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Keywords:

  • Review;
  • Children;
  • Attention;
  • Epilepsy;
  • Antiepileptic drugs;
  • ADHD;
  • Hyperactivity;
  • Behavior

Abstract

  1. Top of page
  2. Abstract
  3. ATTENTIONAL ABILITY IN CHILDREN WITH EPILEPSY
  4. VARIABLES LEADING TO COGNITIVE DYSFUNCTION IN CHILDREN WITH EPILEPSY
  5. PATHOPHYSIOLOGY OF ATTENTION DIFFICULTIES IN EPILEPSY
  6. CONCLUSIONS
  7. Acknowledgments
  8. REFERENCES

Summary:  Attention problems are frequently seen in children with epilepsy. This review gives an overview of the most used constructs of attention and analyzes the available evidence for attention deficits in children with epilepsy, the effects of epilepsy variables on attention, and the possible pathophysiological mechanisms involved. Children with benign childhood epilepsy with centrotemporal spikes (BCECTS) have sustained attention difficulties. Right (R)-sided interictal epileptiform activity in these children interferes with R hemisphere function including sustained attention. Children with BCECTS also show selective and divided attention deficits if they have epileptiform discharges during sleep. Children with complex partial seizures (CPSs) have sustained attention deficits but no difficulties in selective or divided attention. Cognitive difficulties in children with epilepsy arise more frequently the earlier the onset of the epilepsy, and this could influence attentional ability development. Antiepileptic drug treatment is unlikely to impair attention, but phenobarbital has behavioral side effects similar to those in attention deficit–hyperactivity disorder. Concerning pathophysiology, evidence indicates that interictal epileptiform activity in children with BCECTS impairs sustained attention and that ongoing epileptiform discharges during sleep may impair attention. Further systematic studies of different aspects of attention in children with epilepsy are needed. Attention in children with drug-resistant epilepsy has not been addressed, and prospective studies before and after epilepsy surgery could be a useful model to study the influence of seizures on attentional ability.

Epilepsy is considered primarily a disorder of paroxysmal events, but it is a broader-spectrum disease (1) that includes a range of disabilities such as autistic spectrum disorders (2,3), attention deficit–hyperactivity disorder (ADHD) (4,5), learning difficulties, and motor impairments (6). In some patients these “comorbid” impairments may become the main clinical problem.

Attention in children with epilepsy is discussed here within the framework of frequent cognitive and behavioral difficulties associated with childhood epilepsy. Attention is considered as a set of skills necessary for cognition, not from the narrow standpoint of ADHD, although ADHD is a behavioral phenotype frequently seen in children with epilepsy (4,5). The behavioral phenotypes of ADHD, autistic-spectrum disorders, developmental coordination disorder, tics, and obsessive compulsive disorders show a major degree of overlap [i.e., comorbidity (2)], which suggests that Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV and International Statistical Classification of Diseases and Health-related Problems (ICD-10) do not describe biologic entities. Therefore we use a broader cognitive approach to attentional problems in children with epilepsy.

Attention is a construct of cognitive psychology rather than a cognitive function, and it can be considered a building block for other more complex forms of cognitive activity (7). Multiple models have tried to explain its role (8–11), but no unified theory about its nature or a wholly satisfactory model explains its function (for reviews, see 8 and 12). All models propose a multidimensional approach to attention. The most widely accepted components of attention used to define the construct operationally, and those that are considered here, are sustained attention, focused or selective attention, and divided attention (9,10).

Sustained attention is the capacity to maintain focus and alertness over time. Functional brain imaging studies suggest a predominantly right (R)-sided frontoparietal network for this type of attention (13,14). Selective attention is the ability to focus on target information from an array for enhanced processing and to screen out irrelevant stimuli. Neuroimaging studies suggest that the anterior cingulate cortex is critical for this process (15,16). Divided attention or shift is the capacity to change attentive focus in a flexible and adaptive manner, making the subject able to attend to more than one stimulus at the same time. Functional magnetic resonance imaging (MRI) studies show that the prefrontal cortex and the anterior cingulate gyrus activity are required to perform dual task paradigms used to test divided attention (17). These three components of attention regulate information processing (9) by engaging, interrupting, or inhibiting distinct information-processing systems in the brain (18). They organize and select perception to act in nonroutine situations (attention to action) and thus are important for executive functions directed to carry out complex, nonautomatic, goal-directed behavior. These processes are probably carried out not by single isolated brain areas, but by large-scale cortical and subcortical networks acting in parallel, with some anatomic areas being hierarchically more important than others (19,20).

Information processing is possible only in the alert state (i.e., awake or conscious). Alertness is a basic form of attention that allows reception of stimuli without any regulation by other cognitive processes, and can be distinguished from the three elements of attention mentioned earlier. We deal only with attention to action. The tests of attention mentioned in this review are described in Table 1.

Table 1. Tests of attention and impulsiveness
Sustained attentionTest of Variables of Attention (TOVA) Go–no go paradigmTOVA is a computer-administered visual Continuous Performance Test, which provides measures of sustained attention (omissions), ability to inhibit response (commissions), reaction time, and consistency of response (variability). It uses a Go–no go paradigm in which the subject has either to react to a stimulus or to refrain from doing it to another stimulus. The TOVA presents a small yellow box on a black screen over a 22-min period. When the box is at the top of the screen, the participant is instructed to push a button, but if it appears at the bottom of the screen, the button is not to be pushed.
Selective attentionCancellation TaskThe subjects are presented with an array of different letters or figures and are asked to cross out a specific letter or type of figure as quickly as possible.
 Stroop Colour Word Test (SCWT)The task requires the ability to avoid the interference of reading a word while trying to name the color in which it has been printed. For that purpose, the word “red” is printed either in green or in blue ink, the word “green” is printed in red or blue ink, and the same principle applies to the word “blue.” The participant is asked to name the color. Reading the word is a more automatic and easy process, and for this reason, it is difficult to avoid the interference of reading.
Divided attentionTrail Making Test Parts A and B (TMT)Part A of this test requires the subject to match in an orderly fashion the numbers from 1 to 13, arranged in a random way on a sheet of paper. Part B consists of the same task, but matching also letters in an ABC order, combining it with the task A. This means that the subject has to draw a line joining the number 1 to the letter A then the letter A to the number 2, and so on. The ability to divide the attention between the two tasks with the minimum interference is measured by the time the subject needs to complete the test.
ImpulsivenessMatching Familiar Figures Test (MFFT)The test requires matching a figure to one of a display of six different but similar ones. Time required to answer and the number of errors are registered. The shorter the response time and the higher the number of errors, the higher impulsiveness is rated for the subject.

Attentional problems are commonly reported in children with epilepsy. The ADHD prevalence in children with temporal lobe epilepsy (TLE) is increased in epidemiologic studies (4), which also show that 12% of children with any form of epilepsy have ADHD (21). This must be considered within the framework of children with epilepsy being at risk of cognitive impairments (CIs) including reading (22), arithmetic and spelling (23), language (24), and memory (25). Although children with ADHD usually have intelligence within the normal range, and attention deficits may interfere with cognitive function, attention is not the only factor accounting for their learning difficulties (26). Similarly it is likely that attentional difficulties are not the only factor accounting for CIs in children with epilepsy. However, their attention-deficit profile and the underlying mechanisms may be different from those in “pure” ADHD [e.g., more children with epilepsy and ADHD have been classified in the inattentive subgroup (5), whereas the combined subgroup is more prevalent in “pure” ADHD].

The impact of epilepsy on cognitive function is complex, with many variables that can influence cognitive ability and interact. We are interested in how all these variables influence attentional ability, but the scientific literature has looked more at cognitive function in children with epilepsy. Cognition and attention are closely related, and we will review the literature on attention in epilepsy and the epilepsy-related variables that may influence cognitive outcome.

ATTENTIONAL ABILITY IN CHILDREN WITH EPILEPSY

  1. Top of page
  2. Abstract
  3. ATTENTIONAL ABILITY IN CHILDREN WITH EPILEPSY
  4. VARIABLES LEADING TO COGNITIVE DYSFUNCTION IN CHILDREN WITH EPILEPSY
  5. PATHOPHYSIOLOGY OF ATTENTION DIFFICULTIES IN EPILEPSY
  6. CONCLUSIONS
  7. Acknowledgments
  8. REFERENCES

Attention appears to be particularly vulnerable to seizure activity (27). A summary of the studies discussing this and reviewed later is provided in Table 2. In 1973 Stores (28) suggested that attentional difficulties in children with epilepsy might influence academic underachievement. Attention and behavior were studied in 36 boys and 35 girls in a series of reports (29). Teachers rated attentiveness in classroom and motor activity. Selective and sustained attention were tested with cancellation (Table 1) and vigilance–distractibility tasks, respectively. Boys with epilepsy had worse scores than did girls in all measures except for distractibility, but only in the sustained attention task did they differ significantly from control boys (30). Stores (31), by using the Conners' Teacher rating scale, showed that boys with epilepsy had significantly higher scores than control boys in anxiety, inattentiveness, and social isolation. Using four groups [presence of generalized regular 3-Hz or irregular spike-and-waves, and focal R or left (L) temporal discharges], boys with L temporal spikes were the more disturbed, and significantly more hyperactive than were controls. Bennett-Levy and Stores's (32) questionnaire had 41 items of behavior, divided by factor analysis into alertness, concentration, processing, and confidence. Deficits in alertness but not in concentration were reported in children with epilepsy, irrespective of type of epilepsy, school attainments, and medication (32).

Table 2. Studies of attention in children with epilepsy
 Type of epilepsy Design Type of attention Tests Results
  1. BCECTS, benign childhood epilepsy with centrotemporal spikes; CPS, complex partial seizure; EDS, epileptiform discharges during sleep; IOLE, idiopathic occipital lobe epilepsy; SCWT, Stroop Colour Word Test; TMT, Trail-Making Test; TOVA, Test of Variables of Attention.

Stores (1978) (29)MixtureCase–controlSustained, selectiveAuditory vigilance task Cancellation Distractibility test Parents' and teachers' rating scalesDifficulty in sustained attention in second half of vigilance task in boys with epilepsy
Bennet-Levi and Stores (1984) (32)MixtureCase–controlNot specifiedQuestionnaire about concentration and alertnessDeficits in alertness
Oostrom et al. (2002) (33)MixtureCase–controlSelective, sustained, dividedGo–no go, TMTNo deficits in attention. Children with epilepsy, inefficiency to combine accuracy with speed
D'Alessandro et al. (1990) (34)BCECTSCase-controlSelective attention, divided attentionSCWT, TMTReversible deficits in selective and sustained attention
Piccirilli et al. (1994) (35)BCECTSCase–controlSustained attentionCancellation task sensitive to right hemisphere damageDeficits in sustained attention in children with right-sided and bilateral focus
Baglietto et al. (2001) (36)BCECTS with EDSCase–controlDivided attention, selective attentionTMT, SCWT Cancellation taskReversible divided and selective attention deficits
Croona et al. (1999) (39)BCECTSCase–controlDivided attention, distractibility, concentration, impulsivenessTMT, Parents' and teachers' questionnaireTMT did not show divided attention deficits. Parents found distractibility, lack of concentration, and impulsiveness, but teachers did not
Gülgönen et al. (2000) (25)IOLECase–controlAttention scoreDigit span, Number letter, Coding, Symbol search, Finger windows, Picture CompletionOverall attention score impaired, not differences in individual tests
Schoenfeld et al. (1999) (40)CPSCase–controlDivided attention, selective attentionTMT, SCWTNo divided or selective attention deficits
Semrud-Clikeman and Wical (1999) (41)CPSCase–controlResponse inhibition, sustained attentionTOVA (commission errors, omission errors, variability)Sustained attention deficits

Attentional deficits have not been found in all studies of children with heterogeneous types of epilepsy. Fifty-one children with newly diagnosed idiopathic or cryptogenic epilepsy were compared with 48 age- and gender-matched controls in measures of attention (33). Both groups were similar in IQ and attitudes toward school. Reaction time, omission, and commission errors were recorded in three different go–no go tasks (Table 1). Divided attention also was tested by using a Trail Making Test (TMT) variant for children (Table 1). Results were obtained before treatment and at 3 and 12 months' follow-up. Some patients showed more omission errors with slower reaction times, which was interpreted as an inefficiency in combining speed and accuracy rather than attentional error. No group differences were found in divided attention.

Recent reports looked at homogeneous samples with defined epileptic syndromes (Table 2). Forty-four children with benign childhood epilepsy with centrotemporal spikes (BCECTS) were divided into three groups: L, R, or bilateral-sided EEG discharges, and compared on attention, memory, language, and visuomotor abilities with a control group of nine children matched for IQ (34). Inclusion criteria were IQ > 80, no history of perinatal pathology, normal neurologic examination, normal computed tomography scan, seizure onset between ages 5 and 9 years, and no seizures or drug treatment for the preceding 6 months. Subjects with bilateral EEG discharges performed worse than did controls on TMT A and B, and Stroop Colour Word Test (SCWT; Table 1), suggesting deficits in divided and selective attention. A subgroup of 11 of these patients were retested on the tasks in which they performed less well than controls after 4 years of freedom from seizures and EEG abnormalities. No differences were found with a control group of 11 subjects. Thus, subclinical epileptiform discharges might cause these deficits, possibly through the phenomenon of transitory cognitive impairment (TCI). In a study of 43 children (aged 9–13 years) with BCECTS, Piccirilli et al. (35) isolated the influence of interictal EEG activity on attentional and visuospatial abilities from other factors like brain damage, therapy, and seizures. Selection criteria were the same as in the previous study. A cancellation task was carried out, sensitive to R-hemisphere damage (letters were replaced with geometric figures to test visuospatial skills, by using a specific topographic distribution arranged to look at possible hemineglect). Subjects were divided into three groups: L or R unilateral and bilateral discharges, observed in three consecutive EEGs. Patients with R-EEG epileptiform activity performed less well than did controls and patients with L-EEG discharges. This was not a problem of neglect due to selective attention deficits, because no significant R-L visual field differences were found in the number of ignored targets between subjects with R- or L-sided discharges, but a problem of sustained attention and/or visuospatial processing, a dysfunction that suggests R-hemisphere impairment. They concluded that R-hemisphere function is disturbed in children with BCECTS with R-hemisphere subclinical discharges, but it is uncertain whether it represents a problem of sustained attention or visuospatial abilities. Therefore, the type of cognitive dysfunction in some patients with epilepsy appears to be related to the effects of paroxysmal activity through a direct mechanism of functional disturbance in the region of the epileptic focus. Other indirect mechanisms of functional impairment have been suggested in children with BCECTS, such as interictal epileptiform discharges during sleep. In a controlled study, performance of nine children with BCECTS and high rates of discharges during sleep improved significantly in several cognitive measures, including divided (TMT) and selective attention (cancellation task and SCWT), when sleep discharges remitted either spontaneously or after treatment with benzodiazepines (BZDs; 36). This suggests that sleep may be important for cognitive processing, and its disturbance by epileptic discharges can be reversed pharmacologically. It has been proposed that epileptiform discharges causing TCI (i.e., a cognitive seizure) could be responsible for a general problem of attention or language processing (24), but we argue that it is more likely that this constitutes a mild epileptic encephalopathy involving sleep discharges in pathogenesis (37,38).

Other studies not focusing purely on the effect of EEG discharges have demonstrated that children with epilepsy have sustained attention problems, but not divided or selective attention difficulties (Table 2). Seventeen children (aged 7–14 years) with BCECTS did not show divided attention impairment in the TMT in comparison with age- and estimated intelligence-matched controls (39). Parental questionnaires revealed more distractibility, lack of concentration, and impulsiveness in patients than in controls, but teachers did not find this. Twenty-one children with idiopathic occipital lobe epilepsy (IOLE) differed from controls in IQ and aspects of visual and verbal memory (25). The overall attention score was significantly lower in patients with IOLE. However, no significant differences were found for each individual test, suggesting that the effects of IOLE on attention are mild but, if combined, significant.

Complex partial seizures (CPSs) provide a model to investigate attentional ability in symptomatic or cryptogenic localization-related epilepsy. Schoenfeld et al. (40) compared 57 children with CPSs with 27 normal sibling controls. Children with CPSs performed less well in all domains (verbal and nonverbal memory, language, academic achievement, problem solving, mental efficiency, motor skills, and overall cognitive status), but performance in the individual tests (TMT and SCWT) was similar for both groups, suggesting that children with CPSs are not impaired in divided and selective attention. However, impairments in sustained attention were found in children with CPSs in a study comparing four groups of children with CPS-only, ADHD+CPS, ADHD-only, and normal controls, on the test of variables of attention (TOVA) (41). Children with CPS+ADHD performed more poorly than the controls in all TOVA measures; so did CPS-only and ADHD-only groups in all but commission measures. No differences were seen in performance between children with CPS-only and children with ADHD-only. The DSM-IIIR criteria for ADHD used include impulsiveness and attention difficulties. Although it seems clear from this study that children with CPS-only have the same degree of problems of attention as do children with ADHD-only, the mechanisms responsible could be different. This could explain the poorer performance of children with both diagnoses and the accentuation of impulsiveness.

In summary, children with epilepsy have some attentional difficulties, although the evidence as here presented is sometimes contradictory (Table 2). Attentional problems have been found in heterogeneous samples with broad measures like behavioral questionnaires, but whereas some studies have found attention difficulties in cognitive tests (29), others have failed to do so (33). When looking at better-defined syndromes, sustained attentional deficits have been found in children with CPSs (41) and BCECTS (35,39). Some studies have failed to demonstrate divided-attention difficulties in children with these types of epilepsy (39,40), but they may occur in cases with a high rate of epileptiform discharges during sleep (36). Right hemisphere dysfunction, including sustained attention, has been found in children with BCECTS and R-sided discharges on awake EEG (35). Sustained attention deficits are the most commonly found in children with epilepsy, with the main evidence coming from BCECTS and CPSs.

It has been proposed that epilepsy surgery may affect the outcome of attentional ability in children with epilepsy. Two studies examined attention by using checklists in children undergoing the nonresective procedure of corpus callosotomy (CC). After CC, an improvement was found in attention, decreased hyperactivity (HA), and decreased aggressiveness in 81% of a group of 26 children with at least one behavioral problem (42). A good outcome, defined as 90% control of generalized seizures and/or 50% control associated with worthwhile improvement of cognitive and psychosocial function, was found in 75% of patients. Yang et al. (43) also demonstrated better attentional scores, less HA, and improved social skills after CC in 11 of 25 children. Sixty-four percent of subjects had >50% reduction in severity of drop attacks and tonic–clonic seizures. Improvement of attention and HA correlated with seizure outcome. These studies are of interest in the context of the modest results of CC in achieving seizure relief, suggesting that subclinical epileptic activity, particularly bilateral spread, might contribute to attentional problems.

Improvement of behavior after effective control of epilepsy was reported in 50 hemispherectomy patients (44). Violent, impulsive, and hyperactive behavior recorded preoperatively returned to normal in 53% of cases and improved in a further 40%. Sixty-eight per cent of patients were seizure free, and a further 14% had a substantial reduction. A relation between seizure freedom and behavioral improvement was suggested but not studied.

In 20 children (aged 10–16 years) with TLE, no preoperative difference was found in selective attention (d2 cancellation task) from 30 normal controls and 38 patients with epilepsy who were not surgical candidates (45). Twelve months after surgery, patients with TLE improved their scores in the task, but no results were given from the control groups; therefore retest and maturation effects cannot be ruled out. Other authors have looked at the preparatory and inhibitory aspects of attention in children with TLE who had resective epilepsy surgery (46). Reaction times to valid, invalid, and neutral cues were measured in lexical and spatial cue tasks. A sustained attention task (vigilance) also was added. Postoperative results of 17 patients (aged 6–18 years) showed rather nonspecific attentional difficulties in children with L-temporal lobe surgery compared with normal controls, although they were more impaired in attentional inhibition when invalid verbal cues were used. Patients with R-sided foci did not demonstrate sustained attention deficits after surgery. However, presurgical scores were not obtained in this study, and therefore it is not possible to know if the patients were impaired before surgery.

Epilepsy surgery appears to be a useful model for studying the effect of epileptic activity on attention by controlling several variables that can influence cognitive and/or attentional outcome. Well-designed prospective studies of attention in children having epilepsy surgery are needed.

VARIABLES LEADING TO COGNITIVE DYSFUNCTION IN CHILDREN WITH EPILEPSY

  1. Top of page
  2. Abstract
  3. ATTENTIONAL ABILITY IN CHILDREN WITH EPILEPSY
  4. VARIABLES LEADING TO COGNITIVE DYSFUNCTION IN CHILDREN WITH EPILEPSY
  5. PATHOPHYSIOLOGY OF ATTENTION DIFFICULTIES IN EPILEPSY
  6. CONCLUSIONS
  7. Acknowledgments
  8. REFERENCES

Attentional deficits are therefore seen in children with epilepsy. Cognitive development including attention in such children is complex and affected by several variables that can interact, making it difficult to isolate individual contributions to the impairment seen. The variables include etiologic factors (symptomatic vs. idiopathic epilepsy), seizure activity (frequency, severity), side effects of antiepileptic drugs (AEDs), site of brain dysfunction (extent and locus), degree of neurophysiological abnormality as evidenced by EEG, age at seizure onset, comorbid impairments, environmental factors, emotional factors, and genetic background (35,47,48).

Studies on the stability of cognitive function over time in children with epilepsy ideally use the intelligence quotient (IQ) prospectively as an outcome measure. Bourgeois et al. (49) found that the mean IQ of 72 children with any seizure disorder, treated for <1 week at the time of first evaluation, and of their siblings, did not show a significant change after 6 years. A subgroup of eight patients had a consistent reduction of ≥10 points in their IQ scores. This finding has been replicated and is due to a slower increase of mental age rather than to a loss of previously acquired abilities (50). Such patients are more likely to have difficult-to-control epilepsy, drug toxicity, and younger age at onset of epilepsy (49). In a retrospective study of 64 children with epilepsy, 31 whose epilepsy did not remit in a mean follow-up time of 9.6 years had a significant reduction in Performance IQ, Vocabulary, and Picture Arrangement subtests of the Wechsler Intelligence Scale for Children (51). Patients in remission did not show significant IQ changes. Both studies suggest that, although many children with epilepsy do not show a decrease in IQ scores over time, a subgroup exists that does, and this is probably, but not only, related to difficult-to-control epilepsy. The role of attention in the CIs in these children has not been studied.

Age at onset of epilepsy is a strong predictor of cognitive ability (40,52,53). In a retrospective surgical study of 100 children with lesional epilepsy, mean Full Scale IQ (FSIQ) was significantly lower in patients with epilepsy onset within the first 24 months of life. This finding was independent of etiology (focal cortical dysplasia, tumors, and hippocampal sclerosis) and seizure frequency. The combination of daily seizures and early age at onset appeared to have an especially deleterious effect, and 65% of children with both had FSIQ < 70 compared with 46% of patients with early seizure onset regardless of frequency (54). A study of 94 patients showed that >100 lifetime seizures correlated with diminished mental abilities. Convulsive status epilepticus (SE) also has been related to lower mental abilities (55).

AED treatment also influences cognitive outcome, but methodologic problems, particularly polytherapy, limit the evidence for the effect of each AED (56). Polytherapy seems, however, to have greater effects on cognition than does monotherapy in adults (57). Only studies of the effects of continued AED therapy and treatment discontinuation can address the specific cognitive effects for each AED. We refer mainly to pediatric studies that have examined attention and HA. We are not aware of a study assessing the incidence of ADHD as a side effect of AED treatment.

Performance on sustained attention (Continuous Performance Test; Table 1), hyperactivity–impulsivity (Mazes and MFFT; Table 1), and motor steadiness in 50 children with all types of epilepsy, but in remission, was better when tested at peak carbamazepine (CBZ) plasma concentration compared with low concentration (58). However, it does not tell us about performance without CBZ. A study in new cases of childhood epilepsy (generalized tonic–clonic, or partial), who were allocated randomly to phenytoin (PHT), CBZ, or valproic acid (VPA) treatment, showed no differences in selective attention (SWCT) and a cancellation task (59). Again no conclusions about the absolute effect of each AED can be drawn without a control group or comparison between baseline and end-point results.

In an AED-withdrawal study on cognitive function of 83 children who were seizure free for 1 year and taking VPA, CBZ, or PHT monotherapy for 1 year and compared with 83 healthy matched controls, no withdrawal effect was found between baseline and 6 months after withdrawal in information processing, alertness, or memory. Alertness was assessed by a visual search task, indicating selective attention (60).

Studies done in children on phenobarbitone (PB) for febrile convulsions (FCs) (61–67) found cognitive or behavioral side effects (Table 3), mainly HA, irritability, and sleep disturbances (61,62,66,67), which appear greater than with other AEDs. No differences in IQ were found in a randomized controlled study between children with FCs receiving placebo and PB at 1 year (62). Another randomized controlled study found a significant difference of 8.4 points in IQ at 2 years (64). A subgroup of these patients followed up to 3–5 years showed no significant IQ differences (65), although those receiving PB performed less well in reading (Table 3).

Table 3. Side effects of phenobarbitone in children with febrile convulsions
 StudyDesignChildren (n)Side effectsEvaluationFollow-up
  1. BD, behavioral disturbance; DB, double blind; Difs, differences; DZP, diazepam; HA, hyperactivity; IQ, intelligence quotient; NPsych, neuropsychological assessment; PB, phenobarbitone; plac, placebo; PR, parents' report; RC, randomized controlled; SE: side effect; Sn, significant; VPA, valproic acid; WRAT, wide range achievement test.

Studies lookingWolf and ForsytheRC  PR 
 for SEs (1978) (61)1. PB109PB: 42% BD 38% HA  
  2. Plac120Plac: 18% BD 11% HA  
 Camfield et al.RC, DB Irritability PB > plac, none HA on PBPR and Npsych1 year
  (1979) (62)1. PB 35No sn difs IQ  
  2. Plac 30PB: impaired memory + concentration  
 Wolf and ForsytheComparison No sn difs IQ (WISC)Psychometric35 months
  (1981) (63)1. PB 25   
  2. Plac 25   
 Farwell et al.RC, DB IQ sn decreased of 8.4 points on PBPsychometric2 years
  (1990) (64)1. PB 83   
  2. Plac 94   
 Sulzbacher et al.Comparison  Psychometric and3–5 years
  (1999) (65)1. PB139No difs IQ Npsych 
  2. PlacSame subjectsPB scored sn lower on WRAT  
    as in study 3 reading achievement standard  
     scores  
Studies notKnudsen et al.R, comparison  PR1 year
 looking (1978) (66)1. PB 73PB: 20% Drop-out 45% HA, irritability, listlessness  
 for SEs 2. DZP 83DZP: no SE  
 Lee and MelchiorComparison 21% drop-outs for SE: HA and sleep disturbancesPR1 year
  (1981) (67)1. PB 33   
  2. VPA 32   
  3. No treatment 25   

The one randomized controlled study with baseline assessments (68) on children with epilepsy receiving PB (69–73) (Table 4) showed no significant differences in IQ before and after 6 and 12 months of receiving PB. PB was associated with longer P3 latencies on evoked potentials (68), reflecting disturbances in information processing similar to that in children with ADHD (74). Discontinuation of PB monotherapy in children seizure free for 2 years showed significant improvement in divided attention (TMT), indicating reversible effects of PB on attention (70). In one study, randomization to PB was stopped because of the cognitive and behavioral side effects (72) (Table 4). Nevertheless, PB might be necessary in children with severe epilepsy, and it remains the most commonly used and affordable AED in countries with limited resources. Frequency of behavioral side effects was assessed in a randomized controlled trial in rural India of 94 children treated with PHT or PB. At 12 months of follow-up or at discontinuation of treatment, no excess of behavioral side effects was found in children receiving PB (71).

Table 4. Side effects of phenobarbitone in children with epilepsy
 StudyDesignChildren (n)Side effectsEvaluationFollow-up
  1. BQ, behavioral questionnaire; CBZ, carbamazepine; Ctrol, control; DB, double blind; Difs, differences; Epil, epileptic; IQ, intelligence quotient; NPsych, neuropsychological; PB, phenobarbitone; PHT, phenytoin; PR, parents' report; R, randomized; RC, randomized controlled; SEs, side effects; Sn, significant; VPA, valproic acid.

Studies lookingVining et al. (1987) (69)Comparison, DB crossover21PB < VPA in eight Npsych variables of 35PR, BQ, Npsych6 mo
 for SEsChen et al. (1996) (75)RC, comparison No sn difs IQPsychometric1 yr
  1. PB23Decrease in IQ after PB but no sn  
  2. CBZ25No sn difs in Bender Gestalt test  
  3. VPA25Longer P3 latency on PB  
 Riva and Devoti (1996) (70)Discontinuation of PB 9Improvements in memory, attentionNpsych1 yr
    Conclusion: reversible deficits on PB  
 Pal et al. 1998 (71)R  BQ21 mo
  1. PB31No excess of SE on PB  
  2. PHT31Acceptability of PB in developing countries  
Studies not looking for SEsde Silva et al. (1996) (72)R, DB  PR 
  1. PB10Six dropouts of 10 subjects on PB  
  2. PHT54Ceased randomization  
  3. CBZ54   
  4. VPA49   
 Calandre et al.No R, Controlled60 no epilFSIQ and PIQ lower than controls inPsychometric9–12 mo
  (1990) (73)  ctrol subjects on PB at entering study.  
  1. PB32IQ scores increased sn in children on VPA and ctrols at final assessment but not in children on PB  
  2. VPA32   

Therefore evidence exists that PB produces HA as a behavioral side effect and some reversible effects on divided attention in children with epilepsy (Table 4). PB produces a decrease in IQ in children with FCs that appears to be transient, but reading difficulties remain (Table 3). Such an important cognitive side effect must be balanced with the possible consequences of poorly controlled epilepsy.

Studies of the new AEDs in children with intractable epilepsy have shown a high incidence of cognitive and behavioral side effects when topiramate (TPM) was added to other AEDs (75), but were based only on parents' spontaneous reports. In contrast, mild to moderate cognitive effects are seen in children treated with lamotrigine (LTG) or gabapentin (GBP) (76,77). LTG has been found to have beneficial effects on mental status and behavior (78). When it is used in children, behavioral improvement may be seen, although reports with objective measures are lacking (79,80).

From all these studies, it can be concluded that PB must be used with caution. Regarding the new AEDs, TPM may produce some cognitive difficulties, but more prospective studies are needed with objective measures.

PATHOPHYSIOLOGY OF ATTENTION DIFFICULTIES IN EPILEPSY

  1. Top of page
  2. Abstract
  3. ATTENTIONAL ABILITY IN CHILDREN WITH EPILEPSY
  4. VARIABLES LEADING TO COGNITIVE DYSFUNCTION IN CHILDREN WITH EPILEPSY
  5. PATHOPHYSIOLOGY OF ATTENTION DIFFICULTIES IN EPILEPSY
  6. CONCLUSIONS
  7. Acknowledgments
  8. REFERENCES

The pathophysiology of CIs in children with epilepsy is still unknown, but some speculations about attentional skills can be made. Brain damage could be responsible for both the behavioral/cognitive outcome and for the epilepsy, with epilepsy being an epiphenomenon or manifestation of the underlying brain disorder. Conversely, epileptic activity could be the noxious agent, functionally interfering with normal brain development.

The relation between epileptic discharges and attention and cognition may have several facets. Tuberous sclerosis is a model for separating lesions and epilepsy, particularly early-onset epilepsy, as the cause for learning difficulties. Early onset of seizures, presence of epileptiform activity in the temporal lobe, and presence of tubers in the temporal lobe are associated with worse developmental outcome, as measured by the presence of autistic disorder. They are independent predictive factors that also summate (81).

An example of the effect of epileptiform activity on cognitive function is the presence of nonconvulsive SE during sleep in Laudau–Kleffner syndrome, in which selective language, and often wider impairments, occur frequently in association with such activity despite ≥2 years of normal development. The persistence of such activity appears related to severity and outcome for language and cognition (37,38). This syndrome, and others involving SE during sleep, raise the hypothesis that in sleep, important cognitive processing can be disrupted, but may reverse spontaneously or as a result of treatment (36).

The similar but milder model of BCECTS adds significantly to the discussion because of the much milder impairments of language (24) and attention (34–36), which have allowed more precise testing. Again, a high rate of discharges is commonly seen in sleep. BCECTS also is the model used for TCI. Such impairments are quite close to the temporally pervasive language-processing and attention difficulty that is reported. The coincidence of epileptiform discharges strongly supports their designation of “cognitive seizures.” Some studies have demonstrated TCIs (82) relating to EEG discharges in short-term memory (83) and reading (84), but others have not been able to find them (85). Thus the continuous and medium-term reproducibility of these findings does not suggest that the potential for momentary losing track of events is as important as some other effects probably related to discharges in sleep.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. ATTENTIONAL ABILITY IN CHILDREN WITH EPILEPSY
  4. VARIABLES LEADING TO COGNITIVE DYSFUNCTION IN CHILDREN WITH EPILEPSY
  5. PATHOPHYSIOLOGY OF ATTENTION DIFFICULTIES IN EPILEPSY
  6. CONCLUSIONS
  7. Acknowledgments
  8. REFERENCES

Attention problems are frequently reported in children with epilepsy. Most studies using questionnaires are able to report behaviorally evident attentional deficits. Neuropsychologically, children with BCECTS have sustained attention difficulties, and R-sided interictal epileptiform activity in children with BCECTS interferes with R-hemisphere activity including sustained attention. These children also show selective and divided attention difficulties if they have epileptiform discharges during sleep. Children with CPSs have sustained attention deficits but no difficulties in selective or divided attention. Cognitive difficulties in children with epilepsy arise more frequently the earlier the age at onset of the epilepsy, and this factor could influence attentional-ability development. AED treatment is unlikely to impair attentional ability specifically. Nevertheless PB has behavioral side effects (e.g., HA) that could be interpreted as ADHD symptoms, although no studies confirm this. Concerning possible pathophysiologic mechanisms, in BCECTS, some evidence exists that interictal epileptiform activity impairs sustained attention when it occurs in the R hemisphere, where the network for sustained attention has been shown to be active during sustained-attention tasks in studies using functional MRI. Some evidence also exists that ongoing epileptiform discharges during sleep may impair attention.

Prospective studies looking systematically at the different aspects of attention in its visual and auditory modalities are needed, because the studies reported in this review often look at a variety of cognitive functions and are not designed specifically to test attention. Attention in children with severe drug-resistant epilepsy has not yet been addressed and would require adequate control groups with similar levels of cognitive performance. Models of control of epileptic activity while maintaining other variables that can influence attentional outcome must be found, and resective epilepsy surgery appears to be a useful one.

Acknowledgments

  1. Top of page
  2. Abstract
  3. ATTENTIONAL ABILITY IN CHILDREN WITH EPILEPSY
  4. VARIABLES LEADING TO COGNITIVE DYSFUNCTION IN CHILDREN WITH EPILEPSY
  5. PATHOPHYSIOLOGY OF ATTENTION DIFFICULTIES IN EPILEPSY
  6. CONCLUSIONS
  7. Acknowledgments
  8. REFERENCES

Acknowledgment:  Dr. R. Sanchez-Carpintero was supported by the grant “Ex 2001 33419023” from the Ministry of Education, University General Directorate, Spanish Government. Professor Neville is supported by a grant from the Wellcome Trust. We thank Dr. B. Vollmer, Dr. R. Scott, and Dr. R. Chin for their helpful comments.

REFERENCES

  1. Top of page
  2. Abstract
  3. ATTENTIONAL ABILITY IN CHILDREN WITH EPILEPSY
  4. VARIABLES LEADING TO COGNITIVE DYSFUNCTION IN CHILDREN WITH EPILEPSY
  5. PATHOPHYSIOLOGY OF ATTENTION DIFFICULTIES IN EPILEPSY
  6. CONCLUSIONS
  7. Acknowledgments
  8. REFERENCES
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