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A comprehensive neuropsychological description of cognition in drug-refractory juvenile myoclonic epilepsy
Epilepsy & Behavior 36 (2014) 124–129
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Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
A comprehensive neuropsychological description of cognition in drug-refractory juvenile myoclonic epilepsy Rhys H. Thomas a,⁎, Jordana Walsh b, Carla Church a, Graeme J. Sills b, Anthony G. Marson b, Gus A. Baker b, Mark I. Rees a a b
Wales Epilepsy Research Network (WERN), College of Medicine, Swansea University, Swansea SA2 8PP, UK Department of Clinical and Molecular Pharmacology, University of Liverpool, Liverpool, UK
a r t i c l e
i n f o
Article history: Received 16 February 2014 Revised 11 April 2014 Accepted 30 April 2014 Available online xxxx Keywords: Juvenile myoclonic epilepsy Psychology Executive function Memory Cognition
a b s t r a c t The study of juvenile myoclonic epilepsy is important in that: it is common and heterogeneous; the etiology is unknown; and patients report broad cognitive problems. We utilized a broad battery of neuropsychometric tests to assess the following: intellectual function, memory, language and naming, executive function, the impact of epilepsy, and antiepilepsy drug side effects. Sixty people with drug-refractory JME were interviewed, and performance was profoundly impaired across the range of tests. Impairments included the following: full-scale IQ (89, p b 0.001); processing speed (86, p b 0.001); visual memory (immediate and delayed) more affected than verbal memory; verbal fluency and inhibition (p b 0.001); and self-reported drug side effects (p b 0.001). Eighty-three percent of patients exhibited frank executive dysfunction, which was moderate to severe in 66%. Regression modeling confirmed that an early age at onset and the need for polytherapy were associated with poorer cognitive outcomes. This study confirms previous reports of executive dysfunction in a larger cohort and with greater statistical rigor. We also identified a high prevalence of neurotoxicity symptoms such as fatigue and poorer functioning across intellectual and memory tests than had previously been reported. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Juvenile myoclonic epilepsy (JME) is both the most typical and atypical of the genetic generalized epilepsies (GGEs). It is a common electroclinical syndrome that accounts for 5 to 10% of all epilepsies [1]. It is characterized by the following: i) the age at seizure onset; ii) the triad of absence seizures, generalized tonic–clonic seizures, and epileptic myoclonus — of which only myoclonus needs to be present; iii) a tendency for lifelong seizures with an early morning preponderance; and iv) typically, the improvement of seizure control in 80% of individuals with the use of sodium valproate. The atypical features include the following: i) an inconsistency as to how cases are defined [2]; ii) despite the evidence from twin studies and family aggregation studies [3], no convincing gene for this genetic epilepsy has been identified [4]; iii) despite being classified as a generalized epilepsy, focal EEG features are seen in a third of cases [5], and there are focal patterns of neuropsychological deficits [6]; and iv) there is variation in terms of response to antiepileptic drugs and long-term consequences between individuals [7]. There is a current
⁎ Corresponding author at: MRC Centre for Neuropsychiatric Genetics and Genomics, Haydn Ellis Building, Maindy Road, Cardiff CF24 4HQ, UK. Tel.: +44 20688320. E-mail addresses: [email protected] (R.H. Thomas), [email protected] (J. Walsh), [email protected] (C. Church), [email protected] (A.G. Marson), [email protected] (G.A. Baker), [email protected] (M.I. Rees).
http://dx.doi.org/10.1016/j.yebeh.2014.04.027 1525-5050/© 2014 Elsevier Inc. All rights reserved.
consensus that JME is a heterogeneous epilepsy syndrome, considering response to antiepileptic drugs, long-term consequences, and the presence of psychiatric and cognitive comorbidities [8–10]. 1.1. Neuropsychological performance It is not uncommon for people with JME to describe ‘real-world problems’ with planning and sequencing in the context of a preserved IQ [11–14]. These difficulties were recognized in the definitive descriptions of JME by Janz and Christian in 1957 [15]. Impulsivity and greater novelty seeking are also recognized in JME, particularly when seizure control is poor [16]. There is growing evidence of executive function deficits from studies of individuals with predominantly drug-responsive JME [6,17]. 1.2. Hypothesis and aims There is a growing consensus of subtle executive function deficits from studies of individuals with predominantly drug-responsive JME [6, 18]. These findings are consistent with advanced imaging studies, which implicate functional abnormalities in the frontal cortex and thalamus. Consistency within neuropsychological studies has been hampered, however, by the following: i) inadequate sample sizes, ii) clinical heterogeneity between cases, iii) atypical performance in ‘control’ populations, and iv) the utilization of only a limited number of neuropsychological tests.
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Considering the heterogeneity of this syndrome, studies on the subgroup of drug-refractory JME are necessary because of the notable heterogeneity of this syndrome. We, therefore, undertook a comprehensive study of cognition in people with drug-refractory JME. These individuals are most likely to use clinical services and represent the cohort with the greatest social burden. We hypothesized that there would be no differences in cognitive performance between these individuals and standardized control means after correcting for multiple comparisons.
2.2.5. Questionnaires The Aldenkamp–Baker Neuropsychological Assessment Scale (ABNAS) was included to assess the patients' perceived level of cognitive effects of their AEDs [22,23]. The Impact of Epilepsy Scale (IES) was employed to assess the current daily functioning of people with epilepsy, including their relationships with friends and family, social life, employment, health, self-esteem, plans for the future, and standard of living.
2. Methods and materials
2.3. Statistical analysis
2.1. Participants
Means and standard deviations (SDs) were reported for continuous data that met the normal distribution. If data were considered skewed from the normal distribution, the median and interquartile ranges were reported. Participants' scores were compared with the standardized means using one sample t-tests. To analyze the ABNAS, where these means were not available, a clinical sample was chosen for comparison [23]. To control for and assess the impact of education, intellectual functioning scores were correlated with years in education using Pearson's R correlation coefficients. To reduce the likelihood of making Type I errors, the significance level was set at p b 0.01 for all t-tests. To determine the impact of contributory factors (age at onset of epilepsy, duration of epilepsy, types of seizures, number of AEDs and ABNAS) on the neuropsychological profile of the sample, bivariate correlation and regression analyses were conducted. Standard linear regression was chosen to assess the predictive power of all the variables and to identify which factors significantly contributed to the explanation of variance in cognition.
Sixty patients with drug-refractory JME were assessed as part of the multicenter MRC (Medical Research Council)-funded refractory juvenile myoclonic epilepsy cohort (ReJuMEC) study. Ethical approval was granted by the NorthWest (Cheshire) and the South West Wales Research Ethics Committees; written informed consent was obtained from all patients. Participants were recruited from outpatient appointments with epilepsy specialists in the United Kingdom. Patients were classified as having drug-refractory epilepsy if they experience one or more myoclonic, absence, or tonic–clonic seizures per month despite prior or current exposure to a dosage of at least 1000 mg/day of sodium valproate. Care was taken to identify individuals who do not adhere to prescribed medication; these individuals were excluded. Exclusion criteria included abnormal MRI brain scan, alcoholism, a history of drug abuse, and a neurological disorder besides epilepsy. Patients were provided with seizure diaries which documented seizure occurrence and frequency. In addition, none of the patients had experienced a generalized tonic–clonic seizure within the 24 h of the neuropsychological assessment. 2.2. Neuropsychological battery Participants were given a clinical interview, and their medical files were studied to obtain detailed histories. A standardized battery of neuropsychological tests was administered to each participant. The battery was chosen to evaluate key areas of neuropsychological functioning including the following. 2.2.1. Intellectual functioning All subtests from the WAIS-III [17] were administered from which full-scale IQ (FSIQ), verbal IQ (VIQ), performance IQ (PIQ), working memory (WM), and processing speed (PS) index scores were obtained. Scaled scores were calculated using WAIS–WMS writer software for each of the subtests for comparison [19]. 2.2.2. Memory All subtests from the WMS-III [20] were administered from which general memory, working memory, immediate memory, visual immediate and delayed, auditory immediate and delayed, and auditory recognition delayed memory index scores were obtained. Scaled scores were calculated using WAIS–WMS writer software for each of the subtests for comparison [21]. 2.2.3. Language and fluency The verbal fluency test from the Delis–Kaplan Executive Function System (D-KEFS) [21] was used; it not only contains subtests analogous to the FAS test but also assesses semantic fluency. In addition, the Boston Naming Test (BNT) was used to assess visual naming ability. 2.2.4. Attention and executive functions The color-word interference task from the D-KEFS was used to assess control of inhibition, perseveration, mental flexibility, and attention. Working memory was tested using the WMS-III.
2.4. Severity of executive dysfunction Executive function tests were divided into six executive functions, and the z-scores of each of the tests were calculated. In concordance with previous research [16,24], a z-score of ≤−1 (one or more standard deviations below the manual means) on at least one test within each of the six domains was categorized as dysfunction in relation to that domain. As naming ability was measured by only one test, a z-score of ≤−1 on the Boston Naming Test was categorized as dysfunction in relation to naming ability. Low scores in two domains equated to a mild dysfunction, three or four scores to moderate dysfunction, and all five to severe executive dysfunction. The executive function tests were divided into the following six domains: • Working memory, mental control of auditory–visual stimuli, and attention span were assessed using the digit span and letter–number sequencing. • Visual working memory, mental control of visual–spatial stimuli, and attention were assessed using the digit symbol coding and spatial span. • Verbal fluency was assessed using the letter fluency and category fluency. • The ability to switch between categories was assessed using the category switching and the category accuracy. • The ability to inhibit responses to visual–verbal stimuli was assessed using the color-word interference test (verbal inhibition and inhibition switching). • Naming ability was assessed using the Boston Naming Test. 3. Results 3.1. Clinical features Sixty patients with drug-refractory JME were recruited. The median age at seizure onset was 12 years (IQR = 8–15), while the median duration of epilepsy was 21 years (IQR = 10–30.5). Ninety-six percent of patients had at least one generalized convulsion, and 70% had absence
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seizures. Nine patients reported clinical photosensitivity (18%, n = 51). Two-thirds returned seizure diaries; half reported daily myoclonus that persisted (only 7.5% reported abatement of these seizures). If absence seizures were a feature, they were often frequent (25% of those with absence seizures had them daily or more often); 50% described monthly absence attacks. Eleven percent (n = 54) described a prior history of febrile convulsions, and 44% (n = 57) knew of a close family member with epilepsy.
3.1.1. Antiepilepsy medication at testing At the time of the interview, 28 (47%) participants were taking a single antiepilepsy drug; 20 (33%) were taking two; 11 (18%) were taking three; and one individual was taking four. The monotherapy AEDs were valproate (n = 17, mean daily dose of 1464 mg), lamotrigine (n = 5, mean daily dose of 300 mg), and levetiracetam (n = 4, mean daily dose of 2500 mg), and zonisamide and topiramate were both taken by single individuals. In the people taking two AEDs, there were 12 different combinations, the most common of which was valproate and levetiracetam (n = 5) followed by valproate and lamotrigine (n = 3). There were six different combinations of three AEDs taken concurrently, four of these included clobazam as an adjunct.
Table 2 Memory function as measured by the WMS of patients with drug-refractory JME compared with healthy standardized controls. Cognitive test
JME mean (SD)
Published norms (SD)
p value
Immediate memory Immediate visual memory Immediate auditory memory Delayed visual memory Delayed auditory memory Recognition memory (verbal) General memory WMS working memory Logical memory: immediate recall Logical memory: delayed recall Verbal paired associates: immediate recall Verbal paired associates: delayed recall Faces: immediate recognition Faces: delayed recognition Family pictures: immediate recall Family pictures: delayed recall Spatial span
90.5 (13.1) 87.6 (14.1) 95.8 (12.5) 88.2 (19.4) 100.2 (13.0) 100.4 (14.7) 95.2 (13.4) 90.4 (15.5) 9.8 (2.9)
100 (15) 100 (15) 100 (15) 100 (15) 100 (15) 100 (15) 100 (15) 100 (15) 10 (3)
b.001 b.001 .013 b.001 .888 .831 .009 b.001 .660
10.5 (2.6) 8.6 (2.5)
10 (3) 10 (3)
.133 b.001
9.6 (2.6)
10 (3)
.249
8.0 (7.0, 9.0)a 9.0 (7.0, 11.0)a 7.6 (2.8) 8.0 (5.0, 10.0)a 8.0 (6.0, 10.0)a
10 (3) 10 (3) 10 (3) 10 (3) 10 (3)
b.001b .031b b.001 b.001b b.001b
a b
3.1.2. Education The majority of the sample was female (75%), and the median age was 31 years (range = 19–67 years). All patients had achieved at least secondary school education with a median number of years of formal education of 13: 38% had attained a college degree, and 13% graduated from a university. Sixty-five percent were currently employed, 5% were students, and the remainder were unemployed.
3.2. Intellectual function The mean FSIQ was 89 for the cohort (range = 55–117). The VIQ, PIQ, PS, WM, and FSIQ (Table 1) were all significantly lower in people with drug-refractory epilepsy (p b 0.001); PS was lowest. Eight (13%) participants returned FSIQs two SDs below the mean (i.e., an IQ of 70 or below). Of the subtests that contribute to these indices, all bar matrix reasoning and picture completion were significantly lower than the standardized means. The poorest scores were seen in digital symbol coding. Some of the subtests also test sequencing such as block design.
Table 1 Intellectual functioning as measured by the WAIS of patients with drug-refractory JME compared with healthy standardized controls. Cognitive test
JME mean (SD)
Published norms (SD)
p value
Full-scale IQ Verbal IQ Performance IQ Processing speed WAIS working memory Vocabulary Similarities Arithmetic Digit span Information Comprehension Picture completion Digit symbol-coding Block design Matrix reasoning Picture arrangement Letter–number sequencing Symbol search
89.3 (15.2) 88.8 (15.3) 91.4 (15.3) 86.0 (80,99)a 88.8 (14.4) 8.4 (3.2) 8.1 (3.1) 7.4 (3.5) 8.6 (2.9) 8.4 (2.9) 8.0 (3.6) 9.1 (3.4) 7.0 (5.0, 7.0)a 8.6 (2.5) 9.6 (3.2) 8.3 (2.9) 8.7 (3.6) 8.3 (3.3)
100 (15) 100 (15) 100 (15) 100 (15) 100 (15) 10 (3) 10 (3) 10 (3) 10 (3) 10 (3) 10 (3) 10 (3) 10 (3) 10 (3) 10 (3) 10 (3) 10 (3) 10 (3)
b.001 b.001 b.001 b.001b b.001 b.001 b.001 b.001 b.001 b.001 b.001 .038 b.001b b.001 .331 b.001 .009 b.001
a b
Media and interquartile range. Wilcoxon signed-rank test.
Media and interquartile range. Wilcoxon signed-rank test.
3.3. Memory performance Immediate memory (particularly immediate visual memory), delayed visual memory, general memory, and WM were all statistically significantly lower in participants than the mean (Table 2). The lowest scores were seen in immediate visual memory (mean = 88). Of the subtests that compose these indices, verbal paired associates, faces, family pictures (immediate and delayed), and spatial span were all significantly poorly performed. 3.4. Executive function Participants scored significantly worse on all tests of verbal fluency and executive function except the category accuracy task (Table 3). The two most poorly performed tests were inhibition switching and the BNT. The severity of executive dysfunctions was also evaluated. Eighty-three percent of patients demonstrated a degree of executive/ attentional dysfunction, which was moderate–severe in 66% (38/58 patients). When a more conservative value of ≤2 SD below manual means was applied to each test, 45% of the patients presented with a degree of executive dysfunction, and 28% presented with moderate to severe dysfunction. 3.5. Patient questionnaires The Impact of Epilepsy Scale was utilized to assess the impact of epilepsy and AED treatment on various aspects of participants' daily lives. The mean IES score of 26.5 indicated that epilepsy had a moderate impact on their daily lives. However, there were 14 participants who Table 3 Executive functioning of patients with drug-refractory JME compared with healthy standardized controls. Cognitive test
JME mean (SD)
Published norms (SD)
p value
Letter fluency Category fluency Category switch Category accuracy Verbal inhibition Inhibition switch BNT
7.4 (3.3) 7.9 (4.2) 8.6 (3.9) 9.2 (3.7) 7.8 (4.3) 6.0 (4.5) 49.1 (9.0)
10 (3) 10 (3) 10 (3) 10 (3) 10 (3) 10 (3) 55.5 (3.9)
b.001 b.001 .007 .114 b.001 b.001 b.001
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Fig. 1. ABNAS subdomains: histogram illustrating the mean points per question theme. The horizontal line is the mean score per question of a large cohort of people with epilepsy [24]. * denotes a statistically significant difference.
scored 31 or more, indicating that epilepsy had a severe impact on their lives. The mean ABNAS score of 37 demonstrates reports of significantly more subjective neurotoxicity symptoms in people with drugrefractory JME than in a large sample of people with epilepsy [24], (p b 0.0001) (Fig. 1). In particular questions regarding fatigue, slowing and memory symptoms received statistically higher scores (all p b 0.001). 3.6. Regression analysis Regression modeling confirmed that there was a positive correlation between the number of years of education and VIQ [r = .497, p b 0.001], FSIQ [r = .422, p b 0.01], auditory immediate memory [r = .340, p b 0.03], auditory delayed memory [r = .373, p b 0.02], and verbal inhibition [r = .375, p b 0.02]. Statistically significant correlations were identified between cognitive performance and the number of AEDs, duration of epilepsy, experience of all three seizure types, and total ABNAS score. Multiple regression analyses revealed total ABNAS score to be a significant independent predictor of FSIQ, PIQ, and VIQ. An earlier age at onset was associated with poorer executive function (category switching and verbal inhibition performance, p b 0.05). The number of AEDs taken was a significant independent predictor of poor performance across many cognitive domains: FSIQ, PIQ, VIQ, PS, immediate memory (both visual and auditory), visual delayed memory, working memory, letter fluency, category fluency, and the BNT.
size, and (iii) enlarging the battery of tests that were applied. While this test battery was more comprehensive than used in previously documented [16] research, areas such as decision-making could not be tested [25]. Rigor is essential, and, thus, this analysis differs from those that were previously reported in that we have corrected for multiple comparisons and we have used sample means for comparison and not ‘inflated’ control group results. It will be important to compare these data with people with drug-sensitive JME. It is likely that they will report fewer neurotoxicity side effects, but whether the broader range of cognitive defects would be replicated is unknown. 4.1. The age at onset of seizures in JME Our cohort of people with JME had a relatively uniform presentation, for example, not one had CAE (childhood absence epilepsy) evolving to JME. This is surprising as CAE evolving to JME has been reported as a subtype of JME where long-term drug control is necessary [9]. Our cases were young at seizure onset (12 years), and many had all three seizure types; both of these factors have been previously identified as risk factors for suboptimal seizure control [10]. Pascalicchio et al. [13] reported that as the duration of epilepsy increased, the degree of impairment increased. In our study, a long duration of epilepsy was significantly correlated with poor function in immediate memory (overall and auditory), attention, and visual working memory (digit symbol coding and symbol search).
4. Discussion There is little consistency in the reports of how people with JME perform across key areas of neuropsychological functioning. The exception lies with executive function tests, in particular verbal fluency and inhibition [6]. We report that people with drug-refractory JME have unambiguous cognitive difficulties across a range of neuropsychological tests. These impairments are seen in global intellectual functioning, immediate and visual memory, and executive functioning including naming. Furthermore, in support of the anecdotes that people with JME struggle with ‘real-world problems’ [11], they also presented with significantly higher ABNAS scores compared with published norms [23] and reported that epilepsy had a moderate impact on their daily lives. These data provide the clearest picture to date of the scope of cognitive difficulties in an epilepsy that was once thought to be synonymous with preserved intellectual function. This was made possible by (i) focussing on a specific subgroup with JME, (ii) recruiting a sample of sufficient
4.1.1. Antiepileptic drugs Polytherapy was significantly correlated with all of the intellect index scores, the memory index scores (except those pertaining to auditory memory), attention, verbal fluency, and naming ability. Even a cohort of our size is insufficient to tease out the effects of the separate AEDs. It is unclear whether the relationship is explained by the neurotoxic effect of AEDs or whether polytherapy is a proxy for a more difficult-to-control JME. Regression analyses revealed the total ABNAS score to be a significant independent predictor of FSIQ, VIQ, and PIQ. Patients with higher ABNAS scores performed within the borderline and impaired ranges on 7/34 measures of intellect and memory and on 5/7 measures of executive functions. In comparison, the patients with lower ABNAS scores returned normal results across the battery for all tests except on naming ability. These findings corroborate previous knowledge on cognitive functioning and AEDs in different types of epilepsy.
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4.2. Memory Table 2 clearly shows that tests of visual memory were performed less well compared with tests of verbal memory; similarly, immediate memory tests returned lower scores compared with delayed memory tests. In keeping with the WAIS, working memory was also obtunded. Sonmez et al. [26] did identify differences in the WMS; however, it is unclear if these observations would have survived correction for multiple comparisons. 4.3. Executive function The most consistent impairment found in JME is executive dysfunction. Devinsky et al. [27] described impairments that included concept formation, mental flexibility, planning, and cognitive speed. The ‘FAS test’ is associated with left prefrontal function and appears to be very sensitive to the effects of JME. Controversial histopathological studies by Meencke and Janz [27] reported microdysgenesis in JME – reports that although they could not be replicated have come back into fashion as they are in keeping with some genetic and psychological findings in JME. Quantitative analyses of high-resolution MR images implicate the prefrontal cortex as a region of greatest abnormality in JME [28]. Structural imaging does not reveal underlying pathology on an individual level, but microstructural abnormalities have been described on a group level [29]. The supplementary motor area is often implicated and makes an attractive locus, as it is a crucial hub in the thalamofronto-cortical network. The distribution of epileptiform activity seen over frontocentral regions in JME corroborates with poorer executive function; however, test results are heterogeneous within each study — some patients have marked deficits, while others have none. In particular, mental flexibility and concept formation–abstract reasoning are abnormal, even when compared with people with temporal lobe epilepsy [30]. We confirmed that people with JME exhibit considerable heterogeneity in executive dysfunction. This is further complicated by the fact that executive dysfunction takes many forms: people all of whom could reasonably be described as dysexecutive may exhibit markedly different profiles on tests — this has been comprehensively shown by the breadth of abnormalities demonstrated here. Also, neuropsychological tests are not sensitive to many forms of executive dysfunction. There is also a disconnect between test performance and real-world executive ability, so a person who performs normally on a range of ‘frontal’ tests may appear quite abnormal in real-life settings. 4.3.1. Previous studies Although many past studies have found executive dysfunction, they have often differed in the pattern of impairment. Wandschneider et al. [6] reported that impairments in word fluency and color-word interference were the most consistent finding in JME. The color-word interference subtests were all significantly poorly performed by people with drug-refractory JME. Each of the four subcomponents scored in the impaired range by comparison with the mean scaled score (Table 3). Verbal inhibition is an established executive function test, and inhibition switching is a potent test of executive function. In experiments where the sample size exceeds 35, all papers have identified poorer performance on Stroop-like tests [6]. 4.4. Regression modeling Regression modeling confirmed the importance of education for tests of cognition; however, differences in the years of education alone are insufficient to explain the majority of the deficits demonstrated. Increased years of education appear to convey a preferential impact on memory scores and particular tests of verbal memory. Even those who scored least well on tests of verbal memory were at the lower end of the below average range. This indicates that verbal memory per
se may not be impaired in JME, and education level is the main contributor to performance. This pattern, however, was not replicated in related functions such as verbal IQ, where education played a much weaker role. 5. Summary People with drug-refractory JME perform poorly on tests of intellectual function, memory, and executive function. There are many potential reasons for this, which include the number of AEDs taken, interruption to years of schooling, and an earlier age at onset of epilepsy combined with all three seizure types. This study was not designed to be able to attribute causality — instead, it confirms the breadth of deficits and suggests that it is more than just executive function difficulties that must be targeted to support individuals through education and employment. We recommend the use of more routine testing for people with genetic generalized epilepsy, although batteries with greater ecological validity are needed to truly test executive function. Funding Recruitment of cases was funded by the MRC (G0800637) (Refractory Juvenile Myoclonic Epilepsy Cohort, ReJuMEC) to AGM, GAB, and MIR and Epilepsy Research UK (P1104) to RHT, AGM, and MIR. Conflict of interest There are no conflicts of interest to declare. References [1] Camfield CS, Striano P, Camfield PR. Epidemiology of juvenile myoclonic epilepsy. Epilepsy Behav 2013;28(Suppl. 1):S15–7. [2] Kasteleijn-Nolst Trenité DG, Schmitz B, Janz D, Delgado-Escueta AV, Thomas P, Hirsch E, et al. Consensus on diagnosis and management of JME: from founder's observations to current trends. Epilepsy Behav 2013;28(Suppl. 1):S87–90. [3] Kinirons P, Rabinowitz D, Gravel M, Long J, Winawer M, Sénéchal G, et al. Phenotypic concordance in 70 families with IGE-implications for genetic studies of epilepsy. Epilepsy Res 2008;82(1):21–8. [4] Delgado-Escueta AV, Koeleman BP, Bailey JN, Medina MT, Durón RM. The quest for juvenile myoclonic epilepsy genes. Epilepsy Behav 2013;28(Suppl. 1):S52–7. [5] Usui N, Kotagal P, Matsumoto R, Kellinghaus C, Lüders HO. Focal semiologic and electroencephalographic features in patients with juvenile myoclonic epilepsy. Epilepsia 2005;46(10):1668–76. [6] Wandschneider B, Thompson PJ, Vollmar C, Koepp MJ. Frontal lobe function and structure in juvenile myoclonic epilepsy: a comprehensive review of neuropsychological and imaging data. Epilepsia 2012;53(12):2091–8. [7] Camfield CS, Camfield PR. Juvenile myoclonic epilepsy 25 years after seizure onset: a population-based study. Neurology 2009;73(13):1041–5. [8] Thomas RH, Chung SK, Hamandi K, Rees MI, Kerr MP. Translation of genetic findings to clinical practice in juvenile myoclonic epilepsy. Epilepsy Behav 2013;26(3): 241–6. [9] Martínez-Juárez IE, Alonso ME, Medina MT, Durón RM, Bailey JN, López-Ruiz M, et al. Juvenile myoclonic epilepsy subsyndromes: family studies and long-term follow-up. Brain 2006;129(Pt 5):1269–80. [10] Guaranha MS, Filho GM, Lin K, Guilhoto LM, Caboclo LO, Yacubian EM. Prognosis of juvenile myoclonic epilepsy is related to endophenotypes. Seizure 2011;20(1):42–8. [11] Morriston N, Thomas RH, Smith PEM. Patient journey: living with juvenile myoclonic epilepsy. BMJ 2012;344:e360. [12] Roebling R, Scheerer N, Uttner I, Gruber O, Kraft E, Lerche H. Evaluation of cognition, structural, and functional MRI in juvenile myoclonic epilepsy. Epilepsia 2009;50(11): 2456–65. [13] Pascalicchio TF, de Araujo Filho GM, da Silva Noffs MH, Lin K, Caboclo LO, VidalDourado M, et al. Neuropsychological profile of patients with juvenile myoclonic epilepsy: a controlled study of 50 patients. Epilepsy Behav 2007;10(2):263–7. [14] Iqbal N, Caswell HL, Hare DJ, Pilkington O, Mercer S, Duncan S. Neuropsychological profiles of patients with juvenile myoclonic epilepsy and their siblings: a preliminary controlled experimental video-EEG case series. Epilepsy Behav 2009;14(3): 516–21. [15] Janz D, Christian W. Impulsive petit mal. Dtsch Z Nervenheilkd 1957;176(3):346–86. [16] Moschetta SP, Valente KD. Juvenile myoclonic epilepsy: the impact of clinical variables and psychiatric disorders on executive profile assessed with a comprehensive neuropsychological battery. Epilepsy Behav 2012;25(4):682–6. [17] Weschler D. The Weschler Adult Intelligence Scale. Third ed. San Antonio: The Psychological Corporation; 1997. [18] Schmitz B, Yacubian EM, Feucht M, Hermann B, Trimble M. Neuropsychology and behavior in juvenile myoclonic epilepsy. Epilepsy Behav 2013;28(Suppl. 1):S72–3.
R.H. Thomas et al. / Epilepsy & Behavior 36 (2014) 124–129 [19] Tulsky D, Zhu J, Ledbetter M. WAIS-III WMS-III Technical Manual (Wechsler Adult Intelligence Scale & Wechsler Memory Scale). 3rd ed. Harcourt Brace & Company; 1997. [20] Weschler D. The Weschler Memory Scale. Third ed. San Antonio: The Psychological Corporation; 1997. [21] Delis DC, Kaplan E, Kramer JH. The Delis–Kaplan Executive Function System. San Antonio: The Psychological Corporation; 2001. [22] Aldenkamp AP, Baker GA. The Neurotoxicity Scale—II. Results of a patient-based scale assessing neurotoxicity in patients with epilepsy. Epilepsy Res 1997;27(3):165–73. [23] Aldenkamp AP, van Meel HF, Baker GA, Brooks J, Hendriks MP. The A–B neuropsychological assessment schedule (ABNAS): the relationship between patient-perceived drug related cognitive impairment and results of neuropsychological tests. Seizure 2002;11(4):231–7. [24] Rzezak P, Fuentes D, Guimarães CA, Thome-Souza S, Kuczynski E, Li LM, et al. Frontal lobe dysfunction in children with temporal lobe epilepsy. Pediatr Neurol 2007;37(3):176–85.
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[25] Zamarian L, Höfler J, Kuchukhidze G, Delazer M, Bonatti E, Kemmler G, et al. Decision making in juvenile myoclonic epilepsy. J Neurol 2013;260(3):839–46. [26] Sonmez F, Atakli D, Sari H, Atay T, Arpaci B. Cognitive function in juvenile myoclonic epilepsy. Epilepsy Behav 2004;5(3):329–36. [27] Meencke HJ, Janz D. Neuropathological findings in primary generalized epilepsy: a study of eight cases. Epilepsia 1984;25(1):8–21. [28] O'Muircheartaigh J, Vollmar C, Barker GJ, Kumari V, Symms MR, Thompson P, et al. Focal structural changes and cognitive dysfunction in juvenile myoclonic epilepsy. Neurology 2011;76(1):34–40. [29] Vollmar C, O'Muircheartaigh J, Symms MR, Barker GJ, Thompson P, Kumari V, et al. Altered microstructural connectivity in juvenile myoclonic epilepsy: the missing link. Neurology 2012;78(20):1555–9. [30] Devinsky O, Gershengorn J, Brown E, et al. Frontal functions in juvenile myoclonic epilepsy. Neuropsychiatry Neuropsychol Behav Neurol 1997;10:243–6.
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Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
A comprehensive neuropsychological description of cognition in drug-refractory juvenile myoclonic epilepsy Rhys H. Thomas a,⁎, Jordana Walsh b, Carla Church a, Graeme J. Sills b, Anthony G. Marson b, Gus A. Baker b, Mark I. Rees a a b
Wales Epilepsy Research Network (WERN), College of Medicine, Swansea University, Swansea SA2 8PP, UK Department of Clinical and Molecular Pharmacology, University of Liverpool, Liverpool, UK
a r t i c l e
i n f o
Article history: Received 16 February 2014 Revised 11 April 2014 Accepted 30 April 2014 Available online xxxx Keywords: Juvenile myoclonic epilepsy Psychology Executive function Memory Cognition
a b s t r a c t The study of juvenile myoclonic epilepsy is important in that: it is common and heterogeneous; the etiology is unknown; and patients report broad cognitive problems. We utilized a broad battery of neuropsychometric tests to assess the following: intellectual function, memory, language and naming, executive function, the impact of epilepsy, and antiepilepsy drug side effects. Sixty people with drug-refractory JME were interviewed, and performance was profoundly impaired across the range of tests. Impairments included the following: full-scale IQ (89, p b 0.001); processing speed (86, p b 0.001); visual memory (immediate and delayed) more affected than verbal memory; verbal fluency and inhibition (p b 0.001); and self-reported drug side effects (p b 0.001). Eighty-three percent of patients exhibited frank executive dysfunction, which was moderate to severe in 66%. Regression modeling confirmed that an early age at onset and the need for polytherapy were associated with poorer cognitive outcomes. This study confirms previous reports of executive dysfunction in a larger cohort and with greater statistical rigor. We also identified a high prevalence of neurotoxicity symptoms such as fatigue and poorer functioning across intellectual and memory tests than had previously been reported. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Juvenile myoclonic epilepsy (JME) is both the most typical and atypical of the genetic generalized epilepsies (GGEs). It is a common electroclinical syndrome that accounts for 5 to 10% of all epilepsies [1]. It is characterized by the following: i) the age at seizure onset; ii) the triad of absence seizures, generalized tonic–clonic seizures, and epileptic myoclonus — of which only myoclonus needs to be present; iii) a tendency for lifelong seizures with an early morning preponderance; and iv) typically, the improvement of seizure control in 80% of individuals with the use of sodium valproate. The atypical features include the following: i) an inconsistency as to how cases are defined [2]; ii) despite the evidence from twin studies and family aggregation studies [3], no convincing gene for this genetic epilepsy has been identified [4]; iii) despite being classified as a generalized epilepsy, focal EEG features are seen in a third of cases [5], and there are focal patterns of neuropsychological deficits [6]; and iv) there is variation in terms of response to antiepileptic drugs and long-term consequences between individuals [7]. There is a current
⁎ Corresponding author at: MRC Centre for Neuropsychiatric Genetics and Genomics, Haydn Ellis Building, Maindy Road, Cardiff CF24 4HQ, UK. Tel.: +44 20688320. E-mail addresses: [email protected] (R.H. Thomas), [email protected] (J. Walsh), [email protected] (C. Church), [email protected] (A.G. Marson), [email protected] (G.A. Baker), [email protected] (M.I. Rees).
http://dx.doi.org/10.1016/j.yebeh.2014.04.027 1525-5050/© 2014 Elsevier Inc. All rights reserved.
consensus that JME is a heterogeneous epilepsy syndrome, considering response to antiepileptic drugs, long-term consequences, and the presence of psychiatric and cognitive comorbidities [8–10]. 1.1. Neuropsychological performance It is not uncommon for people with JME to describe ‘real-world problems’ with planning and sequencing in the context of a preserved IQ [11–14]. These difficulties were recognized in the definitive descriptions of JME by Janz and Christian in 1957 [15]. Impulsivity and greater novelty seeking are also recognized in JME, particularly when seizure control is poor [16]. There is growing evidence of executive function deficits from studies of individuals with predominantly drug-responsive JME [6,17]. 1.2. Hypothesis and aims There is a growing consensus of subtle executive function deficits from studies of individuals with predominantly drug-responsive JME [6, 18]. These findings are consistent with advanced imaging studies, which implicate functional abnormalities in the frontal cortex and thalamus. Consistency within neuropsychological studies has been hampered, however, by the following: i) inadequate sample sizes, ii) clinical heterogeneity between cases, iii) atypical performance in ‘control’ populations, and iv) the utilization of only a limited number of neuropsychological tests.
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Considering the heterogeneity of this syndrome, studies on the subgroup of drug-refractory JME are necessary because of the notable heterogeneity of this syndrome. We, therefore, undertook a comprehensive study of cognition in people with drug-refractory JME. These individuals are most likely to use clinical services and represent the cohort with the greatest social burden. We hypothesized that there would be no differences in cognitive performance between these individuals and standardized control means after correcting for multiple comparisons.
2.2.5. Questionnaires The Aldenkamp–Baker Neuropsychological Assessment Scale (ABNAS) was included to assess the patients' perceived level of cognitive effects of their AEDs [22,23]. The Impact of Epilepsy Scale (IES) was employed to assess the current daily functioning of people with epilepsy, including their relationships with friends and family, social life, employment, health, self-esteem, plans for the future, and standard of living.
2. Methods and materials
2.3. Statistical analysis
2.1. Participants
Means and standard deviations (SDs) were reported for continuous data that met the normal distribution. If data were considered skewed from the normal distribution, the median and interquartile ranges were reported. Participants' scores were compared with the standardized means using one sample t-tests. To analyze the ABNAS, where these means were not available, a clinical sample was chosen for comparison [23]. To control for and assess the impact of education, intellectual functioning scores were correlated with years in education using Pearson's R correlation coefficients. To reduce the likelihood of making Type I errors, the significance level was set at p b 0.01 for all t-tests. To determine the impact of contributory factors (age at onset of epilepsy, duration of epilepsy, types of seizures, number of AEDs and ABNAS) on the neuropsychological profile of the sample, bivariate correlation and regression analyses were conducted. Standard linear regression was chosen to assess the predictive power of all the variables and to identify which factors significantly contributed to the explanation of variance in cognition.
Sixty patients with drug-refractory JME were assessed as part of the multicenter MRC (Medical Research Council)-funded refractory juvenile myoclonic epilepsy cohort (ReJuMEC) study. Ethical approval was granted by the NorthWest (Cheshire) and the South West Wales Research Ethics Committees; written informed consent was obtained from all patients. Participants were recruited from outpatient appointments with epilepsy specialists in the United Kingdom. Patients were classified as having drug-refractory epilepsy if they experience one or more myoclonic, absence, or tonic–clonic seizures per month despite prior or current exposure to a dosage of at least 1000 mg/day of sodium valproate. Care was taken to identify individuals who do not adhere to prescribed medication; these individuals were excluded. Exclusion criteria included abnormal MRI brain scan, alcoholism, a history of drug abuse, and a neurological disorder besides epilepsy. Patients were provided with seizure diaries which documented seizure occurrence and frequency. In addition, none of the patients had experienced a generalized tonic–clonic seizure within the 24 h of the neuropsychological assessment. 2.2. Neuropsychological battery Participants were given a clinical interview, and their medical files were studied to obtain detailed histories. A standardized battery of neuropsychological tests was administered to each participant. The battery was chosen to evaluate key areas of neuropsychological functioning including the following. 2.2.1. Intellectual functioning All subtests from the WAIS-III [17] were administered from which full-scale IQ (FSIQ), verbal IQ (VIQ), performance IQ (PIQ), working memory (WM), and processing speed (PS) index scores were obtained. Scaled scores were calculated using WAIS–WMS writer software for each of the subtests for comparison [19]. 2.2.2. Memory All subtests from the WMS-III [20] were administered from which general memory, working memory, immediate memory, visual immediate and delayed, auditory immediate and delayed, and auditory recognition delayed memory index scores were obtained. Scaled scores were calculated using WAIS–WMS writer software for each of the subtests for comparison [21]. 2.2.3. Language and fluency The verbal fluency test from the Delis–Kaplan Executive Function System (D-KEFS) [21] was used; it not only contains subtests analogous to the FAS test but also assesses semantic fluency. In addition, the Boston Naming Test (BNT) was used to assess visual naming ability. 2.2.4. Attention and executive functions The color-word interference task from the D-KEFS was used to assess control of inhibition, perseveration, mental flexibility, and attention. Working memory was tested using the WMS-III.
2.4. Severity of executive dysfunction Executive function tests were divided into six executive functions, and the z-scores of each of the tests were calculated. In concordance with previous research [16,24], a z-score of ≤−1 (one or more standard deviations below the manual means) on at least one test within each of the six domains was categorized as dysfunction in relation to that domain. As naming ability was measured by only one test, a z-score of ≤−1 on the Boston Naming Test was categorized as dysfunction in relation to naming ability. Low scores in two domains equated to a mild dysfunction, three or four scores to moderate dysfunction, and all five to severe executive dysfunction. The executive function tests were divided into the following six domains: • Working memory, mental control of auditory–visual stimuli, and attention span were assessed using the digit span and letter–number sequencing. • Visual working memory, mental control of visual–spatial stimuli, and attention were assessed using the digit symbol coding and spatial span. • Verbal fluency was assessed using the letter fluency and category fluency. • The ability to switch between categories was assessed using the category switching and the category accuracy. • The ability to inhibit responses to visual–verbal stimuli was assessed using the color-word interference test (verbal inhibition and inhibition switching). • Naming ability was assessed using the Boston Naming Test. 3. Results 3.1. Clinical features Sixty patients with drug-refractory JME were recruited. The median age at seizure onset was 12 years (IQR = 8–15), while the median duration of epilepsy was 21 years (IQR = 10–30.5). Ninety-six percent of patients had at least one generalized convulsion, and 70% had absence
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seizures. Nine patients reported clinical photosensitivity (18%, n = 51). Two-thirds returned seizure diaries; half reported daily myoclonus that persisted (only 7.5% reported abatement of these seizures). If absence seizures were a feature, they were often frequent (25% of those with absence seizures had them daily or more often); 50% described monthly absence attacks. Eleven percent (n = 54) described a prior history of febrile convulsions, and 44% (n = 57) knew of a close family member with epilepsy.
3.1.1. Antiepilepsy medication at testing At the time of the interview, 28 (47%) participants were taking a single antiepilepsy drug; 20 (33%) were taking two; 11 (18%) were taking three; and one individual was taking four. The monotherapy AEDs were valproate (n = 17, mean daily dose of 1464 mg), lamotrigine (n = 5, mean daily dose of 300 mg), and levetiracetam (n = 4, mean daily dose of 2500 mg), and zonisamide and topiramate were both taken by single individuals. In the people taking two AEDs, there were 12 different combinations, the most common of which was valproate and levetiracetam (n = 5) followed by valproate and lamotrigine (n = 3). There were six different combinations of three AEDs taken concurrently, four of these included clobazam as an adjunct.
Table 2 Memory function as measured by the WMS of patients with drug-refractory JME compared with healthy standardized controls. Cognitive test
JME mean (SD)
Published norms (SD)
p value
Immediate memory Immediate visual memory Immediate auditory memory Delayed visual memory Delayed auditory memory Recognition memory (verbal) General memory WMS working memory Logical memory: immediate recall Logical memory: delayed recall Verbal paired associates: immediate recall Verbal paired associates: delayed recall Faces: immediate recognition Faces: delayed recognition Family pictures: immediate recall Family pictures: delayed recall Spatial span
90.5 (13.1) 87.6 (14.1) 95.8 (12.5) 88.2 (19.4) 100.2 (13.0) 100.4 (14.7) 95.2 (13.4) 90.4 (15.5) 9.8 (2.9)
100 (15) 100 (15) 100 (15) 100 (15) 100 (15) 100 (15) 100 (15) 100 (15) 10 (3)
b.001 b.001 .013 b.001 .888 .831 .009 b.001 .660
10.5 (2.6) 8.6 (2.5)
10 (3) 10 (3)
.133 b.001
9.6 (2.6)
10 (3)
.249
8.0 (7.0, 9.0)a 9.0 (7.0, 11.0)a 7.6 (2.8) 8.0 (5.0, 10.0)a 8.0 (6.0, 10.0)a
10 (3) 10 (3) 10 (3) 10 (3) 10 (3)
b.001b .031b b.001 b.001b b.001b
a b
3.1.2. Education The majority of the sample was female (75%), and the median age was 31 years (range = 19–67 years). All patients had achieved at least secondary school education with a median number of years of formal education of 13: 38% had attained a college degree, and 13% graduated from a university. Sixty-five percent were currently employed, 5% were students, and the remainder were unemployed.
3.2. Intellectual function The mean FSIQ was 89 for the cohort (range = 55–117). The VIQ, PIQ, PS, WM, and FSIQ (Table 1) were all significantly lower in people with drug-refractory epilepsy (p b 0.001); PS was lowest. Eight (13%) participants returned FSIQs two SDs below the mean (i.e., an IQ of 70 or below). Of the subtests that contribute to these indices, all bar matrix reasoning and picture completion were significantly lower than the standardized means. The poorest scores were seen in digital symbol coding. Some of the subtests also test sequencing such as block design.
Table 1 Intellectual functioning as measured by the WAIS of patients with drug-refractory JME compared with healthy standardized controls. Cognitive test
JME mean (SD)
Published norms (SD)
p value
Full-scale IQ Verbal IQ Performance IQ Processing speed WAIS working memory Vocabulary Similarities Arithmetic Digit span Information Comprehension Picture completion Digit symbol-coding Block design Matrix reasoning Picture arrangement Letter–number sequencing Symbol search
89.3 (15.2) 88.8 (15.3) 91.4 (15.3) 86.0 (80,99)a 88.8 (14.4) 8.4 (3.2) 8.1 (3.1) 7.4 (3.5) 8.6 (2.9) 8.4 (2.9) 8.0 (3.6) 9.1 (3.4) 7.0 (5.0, 7.0)a 8.6 (2.5) 9.6 (3.2) 8.3 (2.9) 8.7 (3.6) 8.3 (3.3)
100 (15) 100 (15) 100 (15) 100 (15) 100 (15) 10 (3) 10 (3) 10 (3) 10 (3) 10 (3) 10 (3) 10 (3) 10 (3) 10 (3) 10 (3) 10 (3) 10 (3) 10 (3)
b.001 b.001 b.001 b.001b b.001 b.001 b.001 b.001 b.001 b.001 b.001 .038 b.001b b.001 .331 b.001 .009 b.001
a b
Media and interquartile range. Wilcoxon signed-rank test.
Media and interquartile range. Wilcoxon signed-rank test.
3.3. Memory performance Immediate memory (particularly immediate visual memory), delayed visual memory, general memory, and WM were all statistically significantly lower in participants than the mean (Table 2). The lowest scores were seen in immediate visual memory (mean = 88). Of the subtests that compose these indices, verbal paired associates, faces, family pictures (immediate and delayed), and spatial span were all significantly poorly performed. 3.4. Executive function Participants scored significantly worse on all tests of verbal fluency and executive function except the category accuracy task (Table 3). The two most poorly performed tests were inhibition switching and the BNT. The severity of executive dysfunctions was also evaluated. Eighty-three percent of patients demonstrated a degree of executive/ attentional dysfunction, which was moderate–severe in 66% (38/58 patients). When a more conservative value of ≤2 SD below manual means was applied to each test, 45% of the patients presented with a degree of executive dysfunction, and 28% presented with moderate to severe dysfunction. 3.5. Patient questionnaires The Impact of Epilepsy Scale was utilized to assess the impact of epilepsy and AED treatment on various aspects of participants' daily lives. The mean IES score of 26.5 indicated that epilepsy had a moderate impact on their daily lives. However, there were 14 participants who Table 3 Executive functioning of patients with drug-refractory JME compared with healthy standardized controls. Cognitive test
JME mean (SD)
Published norms (SD)
p value
Letter fluency Category fluency Category switch Category accuracy Verbal inhibition Inhibition switch BNT
7.4 (3.3) 7.9 (4.2) 8.6 (3.9) 9.2 (3.7) 7.8 (4.3) 6.0 (4.5) 49.1 (9.0)
10 (3) 10 (3) 10 (3) 10 (3) 10 (3) 10 (3) 55.5 (3.9)
b.001 b.001 .007 .114 b.001 b.001 b.001
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Fig. 1. ABNAS subdomains: histogram illustrating the mean points per question theme. The horizontal line is the mean score per question of a large cohort of people with epilepsy [24]. * denotes a statistically significant difference.
scored 31 or more, indicating that epilepsy had a severe impact on their lives. The mean ABNAS score of 37 demonstrates reports of significantly more subjective neurotoxicity symptoms in people with drugrefractory JME than in a large sample of people with epilepsy [24], (p b 0.0001) (Fig. 1). In particular questions regarding fatigue, slowing and memory symptoms received statistically higher scores (all p b 0.001). 3.6. Regression analysis Regression modeling confirmed that there was a positive correlation between the number of years of education and VIQ [r = .497, p b 0.001], FSIQ [r = .422, p b 0.01], auditory immediate memory [r = .340, p b 0.03], auditory delayed memory [r = .373, p b 0.02], and verbal inhibition [r = .375, p b 0.02]. Statistically significant correlations were identified between cognitive performance and the number of AEDs, duration of epilepsy, experience of all three seizure types, and total ABNAS score. Multiple regression analyses revealed total ABNAS score to be a significant independent predictor of FSIQ, PIQ, and VIQ. An earlier age at onset was associated with poorer executive function (category switching and verbal inhibition performance, p b 0.05). The number of AEDs taken was a significant independent predictor of poor performance across many cognitive domains: FSIQ, PIQ, VIQ, PS, immediate memory (both visual and auditory), visual delayed memory, working memory, letter fluency, category fluency, and the BNT.
size, and (iii) enlarging the battery of tests that were applied. While this test battery was more comprehensive than used in previously documented [16] research, areas such as decision-making could not be tested [25]. Rigor is essential, and, thus, this analysis differs from those that were previously reported in that we have corrected for multiple comparisons and we have used sample means for comparison and not ‘inflated’ control group results. It will be important to compare these data with people with drug-sensitive JME. It is likely that they will report fewer neurotoxicity side effects, but whether the broader range of cognitive defects would be replicated is unknown. 4.1. The age at onset of seizures in JME Our cohort of people with JME had a relatively uniform presentation, for example, not one had CAE (childhood absence epilepsy) evolving to JME. This is surprising as CAE evolving to JME has been reported as a subtype of JME where long-term drug control is necessary [9]. Our cases were young at seizure onset (12 years), and many had all three seizure types; both of these factors have been previously identified as risk factors for suboptimal seizure control [10]. Pascalicchio et al. [13] reported that as the duration of epilepsy increased, the degree of impairment increased. In our study, a long duration of epilepsy was significantly correlated with poor function in immediate memory (overall and auditory), attention, and visual working memory (digit symbol coding and symbol search).
4. Discussion There is little consistency in the reports of how people with JME perform across key areas of neuropsychological functioning. The exception lies with executive function tests, in particular verbal fluency and inhibition [6]. We report that people with drug-refractory JME have unambiguous cognitive difficulties across a range of neuropsychological tests. These impairments are seen in global intellectual functioning, immediate and visual memory, and executive functioning including naming. Furthermore, in support of the anecdotes that people with JME struggle with ‘real-world problems’ [11], they also presented with significantly higher ABNAS scores compared with published norms [23] and reported that epilepsy had a moderate impact on their daily lives. These data provide the clearest picture to date of the scope of cognitive difficulties in an epilepsy that was once thought to be synonymous with preserved intellectual function. This was made possible by (i) focussing on a specific subgroup with JME, (ii) recruiting a sample of sufficient
4.1.1. Antiepileptic drugs Polytherapy was significantly correlated with all of the intellect index scores, the memory index scores (except those pertaining to auditory memory), attention, verbal fluency, and naming ability. Even a cohort of our size is insufficient to tease out the effects of the separate AEDs. It is unclear whether the relationship is explained by the neurotoxic effect of AEDs or whether polytherapy is a proxy for a more difficult-to-control JME. Regression analyses revealed the total ABNAS score to be a significant independent predictor of FSIQ, VIQ, and PIQ. Patients with higher ABNAS scores performed within the borderline and impaired ranges on 7/34 measures of intellect and memory and on 5/7 measures of executive functions. In comparison, the patients with lower ABNAS scores returned normal results across the battery for all tests except on naming ability. These findings corroborate previous knowledge on cognitive functioning and AEDs in different types of epilepsy.
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4.2. Memory Table 2 clearly shows that tests of visual memory were performed less well compared with tests of verbal memory; similarly, immediate memory tests returned lower scores compared with delayed memory tests. In keeping with the WAIS, working memory was also obtunded. Sonmez et al. [26] did identify differences in the WMS; however, it is unclear if these observations would have survived correction for multiple comparisons. 4.3. Executive function The most consistent impairment found in JME is executive dysfunction. Devinsky et al. [27] described impairments that included concept formation, mental flexibility, planning, and cognitive speed. The ‘FAS test’ is associated with left prefrontal function and appears to be very sensitive to the effects of JME. Controversial histopathological studies by Meencke and Janz [27] reported microdysgenesis in JME – reports that although they could not be replicated have come back into fashion as they are in keeping with some genetic and psychological findings in JME. Quantitative analyses of high-resolution MR images implicate the prefrontal cortex as a region of greatest abnormality in JME [28]. Structural imaging does not reveal underlying pathology on an individual level, but microstructural abnormalities have been described on a group level [29]. The supplementary motor area is often implicated and makes an attractive locus, as it is a crucial hub in the thalamofronto-cortical network. The distribution of epileptiform activity seen over frontocentral regions in JME corroborates with poorer executive function; however, test results are heterogeneous within each study — some patients have marked deficits, while others have none. In particular, mental flexibility and concept formation–abstract reasoning are abnormal, even when compared with people with temporal lobe epilepsy [30]. We confirmed that people with JME exhibit considerable heterogeneity in executive dysfunction. This is further complicated by the fact that executive dysfunction takes many forms: people all of whom could reasonably be described as dysexecutive may exhibit markedly different profiles on tests — this has been comprehensively shown by the breadth of abnormalities demonstrated here. Also, neuropsychological tests are not sensitive to many forms of executive dysfunction. There is also a disconnect between test performance and real-world executive ability, so a person who performs normally on a range of ‘frontal’ tests may appear quite abnormal in real-life settings. 4.3.1. Previous studies Although many past studies have found executive dysfunction, they have often differed in the pattern of impairment. Wandschneider et al. [6] reported that impairments in word fluency and color-word interference were the most consistent finding in JME. The color-word interference subtests were all significantly poorly performed by people with drug-refractory JME. Each of the four subcomponents scored in the impaired range by comparison with the mean scaled score (Table 3). Verbal inhibition is an established executive function test, and inhibition switching is a potent test of executive function. In experiments where the sample size exceeds 35, all papers have identified poorer performance on Stroop-like tests [6]. 4.4. Regression modeling Regression modeling confirmed the importance of education for tests of cognition; however, differences in the years of education alone are insufficient to explain the majority of the deficits demonstrated. Increased years of education appear to convey a preferential impact on memory scores and particular tests of verbal memory. Even those who scored least well on tests of verbal memory were at the lower end of the below average range. This indicates that verbal memory per
se may not be impaired in JME, and education level is the main contributor to performance. This pattern, however, was not replicated in related functions such as verbal IQ, where education played a much weaker role. 5. Summary People with drug-refractory JME perform poorly on tests of intellectual function, memory, and executive function. There are many potential reasons for this, which include the number of AEDs taken, interruption to years of schooling, and an earlier age at onset of epilepsy combined with all three seizure types. This study was not designed to be able to attribute causality — instead, it confirms the breadth of deficits and suggests that it is more than just executive function difficulties that must be targeted to support individuals through education and employment. We recommend the use of more routine testing for people with genetic generalized epilepsy, although batteries with greater ecological validity are needed to truly test executive function. Funding Recruitment of cases was funded by the MRC (G0800637) (Refractory Juvenile Myoclonic Epilepsy Cohort, ReJuMEC) to AGM, GAB, and MIR and Epilepsy Research UK (P1104) to RHT, AGM, and MIR. Conflict of interest There are no conflicts of interest to declare. References [1] Camfield CS, Striano P, Camfield PR. Epidemiology of juvenile myoclonic epilepsy. Epilepsy Behav 2013;28(Suppl. 1):S15–7. [2] Kasteleijn-Nolst Trenité DG, Schmitz B, Janz D, Delgado-Escueta AV, Thomas P, Hirsch E, et al. Consensus on diagnosis and management of JME: from founder's observations to current trends. Epilepsy Behav 2013;28(Suppl. 1):S87–90. [3] Kinirons P, Rabinowitz D, Gravel M, Long J, Winawer M, Sénéchal G, et al. Phenotypic concordance in 70 families with IGE-implications for genetic studies of epilepsy. Epilepsy Res 2008;82(1):21–8. [4] Delgado-Escueta AV, Koeleman BP, Bailey JN, Medina MT, Durón RM. The quest for juvenile myoclonic epilepsy genes. Epilepsy Behav 2013;28(Suppl. 1):S52–7. [5] Usui N, Kotagal P, Matsumoto R, Kellinghaus C, Lüders HO. Focal semiologic and electroencephalographic features in patients with juvenile myoclonic epilepsy. Epilepsia 2005;46(10):1668–76. [6] Wandschneider B, Thompson PJ, Vollmar C, Koepp MJ. Frontal lobe function and structure in juvenile myoclonic epilepsy: a comprehensive review of neuropsychological and imaging data. Epilepsia 2012;53(12):2091–8. [7] Camfield CS, Camfield PR. Juvenile myoclonic epilepsy 25 years after seizure onset: a population-based study. Neurology 2009;73(13):1041–5. [8] Thomas RH, Chung SK, Hamandi K, Rees MI, Kerr MP. Translation of genetic findings to clinical practice in juvenile myoclonic epilepsy. Epilepsy Behav 2013;26(3): 241–6. [9] Martínez-Juárez IE, Alonso ME, Medina MT, Durón RM, Bailey JN, López-Ruiz M, et al. Juvenile myoclonic epilepsy subsyndromes: family studies and long-term follow-up. Brain 2006;129(Pt 5):1269–80. [10] Guaranha MS, Filho GM, Lin K, Guilhoto LM, Caboclo LO, Yacubian EM. Prognosis of juvenile myoclonic epilepsy is related to endophenotypes. Seizure 2011;20(1):42–8. [11] Morriston N, Thomas RH, Smith PEM. Patient journey: living with juvenile myoclonic epilepsy. BMJ 2012;344:e360. [12] Roebling R, Scheerer N, Uttner I, Gruber O, Kraft E, Lerche H. Evaluation of cognition, structural, and functional MRI in juvenile myoclonic epilepsy. Epilepsia 2009;50(11): 2456–65. [13] Pascalicchio TF, de Araujo Filho GM, da Silva Noffs MH, Lin K, Caboclo LO, VidalDourado M, et al. Neuropsychological profile of patients with juvenile myoclonic epilepsy: a controlled study of 50 patients. Epilepsy Behav 2007;10(2):263–7. [14] Iqbal N, Caswell HL, Hare DJ, Pilkington O, Mercer S, Duncan S. Neuropsychological profiles of patients with juvenile myoclonic epilepsy and their siblings: a preliminary controlled experimental video-EEG case series. Epilepsy Behav 2009;14(3): 516–21. [15] Janz D, Christian W. Impulsive petit mal. Dtsch Z Nervenheilkd 1957;176(3):346–86. [16] Moschetta SP, Valente KD. Juvenile myoclonic epilepsy: the impact of clinical variables and psychiatric disorders on executive profile assessed with a comprehensive neuropsychological battery. Epilepsy Behav 2012;25(4):682–6. [17] Weschler D. The Weschler Adult Intelligence Scale. Third ed. San Antonio: The Psychological Corporation; 1997. [18] Schmitz B, Yacubian EM, Feucht M, Hermann B, Trimble M. Neuropsychology and behavior in juvenile myoclonic epilepsy. Epilepsy Behav 2013;28(Suppl. 1):S72–3.
R.H. Thomas et al. / Epilepsy & Behavior 36 (2014) 124–129 [19] Tulsky D, Zhu J, Ledbetter M. WAIS-III WMS-III Technical Manual (Wechsler Adult Intelligence Scale & Wechsler Memory Scale). 3rd ed. Harcourt Brace & Company; 1997. [20] Weschler D. The Weschler Memory Scale. Third ed. San Antonio: The Psychological Corporation; 1997. [21] Delis DC, Kaplan E, Kramer JH. The Delis–Kaplan Executive Function System. San Antonio: The Psychological Corporation; 2001. [22] Aldenkamp AP, Baker GA. The Neurotoxicity Scale—II. Results of a patient-based scale assessing neurotoxicity in patients with epilepsy. Epilepsy Res 1997;27(3):165–73. [23] Aldenkamp AP, van Meel HF, Baker GA, Brooks J, Hendriks MP. The A–B neuropsychological assessment schedule (ABNAS): the relationship between patient-perceived drug related cognitive impairment and results of neuropsychological tests. Seizure 2002;11(4):231–7. [24] Rzezak P, Fuentes D, Guimarães CA, Thome-Souza S, Kuczynski E, Li LM, et al. Frontal lobe dysfunction in children with temporal lobe epilepsy. Pediatr Neurol 2007;37(3):176–85.
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[25] Zamarian L, Höfler J, Kuchukhidze G, Delazer M, Bonatti E, Kemmler G, et al. Decision making in juvenile myoclonic epilepsy. J Neurol 2013;260(3):839–46. [26] Sonmez F, Atakli D, Sari H, Atay T, Arpaci B. Cognitive function in juvenile myoclonic epilepsy. Epilepsy Behav 2004;5(3):329–36. [27] Meencke HJ, Janz D. Neuropathological findings in primary generalized epilepsy: a study of eight cases. Epilepsia 1984;25(1):8–21. [28] O'Muircheartaigh J, Vollmar C, Barker GJ, Kumari V, Symms MR, Thompson P, et al. Focal structural changes and cognitive dysfunction in juvenile myoclonic epilepsy. Neurology 2011;76(1):34–40. [29] Vollmar C, O'Muircheartaigh J, Symms MR, Barker GJ, Thompson P, Kumari V, et al. Altered microstructural connectivity in juvenile myoclonic epilepsy: the missing link. Neurology 2012;78(20):1555–9. [30] Devinsky O, Gershengorn J, Brown E, et al. Frontal functions in juvenile myoclonic epilepsy. Neuropsychiatry Neuropsychol Behav Neurol 1997;10:243–6.