Juvenile myoclonic epilepsy (JME) is an adolescent-onset idiopathic generalized epilepsy syndrome, which constitutes around 5% to 10% of all epilepsies and 18% of generalized epilepsies [
Although patients with JME have average intelligence, JME is usually associated with cognitive impairments in various areas of cognition, including concept formation, abstract reasoning, cognitive speed, planning, and organization [
Several neuropsychological studies have assessed executive functioning in JME [
In recent years, FAB has been progressively used as a brief screening test for identifying subtle executive deficits in neurological disorders of frontal and striatal regions, including amyotrophic lateral sclerosis [
Although FAB is not a comprehensive test for the assessment of executive deficits, it is much easier, cheaper, and shorter to administer, compared to the traditional neuropsychological batteries. Thus, FAB is an optimal test for the assessment of executive deficits in the clinical setting where there is a need for quick and efficient assessment of executive functions in patients with neurological disorders.
In this study, we aimed to evaluate the executive functions in JME patients using FAB. This is the first study, which surveys the utility of FAB in JME patients and its association with clinical and demographic features of JME patients. Some previous studies have hypothesized that seizure proximity, family history of epilepsy, and the number of antiepileptic drugs (AEDs) may affect the cognitive functions [
This is a case-control study, conducted in a group of patients with JME, which were referred from two epilepsy clinics (Yalda clinic and specialized epilepsy clinic of Imam Khomeini Hospital) to Roozbeh Hospital of Tehran University of Medical Sciences (TUMS) for neuropsychological assessment. The eligible patients were selected by simple random sampling from those referred to our center. Healthy controls (HCs) were enrolled using convenience sampling either from family members of JME patients or through online advertisement. An experienced neuropsychiatrist assessed all HCs for neurologic and psychiatric disorders and other exclusion criteria of the study. A total of 110 HCs with no history of neurologic or psychiatric disorders or usage of central nervous system affecting drugs were voluntarily enrolled in our study. Finally, a total of 31 JME patients and 110 HCs were enrolled in this study. Two experienced neurologists made the diagnosis of JME based on clinical features and video-electroencephalography monitoring for confirmation. Also, exclusion criteria were as follows: (1) presence of any concomitant neurologic disease other than epilepsy based on comprehensive history taking and physical examination by an experienced neurologist, (2) having a history of psychiatric diseases based on comprehensive history taking by an experienced psychiatrist, (3) any history of intellectual disability, (4) any history of alcohol or substance abuse, or (5) any other drugs or medical conditions that interfere with cognitive functions. The Wechsler Adult Intelligence Scale (WAIS-111) was used to determine the intelligence quotient of all participants. The patients and HCs were comparable based on intelligence quotient. There was no significant difference between JME patients and HCs regarding sex. Moreover, 45.2% of JME patients and 3.6% of HCs had a family history of seizure, and GTCS was experienced by 83.9% of JME patients. The protocol of this study was approved by the ethical committee of TUMS (the ethics code: IR.TUMS.REC.1395.2470) and is in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki). We acquired informed written consents from all of the study participants.
The detailed information on FAB administration and scoring processes are documented in the previous study on the cognitive status of TLE patients [
According to the FAB scoring system, the minimum and maximum scores for each task are 0 and 3, respectively. Calculated scores for the six subtests of FAB were summed and documented as the “total FAB score,” similar to our previous study [
We used the Statistical Package for the Social Sciences version 23 to execute the statistical analysis of this study. We applied the Shapiro–Wilk test for the assessment of the distribution of study variables. Categorical variables (sex, type of treatment, family history, number of patients with GTCS, and number of patients with and without seizure) were compared by the Chi-square test. Comparison of continuous variables (age, disease duration, FAB total score) was performed using the Student
Demographic and clinical characteristics of the study participants are illustrated in Table
Demographic and clinical characteristics of patients and healthy controls.
(A) JME patients ( | (B) Healthy controls ( | ||
---|---|---|---|
Age ( | 0.005 | ||
Sex (male/female)b | 5/26 | 24/86 | 0.489 |
Disease duration ( | — | — | |
Family history ( | 14 (45.2%) | 4 (3.6%) | <0.00001 |
GTCS ( | 26 (83.9%) | — | — |
Time from the last seizure ( | — | — | |
Within 1 week | 9 (29%) | ||
A week or more | 22 (71%) | ||
Treatment ( | — | — | |
Monotherapy | 18 (58.1%) | ||
Polytherapy | 13 (41.9%) | ||
Total FAB scorea | <0.00001 |
aStudent
Table
Comparing FAB scores between patients and healthy controls controlling for age, sex, family history, disease duration, time from the last seizure, and multiple comparison.
(A) JME patients ( | (B) Healthy controls ( | FDR (Cohen’s | |
---|---|---|---|
Conceptualization ( | <0.00001 (2.26) | ||
Mental flexibility ( | <0.00001 (1.60) | ||
Programming ( | <0.00001 (1.03) | ||
Sensitivity to interference ( | <0.00001 (0.11) | ||
Inhibitory control ( | 0.608 | ||
Environmental autonomy ( | 0.612 |
JME: juvenile myoclonic epilepsy; FDR: false discovery rate; SD: standard deviation.
Comparison of FAB subset scores between JME patients and HCs.
Approximately 45.2% of JME patients had a family history of epilepsy. After controlling for covariates and multiple comparisons, there was no significant difference between these two groups in five subsets of FABs consisting of conceptualization, mental flexibility, inhibitory control, sensitivity to interference, and environmental autonomy as well as total FAB score (
It has been suggested that patients with epilepsy tend to have more severe cognitive impairments in a period after seizures [
Comparing FAB scores within JME patients controlling for age, sex, family history, disease duration, and multiple comparison.
JME | Less than a week ( | A week or more ( | FDR |
---|---|---|---|
Conceptualization ( | 0.635 | ||
Mental flexibility ( | 0.597 | ||
Programming ( | 0.597 | ||
Sensitivity to interference ( | 3.00 | 0.597 | |
Inhibitory control ( | 0.635 | ||
Environmental autonomy ( | 3.00 | 3.00 | 1 |
Total FAB score ( | 1 |
JME: juvenile myoclonic epilepsy; FAB: Frontal Assessment Battery; FDR: false discovery rate; SD: standard deviation.
Comparison of FAB subset scores between JME patients with and without recent seizures.
In order to investigate the effects of AEDs on the performance of patients in FAB, we divided our patients based on their type of treatment into two groups of “monotherapy” and “polytherapy” (Table
Comparing FAB scores between monotherapy and polytherapy groups controlling for age, sex, family history, disease duration, and multiple comparison.
JME | Monotherapy ( | Polytherapy ( | FDR |
---|---|---|---|
Conceptualization ( | 0.063 | ||
Mental flexibility ( | 0.318 | ||
Programming ( | 0.898 | ||
Sensitivity to interference ( | 0.900 | ||
Inhibitory control ( | 0.273 | ||
Environmental autonomy ( | 3.00 | 3.00 | 1 |
Total FAB score ( | 0.063 |
JME: juvenile myoclonic epilepsy; FAB: Frontal Assessment Battery; FDR: false discovery rate; SD: standard deviation.
Comparison of FAB subset scores between JME patients on monotherapy and polytherapy regimen.
Partial correlation analysis controlling for age, sex, family history, and multiple comparisons in patients with JME resulted in no significant associations between disease duration and FAB scores (Table
Partial correlation between disease duration and FAB scores in JME patients controlling for age, sex, family history, and multiple comparison.
Conceptualization | Mental flexibility | Programming | Sensitivity to interference | Inhibitory control | Environmental autonomy | Total FAB | ||
---|---|---|---|---|---|---|---|---|
JME | Disease duration | 0.235 | 0.183 | -0.052 | -0.114 | 0.145 | - | 0.197 |
-The presented values are Pearson correlation coefficients. No significant correlation was found. JME: juvenile myoclonic epilepsy; FAB: Frontal Assessment Battery.
We further conducted partial correlation analysis in two subgroups of with or without recent (within less or more than a week) seizure (Table
Partial correlation between disease duration and FAB scores in “less than a week” and “a week or more” groups of JME patients, controlling for age, sex, and multiple comparison.
Conceptualization | Mental flexibility | Programming | Sensitivity to interference | Inhibitory control | Environmental autonomy | Total FAB | ||
---|---|---|---|---|---|---|---|---|
Less than a week | Disease duration | 0.967 | 0.454 | - | - | 0.967 | ||
A week or more | Disease duration | -0.005 | -0.058 | -0.012 | -0.012 | -0.68 | - | -0.004 |
-The presented values are Pearson correlation coefficients. JME: juvenile myoclonic epilepsy; FAB: Frontal Assessment Battery.
Finally, we used the ROC analysis to examine the value of FAB in discriminating JME patients with HCs and determine the optimal cutoff value for FAB total and subset scores. The value of the AUC was 0.971 (95% confidence interval (CI): 0.947–0.994) for FAB total score (Figure
ROC curve discriminating between JME patients and HCs for FAB total score.
ROC cutoff points for FAB total scores.
Positive if greater than | Sensitivity | Specificity |
---|---|---|
7 | 1 | 1 |
9.5 | 1 | 0.968 |
11.5 | 1 | 0.839 |
12.5 | 1 | 0.742 |
13.5 | 1 | 0.516 |
15.5 | 0.936 | 0.129 |
16.5 | 0.782 | <0.0001 |
17.5 | 0.336 | <0.0001 |
19 | <0.0001 | <0.0001 |
Bold: cutoff point maximizing the sum of sensitivity and specificity.
The diagnostic value of FAB subsets is depicted in Figure
ROC curve discriminating between JME patients and HCs for FAB subset scores.
In this study, executive functioning in JME patients was assessed using an easy-to-administer neuropsychological measure, known as FAB. The major findings of this study are as follows: (1) comparing with HCs, JME patients showed lower total FAB score and lower scores in most domains consisting of conceptualization, mental flexibility, programming, and sensitivity to interference (all domains except inhibitory control and environmental autonomy); (2) disease duration was associated with conceptualization, mental flexibility, inhibitory control, and total FAB score only in JME patients with a recent seizure; (3) duration of the time since the last seizure had no significant effect on JME patients’ FAB scores; (4) the family history of epilepsy showed no significant effect on FAB scores in JME patients; (5) the number of AEDs (polytherapy versus monotherapy) had no significant effect on FAB scores in JME patients; and (6) we found that FAB total score and conceptualization and mental flexibility scores can efficiently discriminate between JME patients and HCs.
We, here, conducted a comprehensive review on the current literature of JME-related executive deficits in order to compare our results from FAB as a bedside screening tool with the results of extended neuropsychological batteries. The majority of reviewed studies have used digit span, TMT, Stroop test, and verbal fluency to investigate the executive deficits in JME patients. Valente et al. [
Furthermore, our diagnostic efficiency analysis demonstrated that FAB total or subset scores could be used as reliable and supplementary bedside tools for the diagnosis of JME. In this regard, FAB total score along with conceptualization and mental flexibility scores showed the highest diagnostic capacity. In line with our findings, previous studies have shown that FAB is also a sensitive discriminant tool in other neurological disorders, including obstructive sleep apnea [
Although it seems that FAB is a more sensitive test for evaluating the frontal lobe function, which has brought about some clinical indications for it in diseases with frontal lobe impairments [
In a previous study on TLE patients, the authors reported that patients with a recent seizure achieved lower scores in mental flexibility domain and total FAB. Animal and human FDG-positron emission tomography studies also demonstrated that duration of time elapsed since the last seizure is in a negative association with brain metabolism [
Similar to our study, several previous studies have evaluated the association between cognitive deficits of JME patients and different clinical variables. Previous results are not entirely consistent. Duration of epilepsy was exhibited to have a significant effect on the cognitive performance of patients with JME [
Eventually, although FAB is an appropriate test for detection of executive deficits in different neurological and psychiatric disorders, it should be noted that it is not a comprehensive test and is not designed to cover all aspects of cognitive functions. Instead, FAB is a brief and feasible bedside measure assisting the clinicians in screening for early frontal-dependent cognitive dysfunctions in patients with neurological disorders like JME. In contrast to other neuropsychological tests, which are highly time-consuming, the succinctness of FAB has made it a handy and feasible measure, which is the reason why it could be widely applied in clinical settings in the future. More comprehensive neuropsychological tests might be administered after FAB in order to determine the exactly affected domains of cognitive functions.
The main limitations of this study were as follows: (1) The source of information for dividing our patients to “less than a week” and “a week or more” subgroups was patient and/or his/her family reports, and we could not double-confirm this with an alternative source. (2) The severity, frequency, and type of seizures were not documented in this study. (3) We did not provide exact information on the level of education in our patients and HCs. (4) The type of AED treatment and age of onset are not documented. (5) FAB is a battery of the bedside type and has been created in clinical and age contexts different from what we used in this study.
Collectively, we demonstrated that patients with JME have deficits in some aspects of frontal-mediated executive functions compared to HCs. FAB is an appropriate clinical tool for evaluation of executive functions in these patients, as it is an available test for identifying frontal-dependent executive deficits. The time elapsed since the last seizure may not be a precise predictor for executive functioning in JME patients. Our study is the first one investigating the FAB as a feasible in-clinic tool in patients with JME and its association with clinical and demographic characteristics of JME. However, given the limitations above, further studies are needed to compare this tool to other neuropsychological measures in JME patients.
The data that support the findings of this study are available from the corresponding author, upon reasonable request.
The authors declare that they have no competing interests.