ

Arieff and Yacorzynski [44]

27 nonorganic epilepsy

16–68 years

1–10 years

IQ, verbal memory

Yacorzynski and Arieff [45]

63 mixed epilepsy

10–57 years

1–7 years

IQ

Falket al. [46]

85 mixed epilepsy

23–63 years

9–14 years

IQ

SomerfeldZiskind and Ziskind [43]

Key results

Duration of epilepsy, with chronological age and number of attacks held constant, was determined to be a significant factor in “loss of efficiency” in people with epilepsy No impairment noted in cognition after one year. No perceptible difference in IQ Patients with organic epilepsy as a group show definite deterioration by 6 IQ points between first and last test Eight patients showed a significant increase in IQ between the first and final tests. One patient showed a significant decrease in IQ. No relationship between reduction in number or severity of seizures and the changes in IQ No evidence of cognitive deterioration was found except in the case of three psychotic patients

265

Continued

Epilepsy and cognition

Study

266

Study

(N) Seizure type

Age

Mean retest interval

Cognitive domains examined

Hilkevitch [47]

66 idiopathic epilepsy

8–53 years

Not reported

IQ

Seidenberg et al. [48]

58 partial elementary, partial complex, partial secondarily generalized, absence, tonicclonic

Mean age 22

18.6 months for seizures improved group (SI); 19.4 months for seizures unimproved group (SU)

IQ, motor speed, processing speed, memory

Key results

Negligible degree of deterioration and much variability during institutionalization. Difference in IQ approximately 4 points between test 1 and 2 means. 17 (65.4%) individuals had a stable or improved IQ on retest. Average of 19-point drop in IQ in 9 (34%) deteriorated cases. Tendency for lower IQ to be related to more frequent attacks; seizure frequency related to change in IQ Retest revealed that 9 of 14 WAIS scores of SI were significantly higher than the SU. Changes in seizure frequency were associated with changes on the test-retest scores. Decrease more likely to be found on VIQ

The Comorbidities of Epilepsy

Table 5 Uncontrolled prospective adult studies—cont’d Adult studies without controls

240 tonic-clonic, complex partial, spike-wave, unspecified epilepsy syndrome

20–57 years

Not reported

IQ

Dodrill and Wilensky [50]

198 unspecified epilepsy syndrome

16 + years

5 years

IQ, attention, executive function, memory, processing speed, language

Selwa et al. [51]

47 temporal lobe epilepsy (TLE)

Mean age surgical group: 31; nonsurgical group: 30

1–8 years

IQ, memory (verbal and visual)

Holmes et al. [52]

35 intractable complex partial epilepsy

16–59 years

10 years

IQ, attention, executive function, memory,

Decline in IQ (15%), mean fall was 21.3. IQ deterioration related to medication use— phenytoin and serum folic acid. 21 (70%) of 30 demonstrated IQ deterioration greater than 15 points. Seizure type, head injury, and AED linked to deterioration For performance IQ, no statistically significant difference could be found with respect to any single group over time using the student t statistic. This study did not find evidence that sustained administration of AEDs was associated with cognitive losses over time Little change occurs in measurable memory or IQ of medically managed TLE patients over relatively long time For most adults with medically intractable complex partial epilepsy, there were no general changes in IQ

267

Continued

Epilepsy and cognition

Trimble [49]

268

Study

(N) Seizure type

Age

Mean retest interval

Cognitive domains examined

processing speed, language

Bjørnaes et al. [53]

34 mixed epilepsy (17 children, 17 adults)

Mean age children: 10; adults: 24

3.5 years (children) and 6.0 years (adults)

IQ

Pai and Tsai [54]

64 partial and nonpartial, symptomatic and idiopathic/ cryptogenic

Mean age high education: 32; low education: 45

1 year

Memory, attention, executive function, language, visuospatial/ constructional

Key results

or neuropsychological functioning after 10 years. Neuropsychological test scores remain reasonably stable over the decade In the children, there was a decline in mean IQ scores during the testretest interval, while the IQ scores increased in the adult group. Recurrent seizures may represent a considerable risk for intellectual decline in children, while intellectual functioning seem to be less vulnerable in adults with early onset epilepsy Decline: attention, mental manipulation Improvement: verbal fluency. No change: memory, language, abstract thinking, orientation, drawing

The Comorbidities of Epilepsy

Table 5 Uncontrolled prospective adult studies—cont’d Adult studies without controls

136 mixed epilepsy

Mean age baseline: 31; follow-up: 44

10 years

IQ, memory, language, executive function

Taylor and Baker [56]

50 newly diagnosed and previously untreated partial, generalized, and unspecified epilepsy syndrome

Baseline: 15–78 years; follow-up: 21–84 years

5 years

Psychomotor speed, memory, executive function, mood, subjective report of cognitive complaints

Mamenisˇkien_e et al. [15]

33 TLE

30–66 years

13 years

Psychomotor speed, attention, verbal (verbal and visual)

Decline: all domains Frequency of GTCS was strongest predictor of decline. Complex partial seizure frequency was associated with decline in memory and executive skills but not in IQ. Periods of remission were associated with better cognitive outcome Decline: reaction time, verbal memory. Trend for worse performance on serial recognition of words, information processing, and computerized visual search. Trend toward improvement on serial recognition of figures and inhibition No significant change in most domains. Nonverbal memory declined

Epilepsy and cognition

Thompson and Duncan [55]

269

270

The Comorbidities of Epilepsy

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