Neuropsychological aspects of benign childhood epilepsy with centrotemporal spikes

Article Outline

• Abstract
• 1. Introduction
• 2. Methods
  • 2.1. Subjects
  • 2.2. EEG
  • 2.3. Neuropsychological assessment
  • 2.4. Statistical analysis
• 3. Results
• 4. Discussion
• References
• Copyright

Abstract 

Purpose

To establish whether the disability in benign epilepsy with centrotemporal spikes (BECTS) is the result of the number of seizures, the anti-epileptic therapy or is an inherent characteristic of the syndrome itself.

Methods

Thirty-six children with BECTS were tested for cognitive functions prior to commencing treatment with anti-epileptic drugs, and the findings were compared with those in 15 children with normal electroencephalograms, performed for unrelated reasons. The data in the study group were further correlated with the laterality of the epileptic focus and the number of seizures.

Results

Scores for verbal functioning on neuropsychological tests were significantly lower in the study group than the control group. There was no relationship between the neuropsychological scores in the patients and either lateralization of the epileptic focus or number of seizures.

Discussion

Children with BECTS have an impaired ability to process verbal information. The deficiency is apparently a result of the pathological electrical discharges that are part of the syndrome and are not dependent on the epileptic focus laterality, the number of seizures, or the anti-epileptic treatment.

Keywords: Rolandic epilepsy, Centrotemporal, Neuropsychological, Verbal

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1. Introduction 

Benign rolandic epilepsy, also known as benign epilepsy with centrotemporal spikes (BECTS), is the most common epileptic disorder in childhood, accounting for 14–20% of cases.¹, ² It is characterized clinically by hemifacial motor seizures with drooling and inability to speak which begin from a state of sleep or near awakening, with or without secondary generalization.³ The interictal spikes on the electroencephalogram (EEG) typically have a diphasic morphology, accompanied by a slow wave. The spikes appear in pairs or groups at the centrotemporal or mid-temporal region, unilaterally or bilaterally. The term ‘benign’ in BECTS refers to the fact that seizure frequency in this type of epilepsy is relatively low and remission usually always occurs before puberty.⁴, ⁵ However, BECTS is not always so benign. Previous studies have shown that children with BECTS have learning and behavioral difficulties, mainly involving verbal functioning, compared with healthy children.⁶, ⁷, ⁸, ⁹, ¹⁰, ¹¹, ¹² Moreover, children with BECTS were found to have difficulties in processing speech in the presence of background noise despite normal hearing.⁹, ¹² It is not clear, however, if the cognitive deficiency derives from the electrical impairment or the seizures, or if they are adverse effects of anti-epileptic drugs. The present study sought to answer this question.

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2. Methods 

2.1. Subjects 

In September 2000, the Epilepsy Unit of Schneider Children's Medical Center of Israel introduced the routine use of neuropsychological testing for all children diagnosed with BECTS. For the present study, we included 36 of the 76 patients diagnosed and treated for BECTS at our center as of June 2005 who underwent neuropsychological testing before starting anti-epileptic treatment, in addition to EEG monitoring. The other patients were excluded from our study because they did not fit our inclusion criteria, which apart from age between 6 and 16 years and a confirmed diagnosis of BECTS, consisted of Hebrew as a main language (as the tests were carried out in Hebrew) and a status of not having begun treatment with anti-epileptic drugs before neuropsychological evaluation.

The control group was recruited from the pool of children who underwent EEG monitoring under the same conditions at our center for reasons other than seizure-related disorders, with normal findings. The inclusion criteria also consisted of age between 6 and 16 years and Hebrew as the main spoken language.

Informed written consent was obtained from the parents of all children included in the study.

The study was approved by the local Helsinki Ethics Committee for Experiments on Human Subjects.

2.2. EEG 

EEG was performed according to the 10–20 international system with CZ referential. The recordings were carried out while the subject was awake, with 3min hyperventilation and photic stimulation, and during spontaneous sleep or after sleep deprivation. At least one sleep-deprived EEG was obtained for each patient.

2.3. Neuropsychological assessment 

A comprehensive battery of neuropsychological tests that measure a wide range of skills and cognitive functions was administered. In all cases, we used the Hebrew version of the tests, which have well-established validity and reliability.

4.Verbal fluency.¹⁵ Tests phonetic and semantic verbal fluency by having the subject generate, within 60s, as many words as possible that begin with certain letters or that belong to certain groups of objects, such as animals and foods.

5.Rey-Osterrieth Complex Figure (ROCF).¹⁶ Tests recall by having the examinee copy a drawing immediately after it was presented and 20min later.

6.Story recall.¹⁷ Tests recall by having the subject repeat as many details as possible from a story immediately after it was presented and 20min later.

7.Rey Auditory Verbal Learning Test (RAVLT).¹⁸ Tests verbal learning by having the subject repeat a list of words read to him/her immediately after it is presented and after 20min of distraction; this procedure is repeated 5 times.

Details of patients’ family and medical history, other clinical findings, and number of seizures were taken from the patients’ files.

The tests were carried out by a skilled neuropsychologist before any anti-epileptic therapy was started.

2.4. Statistical analysis 

All calculations were performed using the SPSS, version 16. Differences in numerical variables between the groups were analyzed by analysis of variance (ANOVA). To adjust for age, we used ANCOVA. The probability of type I error was set at p=0.05.

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3. Results 

The study group ranged in age from 6 to 15 years and the matched control group, from 7 to 15 years. However, ANOVA yielded a statistically significant difference between the groups in mean age (9.53 years in the study group vs 11.20 years in the control group, p=0.021). Therefore, we used ANCOVA to compare the background and neuropsychological data between the groups.

Two patients (5.56%) from the research group had a positive history of seizures in a first-degree relative. One patient (2.78%) had a history of febrile seizures. Two patients (5.56%) were left-handed.

The scores on the neuropsychological tests for the two groups are shown in Table 1. The control group had significantly higher scores than the study group on the WISC-R, in general knowledge, vocabulary, and digit span, and on the Verbal Fluency test, in semantic fluency. There were no statistically significant differences on the other tests or subtests.

Table 1. Comparison of scores on neuropsychological tests (mean, SD) between children with BECTS and controls.

WICHS-R: Wechsler Intelligence Scale for Children-Revised, K-ABC: Kaufman Assessment Battery for Children, ROCF: Rey-Osterrieth Complex Figure, RAVLT: Rey Auditory Learning Test. NS: not significant.

To examine the possible effect of laterality of the epileptic focus on the cognitive results, we divided the study group into three groups according to the dominant focus of the pathological interictal waves on the most recent EEG recording prior to neuropsychological testing: right, left, or bilateral. As there was no difference in age (distribution or mean) among the subgroups, the results were evaluated by ANOVA (Table 2). We found no significant difference in neuropsychological scores by epileptic focus.

Table 2. Comparison of scores on neuropsychological tests (mean, SD) by epileptic focus in children with BECTS.

WICHS-R: Wechsler Intelligence Scale for Children-Revised, K-ABC: Kaufman Assessment Battery for Children, ROCF: Rey-Osterrieth Complex Figure, RAVLT: Rey Auditory Learning Test. NS: not significant.

The number of seizures was recorded for each child starting from the first seizure considered to be part of the disease, even before the formal diagnosis was made, until neuropsychological testing was undertaken. The study group was then divided into those with 3 or fewer seizures and those with more than 3. This cutoff was chosen arbitrarily, because it comfortably divided the patients into almost equal groups of 18 and 17 patients, respectively. As there was no difference in age (distribution or mean) between the subgroups, we used ANOVA to test the relationship of number of seizures with cognitive function. The results, shown in Table 3, showed no differences between the subgroups for any of the neuropsychological tests or subtests. Indeed, the children with more seizures fared marginally significantly better on the WICHS-R Vocabulary subtest and the third reading test on the RAVLT.

Table 3. Comparison of scores on neuropsychological tests (mean, SD) by number of seizures in children with BECTS.

WICHS-R: Wechsler Intelligence Scale for Children-Revised, K-ABC: Kaufman Assessment Battery for Children, ROCF: Rey-Osterrieth Complex Figure, RAVLT: Rey Auditory Learning Test. NS: not significant.

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4. Discussion 

The learning difficulties associated with BECTS are well recognized. Most are related to verbal functions. Several studies reported that cognitive abnormalities are associated with high interictal spike frequency which improved when spike frequency decreased.⁸, ⁹, ¹⁹ Nicolai et al.²⁰ showed in a comprehensive study, that some EEG parameters such as intermittent slow-wave focus during wakefulness, high number of spikes in the first hour of sleep and during the whole night sleep, and multiple asynchronous bilateral spike wave foci are correlated with educational or behavioral impairment in patients with BECTS. These observations reflect the transient cognitive impairment (TCI) concept, which was described by Binnie and Marston²¹ as a momentary interruption of cognitive function due to intense electrical activity in the cortical areas that control them. However, Fonseca et al.²² assessed the occurrence of TCI during rolandic spikes in 33 children with BECTS. Of 13 children with rolandic spikes between visual stimulus presentation and response, only 2 (15.4%) made a significantly greater proportion of errors during rolandic spikes than during rolandic-spike free periods. Moreover, rolandic spikes appeared to be easily inhibited by the visual stimulus. The authors concluded that TCI occurred in a limited number of these patients and suggested to search for other factors that may influence cognitive abilities in children with BECTS.

In benign rolandic epilepsy, it is not only the TCI that leads to learning disabilities, but probably the chronic impact of especially highly frequent nocturnal spikes that result in cognitive difficulties, as shown in our study and previous ones.¹⁹, ²⁰ Moreover, at the extreme end, BECTS can occasionally deteriorate into syndromes with electrical status epilepticus in slow wave sleep (ESES) or continuous spike wave during slow-wave sleep (CSWS) characterized by severe cognitive and behavioral abnormalities.¹⁹, ²⁰

The findings of our study indicate that the learning difficulties in children with BECTS are unrelated to the laterality of the epileptic focus, the number of seizures, or the anti-epileptic treatment. The strength of the study lies in its exclusion of confounding factors: All children in the research group had EEG-proven BECTS, and all children in the control group had completely normal cortical activity, as indicated by their normal EEG findings during wakefulness, drowsiness, and sleep after sleep deprivation. Some earlier studies failed to rule out abnormal electrical activity during sleep in the control group, when critical pathologic paroxysms, many related to impaired cognitive function, occur. Furthermore, many earlier studies did not include a control group at all, or used a self-control design. The number of participants in our study was at least equal to that in previous ones, conferring good validity to our results. Nevertheless, with the inclusion of more children, some of the between-group differences in test scores might have reached statistical significance.

Another important advantage of the present study is the exclusion of patients receiving anti-epileptic treatment. Drug treatment can alter the EEG. There is also evidence that some anti-epileptic drugs may themselves have deleterious effects on cognitive abilities, thereby masking any possible relationships between the disease and cognitive impairments.²³

Unfortunately, although we matched the research and control groups for age range, the mean age of the patients was significantly lower. We had to account for this finding interpreting the results because for all the neuropsychological tests used, except the subtests from the Wechsler and Kaufmann batteries, the higher the subject's age, the higher the expected score. Therefore, we applied ANCOVA to evaluate the between-group results.

Significant differences between our patient and control groups were noted on the WICHS-R subtests of intelligence, vocabulary, and digit span. These findings are in line with the known impairment in verbal ability in children with BECTS. The subtests of intelligence and vocabulary are language-dependent, and the digit span test, which examines short-term auditory working memory, is a strong indicator of language acquisition ability.²⁴

Interestingly, there were no significant differences between the groups on the Kaufmann achievement tests of technical reading, comprehension, and arithmetic. This could indicate that the cognitive impairments in BECTS involve auditory and spoken language more than written language. Although we also found no significant between-group differences in story recall or on the RAVLT, there was a clear tendency towards better scores on those tests in the control group.

The lack of a statistically significant difference in the results on the Corsi Block and ROCF tests is easier to explain. Both these tests examine visual memory. The cortical center for representation of images lies in the occipital lobes, whereas in BECTS, the electrical foci are mainly in the centrotemporal regions.

Regarding verbal fluency, we found a significant between-group difference on the semantic tests but not the phonetic test. Success on the semantic tests requires a high degree of verbal organization and an ability to extract verbal information according to categories. By contrast, success on the phonetic test requires mainly the ability to process information according to sound. It is noteworthy that the between-group difference was much more pronounced when the subjects were asked to name animals (p<0.001) than when they were asked to name foods (p=0.041). This finding may be explained by earlier studies in adults with left hemispheric vascular lesions wherein voxel-based mapping of MRI images revealed that semantic verbal fluency processing takes place mainly in the temporal lobes of the cortex whereas phonetic verbal fluency processing takes place mainly in the frontal lobes.²⁵ In an MRI study, young, right-handed, native English speakers were asked to generate words according to semantic categories: birds, body parts, fruits, articles of clothing.²⁶ The authors found that birds were represented only in the left ventral temporal cortex whereas fruits were represented in the bilateral orbitofrontal cortex in addition to multiple areas in the frontal and temporal lobes of the left hemisphere. The more widespread representation of the class of foods could account for the lesser effect of the interictal electrical discharges in the present study on the subjects’ semantic verbal fluency in food names than in animal names.

The lack of effect of the laterality of the electrical focus on cognitive ability in our patients is in agreement with the study of Weglage et al.⁸ It is of note that in a recent study by Bulgheroni et al.,²⁷ BECTS patients lacked the typical right-ear-left-hemisphere functional advantage, which correlated with multifocal discharges rather than the laterality of the epileptic focus. It is possible that BECTS is inherently bilateral, as suggested by findings that the focus may shift between hemispheres. However, Piccirilli et al.⁷ reported that among children with BECTS, those with a dominant left electrical focus had better scores on attention tests than those with right or bilateral foci. Furthermore, in the children with a left dominant electrical focus, part of the verbal processing took place in the right hemisphere, whereas in the children with a right dominant focus, no verbal processing occurred on the left.²⁸ Further studies are needed to more precisely delineate the effect of focus laterality on various cortical processes.

In our study, the children with a greater number of seizures (more than 3) did not have significantly lower scores than the children with fewer seizures. Indeed, they had significantly better scores on the vocabulary subtest of the Wechsler battery and the 3rd reading in the RAVLT battery. However, the p-values were borderline, making it difficult to derive definitive conclusions. Weglage et al.⁸ investigated the correlation between cognitive difficulties, spike frequency, and number of seizures in children with BECTS. Like the present study, they found no relationship between cognitive difficulties and the number or even the existence of seizures in children with interictal paroxysms. They also did not document any correlation between interictal spike frequency and number of clinical seizures. Both their results, and ours support the hypothesis that the cognitive impairment in BECTS is related to the pathological interictal electrical activity or to a specific synaptic reorganization as a result of the frequent electrical discharges, and not to the clinical seizures themselves.

It should be noted that recently a research group from The Netherlands further demonstrated the strong correlation between interictal electrical activity and cognitive and behavioral impairments: in an analysis of EEG recordings of 28 children with BECTS, significant correlations were found between the aforementioned neuropsychological abnormalities and (1) an intermittent slow-wave focus during wakefulness. (2) a high number of spikes in the first hour of sleep (and during whole-night sleep) and (3) multiple asynchronous bilateral spike-wave foci in the first hour of sleep.¹¹

Recently, Fonseca et al.²⁹ corroborated these results, showing that cognitive difficulties are not linked to seizure-related factors, such as seizure frequency, time since the last seizure, or laterality of the electrical focus.

These findings have important implications for the potential benefit of anti-epileptic treatment on cognitive functioning. Two recent studies of this question yielded conflicting results. In a pilot study, Kossoff et al.³⁰ found that the administration of the anti-epileptic drug Levetiracetam to children with BECTS also led to an improvement in auditory comprehension and verbal memory. However, in another study of 6 children diagnosed with BECTS who underwent neuropsychological tests before and after 6 months of Sulthiame therapy, all the children had a significant deterioration in reading ability, in general memory, attention skills, and mathematics ability despite improvement on the EEG.³¹ This small, but important study raises again the question of the significance of normalizing the interictal EEG in order to improve the cognitive function in these patients.

In conclusion, children with BECTS have verbal difficulties which are unrelated to either spike laterality or anti-epileptic drug treatment. The number of seizures should not, by itself, be a factor in the decision to prescribe anti-epileptic drugs for purposes of preventing cognitive difficulties.

Further research is needed to elucidate the relationship between the cognitive dysfunction of BECTS and the unique brain electrical activity associated with the syndrome. The pathogenesis of the disorder needs to be further investigated, and prospective studies should be designed to test the effect of anti-epileptic drugs on neuropsychological scores. Positive findings could open a new era in the treatment of benign focal epilepsies of childhood.

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