Epilepsy & Behavior 35 (2014) 72–77
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Executive functions and psychiatric symptoms in drug-refractory juvenile myoclonic epilepsy Jordana Walsh a,⁎, Rhys H. Thomas b,c, Carla Church a, Mark I. Rees b,c, Anthony G. Marson a, Gus A. Baker a a b c
Department of Clinical and Molecular Pharmacology, University of Liverpool, Liverpool, UK College of Medicine, Institute of Life Science, Swansea University, Swansea, UK Wales Epilepsy Research Network (WERN), College of Medicine, Swansea University, Swansea, UK
a r t i c l e
i n f o
Article history: Received 15 February 2014 Revised 25 March 2014 Accepted 31 March 2014 Available online 13 May 2014 Keywords: Juvenile myoclonic epilepsy Executive functions Personality Neuroticism Anxiety
a b s t r a c t Purpose: The pattern of executive dysfunction reported in juvenile myoclonic epilepsy (JME) resembles that of patients with cluster B personality disorders. This study examined whether executive dysfunction and maladaptive behavior reported in patients with JME are related. Method: Sixty patients with drug-refractory JME were administered tests of intellect, memory, and executive dysfunction. Anxiety, depression, personality traits, impact of epilepsy, and perceived cognitive effects of antiepileptic drugs were measured. Results: Half of the cohort exhibited moderate to severe anxiety symptoms. The patients performed most poorly on naming ability and inhibition switching. Duration of epilepsy exacerbated poor performance on inhibition switching. Females presented with pathological scores for neurotic and introvert traits and males for introvert traits. Abnormal personality traits and psychiatric disorders were associated with worse intellectual and executive functioning. People with extreme Eysenck Personality Scale — Brief Version (EPQ-BV) scores demonstrated the greatest level of executive impairment. Furthermore, the same degree of dysfunction was not seen in any individual with unremarkable EPQ-BV scores. Conclusion: This study indicates that specific patterns of executive dysfunction are related to maladaptive behavior in JME. Distinct behavioral patterns may be used to identify functional and anatomical differences between people with JME and for stratification to enable gene discovery. © 2014 Published by Elsevier Inc.
1. Introduction Juvenile myoclonic epilepsy (JME) is a common type of idiopathic generalized epilepsy with onset occurring during adolescence and is lifelong in most individuals. Standard diagnostic magnetic resonance imaging is unremarkable, and 40% of members of an expert panel stated that cognition must be intact to make the diagnosis [1]; despite this, impairments in executive function are consistently demonstrated in JME [2–6]. The executive dysfunctions found are similar to those reported in patients with cluster B personality disorders [7,8]. Moreover, researchers have described structural and functional abnormalities in the frontal lobes of patients with JME [9–11], which have also been reported in patients with personality disorders [12,13]. Janz and Christian described the personality of people with JME as typically “characterised by unsteadiness, lack of discipline, hedonism, and an indifference to their disease” [14]. Subsequent research has ⁎ Corresponding author at: Centre for Nursing and Allied Health Research, York House, Great Ormond Street Hospital for Children NHS Trust, Great Ormond Street, London WC1N 3JH, UK. E-mail address: [email protected] (J. Walsh).
http://dx.doi.org/10.1016/j.yebeh.2014.03.026 1525-5050/© 2014 Published by Elsevier Inc.
investigated the psychiatric comorbidities in JME and has found high incidence of anxiety and personality disorders [9,15,16]. It has been proposed that JME is not one disorder but several subtypes [17], and past research has attempted to categorize patients with JME into these subgroups [18]. We have chosen to focus our study on the fifth of patients who do not adequately respond to sodium valproate, the anticonvulsant of choice. Research has revealed different levels of neuropsychological dysfunction, psychiatric disorders, and different personalities in patients with JME [15,19]. De Araujo Filho et al. proposed that the distinct patterns of behavior could be partially explained by the localization of seizure foci and the recruitment of broader networks implicated in epileptogenesis.
1.1. Aims of the study The study aimed to address whether the executive dysfunctions and maladaptive behavior reported in people with juvenile myoclonic epilepsy are related. In addition, we examined the proportion of affective symptoms, personality traits, and executive dysfunctions in a sample of patients with drug-refractory juvenile myoclonic epilepsy.
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2. Materials and methods
2.4. Questionnaires
2.1. Subjects
The Eysenck Personality Questionnaire — Brief Version (EPQ-BV) [27, 28] was administered to examine the presence of personality traits in JME and whether these traits are related to clinical variables, cognitive impairment, and executive dysfunction. The EPQ-BV is a 24-item short version of the EPQ-R, which was developed from the original Eysenck and Eysenck's EPQ (1975). It is a self-report questionnaire that measures two personality dimensions, namely, extroversion (E) and neuroticism (N). The EPQ-BV was chosen over other measures because of its brevity, Likert scale, and good retest reliability and validity [27]. The Hospital Anxiety and Depression Scale (HADS) [29], the Aldenkamp–Baker Neuropsychological Assessment Scale (ABNAS), and the Impact of Epilepsy Scale (IES) were also performed. The HADS is an assessment of an individual's level of anxiety and depression. The ABNAS is a subjective assessment of symptoms of neurotoxicity such as fatigue, whereas the IES to record how disruptive epilepsy has been to the individual's life.
Sixty people with drug-refractory JME were assessed as part of the multicenter MRC-funded refractory juvenile myoclonic epilepsy cohort (ReJuMEC) study. Participants were recruited from outpatient appointments in epilepsy clinics in the Untied Kingdom. Patients were classified as having drug-refractory epilepsy if they experience ≥ 1 seizure per month despite prior or current exposure to a dose of at least 1000 mg of sodium valproate. The definition of drug-refractory epilepsy varies greatly in the literature [20] and has not been defined in JME research. The criteria used were based on a combination of the knowledge of sodium valproate being effective in 85–90% of the patients with most becoming seizure-free [21], the criteria used by others [22,23] and clinical experience of members of the ReJuMEC group. Exclusion criteria included abnormal brain MRI scan, alcoholism, a history of drug abuse, and/or neurological disorder besides epilepsy. In addition, none of the patients had experienced a generalized tonic–clonic seizure within the 24 h prior to the neuropsychological assessment. Ethical approval was granted by the North West 1 Research Ethics Committee — Cheshire, and written informed consent was obtained from all patients. Please see Table 1 for the demographic and clinical characteristics of the current sample. 2.2. Neuropsychological battery Participants were given a clinical interview, and a detailed history was obtained from their clinical records. A standardized comprehensive battery of neuropsychometric tests was chosen to enable the evaluation of intellectual ability, language functioning, verbal and nonverbal memory, and executive functions. For a detailed description of the battery used, please refer to Thomas et al. [24]. 2.2.1. Attention and executive functions The color–word interference task from the D-KEFS and zoo map, key search, and rule shift from the Behavioural Assessment of Dysexecutive Syndrome (BADS) were used to assess control of inhibition, perseveration, mental flexibility, planning ability, and attention. 2.3. Severity of executive dysfunctions 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 [25,26], a z-score of ≤−1.00 (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. If two domains met these criteria, the patient was assessed as having mild executive dysfunction; if three or four domains met the criteria, the patient was assessed as having moderate dysfunction; and if five or more domains met the criteria, the patient was assessed as having severe dysfunction. The six domains were as follows: • Working memory, mental control of auditory–visual stimuli, and attention span: assessed using the digit span and letter–number sequencing. • Visual working memory, mental control of visual–spatial stimuli, and attention: assessed using the digit–symbol coding and spatial span. • Verbal fluency: assessed using letter fluency and category fluency. • The ability to switch between categories: assessed using category switching and category accuracy. • The ability to inhibit responses to visual–verbal stimuli: assessed using the color–word interference test (verbal inhibition and inhibition switching). • Naming ability: assessed using the Boston Naming Test.
2.5. Statistical analysis Means and standard deviations were calculated for the demographic and clinical characteristics and 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. One-sample t-tests (Wilcoxon signed-rank test if skewed) were conducted based on the means and standard deviations given by the assessment manuals to compare the cohort's performance with standardized norms. To reduce the likelihood of making a Type I error, the significance level was set at p b 0.01 for all t-tests. Bonferroni correction was not applied as this would have provided too conservative an alpha statistics estimate, increasing the likelihood of making a Type II error. Those scoring the highest levels of mood symptoms (HADS) and personality traits (EPQ) were identified. A quirk of the normative values provided by Sato for the EPQ-BV is that males and females are analyzed separately [28]; one-sample t-tests were employed (as above). Pearson's correlation analyses were conducted between intellectual functioning, executive functioning, HADS scores, and EPQ-BV scores. Clinical variables and psychometric test scores identified from the Pearson correlation were investigated further with independent sample t-tests. Mann–Whitney U test was used for skewed data. Hierarchical regression was performed to assess the contribution of anxiety and neuroticism on test scores. 3. Results 3.1. Affective symptoms 49% of the patients scored in the moderate to severe range for anxiety symptoms and 16% for depressive symptoms. Nine (24%) people had mild anxiety; 15 (41%) people had moderate anxiety; and three (8.1%) had severe anxiety symptoms. In contrast, seven (19%) people had mild depressive symptoms; five (14%) had moderate depressive symptoms; and one (2.7%) had severe depressive symptoms. Higher anxiety scores were significantly correlated with poorer function on tests of vocabulary, similarities, information, picture completion, verbal IQ, performance IQ, full-scale IQ, and letter fluency. Independent t-tests revealed significantly poorer function on the WAIS subtests vocabulary (p = .004) and information (p = .010). People with high anxiety scores had, on average, 2.77 points lower on vocabulary (d =1.02) and 2.40 points lower on the information subtest (d = 0.89) compared with people with drug-refractory JME and less extreme HADS anxiety scores. Anxiety remained a significant independent predictor of performance on the information subtest when correlated clinical and demographic characteristics (duration of epilepsy and years of education) were controlled for and explained 19% (p = .003) of the
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3.2. Personality traits
Table 1 Demographic and clinical characteristics.
The EPQ-BV identified that females with drug-refractory JME had pathologically high neuroticism scores and low extroversion scores (introvert trait). The males scored in the introverted range also but not in the pathological range for neuroticism (Table 2). People with JME and higher neuroticism scores reported more anxiety symptoms and more concentration and motor difficulties compared with those with lower scores (anxiety: p = .001, d = 1.57; ABNAS concentration: p = .007, d = 1.18; ABNAS motor: p = .006, d = 1.41). People with introverted traits did not differ on the levels of anxiety and depression or on the cognitive problems reported. All groups reported that their epilepsy had a moderate impact on their lives.
n = 60 Gender Age Number of years in formal education (n = 43) Level of education (n = 40)
WAIS full-scale IQ (n = 59) Employment status (n = 39)
Duration of epilepsy (years) (n = 57) Onset of epilepsy (years) (n = 57) Types of seizure
Family history (n = 57) History of febrile seizures (n = 54) Photosensitive (n = 33) Number of AEDs
AED type
Female Male Median IQR Median IQR School College University Mean SD Employed Unemployed Full-time education Median IQR Median IQR Myoclonic GTCS (n = 54) Absences (n-54) Other
1 2 3 or more VPA LEV LTG TPM ZNS CLB CBZ
45 (75.0%) 15 (25.0%) 31.00 24.00, 38.75 13.00 11.00, 13.00 20 (50.0%) 15 (37.5%) 5 (12.5%) 89.25 15.24 26 (66.7%) 11 (28.2%) 2 (5.13%) 20.00 9.50, 30.00 13.00 9.00, 15.00 60 (100%) 52 (96.3%) 38 (70.4%) 2 (3.4%) 25 (43.9%) 6 (11.1%) 9 (27.3%) 28 (46.7%) 20 (33.3%) 12 (20.0%) 35 25 18 10 4 10 2
3.2.1. Personality traits, cognition, and executive functions Individuals with high neuroticism scores performed worse across the battery of cognitive and executive function tests compared with people with less extreme neuroticism scores. People with drug-refractory JME and high neuroticism scores scored lower on the BNT compared with people with lower neuroticism scores. As the data were skewed, the Mann–Whitney U test was used, which revealed a nonsignificant difference (p = .307, r = .166). A significant difference was found between the median score of people with high neuroticism scores and published norms at p b .01 level. People with high neuroticism scores had, on average, 7.5 points below published norms (p =.007, r = .674). People with lower neuroticism scores had, on average, 2.0 points below published norms (p = .045, r = .427). (See Fig. 1.) People with drug-refractory JME and low extroversion (introvert trait) scores scored lower on the BNT compared with people with higher extroversion scores. As the data were skewed, the Mann– Whitney U test was used, which revealed a nonsignificant difference (p = .416, r = .132). A significant difference was found between the median score of people with high introversion scores and published norms at p b .01 level. People with high introversion scores had, on average, 6.0 points below published norms (p = .003, r = .607). People with lower introversion scores had, on average, 1.0 point below published norms (p = .109, r = .429) (Fig. 1).
SD, standard deviation; IQR, interquartile range; WAIS, Wechsler Adult Intelligent Scale; VPA, sodium valproate; LEV, levetiracetam; LTG, lamotrigine; TPM, topiramate; ZNS, zonisamide; CLB, clobazam; CBZ, carbamazepine.
variance. No clinical or demographic characteristics significantly correlated with performance on the information subtest. Although the other test scores were not statistically significant, the real-life difference may be substantial, and medium effect sizes were found. People with high anxiety scores had, on average, 9.10 points lower on verbal IQ (d = 0.627, p = .065) and 9.00 points lower on full-scale IQ (d = 0.654, p = .058) compared with people with lower anxiety scores. Higher depression scores were significantly correlated with poorer function on category fluency. Independent t-tests revealed a nonsignificant difference; however, this was likely to be due to the small number of the cohort presenting with high depressive symptoms. People with higher depression scores had, on average, 2.97 points lower on category fluency (d = 0.918) compared with people with less extreme HADS depression scores.
3.2.2. Preliminary results with the zoo map Significant correlations were revealed between neuroticism and raw scores on both versions one (r = −.540, p = .038) and two (r = −.591, p = .020) of the zoo map. People with high neuroticism scores had, on average, 5.00 points lower compared with people with drug-refractory JME and less extreme neuroticism scores (Fig. 2).
3.3. Severity of executive dysfunctions The majority of people with drug-refractory JME (83%) presented with executive and attentional dysfunction on psychometric testing [24]. High EPQ-BV scores exacerbated this dysfunction, and, when a more conservative value of two SD below manual means was applied,
Table 2 Samples EPQ-BV scores compared with norms reported by Sato. Neuroticism
Males (n = 11) Females (n = 27) ⁎ p b .05. ⁎⁎ p b .01. ⁎⁎⁎ p b .001.
Extroversion
Sample means
Sato norms
p value
Sample means
Sato norms
p value
33.09 (10.34)
26.93 (9.96)
.076
33.72 (12.51)
42.58 (9.11)
.041⁎
39.00 (11.51)
30.54 (9.38)
.001⁎⁎
30.63 (9.94)
42.09 (8.97)
b.001⁎⁎⁎
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people with extreme EPQ-BV scores demonstrated the greatest level of executive dysfunction impairment; 54% presented with dysfunction, and 39% had moderate to severe dysfunction. This degree of dysfunction was not seen in any individual with unremarkable EPQ-BV scores; we found that one (8.3%) person had moderate dysfunction, and three (25%) had mild dysfunction.
levels (41%). Consistent with previous studies [15,16], depressive traits in our study were less prevalent compared with anxiety traits; 35% of the patients had mild to severe depressive symptoms, and the majority of patients had normal scores (65%).
3.4. Worse cognitive performance and clinical and psychological patterns
It is unclear as to how anatomically bounded a function ‘personality’ is, but studies have investigated whether personality is related to structural or functional abnormalities in the frontal lobes [9,19]. People with JME and cluster B personality disorders exhibit significant reductions in gray matter volume in the thalamus and increased volume in the right frontal gyri compared with healthy controls and patients with JME without personality disorders [9]. Others have investigated whether structural brain abnormalities [32,33], functional brain abnormalities [11,32], and focal epilepsies [2,3] are related to neuropsychological and executive functioning. Past research has proposed that the abnormal personality exhibited by patients with JME is related to the executive dysfunctions reported in these patients [6,9,19,34]. A previous study touched on this by examining correlations between executive functioning and history of psychiatric disorders [25]. To the best of our knowledge, this is the first study to investigate the relationship between dysexecutive functions and specific psychiatric and personality trains in patients drug-refractory JME. Using a published method of stratifying executive dysfunction in JME [25], the majority of patients, regardless of EPQ-BV scores, exhibited executive dysfunction. However, when a more conservative analysis was used, over half of the patients with JME with high EPQ-BV scores had dysfunction, with 39% presenting with moderate to severe dysfunction. Conversely, no patient with low EPQ-BV scores presented with severe dysfunction, and only one participant had moderate dysfunction. People with drug-refractory JME and a high anxiety score had significantly poorer intellectual functioning and naming ability. All patients performed worse than published norms on naming ability, but only those with high anxiety scores performed within the borderlineimpaired range and those with high neuroticism performed extremely
People with drug-refractory JME performed poorly across a range of tests, but, as expected, the worst performances were all on executive function tests: 18 (30%) people performed worse on the BNT and 17 (28%) on inhibition switching. People with drug-refractory JME and low BNT scores reported higher levels of motor difficulties (ABNAS motor: p = b .001, d = 1.38) and total neurotoxicity symptoms (total ABNAS: p = .006, d = 1.00) compared with people with drug-refractory JME and high BNT scores. People with drug-refractory JME and low inhibition switching scores had significantly (at p b .05 level) longer duration of epilepsy (p = .019, d = .659), ABNAS fatigue (p = .024, d = .836), and slowing (p = .019, d = .903) compared with people with drug-refractory JME and high inhibition switching scores. On average, people with low inhibition switching scores had JME for 8 years 8 months longer compared with those with higher inhibition switching scores. 4. Discussion Previous studies have found a high percentage of axis II personality disorders (particularly cluster B) and axis I psychiatric disorders (particularly anxiety and depression) in probands with JME and significantly more than in healthy controls [15,30,31]. In our study, there was a high frequency of pathological neurotic and introverted personality traits in people with drug-resistant JME. Females scored in the high range for neurotic and introverted traits, and the males scored high for introverted traits. Seventy-three percent of patients had mild to severe anxiety symptoms, and the majority of patients had moderate
4.1. Affective symptoms, personality, and cognition
56 55 54 Boston naming test mean score
53 52
Published norms
51 50 Whole sample median
49 48
Borderline impaired
47 46 45 Low anxiety
High anxiety
Low introversion
High introversion
Low neuroticism
High neuroticism
44
Fig. 1. Boston Naming Test performance (median scores) of people with drug-refractory JME and different personality traits.
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9 8 7 6 5
high neuroticism
4
low neuroticism
3 2 1 0 Zoo Map Version One
Zoo Map Version Two
Fig. 2. Median scores on versions one and two of the zoomap for drug-refractory JME with high and low neuroticism scores.
closely to this range. Preliminary findings with the BADS revealed significant correlations between poorer planning ability and only a high neuroticism score. The planning ability of those with high neuroticism scores was marginally lower when given the order of places to visit (zoo map version two), but when given a list of places to visit with no guidance on order, patients with high neuroticism scores struggled considerably. The findings with the BADS were only considered as preliminary findings as the BADS was added later in the study, and, therefore, only a small proportion of patients were administered the zoo map. The affective, personality, and cognitive findings indicate the sample as a whole presented with deficits in the inferior (inhibition) and medial (switching) frontal cortex. However, the results indicate a broad network failure in the frontal lobes of a high proportion of those with high neuroticism and/or introversion traits. Furthermore, people with drug-refractory JME and high anxiety scores presented with the greatest impairment in naming ability. Thus, the findings confirm that executive dysfunctions reported in JME are related to personality and affective traits. 4.2. Cognition and clinical patterns People with drug-refractory JME performed least well on tests of mental flexibility and inhibition. People with the poorest naming ability also had high anxiety scores and reported high levels of cognitive problems. Furthermore, they had a higher mean neuroticism score with a small to medium effect size. People with the lowest inhibition switching scores had a longer duration of epilepsy and also reported high levels of cognitive problems. However, the whole sample was borderlineimpaired on inhibition switching. Impaired inhibition is a consistent feature in JME analysis [3–6,32], which suggests that this impairment may be caused by a fundamental structural or functional brain abnormality shared by all people with JME. Past studies that have assessed healthy siblings of patients with JME have also found that they perform worse than healthy unrelated controls [5]. This suggests that impaired inhibition may be genetically determined. The current study indicates that the common impairment in inhibition switching is exacerbated by the duration of epilepsy. 4.3. Strengths and limitations The current study has some strengths and limitations. It is the first study to investigate whether the neuropsychological profile found in JME is related to the personality and psychiatric traits often reported. Furthermore, the study profiled a ‘purer’ subgroup of JME by targeting only patients with drug-refractory JME. The current study corrected for multiple comparisons and used published norms for comparison. However, the study would benefit from a comparison group of patients
with drug-sensitive JME; we did attempt to recruit such a group but were unable to recruit sufficient numbers due to recruitment taking place in tertiary centers, which patients with controlled seizures rarely visit. The main limitation of the study was not all patients completed the EPQ-BV due to loss of funding half way through the study. This reduced the sample size for statistical analyses involving personality and, thus, the power of those tests. A limitation of the EPQ-BV itself is that it only assesses two dimensions of personality. Juvenile myoclonic epilepsy is a heterogeneous disorder, and different genetic etiologies may result in different personality traits and levels of impairment. Despite this, the EPQ-BV has been a worthwhile tool for the current study, as it has revealed that frontal dysfunctions are associated with personality traits. These findings will hopefully be used to encourage further study in this area; for example, future research should use a more comprehensive assessment of personality (such as the Structured Clinical Interview for DSM-IV). Moreover, future research should examine whether distinct behavioral differences are a result of specific brain abnormalities, which lead to the different levels of impairments found in JME. 4.4. Conclusion There have been previous attempts to subcategorize JME [18], but because of the multiple factors and potentially numerous behavioral patterns, it may not be possible to categorize JME into neat subcategories. Nevertheless, distinct behavioral patterns may be used to identify differences in frontal structure/functioning and, ultimately, in genotype. The current findings suggest a subgroup of patients present with a more severe type of JME and may be distinguished by genetic stratification. Acknowledgments The ReJuMEC study was funded by the Medical Research Council (MRC). Declaration of interests All authors report that they have no competing interests. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.yebeh.2014.03.026. References [1] 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(Supplement 1):S87–90. [2] Devinsky O, Gershengorn J, Brown E, Perrine K, Vazquez B, Luciano D. Frontal functions in juvenile myoclonic epilepsy. Neuropsychiatry Neuropsychol Behav Neurol 1997;10(4):243–6. [3] Piazzini A, Turner K, Vignoli A, Canger R, Canevini MP. Frontal cognitive dysfunction in juvenile myoclonic epilepsy. Epilepsia 2008;49(4):657–62. [4] Pascalicchio TF, de Araujo Filho GM, da Silva Noffs MH, Lin K, Caboclo LOSF, 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. [5] 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. [6] Wandschneider B, Kopp UA, Kliegel M, Stephani U, Kurlemann G, Janz D, et al. Prospective memory in patients with juvenile myoclonic epilepsy and their healthy siblings. Neurology 2010;75(24):2161–7. [7] Bergvall ÅH, Nilsson T, Hansen S. Exploring the link between character, personality disorder, and neuropsychological function. Eur Psychiatry 2003;18(7):334–44. [8] Fertuck EA, Lenzenweger MF, Clarkin JF, Hoermann S, Stanley B. Executive neurocognition, memory systems, and borderline personality disorder. Clin Psychol Rev 2006;26(3):346–75. [9] de Araújo Filho GM, Jackowski AP, Lin K, Guaranha MSB, Guilhoto LMFF, da Silva HH, et al. Personality traits related to juvenile myoclonic epilepsy: MRI reveals prefrontal
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Executive functions and psychiatric symptoms in drug-refractory juvenile myoclonic epilepsy Jordana Walsh a,⁎, Rhys H. Thomas b,c, Carla Church a, Mark I. Rees b,c, Anthony G. Marson a, Gus A. Baker a a b c
Department of Clinical and Molecular Pharmacology, University of Liverpool, Liverpool, UK College of Medicine, Institute of Life Science, Swansea University, Swansea, UK Wales Epilepsy Research Network (WERN), College of Medicine, Swansea University, Swansea, UK
a r t i c l e
i n f o
Article history: Received 15 February 2014 Revised 25 March 2014 Accepted 31 March 2014 Available online 13 May 2014 Keywords: Juvenile myoclonic epilepsy Executive functions Personality Neuroticism Anxiety
a b s t r a c t Purpose: The pattern of executive dysfunction reported in juvenile myoclonic epilepsy (JME) resembles that of patients with cluster B personality disorders. This study examined whether executive dysfunction and maladaptive behavior reported in patients with JME are related. Method: Sixty patients with drug-refractory JME were administered tests of intellect, memory, and executive dysfunction. Anxiety, depression, personality traits, impact of epilepsy, and perceived cognitive effects of antiepileptic drugs were measured. Results: Half of the cohort exhibited moderate to severe anxiety symptoms. The patients performed most poorly on naming ability and inhibition switching. Duration of epilepsy exacerbated poor performance on inhibition switching. Females presented with pathological scores for neurotic and introvert traits and males for introvert traits. Abnormal personality traits and psychiatric disorders were associated with worse intellectual and executive functioning. People with extreme Eysenck Personality Scale — Brief Version (EPQ-BV) scores demonstrated the greatest level of executive impairment. Furthermore, the same degree of dysfunction was not seen in any individual with unremarkable EPQ-BV scores. Conclusion: This study indicates that specific patterns of executive dysfunction are related to maladaptive behavior in JME. Distinct behavioral patterns may be used to identify functional and anatomical differences between people with JME and for stratification to enable gene discovery. © 2014 Published by Elsevier Inc.
1. Introduction Juvenile myoclonic epilepsy (JME) is a common type of idiopathic generalized epilepsy with onset occurring during adolescence and is lifelong in most individuals. Standard diagnostic magnetic resonance imaging is unremarkable, and 40% of members of an expert panel stated that cognition must be intact to make the diagnosis [1]; despite this, impairments in executive function are consistently demonstrated in JME [2–6]. The executive dysfunctions found are similar to those reported in patients with cluster B personality disorders [7,8]. Moreover, researchers have described structural and functional abnormalities in the frontal lobes of patients with JME [9–11], which have also been reported in patients with personality disorders [12,13]. Janz and Christian described the personality of people with JME as typically “characterised by unsteadiness, lack of discipline, hedonism, and an indifference to their disease” [14]. Subsequent research has ⁎ Corresponding author at: Centre for Nursing and Allied Health Research, York House, Great Ormond Street Hospital for Children NHS Trust, Great Ormond Street, London WC1N 3JH, UK. E-mail address: [email protected] (J. Walsh).
http://dx.doi.org/10.1016/j.yebeh.2014.03.026 1525-5050/© 2014 Published by Elsevier Inc.
investigated the psychiatric comorbidities in JME and has found high incidence of anxiety and personality disorders [9,15,16]. It has been proposed that JME is not one disorder but several subtypes [17], and past research has attempted to categorize patients with JME into these subgroups [18]. We have chosen to focus our study on the fifth of patients who do not adequately respond to sodium valproate, the anticonvulsant of choice. Research has revealed different levels of neuropsychological dysfunction, psychiatric disorders, and different personalities in patients with JME [15,19]. De Araujo Filho et al. proposed that the distinct patterns of behavior could be partially explained by the localization of seizure foci and the recruitment of broader networks implicated in epileptogenesis.
1.1. Aims of the study The study aimed to address whether the executive dysfunctions and maladaptive behavior reported in people with juvenile myoclonic epilepsy are related. In addition, we examined the proportion of affective symptoms, personality traits, and executive dysfunctions in a sample of patients with drug-refractory juvenile myoclonic epilepsy.
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2. Materials and methods
2.4. Questionnaires
2.1. Subjects
The Eysenck Personality Questionnaire — Brief Version (EPQ-BV) [27, 28] was administered to examine the presence of personality traits in JME and whether these traits are related to clinical variables, cognitive impairment, and executive dysfunction. The EPQ-BV is a 24-item short version of the EPQ-R, which was developed from the original Eysenck and Eysenck's EPQ (1975). It is a self-report questionnaire that measures two personality dimensions, namely, extroversion (E) and neuroticism (N). The EPQ-BV was chosen over other measures because of its brevity, Likert scale, and good retest reliability and validity [27]. The Hospital Anxiety and Depression Scale (HADS) [29], the Aldenkamp–Baker Neuropsychological Assessment Scale (ABNAS), and the Impact of Epilepsy Scale (IES) were also performed. The HADS is an assessment of an individual's level of anxiety and depression. The ABNAS is a subjective assessment of symptoms of neurotoxicity such as fatigue, whereas the IES to record how disruptive epilepsy has been to the individual's life.
Sixty people with drug-refractory JME were assessed as part of the multicenter MRC-funded refractory juvenile myoclonic epilepsy cohort (ReJuMEC) study. Participants were recruited from outpatient appointments in epilepsy clinics in the Untied Kingdom. Patients were classified as having drug-refractory epilepsy if they experience ≥ 1 seizure per month despite prior or current exposure to a dose of at least 1000 mg of sodium valproate. The definition of drug-refractory epilepsy varies greatly in the literature [20] and has not been defined in JME research. The criteria used were based on a combination of the knowledge of sodium valproate being effective in 85–90% of the patients with most becoming seizure-free [21], the criteria used by others [22,23] and clinical experience of members of the ReJuMEC group. Exclusion criteria included abnormal brain MRI scan, alcoholism, a history of drug abuse, and/or neurological disorder besides epilepsy. In addition, none of the patients had experienced a generalized tonic–clonic seizure within the 24 h prior to the neuropsychological assessment. Ethical approval was granted by the North West 1 Research Ethics Committee — Cheshire, and written informed consent was obtained from all patients. Please see Table 1 for the demographic and clinical characteristics of the current sample. 2.2. Neuropsychological battery Participants were given a clinical interview, and a detailed history was obtained from their clinical records. A standardized comprehensive battery of neuropsychometric tests was chosen to enable the evaluation of intellectual ability, language functioning, verbal and nonverbal memory, and executive functions. For a detailed description of the battery used, please refer to Thomas et al. [24]. 2.2.1. Attention and executive functions The color–word interference task from the D-KEFS and zoo map, key search, and rule shift from the Behavioural Assessment of Dysexecutive Syndrome (BADS) were used to assess control of inhibition, perseveration, mental flexibility, planning ability, and attention. 2.3. Severity of executive dysfunctions 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 [25,26], a z-score of ≤−1.00 (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. If two domains met these criteria, the patient was assessed as having mild executive dysfunction; if three or four domains met the criteria, the patient was assessed as having moderate dysfunction; and if five or more domains met the criteria, the patient was assessed as having severe dysfunction. The six domains were as follows: • Working memory, mental control of auditory–visual stimuli, and attention span: assessed using the digit span and letter–number sequencing. • Visual working memory, mental control of visual–spatial stimuli, and attention: assessed using the digit–symbol coding and spatial span. • Verbal fluency: assessed using letter fluency and category fluency. • The ability to switch between categories: assessed using category switching and category accuracy. • The ability to inhibit responses to visual–verbal stimuli: assessed using the color–word interference test (verbal inhibition and inhibition switching). • Naming ability: assessed using the Boston Naming Test.
2.5. Statistical analysis Means and standard deviations were calculated for the demographic and clinical characteristics and 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. One-sample t-tests (Wilcoxon signed-rank test if skewed) were conducted based on the means and standard deviations given by the assessment manuals to compare the cohort's performance with standardized norms. To reduce the likelihood of making a Type I error, the significance level was set at p b 0.01 for all t-tests. Bonferroni correction was not applied as this would have provided too conservative an alpha statistics estimate, increasing the likelihood of making a Type II error. Those scoring the highest levels of mood symptoms (HADS) and personality traits (EPQ) were identified. A quirk of the normative values provided by Sato for the EPQ-BV is that males and females are analyzed separately [28]; one-sample t-tests were employed (as above). Pearson's correlation analyses were conducted between intellectual functioning, executive functioning, HADS scores, and EPQ-BV scores. Clinical variables and psychometric test scores identified from the Pearson correlation were investigated further with independent sample t-tests. Mann–Whitney U test was used for skewed data. Hierarchical regression was performed to assess the contribution of anxiety and neuroticism on test scores. 3. Results 3.1. Affective symptoms 49% of the patients scored in the moderate to severe range for anxiety symptoms and 16% for depressive symptoms. Nine (24%) people had mild anxiety; 15 (41%) people had moderate anxiety; and three (8.1%) had severe anxiety symptoms. In contrast, seven (19%) people had mild depressive symptoms; five (14%) had moderate depressive symptoms; and one (2.7%) had severe depressive symptoms. Higher anxiety scores were significantly correlated with poorer function on tests of vocabulary, similarities, information, picture completion, verbal IQ, performance IQ, full-scale IQ, and letter fluency. Independent t-tests revealed significantly poorer function on the WAIS subtests vocabulary (p = .004) and information (p = .010). People with high anxiety scores had, on average, 2.77 points lower on vocabulary (d =1.02) and 2.40 points lower on the information subtest (d = 0.89) compared with people with drug-refractory JME and less extreme HADS anxiety scores. Anxiety remained a significant independent predictor of performance on the information subtest when correlated clinical and demographic characteristics (duration of epilepsy and years of education) were controlled for and explained 19% (p = .003) of the
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3.2. Personality traits
Table 1 Demographic and clinical characteristics.
The EPQ-BV identified that females with drug-refractory JME had pathologically high neuroticism scores and low extroversion scores (introvert trait). The males scored in the introverted range also but not in the pathological range for neuroticism (Table 2). People with JME and higher neuroticism scores reported more anxiety symptoms and more concentration and motor difficulties compared with those with lower scores (anxiety: p = .001, d = 1.57; ABNAS concentration: p = .007, d = 1.18; ABNAS motor: p = .006, d = 1.41). People with introverted traits did not differ on the levels of anxiety and depression or on the cognitive problems reported. All groups reported that their epilepsy had a moderate impact on their lives.
n = 60 Gender Age Number of years in formal education (n = 43) Level of education (n = 40)
WAIS full-scale IQ (n = 59) Employment status (n = 39)
Duration of epilepsy (years) (n = 57) Onset of epilepsy (years) (n = 57) Types of seizure
Family history (n = 57) History of febrile seizures (n = 54) Photosensitive (n = 33) Number of AEDs
AED type
Female Male Median IQR Median IQR School College University Mean SD Employed Unemployed Full-time education Median IQR Median IQR Myoclonic GTCS (n = 54) Absences (n-54) Other
1 2 3 or more VPA LEV LTG TPM ZNS CLB CBZ
45 (75.0%) 15 (25.0%) 31.00 24.00, 38.75 13.00 11.00, 13.00 20 (50.0%) 15 (37.5%) 5 (12.5%) 89.25 15.24 26 (66.7%) 11 (28.2%) 2 (5.13%) 20.00 9.50, 30.00 13.00 9.00, 15.00 60 (100%) 52 (96.3%) 38 (70.4%) 2 (3.4%) 25 (43.9%) 6 (11.1%) 9 (27.3%) 28 (46.7%) 20 (33.3%) 12 (20.0%) 35 25 18 10 4 10 2
3.2.1. Personality traits, cognition, and executive functions Individuals with high neuroticism scores performed worse across the battery of cognitive and executive function tests compared with people with less extreme neuroticism scores. People with drug-refractory JME and high neuroticism scores scored lower on the BNT compared with people with lower neuroticism scores. As the data were skewed, the Mann–Whitney U test was used, which revealed a nonsignificant difference (p = .307, r = .166). A significant difference was found between the median score of people with high neuroticism scores and published norms at p b .01 level. People with high neuroticism scores had, on average, 7.5 points below published norms (p =.007, r = .674). People with lower neuroticism scores had, on average, 2.0 points below published norms (p = .045, r = .427). (See Fig. 1.) People with drug-refractory JME and low extroversion (introvert trait) scores scored lower on the BNT compared with people with higher extroversion scores. As the data were skewed, the Mann– Whitney U test was used, which revealed a nonsignificant difference (p = .416, r = .132). A significant difference was found between the median score of people with high introversion scores and published norms at p b .01 level. People with high introversion scores had, on average, 6.0 points below published norms (p = .003, r = .607). People with lower introversion scores had, on average, 1.0 point below published norms (p = .109, r = .429) (Fig. 1).
SD, standard deviation; IQR, interquartile range; WAIS, Wechsler Adult Intelligent Scale; VPA, sodium valproate; LEV, levetiracetam; LTG, lamotrigine; TPM, topiramate; ZNS, zonisamide; CLB, clobazam; CBZ, carbamazepine.
variance. No clinical or demographic characteristics significantly correlated with performance on the information subtest. Although the other test scores were not statistically significant, the real-life difference may be substantial, and medium effect sizes were found. People with high anxiety scores had, on average, 9.10 points lower on verbal IQ (d = 0.627, p = .065) and 9.00 points lower on full-scale IQ (d = 0.654, p = .058) compared with people with lower anxiety scores. Higher depression scores were significantly correlated with poorer function on category fluency. Independent t-tests revealed a nonsignificant difference; however, this was likely to be due to the small number of the cohort presenting with high depressive symptoms. People with higher depression scores had, on average, 2.97 points lower on category fluency (d = 0.918) compared with people with less extreme HADS depression scores.
3.2.2. Preliminary results with the zoo map Significant correlations were revealed between neuroticism and raw scores on both versions one (r = −.540, p = .038) and two (r = −.591, p = .020) of the zoo map. People with high neuroticism scores had, on average, 5.00 points lower compared with people with drug-refractory JME and less extreme neuroticism scores (Fig. 2).
3.3. Severity of executive dysfunctions The majority of people with drug-refractory JME (83%) presented with executive and attentional dysfunction on psychometric testing [24]. High EPQ-BV scores exacerbated this dysfunction, and, when a more conservative value of two SD below manual means was applied,
Table 2 Samples EPQ-BV scores compared with norms reported by Sato. Neuroticism
Males (n = 11) Females (n = 27) ⁎ p b .05. ⁎⁎ p b .01. ⁎⁎⁎ p b .001.
Extroversion
Sample means
Sato norms
p value
Sample means
Sato norms
p value
33.09 (10.34)
26.93 (9.96)
.076
33.72 (12.51)
42.58 (9.11)
.041⁎
39.00 (11.51)
30.54 (9.38)
.001⁎⁎
30.63 (9.94)
42.09 (8.97)
b.001⁎⁎⁎
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people with extreme EPQ-BV scores demonstrated the greatest level of executive dysfunction impairment; 54% presented with dysfunction, and 39% had moderate to severe dysfunction. This degree of dysfunction was not seen in any individual with unremarkable EPQ-BV scores; we found that one (8.3%) person had moderate dysfunction, and three (25%) had mild dysfunction.
levels (41%). Consistent with previous studies [15,16], depressive traits in our study were less prevalent compared with anxiety traits; 35% of the patients had mild to severe depressive symptoms, and the majority of patients had normal scores (65%).
3.4. Worse cognitive performance and clinical and psychological patterns
It is unclear as to how anatomically bounded a function ‘personality’ is, but studies have investigated whether personality is related to structural or functional abnormalities in the frontal lobes [9,19]. People with JME and cluster B personality disorders exhibit significant reductions in gray matter volume in the thalamus and increased volume in the right frontal gyri compared with healthy controls and patients with JME without personality disorders [9]. Others have investigated whether structural brain abnormalities [32,33], functional brain abnormalities [11,32], and focal epilepsies [2,3] are related to neuropsychological and executive functioning. Past research has proposed that the abnormal personality exhibited by patients with JME is related to the executive dysfunctions reported in these patients [6,9,19,34]. A previous study touched on this by examining correlations between executive functioning and history of psychiatric disorders [25]. To the best of our knowledge, this is the first study to investigate the relationship between dysexecutive functions and specific psychiatric and personality trains in patients drug-refractory JME. Using a published method of stratifying executive dysfunction in JME [25], the majority of patients, regardless of EPQ-BV scores, exhibited executive dysfunction. However, when a more conservative analysis was used, over half of the patients with JME with high EPQ-BV scores had dysfunction, with 39% presenting with moderate to severe dysfunction. Conversely, no patient with low EPQ-BV scores presented with severe dysfunction, and only one participant had moderate dysfunction. People with drug-refractory JME and a high anxiety score had significantly poorer intellectual functioning and naming ability. All patients performed worse than published norms on naming ability, but only those with high anxiety scores performed within the borderlineimpaired range and those with high neuroticism performed extremely
People with drug-refractory JME performed poorly across a range of tests, but, as expected, the worst performances were all on executive function tests: 18 (30%) people performed worse on the BNT and 17 (28%) on inhibition switching. People with drug-refractory JME and low BNT scores reported higher levels of motor difficulties (ABNAS motor: p = b .001, d = 1.38) and total neurotoxicity symptoms (total ABNAS: p = .006, d = 1.00) compared with people with drug-refractory JME and high BNT scores. People with drug-refractory JME and low inhibition switching scores had significantly (at p b .05 level) longer duration of epilepsy (p = .019, d = .659), ABNAS fatigue (p = .024, d = .836), and slowing (p = .019, d = .903) compared with people with drug-refractory JME and high inhibition switching scores. On average, people with low inhibition switching scores had JME for 8 years 8 months longer compared with those with higher inhibition switching scores. 4. Discussion Previous studies have found a high percentage of axis II personality disorders (particularly cluster B) and axis I psychiatric disorders (particularly anxiety and depression) in probands with JME and significantly more than in healthy controls [15,30,31]. In our study, there was a high frequency of pathological neurotic and introverted personality traits in people with drug-resistant JME. Females scored in the high range for neurotic and introverted traits, and the males scored high for introverted traits. Seventy-three percent of patients had mild to severe anxiety symptoms, and the majority of patients had moderate
4.1. Affective symptoms, personality, and cognition
56 55 54 Boston naming test mean score
53 52
Published norms
51 50 Whole sample median
49 48
Borderline impaired
47 46 45 Low anxiety
High anxiety
Low introversion
High introversion
Low neuroticism
High neuroticism
44
Fig. 1. Boston Naming Test performance (median scores) of people with drug-refractory JME and different personality traits.
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9 8 7 6 5
high neuroticism
4
low neuroticism
3 2 1 0 Zoo Map Version One
Zoo Map Version Two
Fig. 2. Median scores on versions one and two of the zoomap for drug-refractory JME with high and low neuroticism scores.
closely to this range. Preliminary findings with the BADS revealed significant correlations between poorer planning ability and only a high neuroticism score. The planning ability of those with high neuroticism scores was marginally lower when given the order of places to visit (zoo map version two), but when given a list of places to visit with no guidance on order, patients with high neuroticism scores struggled considerably. The findings with the BADS were only considered as preliminary findings as the BADS was added later in the study, and, therefore, only a small proportion of patients were administered the zoo map. The affective, personality, and cognitive findings indicate the sample as a whole presented with deficits in the inferior (inhibition) and medial (switching) frontal cortex. However, the results indicate a broad network failure in the frontal lobes of a high proportion of those with high neuroticism and/or introversion traits. Furthermore, people with drug-refractory JME and high anxiety scores presented with the greatest impairment in naming ability. Thus, the findings confirm that executive dysfunctions reported in JME are related to personality and affective traits. 4.2. Cognition and clinical patterns People with drug-refractory JME performed least well on tests of mental flexibility and inhibition. People with the poorest naming ability also had high anxiety scores and reported high levels of cognitive problems. Furthermore, they had a higher mean neuroticism score with a small to medium effect size. People with the lowest inhibition switching scores had a longer duration of epilepsy and also reported high levels of cognitive problems. However, the whole sample was borderlineimpaired on inhibition switching. Impaired inhibition is a consistent feature in JME analysis [3–6,32], which suggests that this impairment may be caused by a fundamental structural or functional brain abnormality shared by all people with JME. Past studies that have assessed healthy siblings of patients with JME have also found that they perform worse than healthy unrelated controls [5]. This suggests that impaired inhibition may be genetically determined. The current study indicates that the common impairment in inhibition switching is exacerbated by the duration of epilepsy. 4.3. Strengths and limitations The current study has some strengths and limitations. It is the first study to investigate whether the neuropsychological profile found in JME is related to the personality and psychiatric traits often reported. Furthermore, the study profiled a ‘purer’ subgroup of JME by targeting only patients with drug-refractory JME. The current study corrected for multiple comparisons and used published norms for comparison. However, the study would benefit from a comparison group of patients
with drug-sensitive JME; we did attempt to recruit such a group but were unable to recruit sufficient numbers due to recruitment taking place in tertiary centers, which patients with controlled seizures rarely visit. The main limitation of the study was not all patients completed the EPQ-BV due to loss of funding half way through the study. This reduced the sample size for statistical analyses involving personality and, thus, the power of those tests. A limitation of the EPQ-BV itself is that it only assesses two dimensions of personality. Juvenile myoclonic epilepsy is a heterogeneous disorder, and different genetic etiologies may result in different personality traits and levels of impairment. Despite this, the EPQ-BV has been a worthwhile tool for the current study, as it has revealed that frontal dysfunctions are associated with personality traits. These findings will hopefully be used to encourage further study in this area; for example, future research should use a more comprehensive assessment of personality (such as the Structured Clinical Interview for DSM-IV). Moreover, future research should examine whether distinct behavioral differences are a result of specific brain abnormalities, which lead to the different levels of impairments found in JME. 4.4. Conclusion There have been previous attempts to subcategorize JME [18], but because of the multiple factors and potentially numerous behavioral patterns, it may not be possible to categorize JME into neat subcategories. Nevertheless, distinct behavioral patterns may be used to identify differences in frontal structure/functioning and, ultimately, in genotype. The current findings suggest a subgroup of patients present with a more severe type of JME and may be distinguished by genetic stratification. Acknowledgments The ReJuMEC study was funded by the Medical Research Council (MRC). Declaration of interests All authors report that they have no competing interests. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.yebeh.2014.03.026. References [1] 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(Supplement 1):S87–90. [2] Devinsky O, Gershengorn J, Brown E, Perrine K, Vazquez B, Luciano D. Frontal functions in juvenile myoclonic epilepsy. Neuropsychiatry Neuropsychol Behav Neurol 1997;10(4):243–6. [3] Piazzini A, Turner K, Vignoli A, Canger R, Canevini MP. Frontal cognitive dysfunction in juvenile myoclonic epilepsy. Epilepsia 2008;49(4):657–62. [4] Pascalicchio TF, de Araujo Filho GM, da Silva Noffs MH, Lin K, Caboclo LOSF, 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. [5] 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. [6] Wandschneider B, Kopp UA, Kliegel M, Stephani U, Kurlemann G, Janz D, et al. Prospective memory in patients with juvenile myoclonic epilepsy and their healthy siblings. Neurology 2010;75(24):2161–7. [7] Bergvall ÅH, Nilsson T, Hansen S. Exploring the link between character, personality disorder, and neuropsychological function. Eur Psychiatry 2003;18(7):334–44. [8] Fertuck EA, Lenzenweger MF, Clarkin JF, Hoermann S, Stanley B. Executive neurocognition, memory systems, and borderline personality disorder. Clin Psychol Rev 2006;26(3):346–75. [9] de Araújo Filho GM, Jackowski AP, Lin K, Guaranha MSB, Guilhoto LMFF, da Silva HH, et al. Personality traits related to juvenile myoclonic epilepsy: MRI reveals prefrontal
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