A pilot study transitioning children onto levetiracetam monotherapy to improve language dysfunction associated with benign rolandic epilepsy

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Epilepsy & Behavior 11 (2007) 514–517 www.elsevier.com/locate/yebeh

A pilot study transitioning children onto levetiracetam monotherapy to improve language dysfunction associated with benign rolandic epilepsy Eric H. Kossoff *, Jenna G. Los, Dana F. Boatman The Johns Hopkins Hospital, Baltimore, MD, USA Received 13 June 2007; revised 23 July 2007; accepted 27 July 2007 Available online 23 October 2007

Abstract Benign rolandic epilepsy (BRE) and Landau–Kleffner syndrome (LKS) are similar epilepsy syndromes with sleep-accentuated epileptiform activity, sporadic seizures, and language dysfunction. Levetiracetam has been associated with improved language function in LKS and seizure reduction in BRE. We hypothesized levetiracetam would improve language function in children with BRE. A pilot study was performed with six children (aged 6–12) with BRE and evidence of impaired auditory comprehension and verbal memory. Children were transitioned from their current anticonvulsant to 40 mg/kg/day levetiracetam over a 2-week period and retested at 6 months. At 6 months, three of four children with baseline auditory comprehension impairments performed normally (P = 0.06), and five had improved auditory verbal memory (P = 0.08). Seizures improved in five, decreasing from 2.7 to 1.0 seizure per 6 months (P = 0.11). Results from this pilot study suggest that levetiracetam may have a beneficial effect on language in children with BRE. Ó 2007 Elsevier Inc. All rights reserved. Keywords: Levetiracetam; Benign rolandic; Centrotemporal; Language; Seizures; Children

1. Introduction Landau–Kleffner syndrome (LKS) is a childhood-onset epilepsy disorder characterized by occasional seizures, copious sleep-onset epileptiform activity, and a severe, progressive aphasia [1]. Treatment options are notoriously inadequate, and include corticosteroids, intravenous immunoglobulin, benzodiazepines, and multiple subpial transections [2]. Several recent case series have described the beneficial use of levetiracetam in 17 patients with pharmacoresistant LKS or continuous spike–wave activity of sleep (CSWS), typically in doses of 40–60 mg/kg/day [3–6]. Benign rolandic epilepsy (BRE), also referred to as benign epilepsy of childhood with centrotemporal spikes *

Corresponding author. Address: The Johns Hopkins Hospital, Suite 2158, 200 North Wolfe Street, Baltimore, MD 21287-1000, USA. Fax: +1 410 614 2297. E-mail address: ekossoff@jhmi.edu (E.H. Kossoff). 1525-5050/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2007.07.011

(BECTS), is another childhood-onset epilepsy disorder in some ways similar to LKS with frequent sleep-onset epileptiform spikes and rare seizures. There have been at least 12 studies to date describing language deficits in BRE, although not to the degree seen in LKS [7–18]. Although levetiracetam has been demonstrated as effective in BRE for both seizures and EEG abnormalities, there have been no reports of language improvement with treatment to date [19–21]. We hypothesized that in addition to the previously reported improvement in clinical seizures and epileptiform activity in BRE, levetiracetam would also improve language dysfunction. 2. Method Six children (aged 6–12 years) with BRE were prospectively treated after being previously evaluated and treated at our center for BRE by a pediatric epileptologist (E.K.). Five patients were right-handed. Inclusion criteria were prior diagnosis of BRE by clinical and EEG criteria, current use of an anticonvulsant other than levetiracetam for at least 30 days prior

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zure frequency and she continued the study. Another child (Patient 1) felt ‘‘weepy’’ on two anticonvulsants, which resolved on receiving levetiracetam as monotherapy. The median final dose of levetiracetam was 1500 mg/day (range, 1000–2000 mg).

to enrollment, and parent or teacher reports of worsening of language coinciding with the onset of seizures. Objective measures of language abilities (e.g., report cards, handwriting) were evaluated when provided, but not required for inclusion. Exclusion criteria included prior use of levetiracetam, serious psychiatric comorbidity (e.g. major depression, psychosis), use of more than one anticonvulsant, hearing loss, language dysfunction prior to the diagnosis of BRE, another seizure disorder other than BRE, nonepileptic seizures, and history of status epilepticus within the past 6 months. Written parental consent was obtained for all participants. A baseline 30-minute EEG encompassing sleep was recorded, and auditory language testing was performed. Parents were instructed to begin levetiracetam at a dose of 10 mg/kg/day divided twice daily in equal doses, then increase to 20 mg/kg/day after 1 week and to 40 mg/kg/day after 2 weeks for the remainder of the 6-month study. After 1 week on levetiracetam, the baseline anticonvulsant was reduced by 50% and, after the second week, discontinued. Although teacher reports were not a formal outcome measure in this study, parents were asked to avoid discussing the anticonvulsant change with their child’s teacher during the study to help objectively ascertain any school performance improvement. Parents were contacted by phone after 1 month, and children were evaluated in clinic after 3 and 6 months on levetiracetam. After 6 months, children had a repeat EEG and auditory testing. Parents were then given the option to continue levetiracetam or be switched back to the previous anticonvulsant. Behavioral auditory language testing was performed using standardized tests to evaluate low-level speech recognition abilities (SCAN-C/A Test, 1994 and 2000), auditory comprehension (Token Test for Children, 1978), and auditory verbal working memory (Digit Span Test, 1991). The SCAN-C/A test of speech recognition comprises four subtests, all of which were administered by headphones (50-dB presentation level). Children were tested individually in a quiet testing room in a 1-hour session. At the beginning of the study, all children underwent a hearing screening by a clinical audiologist (D.B.) to confirm normal hearing bilaterally. This study was approved by the Johns Hopkins Committee for Clinical Investigation and listed on www.clinicaltrials.gov. Levetiracetam 500-mg tablets were provided free of charge to the patients for the 6-month period. Means were compared using the paired Student t test. The significance level for all tests was P < 0.05.

3.2. Seizure reduction and tolerability Five of six children had a decrease in the number of seizures over the 6-month study period when compared with the previous 6 months on their baseline anticonvulsant (Table 1). The mean number of seizures per 6 months decreased from 2.7 to 1.0 (P = 0.11). Four children were seizure-free during the study period; all had periodic seizures while receiving their baseline anticonvulsant. One child had a slight increase in her seizures (Patient 6). Levetiracetam was well tolerated; the only side effect occurred in Patient 6, who was described as ‘‘moody’’ and she did not improve with oral pyridoxine. This child also had a slight increase in her seizure frequency over the study period. All parents chose to continue levetiracetam after the 6-month study period. The current median duration to date is 12 months (range, 8–23). 3.3. Electroencephalography Baseline EEGs were all abnormal, demonstrating centrotemporal spikes during both waking and sleep, occurring in the left hemisphere (or bilaterally) in five patients (Table 1). The single patient with unilateral right centrotemporal spike waves (Patient 2) had unilateral left discharges on a routine EEG 2 years prior to study enrollment. At the 6-month visit, three children had normal EEGs. Of the three other subjects with persistently abnormal EEGs, Patient 2 had significantly fewer right centrotemporal spike waves, Patient 3 had a change from bilateral frequent discharges to sporadic, unilateral left spike waves, and Patient 6 had no discernible improvement. Of note, Patient 1 underwent a subsequent EEG 12 months after completing the study to consider discontinuation of levetiracetam. Left centrotemporal spikes

3. Results 3.1. Subject demographics Six patients were consented and started the study; details are provided in Table 1. The median age at onset of BRE was 8.5 years (range, 4.6–11.2), with a subsequent median time until study onset of 2.1 years (range, 0.5–4.8). All patients successfully completed the transition onto levetiracetam. One (Patient 6) had a seizure during the second week of titration; however, this was not atypical for her sei-

Table 1 Patient demographics and changes in seizure frequency and epileptiform activity over time Patient

Sex

Age at study (years)

EEG at baseline

Baseline anticonvulsant

Dose (mg/ kg/day)

Seizures in the 6 months prestudy

EEG at 6 months

EEG improved?

Seizures during the 6month study

1 2 3 4 5 6

M F M M M F

6.0 9.5 9.8 10.5 11.3 11.8

Left Right Bilateral Left Left Left

CBZa CBZ CBZ OXC CBZ OXC

11 12 6 11 11 8

2 3 1 5 2 3

Normal Right Left Normal Normal Left

Yes Yes Yes Yes Yes No

0 0 0 1 0 5

a

CBZ, carbamazepine; OXC, oxcarbazepine.

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Table 2 Auditory language test scores at baseline and 6 months Patient

Subjective improvement per parents?

Token Test scorea

Digit Spanb

Baseline

6 months

Baseline

6 months

Baseline

6 months

1 2 3 4 5 6

Yes Yes Yes Yes Yes Yes

483 501 479 NT 492 494

496 502 493 500 506 497

6 6 6 11 8 5

5 7 7 14 10 6

NTd 96 84 84 94 110

94 100 86 91 86 102

a b c d

SCAN-C/Ac

Standard scores (norm: 500 ± 5). Scaled scores (age norm: 10 ± 3). Overall standard scores (age norm: 100 ± 15). NT, not tested at baseline.

during sleep continued.

were

noted,

and

levetiracetam

was

3.4. Language function Within 1 month of starting levetiracetam, the parents of all six subjects reported improvements in reading and writing when queried (Table 2). Four children had documented reading grade improvements on school report cards at the 3-month clinic visit. Three children independently described a recent enjoyment for reading. To more objectively evaluate any change in language function, within-subject comparisons of auditory test scores, baseline versus 6-month follow-up, were performed. There was a trend toward improvement in auditory comprehension (Token Test) scores: four of the five children who were impaired or could not be tested at baseline performed within the normal range on retesting (P = 0.06) (Table 2). Similarly, a trend toward improvement in auditory verbal memory (Digit Span) was noted for three of the four children who were impaired at baseline (P = 0.08). The two children who did not have impaired baseline scores (Patients 4 and 5) improved as well. Standard scores on tests of low-level auditory speech processing (SCAN-C/A) remained largely unchanged (P = 0.59). 4. Discussion The results from this small pilot study suggest that similar to reported language benefits with levetiracetam in LKS, improvements in language may also occur with BRE. Improvement in auditory comprehension appeared to occur in conjunction with both seizure freedom and EEG improvement, but in this small sample size, no definitive correlation between the three outcomes can be made. At the relatively high dose used (60 mg/kg/day), levetiracetam was well tolerated and all parents chose to continue it beyond the study period. In this small study, we cannot determine if levetiracetam was truly beneficial or if the two anticonvulsants used at baseline in this study (carbamazepine and oxcarbazepine) were detrimental to language. There are many other poten-

tial factors that might have led to language improvement, including better seizure control or even spontaneous cognitive maturation over time. There have been reports of worsening of seizures in BRE with carbamazepine, specifically epileptic negative myoclonus [22,23], as well as memory difficulties [24]; however, no reports specifically describe a carbamazepine-induced language dysfunction. Two studies of oxcarbazepine for BRE also did not describe drug-induced language deficits [20,25]. Evidence does exist for both the antiepileptogenic and neuroprotective effects of levetiracetam [26,27], hence the interest in this medication for this population as well as those with LKS and other progressive epilepsy syndromes. Levetiracetam is also structurally similar to piracetam, which has been used to improve cognition, although not specifically language [28]. Future studies with a larger sample size and untreated control group might help determine if the delay to treatment, patient age, EEG, or seizure frequency predicts who would be most likely to show language improvement. Although all of our patients had recent evidence of left centrotemporal epileptiform discharges, there is conflicting evidence in the literature that this laterality is universal with BRE-induced language dysfunction [13,16,18]. In addition, although the target dose of 40 mg/kg/day was chosen as median between a standard dose of 20 mg/kg/ day and the higher 60 mg/kg/day used for LKS [4], we do not know if the lower dose would be sufficient or the higher dose more helpful for language function. In summary, this pilot study provides preliminary evidence for a beneficial effect of levetiracetam on the language dysfunction occasionally associated with BRE. Considering that the majority of anticonvulsants used for BRE improve seizures and epileptiform activity, the possibility that levetiracetam may also improve language function is worth further investigation. Additional prospective studies with larger numbers of children are warranted. Acknowledgment This study was supported in part by a Young Investigator Award from UCB Pharma, Inc.

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