FULL-LENGTH ORIGINAL RESEARCH
Neuropsychological profiles of patients with juvenile myoclonic epilepsy and their siblings: An extended study *Nasur Iqbal, †Helen Caswell, ‡Robin Muir, §Amy Cadden, ¶Stuart Ferguson, ¶Holly Mackenzie, ¶Philip Watson, and §Susan Duncan Epilepsia, 56(8):1301–1308, 2015 doi: 10.1111/epi.13061
SUMMARY
Dr. Nasur Iqbal is a clinical psychologist working for the NHS in Manchester, United Kingdom.
Objective: To examine executive function, intelligence, visuospatial skills, language, memory, attention, reaction time, anxiety, depression, and emotional and behavioral traits most frequently associated with executive dysfunction in patients with juvenile myoclonic epilepsy (JME) compared with a sibling and a normal control group under video–electroencephalography (video-EEG) conditions. Methods: Twenty-two sibling pairs, one with JME, were compared with 44 controls matched for age, gender, and educational level. All participants were administered a comprehensive set of neuropsychological and questionnaire measures during and without video-EEG recording. Results: The JME group differed significantly from controls in measures of phonemic and semantic verbal fluency. They scored significantly higher on the dysexecutive self-rating questionnaire, being more likely to report traits associated with executive dysfunction than both siblings and controls. Patients with JME reported significantly low mood than both controls and their siblings. Unaffected siblings differed significantly from controls on psychomotor speed, phonemic verbal fluency and were considered to exhibit traits associated with executive dysfunction by others. Qualitative inspection of data suggested a convincing trend for patients with JME and their siblings to perform worse than controls on most measures. Significance: This study supports the existence of a distinct neuropsychological profile among patients with JME and their siblings, which is likely to be genetically determined. The similarity of neuropsychological profiles between JME patients and their siblings is independent of antiepileptic drug effects or subclinical EEG activity. The significant differences between the sibling and controls suggests that there is a neurocognitive endophenotype for JME. KEY WORDS: Juvenile myoclonic epilepsy, Cognition, Endophenotype.
Accepted May 15, 2015; Early View publication June 15, 2015. *Department of Clinical Psychology, North Manchester General Hospital, Crumpsall, Manchester, United Kingdom; †Department of Clinical Neuropsychology, Salford Royal Hospital, Salford, Manchester, United Kingdom; ‡Division of Clinical Psychology, University of Liverpool, Brownlow Hill, Liverpool, United Kingdom; §Edinburgh and South East Scotland Epilepsy Service, Department of Clinical Neurosciences, Western General Hospital, Edinburgh, United Kingdom; and ¶Department of Neurophysiology, Western General Hospital, Edinburgh, United Kingdom Address correspondence to Nasur Iqbal, Department of Clinical Psychology, North Manchester General Hospital, Delaunay’s Road, Crumpsall, Manchester M8 5RB, U.K. E-mail: [email protected] Wiley Periodicals, Inc. © 2015 International League Against Epilepsy
JME was first described by Janz1 and is characterized by myoclonus, normal neurologic examination, and magnetic resonance imaging (MRI) imaging, onset between 8 and 36 years, and electroencephalography (EEG) with normal background but with bursts of polyspike and wave.2 It has an estimated incidence of 0.1–0.2/100,000, a prevalence of 5–10% of all epilepsies, comprising 18% of all idiopathic generalized epilepsy (IGE) seen in epilepsy clinics.3 Janz also observed common personality factors in JME such as social immaturity, hedonism, and lack of ambition and endurance.1 One long-term follow-up study revealed that 75% of patients had at least one indicator of psychosocial dysfunction, including depression and social
1301
1302 N. Iqbal et al.
Key Points • • • • •
Cognitive deficits in JME are more global and not limited to the areas of executive functioning Siblings share distinct cognitive and personality traits that closely match their affected brothers and sisters with JME Cognitive deficits in patients with JME and siblings occur independently of subclinical EEG activity JME’s genetic substrate may be implicating similar microstructural abnormalities of the cortex in both groups to varying degrees There is increasing support to suggest there is an endophenotype for JME or idiopathic generalized epilepsy (IGE)
isolation, with seizure frequency or remission not associated with these outcomes.4 In addition to personality traits and EEG changes, people with JME exhibit significant cognitive deficits in mental flexibility, working memory, verbal fluency, psychomotor speed, perseveration, and planning.5–9 Functional neuroimaging and structural studies have confirmed abnormalities in the thalamocortical circuitry and the dorsolateral and mesiofrontal areas, suggesting a biologic substrate for the cognitive deficits reported in neuropsychological findings.10 These findings may explain the phenomenon of neuropsychological activation (NPA7), whereby bursts of polyspike and wave are seen on EEG of people with JME during certain cognitive tasks. Because of JME’s genetic substrate,11 there has been increasing interest in the siblings of individuals with the condition.9,12–14 To our knowledge and in association with our preliminary investigation,13 this remains the first study to explore cognitive functioning of individuals with JME and their siblings under video-EEG conditions.
Method Ethics approval was granted by the South East Scotland Research Ethics Committee. All patients and siblings gave informed consent. A combined total of 22 patients who met the diagnostic criteria for JME, who had siblings who could attend testing,
were recruited from epilepsy clinics. All patients satisfied the diagnostic criteria for JME.2 None of the patients had other neurologic, medical, or psychiatric conditions. All spoke English as their first language. Where possible, a corroborating history was taken from the sibling or a parent. Nineteen of the 22 participants had normal background on routine EEG with bursts of polyspike and wave. One exhibited frequent bursts of polyspike and wave after sleep deprivation. One had a normal routine EEG in our laboratory but a previous ambulatory EEG done in another laboratory had shown clear polyspike and wave. Despite clear history in keeping with JME, one participant had a normal EEG and did not return for a sleep-deprived examination. Participants were all treated with standard antiepileptic drugs (AEDs). Eleven took sodium valproate (VPA) monotherapy, four took levetiracetam (LEV) monotherapy, and two took lamotrigine (LTG) monotherapy. Five took more than one AED: two received VPA/LEV in combination, one LEV/LTG, one LEV/clonazepam, and one LEV/zonisamide. All patients with JME had normal neurologic examination. Sixteen had normal 1.5T MRI imaging; one declined imaging because his epilepsy was so well controlled. Two cited claustrophobia and one did not attend for imaging. A further two were not scanned. Our power calculation indicated 20 participants in each group (N = 60) would have 80% power to detect the desired effect size of 1.4 or more (difference in mean/standard deviation [SD]) in the measures used at 5% significance level. Patients and siblings were matched for age, gender, and education to 44 healthy controls (Table 1). The majority of participants were right-hand dominant (n = 79). The same neuropsychological measures were administered in the same order as in the original study (Table 2); however, two tests were removed following the preliminary investigation (Token Test and the Cognitive Estimate Test), as they did not provide any further information and were not supported by the results of previous investigations. Part of the testing was undertaken under video-EEG recording for two reasons; to ensure subclinical seizure activity was not compromising each subject’s performance and to assess the presence and impact of NPA. Neuropsychological test battery A comprehensive neuropsychological test battery was chosen to examine cognitive functioning (Table 2). The neuropsychological evaluation enabled the investigators to
Table 1. Demographic variables Group (n)
Gender, M/F Age in years, mean (SD) Education in years, mean (SD) Epilepsia, 56(8):1301–1308, 2015 doi: 10.1111/epi.13061
JME (22)
Siblings (22)
Controls (44)
Kruskal-Wallis test v2 (2)
p-Value
7/15 26.7 (7.3) 14.6 (2.9)
12/10 26.6 (10.9) 15 (3.5)
21/23 25.7 (7.8) 14.6 (2.9)
0.387 2.447 1.146
0.8 0.3 0.6
1303 Cognitive and Personality Traits in JME Table 2. Summary of neuropsychological measures Order
Abbreviation
Name
During videoEEG recording
CVLT-II (UK Version) RCFT
California Verbal Learning Test 2nd Edition17 Rey-Osterrieth Complex Figure Test18,19 Stroop Test; Color word score20 Grooved Peg Board21 The Wechsler Memory Scale – Third Edition22 Brixton Spatial Anticipation Test (Taken from the Hayling and Brixton Tests)23 Phonemic Fluency24 Semantic Fluency24 The Wechsler Abbreviated Scale of Intelligence25 Hospital Anxiety and Depression Scale15 The DEX questionnaire (The Dysexecutive Questionnaire; taken from the Behavioural Assessment of the Dysexecutive Syndrome, BADS)16
Stroop GPB WMS-III Without videoEEG recording
Brixton
FAS Animals WASI Questionnaires
HADS DEX
examine a range of cognitive abilities, including those not previously assessed in other studies. In addition, two validated questionnaires were administered—the Hospital Anxiety and Depression Scale (HADS15) and the Dysexecutive (DEX) Questionnaire (a questionnaire inquiring into behaviors associated with the dysexecutive syndrome16) – . The DEX questionnaires were also completed by a close family member of each participant so that the ratings of the participant could be compared with a close third party to investigate issues such as insight. Procedure All video-EEGs were performed on XLTEK equipment and software (version 5.4.0, copyright 1998–2006). The International 10-20 measurement system was used to attach electrodes, and all aspects of recordings adhered to local protocols and national guidelines. High and low frequency filters were set at 70 and 0.5 Hz, respectively. All EEG studies were reviewed by nationally accredited clinical physiologists and consultant neurophysiologists or consultant neurologists. Each participant at the time of testing underwent an initial baseline EEG recording by senior neurophysiologists for 3 min with eyes open and eyes closed, which was used to contrast any abnormal EEG activity before and during testing. All patients and siblings were asked to ensure that they were not sleep deprived and had eaten lunch. All testing was done from 14:00 h onward. Testing done under video-EEG recording took on average of 50 min, during which time neurophysiologists monitored and noted any EEG and behavioral changes that occurred. Thereafter, the electrodes were removed and the partici-
pants moved to an adjunct room where the remaining measures were completed. On completing the neuropsychological assessment, the participants then completed the HADS and DEX questionnaire measures. The tests administered under video-EEG conditions were those thought to potentially elicit EEG changes based on the results of previous studies.7 Statistical analysis A between-group comparison design was used, comparing three independent groups. The raw scores obtained from each individual’s performance on the various neuropsychological measures were pooled to provide a mean score for the respective group (Table 3). z-Scores were obtained from the JME and sibling group based on the standard deviation of the control group so that differences in performance from that of controls could be quantitatively presented (Fig. 1).
Results Qualitative trends in data The JME and sibling group exhibited a remarkable similarity in neuropsychological profiles when their z-scores where compared with the control group (Fig. 1). Unaffected siblings also seem to “underperform” somewhere between patients with JME and controls. Taken together, patients with JME and siblings demonstrated subtle deficits in the areas of verbal memory (California Verbal Learning Test 2nd Edition [CVLT-II]); the time taken to copy the figure drawing (Rey-Osterrieth Complex Figure Test [RCFT]); selective attention and cognitive flexibility (Stroop Test); psychomotor speed using both their dominant and nondominant hand (Grooved Peg Board); sustained visual attention (spatial span, The Wechsler Memory Scale Third Edition [WMS-III]); rule attainment (Brixton Spatial Anticipation Test); phonemic and semantic verbal fluency (FAS, Animals); general IQ as assessed by two domains (The Wechsler Abbreviated Scale of Intelligence [WASI]); anxiety (Hospital Anxiety and Depression Scale [HADS]); and were rated by others as exhibiting behavioral, motivational, cognitive, and emotional changes most commonly associated with executive dysfunction. In contrast, they performed relatively equal to controls on measures assessing visual memory (RCFT) and sustained verbal attention (WMS-III). Comparative analysis Statistically significant differences between the groups were observed for the following: Grooved Peg Board— using the participants dominant hand (F2,55 = 3.75, p < 0.03); Verbal (phonemic) fluency using letters of the alphabet (FAS; F2,55 = 6.35, p < 0.003); Verbal (semantic) fluency using a category (Animals; F2,55 = 5.97, p < 0.005); HADS questionnaire yielding a score for depression (F2,55 = 7.80, p < 0.001); the DEX questionEpilepsia, 56(8):1301–1308, 2015 doi: 10.1111/epi.13061
1304 N. Iqbal et al. Table 3. Summary of mean raw scores and significance obtained on neuropsychological measures, stratified by group Group JME Neuropsychological measure Under video-EEG surveillance California Verbal Learning Test 5 Trials Free recall Delayed recall Recognition Total repetitions Total intrusions Rey-Osterrieth Complex Figure Test Copy Time to copy (s) Immediate recall Delayed recall Recognition trial Stroop (Color-Word) Grooved Peg Board Dominant hand Nondominant hand Digit span Spatial span Without video-EEG surveillance Brixton FAS Animals Vocabulary Block design Matrix reasoning General IQ Questionnaires Hospital Anxiety and Depression Scale Anxiety score Depression score DEX Questionnaire Self Independent rater a
Sibling
Group comparison Control
Mean score/SD
F value
p-Value
50.1/10.9 0.0/0.9 0.0/1.2 0.3/1.0 0.4/1.2 0.5/1.0
47.9/15.2 0.4/1.3 0.5/1.6 0.6/1.4 0.5/1.3 0.2/1.2
53.9/12.1 0.6/1.2 0.1/1.1 0.4/1.0 0.4/1.2 0.3/1.3
1.44 0.55 1.11 0.02 0.62 0.249
0.245 0.580 0.336 0.981 0.541 0.780
34.5/2.4 184.4/108.6 29.6/11.9 31.4/13.6 27.6/12.8 106.6/9.7
34.5/2.7 149.2/60.4 29.2/16.9 30.1/16.7 31.1/15.2 104.2/12.0
33.6/3.3 124.5/42.5 28.4/15.4 28.7/15.9 30.4/15.3 107.3/8.5
1.23 2.00 0.14 0.08 1.10 0.33
0.300 0.145 0.871 0.926 0.340 0.724
82.8/13.8 93.1/16.5 9.8/3.4 9.7/3.2
82.7/11.6 88.8/12.8 10.3/3.6 10.5/3.0
75.9/19.0 84.8/18.3 10.0/2.9 9.6/2.2
3.75 1.73 0.16 0.55
0.03a 0.187 0.856 0.582
7.0/1.9 30.1/7.8 18.2/4.9 48.2/10.4 50.8/8.9 52.0/9.8 100.4/12.3
7.0/2.5 35.6/11.8 18.6/4.8 52.1/11.7 54.9/9.3 52.9/11.0 104.5/17.7
7.3/1.9 43.3/13.6 22.9/5.4 55.3/10.3 54.6/11.3 54.9/9.4 109.0/15.4
0.38 6.35 5.97 2.23 0.98 0.68 1.75
0.688 0.003a 0.005a 0.118 0.381 0.513 0.184
8.0/4.1 4.1/2.8
6.8/4.4 2.0/1.7
5.9/3.9 1.8/2.3
1.81 7.80
0.174 0.001a
26.1/12.9 19.1/8.8
17.3/9.4 22.8/13.5
17.2/12.9 13.2/12.5
5.58 3.40
0.006a 0.041a
p > 0.05.
naire, which was both self-administered as well as being rated by an independent rater (F2,55 = 5.58, p < 0.006, and F2,55 = 3.40, p < 0.041, respectively). Post hoc analyses using the Scheffe test was conducted to determine where these differences occurred (Table 4). There were significant differences between the JME group and controls on the Grooved Peg Board using the dominant hand. There were significant differences between the JME group and the control groups on both phonemic and semantic fluency, with the JME patients generating significantly fewer words than controls. Siblings also took significantly longer than controls to complete the Grooved Peg Board using their dominant hand. Siblings also generated significantly fewer words on semantic verbal fluency testing than controls. Epilepsia, 56(8):1301–1308, 2015 doi: 10.1111/epi.13061
A statistically significant difference was found on the HADS depression subscale between patients with JME, their siblings, and the control group. Patients with JME reported significantly more symptoms of depression than the other two groups, and the mean score was consistent with mild symptoms of depression as a group. On the DEXself-questionnaire, patients with JME rated themselves significantly higher on statements of behavioral, motivational, cognitive, and emotional changes most commonly associated with executive function in comparison with controls and their siblings. On the DEX-other questionnaire, there was a significant difference between siblings and controls, whereby the siblings were rated by a person who knew them well as exhibiting behavioral, cognitive, motivational, and emotional changes more commonly associated with executive dys-
1305 Cognitive and Personality Traits in JME
Figure 1. Qualitative representation of the trends in data. Epilepsia ILAE
Table 4. Comparative analysis; significant differences between the groups Test Grooved Peg Board; dominant hand FAS Animals HADS – depression DEX-self DEX-other
JME 82.8 (13.8)
Sibling
Control a
82.7 (11.6)
75.9 (19.0)
EEG remained within normal parameters for all participants during testing.
p-Value 0.05a
30.1 (7.8)b 18.2 (4.9)b 8.0 (4.1)b
35.6 (11.8) 18.6 (4.6)a 6.8 (4.4)c
43.3 (13.6) 22.9 (5.4) 5.9 (3.9)
0.004 0.02b, 0.02a 0.002b, 0.013c
26.1 (12.9)b,c 19.1 (8.8)
17.3 (9.4) 22.8 (13.5)a
17.2 (12.9) 13.2 (12.5)
0.01b, 0.02c 0.04
a
Siblings compared with control. JME compared with control. JME compared with sibling.
b c
function. Siblings did not rate themselves as being different from the control group. Video-EEG findings As with the original preliminary investigation, the current study did not demonstrate any clinically meaningful effects or influence of EEG activity on cognitive performance. The
Discussion To our knowledge this is the first study that comprehensively evaluates cognitive, emotional, and behavioral profiles of patients with JME, their siblings, and matched controls under video-EEG recording. It is the first to demonstrate a significant difference between siblings of people with JME and controls, and to show that those differences principally affect the same domains as those of the probands. These findings support the results of our earlier study.13 Our results are in keeping with three other studies of patients with IGE and their siblings, all of which showed a clear trend for siblings to have similar neuropsychological deficits as their affected brothers and sisters.9,12,14 Our study design was different from these studies in that we did not recruit a generic control group, but rather matched each sibling and each patient with JME with their own age-/education-matched control. This increased the statistical power of the study. In addition, we took care to match for test conditions by using the same controlled environment on each occasion and testing at the same time of day because of the well-known chronodependency of JME.26 Epilepsia, 56(8):1301–1308, 2015 doi: 10.1111/epi.13061
1306 N. Iqbal et al. A unique feature of our study was that some of our testing was conducted under EEG surveillance. This was done both to assess the impact of subclinical EEG discharges on the results of neuropsychological testing and to assess the presence in our population of neuropsychological activation (NPA7). Neither probands nor siblings exhibited NPA in the 50 min of testing under video-EEG conditions, sufficient to capture any such activity. Two patients did exhibit very brief spike and wave during testing, which did not interfere with their ability to perform the task at hand.13 It is interesting to note that the cognitive deficits we identified were not likely to be associated with EEG activity. Thus we are confident that our results are robust and are likely to be a stable profile rather than the transient effects of changing electrical activity in the brain. There may be a number of explanations for this lack of activation. First, there may be differences in cortical activation between Japanese ideograms and roman script. Second, with one exception, our sample of patients with JME had good seizure control. Third, our testing was done in people we had asked to arrive in the early afternoon, the time of day when seizures are least likely to occur in JME. Siblings in our study generated fewer words on the semantic fluency task than controls. Verbal fluency is sensitive to frontal lobe changes,27 in particular the left frontal lobe, and correlates with other measures of executive function. Two recent studies using functional magnetic resonance imaging (fMRI) of patients with JME and their siblings have demonstrated very similar abnormal patterns of activation in the motor cortex and increased functional connectivity.28,29 Equally interesting, the same group reported impaired connectivity between the presupplementary motor region and the frontopolar cortex, and suggested that this may explain the impairments seen in frontal lobe function in patients with JME.27 The implication of these results would indicate that given JME’s genetic substrate, first-degree relatives may have a similar (although less severe) microstructural abnormality of the same areas of the cortex. Our neuropsychological results support these anatomic findings, with our sibling sample demonstrating similar—if less marked—abnormalities on testing as their affected brothers and sisters. Siblings took significantly longer to complete the Grooved Peg Board test, indicating reduced psychomotor speed. This has been reported in patients with JME.12 This observation is noteworthy because psychomotor slowing is seen in people exposed to AEDs,30 and therefore this significant difference on the Grooved Peg Board between siblings and controls suggests it was not likely due to the drug effect as neither of these groups were taking AEDs. The finding may reflect white matter ultrastructural changes in the corona radiate and corpus callosum, as well as the prefrontal motor and supplementary motor areas.8 Once again, our results are congruent with structural and functional imaging. As with semantic fluency, the results Epilepsia, 56(8):1301–1308, 2015 doi: 10.1111/epi.13061
suggest that abnormalities occur in both patients with JME and siblings. Adolescence sees the development of the individual’s ability to think in abstract terms, formulate the potential outcomes of different courses of actions, and assess risk,31 cognitive changes that are thought to reflect myelination. Brain development continues until the early twenties, and during adolescence the brain exhibits growth, increased connectivity, and synaptic pruning.31 This phase of maturation, which occurs at the same age as JME first appears, may be connected. One candidate gene for JME32 has been implicated in the changes in several neuronal maturational steps including apoptosis, which may lead to hyperexcitable neurons not being destroyed as part of maturation. This may explain cognitive activation of myoclonic jerks. This gene also plays a role in neuronal migration and formation of connections, any of which if disrupted could lead to a susceptibility to seizures and the neuropsychological effects which have been reported.33 Patients with JME reported more symptoms associated with depression than siblings and controls. Although this difference may not necessarily reflect a clinical concern, it is noteworthy due to the prevalence of mood and anxiety disorders in people with JME when compared with the population at large, being more marked in those who have poorly controlled seizures.34 Our sample was composed primarily of people with well-controlled seizures, which is reflected in the relatively low HADS scores, which measured mood and anxiety. Moreover, although anxiety and depression as judged by the HADS was not a significant finding in our sample, this suggests the differences between the groups were not due to the individual’s mental health. Poor social adjustment in people with epilepsy was first described by Janz in the 1950’s1 and probably reflects a mixture of the cognitive and behavioral impact of frontal lobe dysfunction as well as the psychosocial impact of epilepsy. More recent studies have reported poor social adjustment in work and family relationships in people with epilepsy, with these difficulties associated with impulsive traits and seizure frequency but not cognitive impairment. Because siblings appear to have similar neuropsychological profiles on formal cognitive tests, it seems not unreasonable to postulate that they might exhibit a constellation of personality traits in keeping with a dysexecutive syndrome. To our knowledge this has never been explored before in siblings. The DEX self-rating scale showed significant differences between the JME group and the controls and siblings. The JME group rated themselves more highly on statements about motivational, cognitive, behavioral, and emotional changes most often associated with executive dysfunction. On the DEX-other scale, for which a person who knows the subject completes the questionnaire a different pattern emerged. In this, both siblings and JME patients were rated as having significantly more traits associated with executive dysfunction than controls. It is
1307 Cognitive and Personality Traits in JME interesting that siblings did not rate themselves as having increased signs of dysexecutive syndrome on the DEX. One possible explanation for this is that the siblings may lack insight into such sequelae. Recently the existence of a JME endophenotype has been proposed.29 Endophenotypes are traits manifest in an individual irrespective of whether the condition is active, are heritable, and are found more frequently in nonaffected family members of affected individuals than in the general population.35 Evidence from imaging studies are persuasive, as are the studies that have included JME along with other IGEs.14 In this study we have demonstrated that our siblings exhibit cognitive and personality traits similar to their affected sibling, but without seizures or myoclonus. In our opinion they are endophenotypes. This raises some interesting questions. Should other members of these families be offered neuropsychological assessment with a view to help in school or the workplace? Even more interesting could the presence of a JME or IGE endophenotype contribute to reduced cognitive abilities in some children of mothers with JME exposed to sodium valproate in utero? In this study we sought to improve the design and limit possible confounding factors further following the preliminary study. It is possible that in controlling the environment including time of day and only testing patients with well-controlled JME, we missed the possible effects of changes in EEG pattern on cognitive function. It would be interesting to assess patients with poorly controlled JME under video-EEG conditions and to vary the time of day. It would also be useful to assess the functional impact of these cognitive and behavioral differences on employment, social relationships, and academic achievements. A recent study by Jiang et al.36 showed problems with some aspects of emotional recognition and empathy in patients with IGE. These difficulties were correlated with cognitive deficits associated with frontal lobe dysfunction. Our study highlights the importance of investigating the wider psychosocial impact of epilepsy in patients with JME and their families.
Acknowledgment Study Funding: British Epilepsy Association.
Disclosure None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
References 1. Janz D, Christian W. Impulsive-petit mal. Dtsch Z Nervenheilkd 1957;176:344–386. 2. Camfield CS, Striano P, Camfield PR. Epidemiology of juvenile myoclonic epilepsy. Epilepsy Behav 2013;28 (Suppl. 1):S15–S17.
3. Camfield P. Issues in epilepsy classification for population studies. Epilepsia 2012;53 (Suppl. 2):10–13. 4. Camfield CS, Camfield PR. Juvenile myoclonic epilepsy 25 years after seizure onset: a population-based study. Neurology 2009;73:1041– 1045. 5. O’Muircheartaigh J, Vollmar C, Barker GJ, et al. Focal structural changes and cognitive dysfunction in juvenile myoclonic epilepsy. Neurology 2011;76:34–40. 6. Sonmez F, Atakli D, Sari H, et al. Cognitive function in juvenile myoclonic epilepsy. Epilepsy Behav 2004;5:329–336. 7. Matsuoka H, Nakamura M, Ohno T, et al. The role of cognitive motor function in precipitation and inhibition of epileptic seizures. Epilepsia 2005;1:17–20. 8. Kim JH, Suh SI, Park SY, et al. Microstructural white matter abnormality and frontal cognitive dysfunctions in juvenile myoclonic epilepsy. Epilepsia 2012;53:1371–1378. 9. Wandschneider B, Kopp UA, Kliegel M, et al. Prospective memory in patients with juvenile myoclonic epilepsy and their healthy siblings. Neurology 2010;75:2161–2167. 10. Koepp MJ, Woermann F, Savic I, et al. Juvenile myoclonic epilepsy – neuroimaging findings. Epilepsy Behav 2013;28 (Suppl. 1):S40–S44. 11. Steffens M, Leu C, Ruppert AK, et al. Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32. Hum Mol Genet 2012;21:5359– 5372. 12. Levav M, Mirsky AF, Herault J, et al. Familial association of neuropsychological traits in patients with generalized and partial seizure disorders. J Clin Exp Neuropsychol 2002;3:311–326. 13. Iqbal N, Caswell HL, Hare DJ, et al. Neuropsychological profiles of patients with juvenile myoclonic epilepsy and their siblings: a preliminary controlled experimental video-EEG case series. Epilepsy Behav 2009;14:516–521. 14. Chowdhury FA, Elwes RDC, Koutroumanidis M, et al. Impaired cognitive function in idiopathic generalised epilepsy and unaffected family members: an epilepsy endophenotype. Epilepsia 2014;55:835–840. 15. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983;67:361–370. 16. Wilson BA, Alderman N, Burgess P, et al. The behavioural assessment of the dysexecutive syndrome. Flempton: Thames Valley Test Co.; 1996. 17. Delis DC, Kramer JH, Kaplan E, et al. California verbal learning test, second edition, adult version. San Antonio, TX: Psychological Corp; 2000. 18. Rey A. L’examen psychologique dans les cas d’encephalopathie traumatique. Arch Psychol 1941;28:286–340. 19. Osterrieth PA. Le test de copie d’une fugure complex: contributiona l’etude de la perception et de la memoire. Arch Psychol 1944;30:286– 356. 20. Stroop JR. Studies of interference in serial verbal reaction. J Exp Psychol 1935;18:643–662. 21. Matthews CG, Klove K. Instruction manual for the adult neuropsychology test battery. Madison, WI: University of Wisconsin Medical School; 1964. 22. Wechsler D. WMS-III administration and scoring manual. San Antonio, TX: Psychological Corp; 1997. 23. Burgess PW, Shallice T. The Hayling and Brixton tests. Thurston, Suffolk: Thames Valley Test Co.; 1997. 24. Benton AL, Hamsher K. Multilingual aphasia examination. Iowa City, IA: AJA Associates; 1989. 25. Wechsler D. WASI administration and scoring manual. San Antonio, TX: Psychological Corp; 1999. 26. Kasteleijn-Nolst Trenite DG, de Weerd A, Beniczky S. Chronodependency and provocative factors in juvenile myoclonic epilepsy. Epilepsy Behav 2013;28:s25–s29. 27. Costafreda SG, Fu CH, Lee L, et al. A systematic review and quantitative appraisal of fMRI studies of verbal fluency: role of the left inferior frontal gyrus. Hum Brain Mapp 2006;27:799–810. 28. Vollmar C, O’Muircheartaigh J, Barker GJ, et al. Motor system hyperconnectivity in juvenile myoclonic epilepsy: a cognitive functional magnetic resonance imaging study. Brain 2011;134:1710–1719. 29. Wandschneider B, Centeno M, Vollmar C, et al. Motor co-activation in siblings of patients with juvenile myoclonic epilepsy: an imaging endophenotype? Brain 2014;137:2469–2479. Epilepsia, 56(8):1301–1308, 2015 doi: 10.1111/epi.13061
1308 N. Iqbal et al. 30. Eddy CM, Rickards HE, Cavanna AE. The cognitive impact of antiepileptic drugs. Ther Adv Neurol Disord 2011;4:385–407. 31. Christie D, Viner R. Adolescent development. BMJ 2005;330:301– 304. 32. Toga A, Thompson P, Sowell E. Mapping brain maturation. Trends Neurosci 2006;29:148–159. 33. de Nijis L, Wolkoff N, Grisar T, et al. Juvenile myoclonic epilepsy as a possible neurodevelopmental disease: role of EFHC1 or myoclonic 1. Epilepsy Behav 2013;28:s58–s60.
Epilepsia, 56(8):1301–1308, 2015 doi: 10.1111/epi.13061
34. de Araujo Filho GM, Mazetto L, da Silva JM, et al. Psychiatric comorbidity in patients with two prototypes of focal versus generalized epilepsy syndromes. Seizure 2011;20:383–386. 35. Gottesman II, Gould TD. The endophenotype concept in psychiatry, etymology and strategic intentions. Am J Psychiatry 2003;160:636– 645. 36. Jiang Y, Hu Y, Wang Y, et al. Empathy and emotion recognition in patients with idiopathic generalized epilepsy. Epilepsy Behav 2014;9:139–144.
Neuropsychological profiles of patients with juvenile myoclonic epilepsy and their siblings: An extended study *Nasur Iqbal, †Helen Caswell, ‡Robin Muir, §Amy Cadden, ¶Stuart Ferguson, ¶Holly Mackenzie, ¶Philip Watson, and §Susan Duncan Epilepsia, 56(8):1301–1308, 2015 doi: 10.1111/epi.13061
SUMMARY
Dr. Nasur Iqbal is a clinical psychologist working for the NHS in Manchester, United Kingdom.
Objective: To examine executive function, intelligence, visuospatial skills, language, memory, attention, reaction time, anxiety, depression, and emotional and behavioral traits most frequently associated with executive dysfunction in patients with juvenile myoclonic epilepsy (JME) compared with a sibling and a normal control group under video–electroencephalography (video-EEG) conditions. Methods: Twenty-two sibling pairs, one with JME, were compared with 44 controls matched for age, gender, and educational level. All participants were administered a comprehensive set of neuropsychological and questionnaire measures during and without video-EEG recording. Results: The JME group differed significantly from controls in measures of phonemic and semantic verbal fluency. They scored significantly higher on the dysexecutive self-rating questionnaire, being more likely to report traits associated with executive dysfunction than both siblings and controls. Patients with JME reported significantly low mood than both controls and their siblings. Unaffected siblings differed significantly from controls on psychomotor speed, phonemic verbal fluency and were considered to exhibit traits associated with executive dysfunction by others. Qualitative inspection of data suggested a convincing trend for patients with JME and their siblings to perform worse than controls on most measures. Significance: This study supports the existence of a distinct neuropsychological profile among patients with JME and their siblings, which is likely to be genetically determined. The similarity of neuropsychological profiles between JME patients and their siblings is independent of antiepileptic drug effects or subclinical EEG activity. The significant differences between the sibling and controls suggests that there is a neurocognitive endophenotype for JME. KEY WORDS: Juvenile myoclonic epilepsy, Cognition, Endophenotype.
Accepted May 15, 2015; Early View publication June 15, 2015. *Department of Clinical Psychology, North Manchester General Hospital, Crumpsall, Manchester, United Kingdom; †Department of Clinical Neuropsychology, Salford Royal Hospital, Salford, Manchester, United Kingdom; ‡Division of Clinical Psychology, University of Liverpool, Brownlow Hill, Liverpool, United Kingdom; §Edinburgh and South East Scotland Epilepsy Service, Department of Clinical Neurosciences, Western General Hospital, Edinburgh, United Kingdom; and ¶Department of Neurophysiology, Western General Hospital, Edinburgh, United Kingdom Address correspondence to Nasur Iqbal, Department of Clinical Psychology, North Manchester General Hospital, Delaunay’s Road, Crumpsall, Manchester M8 5RB, U.K. E-mail: [email protected] Wiley Periodicals, Inc. © 2015 International League Against Epilepsy
JME was first described by Janz1 and is characterized by myoclonus, normal neurologic examination, and magnetic resonance imaging (MRI) imaging, onset between 8 and 36 years, and electroencephalography (EEG) with normal background but with bursts of polyspike and wave.2 It has an estimated incidence of 0.1–0.2/100,000, a prevalence of 5–10% of all epilepsies, comprising 18% of all idiopathic generalized epilepsy (IGE) seen in epilepsy clinics.3 Janz also observed common personality factors in JME such as social immaturity, hedonism, and lack of ambition and endurance.1 One long-term follow-up study revealed that 75% of patients had at least one indicator of psychosocial dysfunction, including depression and social
1301
1302 N. Iqbal et al.
Key Points • • • • •
Cognitive deficits in JME are more global and not limited to the areas of executive functioning Siblings share distinct cognitive and personality traits that closely match their affected brothers and sisters with JME Cognitive deficits in patients with JME and siblings occur independently of subclinical EEG activity JME’s genetic substrate may be implicating similar microstructural abnormalities of the cortex in both groups to varying degrees There is increasing support to suggest there is an endophenotype for JME or idiopathic generalized epilepsy (IGE)
isolation, with seizure frequency or remission not associated with these outcomes.4 In addition to personality traits and EEG changes, people with JME exhibit significant cognitive deficits in mental flexibility, working memory, verbal fluency, psychomotor speed, perseveration, and planning.5–9 Functional neuroimaging and structural studies have confirmed abnormalities in the thalamocortical circuitry and the dorsolateral and mesiofrontal areas, suggesting a biologic substrate for the cognitive deficits reported in neuropsychological findings.10 These findings may explain the phenomenon of neuropsychological activation (NPA7), whereby bursts of polyspike and wave are seen on EEG of people with JME during certain cognitive tasks. Because of JME’s genetic substrate,11 there has been increasing interest in the siblings of individuals with the condition.9,12–14 To our knowledge and in association with our preliminary investigation,13 this remains the first study to explore cognitive functioning of individuals with JME and their siblings under video-EEG conditions.
Method Ethics approval was granted by the South East Scotland Research Ethics Committee. All patients and siblings gave informed consent. A combined total of 22 patients who met the diagnostic criteria for JME, who had siblings who could attend testing,
were recruited from epilepsy clinics. All patients satisfied the diagnostic criteria for JME.2 None of the patients had other neurologic, medical, or psychiatric conditions. All spoke English as their first language. Where possible, a corroborating history was taken from the sibling or a parent. Nineteen of the 22 participants had normal background on routine EEG with bursts of polyspike and wave. One exhibited frequent bursts of polyspike and wave after sleep deprivation. One had a normal routine EEG in our laboratory but a previous ambulatory EEG done in another laboratory had shown clear polyspike and wave. Despite clear history in keeping with JME, one participant had a normal EEG and did not return for a sleep-deprived examination. Participants were all treated with standard antiepileptic drugs (AEDs). Eleven took sodium valproate (VPA) monotherapy, four took levetiracetam (LEV) monotherapy, and two took lamotrigine (LTG) monotherapy. Five took more than one AED: two received VPA/LEV in combination, one LEV/LTG, one LEV/clonazepam, and one LEV/zonisamide. All patients with JME had normal neurologic examination. Sixteen had normal 1.5T MRI imaging; one declined imaging because his epilepsy was so well controlled. Two cited claustrophobia and one did not attend for imaging. A further two were not scanned. Our power calculation indicated 20 participants in each group (N = 60) would have 80% power to detect the desired effect size of 1.4 or more (difference in mean/standard deviation [SD]) in the measures used at 5% significance level. Patients and siblings were matched for age, gender, and education to 44 healthy controls (Table 1). The majority of participants were right-hand dominant (n = 79). The same neuropsychological measures were administered in the same order as in the original study (Table 2); however, two tests were removed following the preliminary investigation (Token Test and the Cognitive Estimate Test), as they did not provide any further information and were not supported by the results of previous investigations. Part of the testing was undertaken under video-EEG recording for two reasons; to ensure subclinical seizure activity was not compromising each subject’s performance and to assess the presence and impact of NPA. Neuropsychological test battery A comprehensive neuropsychological test battery was chosen to examine cognitive functioning (Table 2). The neuropsychological evaluation enabled the investigators to
Table 1. Demographic variables Group (n)
Gender, M/F Age in years, mean (SD) Education in years, mean (SD) Epilepsia, 56(8):1301–1308, 2015 doi: 10.1111/epi.13061
JME (22)
Siblings (22)
Controls (44)
Kruskal-Wallis test v2 (2)
p-Value
7/15 26.7 (7.3) 14.6 (2.9)
12/10 26.6 (10.9) 15 (3.5)
21/23 25.7 (7.8) 14.6 (2.9)
0.387 2.447 1.146
0.8 0.3 0.6
1303 Cognitive and Personality Traits in JME Table 2. Summary of neuropsychological measures Order
Abbreviation
Name
During videoEEG recording
CVLT-II (UK Version) RCFT
California Verbal Learning Test 2nd Edition17 Rey-Osterrieth Complex Figure Test18,19 Stroop Test; Color word score20 Grooved Peg Board21 The Wechsler Memory Scale – Third Edition22 Brixton Spatial Anticipation Test (Taken from the Hayling and Brixton Tests)23 Phonemic Fluency24 Semantic Fluency24 The Wechsler Abbreviated Scale of Intelligence25 Hospital Anxiety and Depression Scale15 The DEX questionnaire (The Dysexecutive Questionnaire; taken from the Behavioural Assessment of the Dysexecutive Syndrome, BADS)16
Stroop GPB WMS-III Without videoEEG recording
Brixton
FAS Animals WASI Questionnaires
HADS DEX
examine a range of cognitive abilities, including those not previously assessed in other studies. In addition, two validated questionnaires were administered—the Hospital Anxiety and Depression Scale (HADS15) and the Dysexecutive (DEX) Questionnaire (a questionnaire inquiring into behaviors associated with the dysexecutive syndrome16) – . The DEX questionnaires were also completed by a close family member of each participant so that the ratings of the participant could be compared with a close third party to investigate issues such as insight. Procedure All video-EEGs were performed on XLTEK equipment and software (version 5.4.0, copyright 1998–2006). The International 10-20 measurement system was used to attach electrodes, and all aspects of recordings adhered to local protocols and national guidelines. High and low frequency filters were set at 70 and 0.5 Hz, respectively. All EEG studies were reviewed by nationally accredited clinical physiologists and consultant neurophysiologists or consultant neurologists. Each participant at the time of testing underwent an initial baseline EEG recording by senior neurophysiologists for 3 min with eyes open and eyes closed, which was used to contrast any abnormal EEG activity before and during testing. All patients and siblings were asked to ensure that they were not sleep deprived and had eaten lunch. All testing was done from 14:00 h onward. Testing done under video-EEG recording took on average of 50 min, during which time neurophysiologists monitored and noted any EEG and behavioral changes that occurred. Thereafter, the electrodes were removed and the partici-
pants moved to an adjunct room where the remaining measures were completed. On completing the neuropsychological assessment, the participants then completed the HADS and DEX questionnaire measures. The tests administered under video-EEG conditions were those thought to potentially elicit EEG changes based on the results of previous studies.7 Statistical analysis A between-group comparison design was used, comparing three independent groups. The raw scores obtained from each individual’s performance on the various neuropsychological measures were pooled to provide a mean score for the respective group (Table 3). z-Scores were obtained from the JME and sibling group based on the standard deviation of the control group so that differences in performance from that of controls could be quantitatively presented (Fig. 1).
Results Qualitative trends in data The JME and sibling group exhibited a remarkable similarity in neuropsychological profiles when their z-scores where compared with the control group (Fig. 1). Unaffected siblings also seem to “underperform” somewhere between patients with JME and controls. Taken together, patients with JME and siblings demonstrated subtle deficits in the areas of verbal memory (California Verbal Learning Test 2nd Edition [CVLT-II]); the time taken to copy the figure drawing (Rey-Osterrieth Complex Figure Test [RCFT]); selective attention and cognitive flexibility (Stroop Test); psychomotor speed using both their dominant and nondominant hand (Grooved Peg Board); sustained visual attention (spatial span, The Wechsler Memory Scale Third Edition [WMS-III]); rule attainment (Brixton Spatial Anticipation Test); phonemic and semantic verbal fluency (FAS, Animals); general IQ as assessed by two domains (The Wechsler Abbreviated Scale of Intelligence [WASI]); anxiety (Hospital Anxiety and Depression Scale [HADS]); and were rated by others as exhibiting behavioral, motivational, cognitive, and emotional changes most commonly associated with executive dysfunction. In contrast, they performed relatively equal to controls on measures assessing visual memory (RCFT) and sustained verbal attention (WMS-III). Comparative analysis Statistically significant differences between the groups were observed for the following: Grooved Peg Board— using the participants dominant hand (F2,55 = 3.75, p < 0.03); Verbal (phonemic) fluency using letters of the alphabet (FAS; F2,55 = 6.35, p < 0.003); Verbal (semantic) fluency using a category (Animals; F2,55 = 5.97, p < 0.005); HADS questionnaire yielding a score for depression (F2,55 = 7.80, p < 0.001); the DEX questionEpilepsia, 56(8):1301–1308, 2015 doi: 10.1111/epi.13061
1304 N. Iqbal et al. Table 3. Summary of mean raw scores and significance obtained on neuropsychological measures, stratified by group Group JME Neuropsychological measure Under video-EEG surveillance California Verbal Learning Test 5 Trials Free recall Delayed recall Recognition Total repetitions Total intrusions Rey-Osterrieth Complex Figure Test Copy Time to copy (s) Immediate recall Delayed recall Recognition trial Stroop (Color-Word) Grooved Peg Board Dominant hand Nondominant hand Digit span Spatial span Without video-EEG surveillance Brixton FAS Animals Vocabulary Block design Matrix reasoning General IQ Questionnaires Hospital Anxiety and Depression Scale Anxiety score Depression score DEX Questionnaire Self Independent rater a
Sibling
Group comparison Control
Mean score/SD
F value
p-Value
50.1/10.9 0.0/0.9 0.0/1.2 0.3/1.0 0.4/1.2 0.5/1.0
47.9/15.2 0.4/1.3 0.5/1.6 0.6/1.4 0.5/1.3 0.2/1.2
53.9/12.1 0.6/1.2 0.1/1.1 0.4/1.0 0.4/1.2 0.3/1.3
1.44 0.55 1.11 0.02 0.62 0.249
0.245 0.580 0.336 0.981 0.541 0.780
34.5/2.4 184.4/108.6 29.6/11.9 31.4/13.6 27.6/12.8 106.6/9.7
34.5/2.7 149.2/60.4 29.2/16.9 30.1/16.7 31.1/15.2 104.2/12.0
33.6/3.3 124.5/42.5 28.4/15.4 28.7/15.9 30.4/15.3 107.3/8.5
1.23 2.00 0.14 0.08 1.10 0.33
0.300 0.145 0.871 0.926 0.340 0.724
82.8/13.8 93.1/16.5 9.8/3.4 9.7/3.2
82.7/11.6 88.8/12.8 10.3/3.6 10.5/3.0
75.9/19.0 84.8/18.3 10.0/2.9 9.6/2.2
3.75 1.73 0.16 0.55
0.03a 0.187 0.856 0.582
7.0/1.9 30.1/7.8 18.2/4.9 48.2/10.4 50.8/8.9 52.0/9.8 100.4/12.3
7.0/2.5 35.6/11.8 18.6/4.8 52.1/11.7 54.9/9.3 52.9/11.0 104.5/17.7
7.3/1.9 43.3/13.6 22.9/5.4 55.3/10.3 54.6/11.3 54.9/9.4 109.0/15.4
0.38 6.35 5.97 2.23 0.98 0.68 1.75
0.688 0.003a 0.005a 0.118 0.381 0.513 0.184
8.0/4.1 4.1/2.8
6.8/4.4 2.0/1.7
5.9/3.9 1.8/2.3
1.81 7.80
0.174 0.001a
26.1/12.9 19.1/8.8
17.3/9.4 22.8/13.5
17.2/12.9 13.2/12.5
5.58 3.40
0.006a 0.041a
p > 0.05.
naire, which was both self-administered as well as being rated by an independent rater (F2,55 = 5.58, p < 0.006, and F2,55 = 3.40, p < 0.041, respectively). Post hoc analyses using the Scheffe test was conducted to determine where these differences occurred (Table 4). There were significant differences between the JME group and controls on the Grooved Peg Board using the dominant hand. There were significant differences between the JME group and the control groups on both phonemic and semantic fluency, with the JME patients generating significantly fewer words than controls. Siblings also took significantly longer than controls to complete the Grooved Peg Board using their dominant hand. Siblings also generated significantly fewer words on semantic verbal fluency testing than controls. Epilepsia, 56(8):1301–1308, 2015 doi: 10.1111/epi.13061
A statistically significant difference was found on the HADS depression subscale between patients with JME, their siblings, and the control group. Patients with JME reported significantly more symptoms of depression than the other two groups, and the mean score was consistent with mild symptoms of depression as a group. On the DEXself-questionnaire, patients with JME rated themselves significantly higher on statements of behavioral, motivational, cognitive, and emotional changes most commonly associated with executive function in comparison with controls and their siblings. On the DEX-other questionnaire, there was a significant difference between siblings and controls, whereby the siblings were rated by a person who knew them well as exhibiting behavioral, cognitive, motivational, and emotional changes more commonly associated with executive dys-
1305 Cognitive and Personality Traits in JME
Figure 1. Qualitative representation of the trends in data. Epilepsia ILAE
Table 4. Comparative analysis; significant differences between the groups Test Grooved Peg Board; dominant hand FAS Animals HADS – depression DEX-self DEX-other
JME 82.8 (13.8)
Sibling
Control a
82.7 (11.6)
75.9 (19.0)
EEG remained within normal parameters for all participants during testing.
p-Value 0.05a
30.1 (7.8)b 18.2 (4.9)b 8.0 (4.1)b
35.6 (11.8) 18.6 (4.6)a 6.8 (4.4)c
43.3 (13.6) 22.9 (5.4) 5.9 (3.9)
0.004 0.02b, 0.02a 0.002b, 0.013c
26.1 (12.9)b,c 19.1 (8.8)
17.3 (9.4) 22.8 (13.5)a
17.2 (12.9) 13.2 (12.5)
0.01b, 0.02c 0.04
a
Siblings compared with control. JME compared with control. JME compared with sibling.
b c
function. Siblings did not rate themselves as being different from the control group. Video-EEG findings As with the original preliminary investigation, the current study did not demonstrate any clinically meaningful effects or influence of EEG activity on cognitive performance. The
Discussion To our knowledge this is the first study that comprehensively evaluates cognitive, emotional, and behavioral profiles of patients with JME, their siblings, and matched controls under video-EEG recording. It is the first to demonstrate a significant difference between siblings of people with JME and controls, and to show that those differences principally affect the same domains as those of the probands. These findings support the results of our earlier study.13 Our results are in keeping with three other studies of patients with IGE and their siblings, all of which showed a clear trend for siblings to have similar neuropsychological deficits as their affected brothers and sisters.9,12,14 Our study design was different from these studies in that we did not recruit a generic control group, but rather matched each sibling and each patient with JME with their own age-/education-matched control. This increased the statistical power of the study. In addition, we took care to match for test conditions by using the same controlled environment on each occasion and testing at the same time of day because of the well-known chronodependency of JME.26 Epilepsia, 56(8):1301–1308, 2015 doi: 10.1111/epi.13061
1306 N. Iqbal et al. A unique feature of our study was that some of our testing was conducted under EEG surveillance. This was done both to assess the impact of subclinical EEG discharges on the results of neuropsychological testing and to assess the presence in our population of neuropsychological activation (NPA7). Neither probands nor siblings exhibited NPA in the 50 min of testing under video-EEG conditions, sufficient to capture any such activity. Two patients did exhibit very brief spike and wave during testing, which did not interfere with their ability to perform the task at hand.13 It is interesting to note that the cognitive deficits we identified were not likely to be associated with EEG activity. Thus we are confident that our results are robust and are likely to be a stable profile rather than the transient effects of changing electrical activity in the brain. There may be a number of explanations for this lack of activation. First, there may be differences in cortical activation between Japanese ideograms and roman script. Second, with one exception, our sample of patients with JME had good seizure control. Third, our testing was done in people we had asked to arrive in the early afternoon, the time of day when seizures are least likely to occur in JME. Siblings in our study generated fewer words on the semantic fluency task than controls. Verbal fluency is sensitive to frontal lobe changes,27 in particular the left frontal lobe, and correlates with other measures of executive function. Two recent studies using functional magnetic resonance imaging (fMRI) of patients with JME and their siblings have demonstrated very similar abnormal patterns of activation in the motor cortex and increased functional connectivity.28,29 Equally interesting, the same group reported impaired connectivity between the presupplementary motor region and the frontopolar cortex, and suggested that this may explain the impairments seen in frontal lobe function in patients with JME.27 The implication of these results would indicate that given JME’s genetic substrate, first-degree relatives may have a similar (although less severe) microstructural abnormality of the same areas of the cortex. Our neuropsychological results support these anatomic findings, with our sibling sample demonstrating similar—if less marked—abnormalities on testing as their affected brothers and sisters. Siblings took significantly longer to complete the Grooved Peg Board test, indicating reduced psychomotor speed. This has been reported in patients with JME.12 This observation is noteworthy because psychomotor slowing is seen in people exposed to AEDs,30 and therefore this significant difference on the Grooved Peg Board between siblings and controls suggests it was not likely due to the drug effect as neither of these groups were taking AEDs. The finding may reflect white matter ultrastructural changes in the corona radiate and corpus callosum, as well as the prefrontal motor and supplementary motor areas.8 Once again, our results are congruent with structural and functional imaging. As with semantic fluency, the results Epilepsia, 56(8):1301–1308, 2015 doi: 10.1111/epi.13061
suggest that abnormalities occur in both patients with JME and siblings. Adolescence sees the development of the individual’s ability to think in abstract terms, formulate the potential outcomes of different courses of actions, and assess risk,31 cognitive changes that are thought to reflect myelination. Brain development continues until the early twenties, and during adolescence the brain exhibits growth, increased connectivity, and synaptic pruning.31 This phase of maturation, which occurs at the same age as JME first appears, may be connected. One candidate gene for JME32 has been implicated in the changes in several neuronal maturational steps including apoptosis, which may lead to hyperexcitable neurons not being destroyed as part of maturation. This may explain cognitive activation of myoclonic jerks. This gene also plays a role in neuronal migration and formation of connections, any of which if disrupted could lead to a susceptibility to seizures and the neuropsychological effects which have been reported.33 Patients with JME reported more symptoms associated with depression than siblings and controls. Although this difference may not necessarily reflect a clinical concern, it is noteworthy due to the prevalence of mood and anxiety disorders in people with JME when compared with the population at large, being more marked in those who have poorly controlled seizures.34 Our sample was composed primarily of people with well-controlled seizures, which is reflected in the relatively low HADS scores, which measured mood and anxiety. Moreover, although anxiety and depression as judged by the HADS was not a significant finding in our sample, this suggests the differences between the groups were not due to the individual’s mental health. Poor social adjustment in people with epilepsy was first described by Janz in the 1950’s1 and probably reflects a mixture of the cognitive and behavioral impact of frontal lobe dysfunction as well as the psychosocial impact of epilepsy. More recent studies have reported poor social adjustment in work and family relationships in people with epilepsy, with these difficulties associated with impulsive traits and seizure frequency but not cognitive impairment. Because siblings appear to have similar neuropsychological profiles on formal cognitive tests, it seems not unreasonable to postulate that they might exhibit a constellation of personality traits in keeping with a dysexecutive syndrome. To our knowledge this has never been explored before in siblings. The DEX self-rating scale showed significant differences between the JME group and the controls and siblings. The JME group rated themselves more highly on statements about motivational, cognitive, behavioral, and emotional changes most often associated with executive dysfunction. On the DEX-other scale, for which a person who knows the subject completes the questionnaire a different pattern emerged. In this, both siblings and JME patients were rated as having significantly more traits associated with executive dysfunction than controls. It is
1307 Cognitive and Personality Traits in JME interesting that siblings did not rate themselves as having increased signs of dysexecutive syndrome on the DEX. One possible explanation for this is that the siblings may lack insight into such sequelae. Recently the existence of a JME endophenotype has been proposed.29 Endophenotypes are traits manifest in an individual irrespective of whether the condition is active, are heritable, and are found more frequently in nonaffected family members of affected individuals than in the general population.35 Evidence from imaging studies are persuasive, as are the studies that have included JME along with other IGEs.14 In this study we have demonstrated that our siblings exhibit cognitive and personality traits similar to their affected sibling, but without seizures or myoclonus. In our opinion they are endophenotypes. This raises some interesting questions. Should other members of these families be offered neuropsychological assessment with a view to help in school or the workplace? Even more interesting could the presence of a JME or IGE endophenotype contribute to reduced cognitive abilities in some children of mothers with JME exposed to sodium valproate in utero? In this study we sought to improve the design and limit possible confounding factors further following the preliminary study. It is possible that in controlling the environment including time of day and only testing patients with well-controlled JME, we missed the possible effects of changes in EEG pattern on cognitive function. It would be interesting to assess patients with poorly controlled JME under video-EEG conditions and to vary the time of day. It would also be useful to assess the functional impact of these cognitive and behavioral differences on employment, social relationships, and academic achievements. A recent study by Jiang et al.36 showed problems with some aspects of emotional recognition and empathy in patients with IGE. These difficulties were correlated with cognitive deficits associated with frontal lobe dysfunction. Our study highlights the importance of investigating the wider psychosocial impact of epilepsy in patients with JME and their families.
Acknowledgment Study Funding: British Epilepsy Association.
Disclosure None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
References 1. Janz D, Christian W. Impulsive-petit mal. Dtsch Z Nervenheilkd 1957;176:344–386. 2. Camfield CS, Striano P, Camfield PR. Epidemiology of juvenile myoclonic epilepsy. Epilepsy Behav 2013;28 (Suppl. 1):S15–S17.
3. Camfield P. Issues in epilepsy classification for population studies. Epilepsia 2012;53 (Suppl. 2):10–13. 4. Camfield CS, Camfield PR. Juvenile myoclonic epilepsy 25 years after seizure onset: a population-based study. Neurology 2009;73:1041– 1045. 5. O’Muircheartaigh J, Vollmar C, Barker GJ, et al. Focal structural changes and cognitive dysfunction in juvenile myoclonic epilepsy. Neurology 2011;76:34–40. 6. Sonmez F, Atakli D, Sari H, et al. Cognitive function in juvenile myoclonic epilepsy. Epilepsy Behav 2004;5:329–336. 7. Matsuoka H, Nakamura M, Ohno T, et al. The role of cognitive motor function in precipitation and inhibition of epileptic seizures. Epilepsia 2005;1:17–20. 8. Kim JH, Suh SI, Park SY, et al. Microstructural white matter abnormality and frontal cognitive dysfunctions in juvenile myoclonic epilepsy. Epilepsia 2012;53:1371–1378. 9. Wandschneider B, Kopp UA, Kliegel M, et al. Prospective memory in patients with juvenile myoclonic epilepsy and their healthy siblings. Neurology 2010;75:2161–2167. 10. Koepp MJ, Woermann F, Savic I, et al. Juvenile myoclonic epilepsy – neuroimaging findings. Epilepsy Behav 2013;28 (Suppl. 1):S40–S44. 11. Steffens M, Leu C, Ruppert AK, et al. Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32. Hum Mol Genet 2012;21:5359– 5372. 12. Levav M, Mirsky AF, Herault J, et al. Familial association of neuropsychological traits in patients with generalized and partial seizure disorders. J Clin Exp Neuropsychol 2002;3:311–326. 13. Iqbal N, Caswell HL, Hare DJ, et al. Neuropsychological profiles of patients with juvenile myoclonic epilepsy and their siblings: a preliminary controlled experimental video-EEG case series. Epilepsy Behav 2009;14:516–521. 14. Chowdhury FA, Elwes RDC, Koutroumanidis M, et al. Impaired cognitive function in idiopathic generalised epilepsy and unaffected family members: an epilepsy endophenotype. Epilepsia 2014;55:835–840. 15. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983;67:361–370. 16. Wilson BA, Alderman N, Burgess P, et al. The behavioural assessment of the dysexecutive syndrome. Flempton: Thames Valley Test Co.; 1996. 17. Delis DC, Kramer JH, Kaplan E, et al. California verbal learning test, second edition, adult version. San Antonio, TX: Psychological Corp; 2000. 18. Rey A. L’examen psychologique dans les cas d’encephalopathie traumatique. Arch Psychol 1941;28:286–340. 19. Osterrieth PA. Le test de copie d’une fugure complex: contributiona l’etude de la perception et de la memoire. Arch Psychol 1944;30:286– 356. 20. Stroop JR. Studies of interference in serial verbal reaction. J Exp Psychol 1935;18:643–662. 21. Matthews CG, Klove K. Instruction manual for the adult neuropsychology test battery. Madison, WI: University of Wisconsin Medical School; 1964. 22. Wechsler D. WMS-III administration and scoring manual. San Antonio, TX: Psychological Corp; 1997. 23. Burgess PW, Shallice T. The Hayling and Brixton tests. Thurston, Suffolk: Thames Valley Test Co.; 1997. 24. Benton AL, Hamsher K. Multilingual aphasia examination. Iowa City, IA: AJA Associates; 1989. 25. Wechsler D. WASI administration and scoring manual. San Antonio, TX: Psychological Corp; 1999. 26. Kasteleijn-Nolst Trenite DG, de Weerd A, Beniczky S. Chronodependency and provocative factors in juvenile myoclonic epilepsy. Epilepsy Behav 2013;28:s25–s29. 27. Costafreda SG, Fu CH, Lee L, et al. A systematic review and quantitative appraisal of fMRI studies of verbal fluency: role of the left inferior frontal gyrus. Hum Brain Mapp 2006;27:799–810. 28. Vollmar C, O’Muircheartaigh J, Barker GJ, et al. Motor system hyperconnectivity in juvenile myoclonic epilepsy: a cognitive functional magnetic resonance imaging study. Brain 2011;134:1710–1719. 29. Wandschneider B, Centeno M, Vollmar C, et al. Motor co-activation in siblings of patients with juvenile myoclonic epilepsy: an imaging endophenotype? Brain 2014;137:2469–2479. Epilepsia, 56(8):1301–1308, 2015 doi: 10.1111/epi.13061
1308 N. Iqbal et al. 30. Eddy CM, Rickards HE, Cavanna AE. The cognitive impact of antiepileptic drugs. Ther Adv Neurol Disord 2011;4:385–407. 31. Christie D, Viner R. Adolescent development. BMJ 2005;330:301– 304. 32. Toga A, Thompson P, Sowell E. Mapping brain maturation. Trends Neurosci 2006;29:148–159. 33. de Nijis L, Wolkoff N, Grisar T, et al. Juvenile myoclonic epilepsy as a possible neurodevelopmental disease: role of EFHC1 or myoclonic 1. Epilepsy Behav 2013;28:s58–s60.
Epilepsia, 56(8):1301–1308, 2015 doi: 10.1111/epi.13061
34. de Araujo Filho GM, Mazetto L, da Silva JM, et al. Psychiatric comorbidity in patients with two prototypes of focal versus generalized epilepsy syndromes. Seizure 2011;20:383–386. 35. Gottesman II, Gould TD. The endophenotype concept in psychiatry, etymology and strategic intentions. Am J Psychiatry 2003;160:636– 645. 36. Jiang Y, Hu Y, Wang Y, et al. Empathy and emotion recognition in patients with idiopathic generalized epilepsy. Epilepsy Behav 2014;9:139–144.
