Oxcarbazepine monotherapy in benign childhood epilepsy with centrotemporal spikes: A clinical and cognitive evaluation

Epilepsy & Behavior 7 (2005) 458–467 www.elsevier.com/locate/yebeh

Oxcarbazepine monotherapy in benign childhood epilepsy with centrotemporal spikes: A clinical and cognitive evaluation Maria Tzitiridou a, Theodora Panou b, Georgia Ramantani c, Athanasios Kambas b, Kleomenis Spyroglou b, Christos Panteliadis b,* b

a Dr. von Haunersches Kinderspital, University of Munich, Munich, Germany III Pediatric Department, Aristotle University, Hippokration Hospital, Thessaloniki, Greece c Department of Pediatric Neurology, University of Heidelberg, Heidelberg, Germany

Received 17 March 2005; revised 30 June 2005; accepted 17 July 2005 Available online 12 September 2005

Abstract We report on 70 patients (aged 5.2–11.6 years) newly diagnosed with benign childhood epilepsy with centrotemporal spikes (BECTS) who were assigned to oxcarbazepine (OXC) monotherapy. All of them underwent clinical and electroencephalographic examination at baseline and at 3- to 6-month intervals during the study. Psychometric assessment was performed at baseline and after 18 months of treatment with the WISC-III, Illinois Test of Psychomotor Abilities, DSM-IV, and Bender–Santucci test. The Mann–Whitney U test was used to describe differences in the frequency of abnormal findings: (1) at initial evaluation, comparing patients with a matched group of 45 healthy controls, and (2) after 18 months of OXC monotherapy, as an individual follow-up in the patient group. Cognitive assessment at baseline revealed mild learning disabilities in 9% of patients and 7% of controls; all participants had a normal intelligence quotient. During the follow-up, sustained cessation of seizures under medication was observed in 53% of patients; an additional 21% had some relapse but were subsequently rendered seizure free, 21% experienced a >50% improvement, and 5% showed no improvement. Normalization of interictal epileptiform activity was observed in 58% of patients, 35% showed an improvement in the grade of electroencephalographic pathology, and 7% manifested no change at all. The initial mildly weak scores in isolated cognitive domains did not deteriorate, and even improved in some cases, during the course of the study, with concomitant electroencephalographic improvement or normalization and effective seizure control. The results of this study suggest that OXC is effective in preventing seizures and normalizing electroencephalograms and seems to preserve cognitive functions and behavioral abilities as long-term monotherapy in children with typical BECTS.
2005 Elsevier Inc. All rights reserved. Keywords: Oxcarbazepine; Benign childhood epilepsy with centrotemporal spikes; Cognitive functions; Learning disabilities

1. Introduction Several studies on the safety and efficacy of oxcarbazepine in children have included some standard cognitive measures, although no systematic research has been performed so far. No change in IQ scores was associated with OXC in a small open-label monotherapy trial [1], but the small sample size, insensitive cognitive *

Corresponding author. Fax: +30 2310/854429. E-mail address: [email protected] (C. Panteliadis).

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2005 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2005.07.012

measures, and short duration (6 months) were critical limitations of that study. In a larger randomized, placebo-controlled study of children receiving OXC adjunctive therapy, somnolence was reported at a higher frequency in the OXC group [2]. In a comparative monotherapy study of OXC and phenytoin (PHT), the frequency of apathy was the same in both groups, whereas greater somnolence and less nervousness were associated with OXC [3]. These studies, as well as some others on smaller numbers of individuals, demonstrated a rather favorable cognitive profile for OXC [4–6].

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Cognitive and behavioral functions in individuals with epilepsy represent the outcome of multifactorial processes; underlying brain pathology and seizure frequency are the most critical aspects, apart from the detrimental effects of antiepileptic drugs (AEDs) [7]. Furthermore, there is some evidence to suggest that transient cognitive impairment during subclinical epileptiform discharges can affect attention and cognitive function even in the absence of clinical seizures [8–11] in benign epilepsy syndromes such as benign partial epilepsy with centrotemporal spikes (BECTS), although the magnitude of this effect remains controversial and difficult to demonstrate [12]. Indeed, BECTS has been shown to have an excellent prognosis [13], with the vast majority of children going into remission by adolescence [14–16] without serious cognitive sequelae [17,18]. The majority of these patients do not require treatment [19]; however, in those cases where treatment is justified due to frequent or severe seizures [20,21], the safest and most effective medication with a benign cognitive profile should be selected. Drugs reportedly used for patients with BECTS, commonly in low doses and with so far comparable efficacy, include phenytoin (PHT), phenobarbital (PB), valproate (VPA), carbamazepine (CBZ), sulthiame (STM), and clonazepam (CZP). Treatment failure is reported to occur in 20% of patients with BECTS [16]. However, according to recent studies, some of these medications seem to have serious cognitive sequelae (PB, CZP) [21], and others may aggravate EEG pathology (PHT, CBZ) [22]; also, STM is not available in some countries, including Greece. This is the first report of a prospective, long-term study of OXC as a primary agent in a homogenous subgroup of patients with BECTS. Our study aims (1) to investigate differences in cognitive functions between typical patients with BECTS at epilepsy onset and matched unaffected controls and (2) to evaluate first-line OXC treatment over 18 months with respect to seizure control, electroencephalographic normalization, and cognitive profile in the same subgroup of patients. Considering the benign nature of the syndrome, we placed an emphasis on the preservation of psychodynamics and cognition under treatment.

2. Methods 2.1. Patient group A total of 70 children with typical clinical and EEG features of BECTS according to the International League Against Epilepsy (ILAE) classification [23] were admitted to an open-label, long-term study. All participants were recruited from and evaluated in the 3rd Pediatric Department, University of Thessaloniki, Thessaloniki, Greece, between 1998 and 2004.

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Inclusion criteria were: (1) newly diagnosed epilepsy; (2) two or more seizures during the past 6 months, including nocturnal seizures and seizures on awakening, that were judged to require therapeutic intervention; (3) no pretreatment with an AED; and (4) brain magnetic resonance imaging (MRI) examination (Philips Gyroscan NT, 0.5 T; T1 sagittal slices, 6-mm thickness, and T2-weighted images) confirming the absence of a macroscopic lesion. Patients with cardiac, hepatic, endocrine, gastrointestinal, renal, hematologic, or oncologic disorders and seizures of metabolic, neoplastic, or active infectious origin were excluded from the study. Written informed consent was obtained from all participantsÕ guardians before admission to the study. 2.2. Clinical aspects of selected children The study group consisted of 45 male and 25 female subjects, ranging in age from 5.2 to 11.6 years (mean age, 8.4 ± 1.2 years) and exhibiting the typical clinical and electroencephalographic features of BECTS [23]. Seventy-four percent of the children had episodic partial motor seizures, while 13% had episodic partial motor seizures with secondary generalization and 13% had exclusively generalized tonic–clonic seizures. All 70 patients had uneventful perinatal histories. Early development and neurologic status, including fine and gross motor skills, were normal. Systematic inquiry revealed a family history positive for febrile convulsions in 14% of children and epilepsy in 19%, including 9% with a BECTS history. Furthermore, 19% patients had febrile convulsions. All children were native Greek speakers. 2.3. Trial design Oxcarbazepine was initially administered at a dosage of 10 mg/kg/day, which was increased to 20 and 25 mg/ kg/day in the second and third weeks, respectively, according to a set plan that was given to the parents along with the first prescription. At the end of the fourth week, the clinical situation was assessed by the physicians, and if seizure control had not been achieved, the dosage was further increased to 30 mg/kg/day. This slight increase in dosage was also made for patients who were seizure free at the end of the first month but had relapsed at one of the follow-up evaluations. Before OXC introduction (T0), 1 month after treatment initiation, and at 6-month intervals up to completion of the trial (T1), patients underwent clinical, electrophysiologic, and neuropsychologic examinations; an electrocardiogram (ECG); blood tests for OXC plasma concentrations (MHD); a blood count; and liver, renal, and thyroid function tests. According to the study protocol, EEGs (10–20 electrode positions, 20–40 minutes), both while awake and when sleeping, were record-

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ed at screening, 3 months after treatment initiation, and at 6-month intervals up to 18 months of treatment. The EEGs were recorded at 08:00–10:00 in the morning, prior to blood sampling and neuropsychologic evaluation. Blood sampling was performed 1 month after treatment initiation, 3 months after baseline, and at 6-month intervals up to completion of the study. At T0, the same neuropsychological assessment performed in the patient group was undertaken in a control group consisting of 45 unaffected subjects matched for age at testing, gender, and socioeconomic status (20 males, 25 females; aged 6.8–11.7 years, mean ± SD 8.1 ± 0.9). The controls were collected from the hospitalÕs pediatric outpatient clinic and none of them had a neurologic or other chronic disease. A thorough neuropsychologic reassessment was performed 18 months after treatment initiation (T1) in the patient group.

to rule out attention deficit and hyperactivity disorder, which negatively affects school performance and aggravates learning disabilities. The neuropsychologic evaluation was performed in an identical sequence, at a fixed time (10:00 AM), and was administered by the same neuropsychologist (T.P.). Developmental history was recorded with special attention to possible cognitive stagnation or regression or behavior problems that occurred prior to epilepsy onset. Furthermore, parents were questioned with respect to the school their children attended, whether they were in an age-appropriate grade, their general performance in school, and if they presented any particular weaknesses in the subjects of the school curriculum. This information was used as an additional indication of the educational performance of patients with BECTS compared with controls.

2.4. Neuropsychological assessment

2.5. Statistical analysis

Cognitive functions were explored by means of wellstandardized test batteries at enrollment in the control group and 1 to 3 weeks subsequent to diagnosis (T0) in the patient group. The evaluation was performed at least 48 hours after the last seizure to avoid transient effects on cognition and behavior. Subjects were tested individually in 90-minute sessions. Full Scale (FSIQ), Verbal Scale (VSIQ), and Performance Scale (PSIQ) Intelligence Quotients were evaluated by means of the Greek version of the Wechsler Intelligence Scale for Children—Third Edition (WISCIII) [24], according to age at epilepsy onset. The test was standardized in 1997 in Greece. The internal consistency of the Greek version of WISC-III lies between 0.43 and 0.85, with a mean value of 0.73 (s = 0.05). The verbal scale is divided into five subscales—Information, Similarities, Vocabulary, Arithmetical, and Comprehension—which test verbal comprehension, learning ability, long-term memory, speed of mental processing, and logical abstract thinking. The performance scale is similarly divided into five subscales—Picture Completion, Coding, Picture Arrangement, Block Design, and Object Assembly—testing perceptual organization, ability to concentrate, visual short-term memory, and sequential processing. The Illinois Test of Psychomotor Abilities (ITPA) [25] was applied in the evaluation of phonological awareness, visuospatial organization, long-term verbal memory, auditory sequencing, and short-term memory. The test was standardized in Greece in 1999, and the internal consistency for the subscales lies between 0.80 and 0.90. Visuospatial function, opticokinetic coordination, and visual short-term memory were assessed using the Bender–Santucci test [26]. In addition, the Diagnostic and Statistical Manual of Mental Disorders—Fourth Edition (DSM-IV) [27] diagnostic battery was applied

Statistical analysis of the Wechsler Intelligence Scale for Children data was performed using means and their corresponding relative SDs; raw scores were converted into age-based normalized T scores (mean 50, SD 10), and then means and SDs were obtained. We used nonparametric tests for statistical analysis of the data. The hypothesis of significant differences between the independent scores obtained by patients with BECTS and control participants at T0, as well as by patients with BECTS at T0 and T1, was tested using the Mann–Whitney U test. PearsonÕs v2 test was employed to analyze the Bender–Santucci test results. A P value <0.05 was regarded as significant.

3. Results 3.1. Oxcarbazepine efficacy in seizure control Sixty-four percent of OXC-treated patients were seizure free from the first day of OXC therapy to the end of the trial, whereas an additional 21% of patients experienced a >50% improvement in seizure frequency. Seizure relapse was observed in 23% patients (Fig. 1). During the follow-up, sustained cessation of seizures under medication was observed in 53% patients, 21% had some relapse but were subsequently rendered seizure free, 21% had >50% improvement, and 5% showed no improvement. In 13% of cases, partial seizures were documented under OXC monotherapy; generalized tonic– clonic seizures occurred in 10%. In these cases, relatively low plasma levels of OXC (<10 lg/ml) were detected. Subsequent dose adjustment, according to study protocol, led to seizure control in most cases. However, several children who remained seizure free throughout the study had rather low plasma levels of OXC as well.

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80

Number of patients

70 60 50

seizure relapse no changes

40

improvement seizure free

30 20 10 0 1 month

3 months

6 months

12 months

18 months

Fig. 1. Number of patients who were seizure free in control intervals during the trial.

Plasma levels of MHD during the study generally ranged from 9.4 to 14.6 lg/ml (mean 11.9 lg/ml, SD 1.19). Transient side effects were observed, including headache (n = 4), drowsiness (n = 3), irritability (n = 1), skin rash (n = 1), weight gain (n = 3), and insomnia (n = 1). Although there was a trend toward lower sodium values in the OXC-treated patients, only one patient had a clinically significant hyponatremia (125 mEq/L). This patient was asymptomatic and serum sodium concentrations returned to normal values (136 mEq/L) within 1 month, while the patient continued on the same daily dose of OXC (27 mg/kg/day). No intolerable adverse effects necessitating drug withdrawal were experienced. 3.2. Electroencephalographic results Against a normal background activity in wakefulness and good sleep organization, all EEGs of patients with BECTS revealed unilateral or bilateral centrotemporal spikes with variable distribution. Characteristically, slow diphasic high-voltage spikes recurred at short intervals, often in clusters, occasionally followed by a slow wave. Several EEGs demonstrated marked activation of epileptogenic activity in sleep, but none showed dif-

fuse continuous spike–wave discharges (CSWS) or other patterns suggestive of subclinical EEG seizures. Interictal EEG patterns such as intermittent slow wave foci, multiple asynchronous slow wave foci, or long slow wave clusters suggesting an atypical course of BECTS were not observed. Focal electroencephalographic discharges in the right hemisphere were documented in 67% of cases and in the left hemisphere in 33% of patients, while 7% showed a tendency to generalization. Nine percent had bilateral independent epileptiform activity. EEG normalization was achieved in 42% of patients by the sixth month, and an additional 33% of patients reached normalization by the end of the trial. Nineteen percent of EEGs showed an improvement in the grade of pathology, while 7% showed no change at all (Fig. 2). Subsequent to the initial evaluation, we focused on sleep EEGs exclusively, to assess epileptiform activity in the same stage of vigilance 3.3. Neuropsychological findings None of the children exhibited major psychopathology or had a history or behavior suggestive of attention deficit and hyperactivity disorder, according to DSM-

80

Number of EEGs

70 60 50

deterioration no changes improvement normalization

40 30 20 10 0 1 month

3 months

6 months

12 months

18 months

Fig. 2. Evolution of EEG pathology over time in patients with BECTS. Deterioration refers to a comparison with the previous EEG for the same patient.

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IV evaluation. These findings are generally in keeping with the subjective well-being reported by patients and families throughout the study. Furthermore, no marked changes in academic progress were reported during treatment. 3.4. Comparison between patients and control group participants at T0 Scores reported for patients and control participants at T0 are listed in Table 1. At T0, patientsÕ mean FSIQ scores were within the normal standard range (>85) and matched that of control participants. However, patientsÕ scores differed significantly (Mann–Whitney U test) from those of control participants on the subtest Information (P < 0.010), measuring verbal comprehension, long-term verbal memory, and learning ability. Furthermore, the ITPA revealed sectorial cognitive disabilities in 6 of 70 patients and 3 of 45 control participants (Table 2). In this subgroup of subjects, marked deficits in reasoning, associated with low reading ability in logical abstract thought, computational skill, phonological awareness, and short-term visuospatial memory were exposed. According to the learning evaluation, this subgroup had low reading ability and difficulties in reading comprehension and in written speech. It must be noted that all children with sequencing learning difficulties had a normal intelligence quotient Statistical analysis of the Bender–Santucci test revealed no statistical difference between patient and control groups at T0. Thirty-one percent of patients presented with isolated mild deficits in visuospatial func-

tion, opticokinetic coordination, and visual short-term memory, whereas 24% of controls had mild deficits in visual short-term memory. 3.5. Interindividual comparison between patients at T0 and T1 A slight improvement in the performance of patients was observed in the Information (P < 0.043), Picture Completion (P < 0.045), and Picture Arrangement (P < 0.033) subtests. As a result, statistically significant improvements in FSIQ (P < 0.030) and PIQ (P < 0.048) were recorded (Table 3). In the ITPA, progress was recorded on measures of verbal comprehension, long-term verbal memory, learning ability, visuospatial organization, simultaneous processing, and long-term memory sequential processing (Table 2). The Bender–Santucci test revealed a slight improvement in opticokinetic coordination and visual shortterm memory in the patient group (Table 2). This progress lies within the normal limits (P = 0.031). 3.6. Correlation between EEG focus lateralization and neuropsychologic findings In the children without neuropsychologic impairment, 86% had unilateral foci (57% on the right side, 29% on the left side) and 6% had bilateral foci or a clear tendency toward generalization. Of the six children with cognitive impairment, five had unilateral foci (three on the right side, two on the left side) and one showed a

Table 1 Test battery scores for the neuropsychologic evaluation of patients and controls at treatment initiation (T0) WISC-III Full Scale IQ Verbal IQ Information Similarities Arithmetic Vocabulary Comprehension Performance IQ Picture Completion Coding

Block Design Picture Arrangement Object Assembly a b

Mean (SD). Nonsignificant, P > 0.05.

Construct measured

Verbal comprehension, long-term verbal memory, learning ability Logical abstract thinking, verbal comprehension Computational skill, long-term memory, mental processing speed Verbal comprehension, logical abstract thinking Verbal comprehension Visuospatial organization, simultaneous processing, long-term memory Opticokinetic coordination, short-term visuospatial memory, concentration, sequential processing Opticokinetic coordination, visuospatial organization, simultaneous processing Visuospatial organization, sequential processing Visuospatial organization, simultaneous processing

Patients mean (SD)

Controls mean (SD)

P

102.69 (14.13)a 105.19 (11.43) 88.05 (13.10)

101.80 (12.44) 101.84 (12.87) 93.44 (11.02)

NSb NS <0.010

91.72 (12.58) 91.91 (15.77)

90.89 (11.20) 88.11 (8.94)

NS NS

95.29 (13.79) 98.97 (13.36)

89.78 (13.05) 96.89 (12.72)

NS NS

102.47 (17.38) 93.09 (19.93)

101.13 (10.84) 97.44 (11.61)

NS NS

90.57 (16.20)

85.78 (13.77)

NS

90.93 (14.61)

90.33 (12.17)

NS

90.81 (15.27) 89.88 (15.29)

92.78 (13.63) 86.67 (11.38)

NS NS

T1 T0 T1

— o — — o — * * *

T0

— o o — o — — — —

— o o o — o * * *

tendency toward generalization. The three children with learning disabilities and right EEG foci scored lower in visuomotor processing compared with those with a left focus. However, no definite correlation could be made between the nature of cognitive impairment and the lateralization/bilaterality of EEG foci in those six patients in whom cognitive deficits were established (Table 4).

— — o o o o o — o

Phonological awareness Opticokinetic coordination

463

—, deficit; o, adequate.

No variation was established between T0 and T1.

The controls were tested only at baseline. c

b

a

T1 T0

— o o — — — o — — o o o — o o * * *

T1 T0

o o o o o o o — o o — o o o — * * *

T1 T0

o — o o o o o — o — o — — — — * * *

T1 T0

—b o o — o — o — —

— o — — — — — o —

T1

— o o — o — * * *

T0 T1

89 (88,92) 117 (103,129) 100 (94,107) 99 (100,99) 11 (103,116) 104 (117,89) *c *c *c 90 (92,90) 116 (104,124) 98 (90,107) 96 (96,97) 110 (107,112) 99 (111,87) 105 (112,96) 91 (94,90) 98 (109,86)

T0 T0

9.7 6.6 9.0 10.2 7.0 6.5 6.6 8.5 10.11 P1 P2 P3 P4 P5 P6 C1 C2 C3

Visuospatial organization Long–term verbal memory Auditory sequencing short-term memory

Illinois Test of Psychomotor Abilities

Short-term visual memory WISC-III FSIQ (VIQ, PIQ) Age at 10 (years)

Bender– Santucci testa

— — o — — — * * *

4. Discussion

Subjects

Table 2 Results of initial assessment with WISC-III, Illinois Test of Psychomotor Abilities, and Bender–Santucci test in the six patients (P1–P6) and three controls (C1–C3) with cognitive deficits at baseline (T0) and after 18 months of oxcarbazepine treatment (T1)

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Several clinical trials have demonstrated that OXC is safe and efficacious in the treatment of partial seizures in childhood across a wide range of situations (recent onset to treatment-resistant epilepsy) and uses (monotherapy and adjunctive therapy) [28,29]. Furthermore, there is recent evidence supporting its favorable cognitive profile in a wide range of age groups [5,6]. We report the first investigation of OXC monotherapy in newly diagnosed patients with typical clinical and electroencephalographic features of BECTS. In this epilepsy syndrome, it is of utmost importance not only to control clinical seizures, but, if possible, also to improve the EEG, and to preserve neuropsychologic function and behavior. The efficacy of OXC monotherapy in patients with BECTS was clearly demonstrated in this trial, as 74% of OXC-treated patients were seizure free at the end of the first 6 months, a percentage comparable to the 81% of patients with BECTS treated with STM and markedly higher than that reported for placebo-treated patients (29%) in a recent double-blind study [30]. This effect obviously exceeds by far that expected through the natural course of BECTS and suggests a therapeutic benefit of OXC. Furthermore, 21% had a relapse at about 6 months of treatment, but subsequently remained seizure free to the end of the trial, while 21% showed improvement and 5% showed no change in seizure frequency at all. An important finding in our study was the prompt electroencephalographic normalization in the majority of patients with BECTS. According to our results, the sleep EEG was found to be normalized in 42% of patients by the sixth month, and this percentage rose to 74% by the end of the trial. Fifty-eight percent of EEGs showed some improvement in the first 6 months, 33% of which was transient. At the end of the study period, a mere 7% of all EEGs demonstrated no improvement at all, while no constant deterioration was documented. The rate of EEG normalization by 6 months is comparable to that provided by sulthiame treatment, which amounted to 68% in a recent study [31]. In this same study, spontaneous normalization in the placebo group occurred in 14% and reflects the wide spectrum of individual courses that must be considered when analyzing drug effects on the EEG in BECTS.

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Table 3 Test battery scores for the neuropsychologic evaluation at baseline (T0) and 18 months later (T1) WISC-III Full Scale IQ Verbal IQ Information Similarities Arithmetic Vocabulary Comprehension Performance IQ Picture Completion Coding Block Design Picture Arrangement Object Assembly a b

Construct measured

Session 1 (T0)

Session 2 (T1)

P

102.69 (14.13) 105.19 (11.43) 88.05 (13.10)

104.92 (14.74) 103.50 (11.61) 90.72 (12.77)

<0.020 NSb <0.043

91.72 (12.58) 91.91 (15.77)

92.62 (10.03) 89.22 (15.42)

NS NS

95.29 (13.79) 98.97 (13.36)

94.50 (8.75) 98.73 (14.98)

NS NS

102.47 (17.38) 93.09 (19.93)

106.61(18.67) 98.79 (12.99)

90.57 (16.20)

89.61 (19.71)

NS

90.93 (14.61)

94.00 (26.95)

NS

90.81 (15.27) 89.88 (15.29)

98.33 (21.44) 95.76 (14.52)

<0.033 NS

a

Verbal comprehension, long-term verbal memory, learning ability Logical abstract thinking, verbal comprehension Computational skill, long-term memory, mental processing speed Verbal comprehension, logical abstract thinking Verbal comprehension Visuospatial organization, simultaneous processing, long-term memory Opticokinetic coordination, short-term visuospatial memory, concentration, sequential processing Opticokinetic coordination, visuospatial organization, simultaneous processing Visuospatial organization, sequential processing Visuospatial organization, simultaneous processing

<0.048 0.045

Mean (SD). Nonsignificant, P < 0.05.

Table 4 Course of six children with transient cognitive disabilities Patient

1 2 3 4 5 6

Age at treatment begin (yr)

9.7 6.6 9.0 10.2 7.0 6.5

Test domain initially affected Memory

Language

Visuospatial

Ba C B A B B

G, H F F, G — G, H —

E D E D — E

EEG focus

Course of paroxysmal EEG activity

Seizure recurrence

Lfp+Gb Lct Lo Rct Lct Rct Rct

Disappear flc Persistent focus Disappear fl fl

>5 seizures None >5 seizures None None None

a A, long-term verbal memory; B, short-term visuospatial memory; C, short-term auditory memory; D, visuospatial organization; E, opticokinetic coordination; F, lexicon; G, reading; H, spelling. b L, left; R, right; G, generalized; Lct, left centrotemporal abnormalities; Rct, right centrotemporal; Lfp, left frontoparietal; Lo, left occipital. c fl, decrease in spike frequency (improved but not disappeared).

This finding is of special significance as OXC is chemically related to carbamazepine, which was reported to adversely affect EEG recordings [32–34] and even precipitate epilepsy with continuous spikes and waves during sleep in a considerable number of patients [35,36]; however, this drug-induced aggravation is controversial [23]. Up to now, only two drugs, CZP [37,38] and STM [31,38], have been proven to have marked positive effects on the EEG in BECTS, apart from efficacy in seizure control. Some authors [40–42] support the hypothesis that the epileptic focus may play a role in the genesis of cognitive dysfunction. On the other hand, transitory cognitive impairments, especially attention deficits during subclinical discharges, have been demonstrated by associating EEG and computerized neuropsychologic testing [43– 47]. Some other authors [48] also hypothesize an influence of spike and wave frequency in the EEG on test results. In addition, continuous spikes and waves in slow

wave sleep may occur in atypical cases, resulting in neurocognitive dysfunction [49–51]. Initial cognitive assessment revealed normal IQ values in the patient group, in keeping with the subjective well-being reported by patients and families. However, analysis of the WISC-III performance subscale Information revealed a mild deficit in verbal comprehension, long-term verbal memory, and learning ability. This could be partly explained by a low motivation level and limited range of general knowledge. No discrepancy in general intelligence quotient between patients and controls was identified, and this finding is in line with previous studies [52,53]. Furthermore, isolated mild cognitive deficits were identified in 6 of 70 patients and 3 of 45 controls, according to the ITPA subscales. In this subgroup of patients, marked deficits in reasoning, associated with low reading ability in logical abstract thought, computational skill, phonological awareness, and short-term visuo-

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spatial memory were exposed. According to their learning evaluation, they had low reading ability and difficulties in reading comprehension and written speech. The Bender–Santucci test showed no statistical difference between patients and controls, while minor deficits were established in equal rates in both groups. No child had a history of behavior suggestive of attention deficit and hyperactivity disorder, although some children had poor results on some attention tasks which could have affected their academic progress. Our sample size was small, but no trends in neuropsychologic worsening were seen. We could not find a single pattern of dysfunction such as language disability [9,54,55] or visuospatial problems [48] as reported in other BECTS studies. IQ scores were in the normal range, in concordance with numerous studies [13,56] showing that children with idiopathic generalized or localization-related epilepsy have higher IQ scores and a higher probability of mainstream schooling than those with symptomatic or cryptogenic generalized epilepsies or undetermined epileptic syndromes [57,40]. Several authors support the hypothesis that the epileptic focus in BECTS may play a role in the origin of cognitive dysfunction [40,41]. However, WISC-III performance scores demonstrated that no definite relationship could be established between the focus of epileptic activity on the EEG and its influence on mental processing (simultaneous processing and sequential processing of information). This could be attributed to a frequent shift in the lateralization of the focus in BECTS patients. However, children with a right-sided focus often had difficulties in sequential processing in which the right hemisphere is involved, as well as difficulties in both types of mental processing [41]. In five of the six children with isolated learning disabilities, improvement or complete normalization was established by the 18-month follow-up that corresponded with a decrease in or disappearance of the EEG epileptic activity; in no participant was deterioration noted. These findings suggest that either there was a transient cognitive impairment related to focal EEG discharges at the time of the initial tests [46,58] or the epilepsy and cognitive impairments arise from a common pathophysiologic substrate [59,32]. Alternatively, maturing cognitive deficits may be involved that are dependent or subserved by a particular cortical area not directly related to the epileptic focus, but susceptible to interference with epilepsy [52,53]. Spontaneous normal neuropsychologic evolution in BECTS by spontaneous remission of EEG paroxysmal activity in adolescence has been confirmed in a number of studies [11,60]. Furthermore, it cannot be ruled out that practice effects may have contributed to the improved scores, although the test–retest interval was long. Nevertheless, OXC effectiveness in clinical seizure control and electroencephalographic improvement in most

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patients seems to have contributed to this positive outcome. Our findings are in keeping with recent studies that have failed to find serious detrimental cognitive or behavioral effects of OXC in groups of children with focal epilepsy [7,9,59,61]. In our study, none of the patients exhibited atypical BECTS features, including reversible or persistent serious epileptic events, such as status epilepticus, evolution into Landau–Kleffner syndrome, or CSWS epilepsy. All children had exhibited previously normal development, and development of stagnation or regression of language, cognition, or behavior in temporal proximity to BECTS was not established during the study. Our patients thus belonged to the mild end of the spectrum with an initially ‘‘active rolandic focus,’’ but relatively low seizure frequency and duration, while there was no indication of grave neurocognitive or behavioral dysfunction related to seizure onset and CSWS or other atypical EEG patterns. Children with a truly benign disorder, such as typical BECTS, call for a particularly careful risk–benefit analysis when considering the choice of AED therapy. The anticonvulsant efficacy of OXC, its apparent effects on functional EEG discharges, and its favorable cognitive profile support its use in the treatment of BECTS. Other AEDs, such as CBZ, VPA, and PHT, also have proven efficacious in seizure control in BECTS. However, despite good tolerability, these drugs present certain drawbacks and rare serious side effects [62]. Carbamazepine, the drug most often prescribed for BECTS, has the disadvantage of aggravating EEG pathology and precipitating CSWS in a considerable number of patients [63,35]. Oxcarbazepine should therefore be considered for patients with BECTS in need of treatment, especially in countries where STM is not available [39]. In an attempt to minimize potentially confounding variables and thereby increase sensitivity, we restricted our sample to a mild epileptic syndrome, so generalizations to other patient populations and epilepsy syndromes should be made with caution. Identifying and minimizing the cognitive effects of AEDs are even more important in children, as they are more vulnerable to the long-term consequences of AED-induced cognitive impairment. Additional double-blind, controlled studies using homogenous groups, comprehensive assessments without methodologic limitations, and individual subject analyses are needed to replicate the above findings and determine the frequency and characteristics of susceptible patients.

5. Conclusion According to our results, OXC appears to be an effective antiepileptic agent in BECTS, establishing seizure control and EEG normalization and sparing young pa-

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tients the performance decrement often associated with AEDs. Spontaneous normal neuropsychologic evolution in BECTS has been confirmed in recent studies, combined with spontaneous remission of EEG paroxysmal activity. However, the possible neuropsychologic disturbances during the course of the condition, lasting several years and occurring at a crucial point in the childÕs social and psychologic development, may interfere with school performance and lead to secondary behavioral problems. In our opinion, medical treatment aimed at reducing clinical seizures and interictal EEG paroxysms should be tried to shorten the time to spontaneous recovery. In this age group, the preservation of psychodynamics and cognitive development should be a major goal of any therapeutic intervention, and OXC may prove a key medication for improving the outcome of patients with this epilepsy syndrome.

Acknowledgments The authors thank Georgios Arsos, M.D., for study coordination. This work was supported by an investigator-initiated research grant from NOVARTIS Pharmaceuticals.

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