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Efficacy of Levetiracetam in Electrical Status Epilepticus During Sleep of Children: A Multicenter Experience
Pediatric Neurology 50 (2014) 243e249
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Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Original Article
Efficacy of Levetiracetam in Electrical Status Epilepticus During Sleep of Children: A Multicenter Experience Xiao-Qiao Chen MD a, Wei-Na Zhang MD a, Zhi-Xian Yang PhD b, Meng Zhao MD PhD a, Fang-Cheng Cai MD c, Shao-Ping Huang MD d, Li Gao MD e, Bao-Dong Pang MD f, Xi Chen MD g, Li-Ping Zou MD PhD a, * a
Department of Pediatrics, Chinese PLA General Hospital, Beijing, China Department of Pediatrics, Peking University First Hospital, Beijing, China c Department of Neurology, Children’s Hospital of Chongqing Medical University, Chongqing, China d Department of Pediatrics, the Second Affiliated Hospital of Medical College, Xi’an Jiao Tong University, Xi’an, China e Department of Pediatrics, Henan provincial People’s Hospital, Zhengzhou, China f Department of Pediatrics, Tangshan Maternal and Health Care Hospital, Tangshan, China g Department of Neurology, Urumqi Children’s Hospital, Urumqi, China b
abstract BACKGROUND: Electrical status epilepticus during sleep is characterized by epilepsy, a specific electroencephalographic pattern, and neuropsychological impairment. This study aims to evaluate the efficacy and safety of levetiracetam in treating children with electrical status epilepticus during sleep. METHODS: A multicenter, retrospective, open-label study enrolled 73 children (mean age: 8 years) affected by electrical status epilepticus during sleep. The efficacy was rated according to the seizure frequency and electroencephalography response. RESULTS: After a mean treatment period of 19 months (range: 6 to 24 months), 33 (63.5%) of 52 patients became seizure-free or had experienced remarkable reduction in seizures. The electrical status epilepticus of 41 (56.2%) of 73 patients disappeared off their electroencephalography. The electroencephalography efficacy of levetiracetam treatment was noted in the monotherapy (61.9%) and add-on (53.9%) groups. The clinical (67.7%) and electroencephalography (64.3%) response rates of the idiopathic group were better than those of the symptomatic group (57.1% and 45.2%, respectively). No patient discontinued the trial because of intolerability of side effects. CONCLUSIONS: Levetiracetam is effective in individuals with electrical status epilepticus during sleep with tolerable side effects. Keywords: electrical status epilepticus during sleep, levetiracetam, children, idiopathic, symptomatic, treatment
Pediatr Neurol 2014; 50: 243-249 Ó 2014 Elsevier Inc. All rights reserved.
Introduction
Electrical status epilepticus during sleep (ESES) is an electroencephalography (EEG) phenomenon that was first described by Patry in 1971.1 Tassinari et al. subsequently reported similar patients and introduced the term ESES. In these patients, the term “continuous spikes and waves
X.-Q.C., W.-N.Z., and Z.-X.Y. contributed equally to this work.
Article History: Received August 2, 2013; Accepted in final form October 28, 2013 * Communications should be addressed to: Dr. Zou; Department of Pediatrics; Chinese PLA General Hospital; 100853 Beijing, China. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2013.10.015
during slow sleep” (CSWS) was considered synonymous to ESES.2 The International League Against Epilepsy suggested that epileptic encephalopathy with status epilepticus during sleep is an age-related and self-limited disorder. It is characterized by epilepsy with different seizure types, neuropsychological impairment, and a specific electroencephalographic pattern of continuous spikes and waves during nonrapid eye movement sleep.3 The characteristic EEG pattern consists of continuous and diffused spike waves mainly at 1.5 Hz to 2.5 Hz during slow sleep.2 Spikeewave index (SWI) has a central function in the diagnostic criteria of ESES/CSWS. However, various criteria have been used, including an SWI of at least 90%, 85%, 60%, 50%, and 25%.4 The International League Against Epilepsy did not
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provide an exact cutoff value and merely reported a strong activation of epileptiform activity during sleep.5 Clinical variants associated with an EEG pattern of ESES/CSWS are encephalopathy with CSWS/ESES, Landau-Kleffner syndrome, and atypical benign childhood epilepsy with centrotemporal spikes.6 The clinical manifestations and epileptiform discharges of ESES, as an age-related and self-limited disorder, will improve or even disappear with advancement in age. However, epileptic disturbances during the maturation of the cortical network may result in permanent impairment of the network. A study on the cognitive impairment of patients with ESES has demonstrated that good cognitive recovery after disappearance of ESES occurs in only one of 10 children, and partial recovery in four.7 Urgent treatment is needed to prevent neuropsychological and motor impairment. Currently, a systematic therapeutic strategy for ESES and its related syndromes has not been established. Available treatment options primarily include antiepileptic drugs, corticosteroids,8 adrenocorticotropic hormone,9 intravenous immunoglobulins,10 ketogenic diet,11 and surgeries.12 For antiepileptic drugs, benzodiazepines,13 valproate combined with ethosuximide,9 and levetiracetam have all been used to treat ESES. Sulthiame was also reported to be effective for ESES.14 Levetiracetam is a second-generation antiepileptic drug that is considered beneficial in the treatment of childhood epilepsy because of its favorable tolerability, little interaction with other antiepileptic drugs, and neuroprotective ability.15,16 After its approval for use in partial-onset seizures in adults and children aged 4 years,17 some studies have shown that adjunctive levetiracetam is efficacious and welltolerated for partial-onset seizures in infants and young children.18 Unlike traditional antiepileptic drugs, levetiracetam has a unique mechanism of action. The binding site of levetiracetam was identified as synaptic vesicle protein 2A, which inhibits calcium release from intraneuronal stores. Thus, it opposes the activity of negative modulators of gamma-aminobutyric acid and glycin-gated currents.19 It lacks cytochrome P450 isoenzymeeinducing potential.19 Approximately 66% of the drug is excreted unchanged in urine.16 Some reports that studied a limited number of patients have suggested that levetiracetam is effective for ESES.20,21 In addition, one study has found that CSWS is a definite target of levetiracetam.22 The current study investigated the efficacy of levetiracetam in improving the clinical manifestations and EEG pattern of 73 children with ESES.
blood count, and biochemical tests. The ESES of the patients who had received other antiepileptic drugs before inclusion in this study was not prevented or controlled. Levetiracetam was then administered to all patients either as monotherapy or add-on therapy. Levetiracetam therapy was started at a dosage of 20 mg/kg per day. The dosage was increased by 10 mg/kg per day increments every week, and the subsequent dosage ranged from 30 to 60 mg/kg per day. During the treatment and evaluation period, the patients were evaluated at 1 and 3 months after levetiracetam administration and then every 3 months thereafter. The follow-up duration for each patient was no less than 6 months. School performance was evaluated according to clinical judgment. All-night video-EEG was performed at least three times at every evaluation visit. The international 10/20 electrode placement system was used. The openeclosed eye test and hyperventilation were involved in every video-EEG test. The patients were divided into idiopathic and symptomatic groups according to etiology. The new International League Against Epilepsy report proposes to replace the terms “idiopathic,” “symptomatic,” and “cryptogenic” with “genetic,” “structuralemetabolic,” and “unknown,” respectively. In this study, the previous terms were maintained. The efficacy of levetiracetam in the monotherapy and add-on therapy groups was also observed in this study. Patients in the monotherapy group were treated using levetiracetam as an independent drug, whereas those in the add-on therapy group were treated by adding levetiracetam to the antiepileptic drugs that the patients previously received. Patients
All patients met the following inclusion criteria: (1) onset of focal seizures or focal EEG discharges; (2) further occurrence of new clinical manifestations, such as atypical absences, atonic, myoclonic, and negative myoclonic seizures; and (3) characterized epileptic activity of ESES according to video-EEG; during nonrapid eye movement, the focal or diffuse spikes and waves became continuous with SWI 50%. The SWI was confirmed by two physicians trained in electrophysiological images. The exclusion criteria were as follows: (1) Lennox-Gastaut syndrome and West syndrome that do not fulfill the criteria for ESES and (2) patients who had previously received levetiracetam. Assessment
Throughout the study, the patients’ parents or legal caregivers kept diaries to record seizure types and frequencies. The efficacy of levetiracetam was measured by seizure frequency and the reduction in SWI that were compared with data gathered during the baseline period. Clinical response to therapy was graded as seizure-free, significant reduction in seizures, and no change or increase in seizures. EEG response to therapy was divided into three categories: 50% reduction in SWI, <50% reduction in SWI, and with no change or increase in SWI. Statistical analysis
Mann-Whitney U test was used to compare the efficacy between the idiopathic and symptomatic groups with a 0.05 two-sided significance level.
Results Materials and Methods Study design
This research was designed as a multicenter, retrospective, openlabel study. Between 2009 and 2013, 73 patients were diagnosed with ESES at seven pediatric centers in China. The trial was conducted in accordance with the international rules of good clinical practice and was by the Ethical Committee of the Chinese PLA General Hospital. Informed consent was obtained from each patient’s parents before the initiation of the trial-related procedures. The first month before the patients’ arrival at the research clinics was considered the baseline period. After being diagnosed with ESES, all patients underwent videoEEG, cerebral magnetic resonance imaging, urine analysis, complete
Demographics and baseline clinical characteristics
The clinical and EEG outcomes of 73 patients with ESES were analyzed in this study. The median follow-up duration was 19 months (range: 6 to 24 months). The 73 patients comprised 45 males and 28 females. All urine analysis, complete blood count, and biochemical test results were normal during the follow-up period. The median age of the patients was 8 years. The age at onset of focal epilepsy was 4 months to 10 years and 3 months, with a median age of 2 years. The age at onset of ESES was 1 year and 1 month to 11 years and 8 months, with a median age
X.-Q. Chen et al. / Pediatric Neurology 50 (2014) 243e249 TABLE 1. Demographics and baseline characteristics of the 73 patients
Number of Patients (n ¼ 73) Gender Male/female (n, %) Median age Age at onset of epilepsy Age at onset of ESES Seizure types before ESES Complex focal seizures (n, %) Myoclonic seizures (n, %) Atypical absences (n, %) Focal seizures with secondary generalization (n, %) Epilepsy syndromes ABECT (n, %) CSWS (n, %) LKS (n, %) Psychomotor impairment (n, %)
45 (61.6)/28 (38.4) 8 yrs. 2 yr (4 mo to 10 yr, 3 mo) 5.5 yr (1 yr, 1 mo to 11 yr, 8 mo) 45 12 9 7
(61.6) (16.4) (12.3) (9.6)
38 19 4 39
(52.1) (26.0) (5.5) (53.4)
Abbreviations: ABECT ¼ Atypical benign childhood epilepsy with centrotemporal spikes CSWS ¼ Continuous spikes and waves during sleep LKS ¼ Landau Kleffner syndrome
of 5.5 years. The median time between the onset of first seizures and onset of ESES was 3.5 years. Before the onset of ESES, 45 patients experienced complex focal seizures, 12 had myoclonic seizures, nine had atypical absences, and seven had focal seizures with secondary generalization. Fifty-five patients experienced seizures during sleep. After the onset of ESES, 59 of the 73 patients exhibited new types of seizures, including negative myoclonus, positive myoclonus, atypical absences, and atonic seizures. Then, 39 (53.4%) of the 73 patients exhibited cognitive delays, of whom 28 exhibited delays on all the three aspects of motor, language, and cognition. Two patients had expressive language disturbances and learning difficulties. Seven patients exhibited intellectual deterioration, whereas one patient showed only motor impairment. Attention deficit hyperactivity disorder was detected in two children. In addition, two children exhibited autistic behavior (Table 1). According to the etiology, 42 patients were classified into the idiopathic group, among whom atypical benign childhood
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epilepsy with centrotemporal spikes was diagnosed in 38 children, and Landau-Kleffner syndrome was diagnosed in four. Conversely, 31 patients were in the symptomatic group. Among the 31 patients, six had cerebral palsy, five had perinatal hypoxia-ischemia encephalopathy, five had hydrocephalus, four had polymicrogyria, two had autism, two had encephalitis, and one had schizencephaly according to magnetic resonance imaging (Fig 1). Six patients were identified as either “cryptogenic” or “unknown.” They were reported to have normal magnetic resonance imaging scans and no definite signs of lesions in neurological examinations; their etiology was undetermined. These six patients were included in the analysis of the symptomatic group results. In addition, 21 patients were in the monotherapy group and 52 patients were in the add-on therapy group (Table 2). Efficacy Clinical and EEG efficacy of levetiracetam in idiopathic and symptomatic groups
During the baseline period, 21 patients had no seizure and only exhibited abnormal EEG discharges. Eleven of these patients were in the idiopathic group and 10 were in the symptomatic group. Of the 52 patients who exhibited clinical manifestations and returned for evaluation visits during months 1 to 24, 11 were seizure free (21.2%) and 22 (42.3%) showed significantly reduced seizures. In addition, 19 patients (36.5%) experienced no change or increase in seizures. The total clinical response rate of the 52 patients was 63.5%. Of the 31 patients in the idiopathic group, seven (22.6%) were seizure free, 14 (45.2%) showed significantly reduced seizures, and 10 (32.6%) showed no change or increase in seizures. Of the 21 patients in the symptomatic group, four (19.1%) were seizure free, eight (38.1%) showed significantly reduced seizures, and nine (42.9%) had no change or increase in seizures. The response rates of the idiopathic and symptomatic groups were 67.7% and 57.1%, respectively (Table 3A, Fig 2A). No significant difference was found in the clinical efficacy of levetiracetam between the idiopathic and symptomatic groups (Z ¼ 0.691, P ¼ 0.489 > 0.05).
FIGURE 1. (A) Sleep electroencephalogram demonstrating continuous spikes and waves during slow sleep. (B) Axial T2-weighted magnetic resonance image showing schizencephaly of the left parietal lobe (arrow) and dysplastic gray matter lining the cleft.
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TABLE 2. Group distribution of the 73 patients
Grouping Method
Group Name
Number of Patients (n)
Etiology
Idiopathic group Symptomatic group Monotherapy group Add-on therapy group
42 31 21 52
Therapy strategy of levetiracetam
For EEG efficacy, of the 73 patients who were evaluated during months 1 through 24, 15 (20.6%) exhibited 50% reduction in SWI, 26 (35.6%) exhibited <50% reduction in SWI, and 32 (43.8%) exhibited no change or increase in SWI. The total EEG response rate was 56.2%. When analyzed separately, 50% reduction in SWI was observed in 10 (23.8%) of the 42 patients in the idiopathic group and in five (16.1%) of the 31 patients in the symptomatic group. The EEG of six patients in the idiopathic group even normalized during months 1 to 6. A <50% reduction in SWI in the EEG was observed in 17 patients (40.9%) in the idiopathic group and in nine (29.0%) in the symptomatic group. No change or increase in SWI was observed in 15 (35.7%) and 17 (54.8%) patients in the idiopathic and symptomatic groups, respectively. The response rates of the idiopathic and symptomatic groups were 64.3% and 45.2%, respectively (Table 3B, Fig 2B). Similarly, no significant difference was found in the EEG efficacy of levetiracetam between the idiopathic and symptomatic groups (Z ¼ 1.527, P ¼ 0.127 > 0.05). Clinical and EEG efficacy of levetiracetam as monotherapy and addon therapy
Fifty-two patients received levetiracetam as add-on therapy. The main concomitant antiepileptic drugs were valproate, oxcarbazepine, topiramate, lamotrigine, carbamazepine, clonazepam, nitrazepam, and corticosteroid (four patients). Twenty-one patients received levetiracetam as monotherapy. During the baseline period, 21 patients had no seizure and only exhibited abnormal EEG discharges. Among the 21 patients, eight were in the monotherapy group and 13 were in the add-on therapy group. Of the 52 patients who exhibited clinical manifestations, five (38.5%) of the 13 monotherapy patients and six (15.4%) of the 39 add-on therapy patients were seizure-free. A significant reduction in seizures was observed in four patients (30.8%) in the monotherapy group and in 18 patients (46.2%) in the add-on therapy group. No change or increase in seizures was observed in four patients (30.8%) in the monotherapy group and in 15 patients (38.5%) in the add-on therapy group. The response rates of the monotherapy and add-on
therapy groups were 69.2% and 61.5%, respectively (Table 3C, Fig 2C). For the respective EEG efficacies of levetiracetam in the monotherapy and the add-on therapy groups, 50% reduction in SWI was observed in six (28.6%) of the 21 patients in the monotherapy group and in nine (17.3%) of the 52 patients in the add-on therapy group. A <50% reduction in SWI on the EEG was found in seven patients (33.3%) in the monotherapy group and in 19 patients (36.5%) in the add-on therapy group. SWI did not change or increase in eight (38.1%) and 24 (46.2%) patients of the monotherapy and add-on therapy groups, respectively. The response rates of the monotherapy and the add-on therapy groups were 61.9% and 53.9%, respectively (Table 3D, Fig 2D). Notably, 18 patients relapsed during follow-up, of which eight relapsed clinically and electroencephalographically, eight relapsed electroencephalographically, and two relapsed clinically only. Among the eight patients who relapsed electroencephalographically, one had no clinical response after levetiracetam was introduced and four had no seizure during the baseline period and follow-up. The two patients who relapsed clinically had no EEG response toward levetiracetam. Discussion
We analyzed the efficacy of levetiracetam in 73 patients with ESES. The follow-up period was 6 months to 2 years. Levetiracetam has good efficacy for clinical manifestations and EEG epileptiform discharges of children with ESES. To date, no ESES treatment protocol has been published. The absence of seizures, normalized EEG discharges, and improvement of neuropsychological impairment are the most important goals to achieve in treating patients with ESES. Previous studies have reported different ESES treatment options. Among the traditional antiepileptic drugs, valproate combined with ethosuximide and benzodiazepines are reportedly effective for ESES.13 However, some reports have suggested that the efficacy of these antiepileptic drugs is transient and partial.23 In a prospective, longterm, follow-up trial, a combination of valproate and ethosuximide was reported to be effective in the treatment of ESES.24 Several studies have demonstrated that antiepileptic drugs such as carbamazepine and phenobarbital may even induce or worsen ESES.25 Oxcarbazepine was reported to have caused electroclinical deterioration in three patients with benign childhood epilepsy with centrotemporal spikes, among whom two patients manifested atypical absences, neuropsychological disturbances, and generalized spikeand-wave discharges in their EEGs that became continuous during sleep.26 In the current study, two patients had ESES
TABLE 3A. Clinical efficacy of levetiracetam in idiopathic and symptomatic groups (n, %)
Idiopathic Symptomatic Total
Seizure-Free
Significant Reduction
No Change or Increase
Total
Response Rate (%)
7 (22.6%) 4 (19.1%) 11 (21.2%)
14 (45.2%) 8 (38.1%) 22 (42.3%)
10 (32.3%) 9 (42.9%) 19 (36.5%)
31 21 52
67.7 57.1 63.5
Twenty-one patients had no seizure during the baseline period, 11 were in the idiopathic group and 10 in the symptomatic group. Mann-Whitney U: Z ¼ 0.691, P ¼ 0.489 > 0.05.
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FIGURE 2. (A) Efficacy of levetiracetam treatment in the idiopathic group (black columns) and symptomatic group (white columns). Numbers of patients without seizures, with significant reduction in seizures, and with no change or with increase in seizures are shown. (B) Efficacy of levetiracetam treatment in the idiopathic (black columns) and symptomatic (white columns) groups. Numbers of patients with 50% reduction in spikeewave index (SWI), with <50% reduction in SWI, and with no change or increase in SWI are shown. (C) Efficacy of levetiracetam treatment given as monotherapy (black columns) and addon therapy (white columns). Numbers of patients without seizures, with significant reduction in seizures and with no change or increase in seizures are shown. (D) Efficacy of levetiracetam treatment given as monotherapy (black columns) and add-on therapy (white columns). Numbers of patients with 50% reduction in SWI, with <50% reduction in SWI, and with no change or with increase in SWI are shown.
after the independent introduction of oxcarbazepine and carbamazepine. Reports indicate that “new” antiepileptic drugs, such as topiramate,27 have some efficacy in the control of ESES. However, most of these reports are anecdotal
and involved a limited number of patients. Most of the patients in the present study had received several antiepileptic drugs, such as valproate, lamotrigine, topiramate, carbamazepine, and oxcarbazepine, before levetiracetam was
TABLE 3B. EEG efficacy of levetiracetam in idiopathic and symptomatic groups (n, %)
Idiopathic Symptomatic Total
Reduction of SWI 50%
Reduction of SWI <50%
No Change or Increase
Total
Response Rate (%)
10 (23.8%) 5 (16.1%) 15 (20.6%)
17 (40.5%) 9 (29.0%) 26 (35.6%)
15 (35.7%) 17 (54.8%) 32 (43.8%)
42 31 73
64.3 45.2 56.2
Mann-Whitney U: Z ¼ 1.527, P ¼ 0.127 > 0.05.
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TABLE 3C. Clinical efficacy of levetiracetam in monotherapy and add-on therapy groups (n, %)
Monotherapy Add-on therapy Total
Seizure-Free
Significant Reduction
No Change or Increase
Total
Response Rate (%)
5 (38.5%) 6 (15.4%) 11 (21.2%)
4 (30.8%) 18 (46.2%) 22 (42.3%)
4 (30.8%) 15 (38.5%) 19 (36.5%)
13 39 52
69.2 61.5 63.5
Twenty-one patients had no seizure during the baseline period: eight were in the monotherapy group and 13 were in the add-on therapy group.
introduced. Despite the transient efficacy in the beginning, these drugs could not prevent the onset of ESES and persistent EEG epileptiform discharges. Steroids or adrenocorticotropic hormone are other alternative therapeutic options for ESES,9 particularly for refractory cases. However, many patients may relapse on termination of the steroids or adrenocorticotropic hormone or experience severe side effects of long-term hormone therapies. In this study, four patients received steroids before levetiracetam was administered. ESES disappeared in one patient after levetiracetam was given as add-on therapy; however, the patient relapsed 1 month after the steroids was stopped. Levetiracetam can reduce the incidence of seizures and interictal epileptiform complexes in patients who have idiopathic generalized and focal epilepsy.28,29 Kramer et al. evaluated the efficacy of several antiepileptic drugs in ESES. Results showed that levetiracetam had a positive response rate of 41%. The response rates of clobazam, steroids, diazepam, and sulthiame are 31%, 65%, and 37%, respectively. Meanwhile, valproate, lamotrigine, and topiramate did not show any efficacy.30 A prospective open-labeled study suggested that CSWS patients with two of three responders, 50% seizure free, and no aggravation are targets of levetiracetam.22 A recent placebo-controlled, doubleblind crossover study has demonstrated that levetiracetam can efficiently reduce the SWI of patients with ESES. The study revealed that 50% of the patients have >50% reduction in SWI.31 In the present study, 33 of 52 patients who had clinical manifestations before inclusion exhibited positive clinical response to levetiracetam, with a clinical response rate of 63.5%. Furthermore, 41 (56.2%) of the 73 patients with an EEG pattern of ESES had an EEG-positive response to levetiracetam. Hence, the results of the present study are consistent with those of previous reports. Interestingly, levetiracetam was more effective in controlling seizures than in reducing SWI. However, this discovery needs to be confirmed by further studies and statistical analysis. Regarding the efficacy of levetiracetam in patients with ESES of different etiologies, a retrospective study about ESES showed that the outcome depends on etiology. The idiopathic group had an excellent prognosis.32 The
present study show that the clinical (67.7%) and EEG response rates (64.3%) of the idiopathic group were better than those of the symptomatic group (57.1% and 45.2%, respectively) and that the EEG of six patients in the idiopathic group normalized after levetiracetam treatment. However, no significant difference was found through the Mann-Whitney U test. This result may be attributed to the limited number of patients in this study. In addition, during follow-up, 18 patients relapsed, a concern that can be solved using levetiracetam to treat ESES. Moreover, the inclusion of 38 atypical benign childhood epilepsy with centrotemporal spike patients may result in a higher response rate. Despite this deficiency, levetiracetam was revealed to be an efficient therapeutic intervention for ESES. Levetiracetam has an acceptable safety profile and has no significant drugedrug interaction with other antiepileptic drugs because of its unique mechanism of action and favorable pharmacokinetics.16 The most common adverse effects are somnolence, asthenia, dizziness, accidental injury, hostility, nervousness, and nausea.33 This study demonstrated the positive safety profile of levetiracetam; no patient discontinued the trial because of intolerable side effects. The main side effects reported were somnolence (six patients), anorexia (five patients), and nausea (three patients), which usually appear early after initiation of levetiracetam therapy and were generally resolved without medication withdrawal. ESES syndrome is characterized by neuropsychological and motor impairment. Reports have indicated that levetiracetam is not associated with cognitive impairment19 and that it specifically acts to protect against neurobiological changes.34 The trial conducted in this study focused on the clinical and EEG efficacy of levetiracetam in ESES. Further research can evaluate the efficacy of levetiracetam in improving behavior and cognition. Overall, this retrospective study suggests that levetiracetam has good efficacy in ESES. With its safety profile, little interaction with other antiepileptic drugs, and neuroprotective ability, levetiracetam is considered a good choice for patients with ESES. More randomized controlled trials should be encouraged to
TABLE 3D. EEG efficacy of levetiracetam in monotherapy and add-on therapy groups (n, %)
Monotherapy Add-on therapy Total
Reduction of SWI 50%
Reduction of SWI <50%
No Change or Increase
Total
Response Rate (%)
6 (28.6%) 9 (17.3%) 15 (20.6%)
7 (33.3%) 19 (36.5%) 26 (35.6%)
8 (38.1%) 24 (46.2%) 32 (43.8%)
21 52 73
61.9 53.9 56.2
Abbreviations: EEG ¼ Electroencephalograph SWI ¼ Spike wave index
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explore the efficacy and usage of levetiracetam in patients with ESES. The authors thank all physicians, children, and families of the children who provided clinical information. This study was funded by the National Natural Science Foundation of China (grant nos. 30801249, 30770747, and 81071055), the Natural Science Foundation of Beijing (grant nos. 7042024 and 7081002), the National Basic Research Program of China (973) (no. 2012CB517903), and the Peking-Tsinghua Center for Life Sciences and Center of Epilepsy, Beijing Institute for Brain Disorders (BIBD-PXM2013_014226_07_000084).
References 1. Patry G, Lyagoubi S, Tassinari CA. Subclinical “electrical status epilepticus” induced by sleep in children. A clinical and electroencephalographic study of six cases. Arch Neurol. 1971;24:242-252. 2. Tassinari CA, Rubboli G, Volpi L, et al. Encephalopathy with electrical status epilepticus during slow sleep or ESES syndrome including acquired aphasia. Clin Neurophysiol. 2000;111(Suppl 2): S94-S102. 3. Engel J. A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE Task Force on Classification and Terminology. Epilepsia. 2001;42:796-803. 4. Scheltens-de Boer M. Guidelines for EEG in encephalopathy related to ESES/CSWS in children. Epilepsia. 2009;50(Suppl 7):13-17. 5. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia. 1989;30:389-399. 6. Brazzo D, Pera MC, Fasce M, Papalia G, Balottin U, Veggiotti P. Epileptic encephalopathies with status epilepticus during sleep: new techniques for understanding pathophysiology and therapeutic options. Epilepsy Res Treat. 2012;2012:642725. 7. Scholtes FB, Hendriks MP, Renier WO. Cognitive deterioration and electrical status epilepticus during slow sleep. Epilepsy Behav. 2005; 6:167-173. 8. Santos LH, Antoniuk SA, Rodrigues M, Bruno S, Bruck I. LandauKleffner syndrome: study of four cases. Arq Neuropsiquiatr. 2002;60: 239-241. 9. Inutsuka M, Kobayashi K, Oka M, Hattori J, Ohtsuka Y. Treatment of epilepsy with electrical status epilepticus during slow sleep and its related disorders. Brain Dev. 2006;28:281-286. 10. Arts WF, Aarsen FK, Scheltens-de Boer M, Catsman-Berrevoets CE. Landau-Kleffner syndrome and CSWS syndrome: treatment with intravenous immunoglobulins. Epilepsia. 2009;50(Suppl 7):55-58. 11. Nikanorova M, Miranda MJ, Atkins M, Sahlholdt L. Ketogenic diet in the treatment of refractory continuous spikes and waves during slow sleep. Epilepsia. 2009;50:1127-1131. 12. Peltola ME, Liukkonen E, Granström ML, et al. The effect of surgery in encephalopathy with electrical status epilepticus during sleep. Epilepsia. 2011;52:602-609. 13. Kawakami Y, Matsumoto Y, Hashimoto K, et al. Treatment with flunitrazepam of continuous spikes and waves during slow wave sleep (CSWS) in children. Seizure. 2007;16:190-192. 14. Fejerman N, Caraballo R, Cersósimo R, Ferraro SM, Galicchio S, Amartino H. Sulthiame add-on therapy in children with focal epilepsies associated with encephalopathy related to electrical status epilepticus during slow sleep (ESES). Epilepsia. 2012;53: 1156-1161. 15. Briggs DE, French JA. Levetiracetam safety profiles and tolerability in epilepsy patients. Expert Opin Drug Saf. 2004;3:415-424.
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16. Sirsi D, Safdieh JE. The safety of levetiracetam. Expert Opin Drug Saf. 2007;6:241-250. 17. Glauser TA, Ayala R, Elterman RD, et al. Double-blind placebocontrolled trial of adjunctive levetiracetam in pediatric partial seizures. Neurology. 2006;66:1654-1660. 18. Piña-Garza JE, Nordli Jr DR, Rating D, Yang H, Schiemann-Delgado J, Duncan B. Adjunctive levetiracetam in infants and young children with refractory partial-onset seizures. Epilepsia. 2009;50: 1141-1149. 19. Lyseng-Williamson KA. Spotlight on levetiracetam in epilepsy. CNS Drugs. 2011;25:901-905. 20. Hoppen T, Sandrieser T, Rister M. Successful treatment of pharmacoresistant continuous spike wave activity during slow sleep with levetiracetam. Eur J Pediatr. 2003;162:59-61. 21. Capovilla G, Beccaria F, Cagdas S, Montagnini A, Segala R, Paganelli D. Efficacy of levetiracetam in pharmacoresistant continuous spikes and waves during slow sleep. Acta Neurol Scand. 2004; 110:144-147. 22. Chhun S, Troude P, Villeneuve N, et al. A prospective open-labeled trial with levetiracetam in pediatric epilepsy syndromes: continuous spikes and waves during sleep is definitely a target. Seizure. 2011;20:320-325. 23. Marescaux C, Hirsch E, Finck S, et al. Landau-Kleffner syndrome. A pharmacologic study of five cases. Epilepsia. 1990;31:768-777. 24. Liukkonen E, Kantola-Sorsa E, Paetau R, Gaily E, Peltola M, Granström ML. Long-term outcome of 32 children with encephalopathy with status epilepticus during sleep, or ESES syndrome. Epilepsia. 2010;51:2023-2032. 25. Veggiotti P, Beccaria F, Guerrini R, Capovilla G, Lanzi G. Continuous spike-and-wave activity during slow-wave sleep: syndrome or EEG pattern? Epilepsia. 1999;40:1593-1601. 26. Grosso S, Balestri M, Di Bartolo RM, et al. Oxcarbazepine and atypical evolution of benign idiopathic focal epilepsy of childhood. Eur J Neurol. 2006;13:1142-1145. 27. Glauser TA. Topiramate in the catastrophic epilepsies of childhood. J Child Neurol. 2000;15(Suppl 1):S14-S21. 28. Gallagher MJ, Eisenman LN, Brown KM, et al. Levetiracetam reduces spike-wave density and duration during continuous EEG monitoring in patients with idiopathic generalized epilepsy. Epilepsia. 2004;45:90-91. 29. Stodieck S, Steinhoff BJ, Kolmsee S, van Rijckevorsel K. Effect of levetiracetam in patients with epilepsy and interictal epileptiform discharges. Seizure. 2001;10:583-587. 30. Kramer U, Sagi L, Goldberg-Stern H, Zelnik N, Nissenkorn A, BenZeev B. Clinical spectrum and medical treatment of children with electrical status epilepticus in sleep (ESES). Epilepsia. 2009;50: 1517-1524. 31. Larsson GP, Bakke KA, Bjørnæs H, et al. The effect of levetiracetam on focal nocturnal epileptiform activity during sleep d a placebocontrolled double-blind cross-over study. Epilepsy Behav. 2012;24: 44-48. 32. Caraballo RH, Veggiotti P, Kaltenmeier MC, et al. Encephalopathy with status epilepticus during sleep or continuous spikes and waves during slow sleep syndrome: a multicenter, long-term follow-up study of 117 patients. Epilepsy Res. 2013;105:164-173. 33. Betts T, Waegemans T, Crawford P. A multicentre, double-blind, randomized, parallel group study to evaluate the tolerability and efficacy of two oral doses of levetiracetam, 2000 mg daily and 4000 mg daily, without titration in patients with refractory epilepsy. Seizure. 2000;9:80-87. 34. Klitgaard H, Pitkänen A. Antiepileptogenesis, neuroprotection, and disease modification in the treatment of epilepsy: focus on levetiracetam. Epileptic Disord. 2003;5(Suppl 1):S9-S16.
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Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Original Article
Efficacy of Levetiracetam in Electrical Status Epilepticus During Sleep of Children: A Multicenter Experience Xiao-Qiao Chen MD a, Wei-Na Zhang MD a, Zhi-Xian Yang PhD b, Meng Zhao MD PhD a, Fang-Cheng Cai MD c, Shao-Ping Huang MD d, Li Gao MD e, Bao-Dong Pang MD f, Xi Chen MD g, Li-Ping Zou MD PhD a, * a
Department of Pediatrics, Chinese PLA General Hospital, Beijing, China Department of Pediatrics, Peking University First Hospital, Beijing, China c Department of Neurology, Children’s Hospital of Chongqing Medical University, Chongqing, China d Department of Pediatrics, the Second Affiliated Hospital of Medical College, Xi’an Jiao Tong University, Xi’an, China e Department of Pediatrics, Henan provincial People’s Hospital, Zhengzhou, China f Department of Pediatrics, Tangshan Maternal and Health Care Hospital, Tangshan, China g Department of Neurology, Urumqi Children’s Hospital, Urumqi, China b
abstract BACKGROUND: Electrical status epilepticus during sleep is characterized by epilepsy, a specific electroencephalographic pattern, and neuropsychological impairment. This study aims to evaluate the efficacy and safety of levetiracetam in treating children with electrical status epilepticus during sleep. METHODS: A multicenter, retrospective, open-label study enrolled 73 children (mean age: 8 years) affected by electrical status epilepticus during sleep. The efficacy was rated according to the seizure frequency and electroencephalography response. RESULTS: After a mean treatment period of 19 months (range: 6 to 24 months), 33 (63.5%) of 52 patients became seizure-free or had experienced remarkable reduction in seizures. The electrical status epilepticus of 41 (56.2%) of 73 patients disappeared off their electroencephalography. The electroencephalography efficacy of levetiracetam treatment was noted in the monotherapy (61.9%) and add-on (53.9%) groups. The clinical (67.7%) and electroencephalography (64.3%) response rates of the idiopathic group were better than those of the symptomatic group (57.1% and 45.2%, respectively). No patient discontinued the trial because of intolerability of side effects. CONCLUSIONS: Levetiracetam is effective in individuals with electrical status epilepticus during sleep with tolerable side effects. Keywords: electrical status epilepticus during sleep, levetiracetam, children, idiopathic, symptomatic, treatment
Pediatr Neurol 2014; 50: 243-249 Ó 2014 Elsevier Inc. All rights reserved.
Introduction
Electrical status epilepticus during sleep (ESES) is an electroencephalography (EEG) phenomenon that was first described by Patry in 1971.1 Tassinari et al. subsequently reported similar patients and introduced the term ESES. In these patients, the term “continuous spikes and waves
X.-Q.C., W.-N.Z., and Z.-X.Y. contributed equally to this work.
Article History: Received August 2, 2013; Accepted in final form October 28, 2013 * Communications should be addressed to: Dr. Zou; Department of Pediatrics; Chinese PLA General Hospital; 100853 Beijing, China. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2013.10.015
during slow sleep” (CSWS) was considered synonymous to ESES.2 The International League Against Epilepsy suggested that epileptic encephalopathy with status epilepticus during sleep is an age-related and self-limited disorder. It is characterized by epilepsy with different seizure types, neuropsychological impairment, and a specific electroencephalographic pattern of continuous spikes and waves during nonrapid eye movement sleep.3 The characteristic EEG pattern consists of continuous and diffused spike waves mainly at 1.5 Hz to 2.5 Hz during slow sleep.2 Spikeewave index (SWI) has a central function in the diagnostic criteria of ESES/CSWS. However, various criteria have been used, including an SWI of at least 90%, 85%, 60%, 50%, and 25%.4 The International League Against Epilepsy did not
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provide an exact cutoff value and merely reported a strong activation of epileptiform activity during sleep.5 Clinical variants associated with an EEG pattern of ESES/CSWS are encephalopathy with CSWS/ESES, Landau-Kleffner syndrome, and atypical benign childhood epilepsy with centrotemporal spikes.6 The clinical manifestations and epileptiform discharges of ESES, as an age-related and self-limited disorder, will improve or even disappear with advancement in age. However, epileptic disturbances during the maturation of the cortical network may result in permanent impairment of the network. A study on the cognitive impairment of patients with ESES has demonstrated that good cognitive recovery after disappearance of ESES occurs in only one of 10 children, and partial recovery in four.7 Urgent treatment is needed to prevent neuropsychological and motor impairment. Currently, a systematic therapeutic strategy for ESES and its related syndromes has not been established. Available treatment options primarily include antiepileptic drugs, corticosteroids,8 adrenocorticotropic hormone,9 intravenous immunoglobulins,10 ketogenic diet,11 and surgeries.12 For antiepileptic drugs, benzodiazepines,13 valproate combined with ethosuximide,9 and levetiracetam have all been used to treat ESES. Sulthiame was also reported to be effective for ESES.14 Levetiracetam is a second-generation antiepileptic drug that is considered beneficial in the treatment of childhood epilepsy because of its favorable tolerability, little interaction with other antiepileptic drugs, and neuroprotective ability.15,16 After its approval for use in partial-onset seizures in adults and children aged 4 years,17 some studies have shown that adjunctive levetiracetam is efficacious and welltolerated for partial-onset seizures in infants and young children.18 Unlike traditional antiepileptic drugs, levetiracetam has a unique mechanism of action. The binding site of levetiracetam was identified as synaptic vesicle protein 2A, which inhibits calcium release from intraneuronal stores. Thus, it opposes the activity of negative modulators of gamma-aminobutyric acid and glycin-gated currents.19 It lacks cytochrome P450 isoenzymeeinducing potential.19 Approximately 66% of the drug is excreted unchanged in urine.16 Some reports that studied a limited number of patients have suggested that levetiracetam is effective for ESES.20,21 In addition, one study has found that CSWS is a definite target of levetiracetam.22 The current study investigated the efficacy of levetiracetam in improving the clinical manifestations and EEG pattern of 73 children with ESES.
blood count, and biochemical tests. The ESES of the patients who had received other antiepileptic drugs before inclusion in this study was not prevented or controlled. Levetiracetam was then administered to all patients either as monotherapy or add-on therapy. Levetiracetam therapy was started at a dosage of 20 mg/kg per day. The dosage was increased by 10 mg/kg per day increments every week, and the subsequent dosage ranged from 30 to 60 mg/kg per day. During the treatment and evaluation period, the patients were evaluated at 1 and 3 months after levetiracetam administration and then every 3 months thereafter. The follow-up duration for each patient was no less than 6 months. School performance was evaluated according to clinical judgment. All-night video-EEG was performed at least three times at every evaluation visit. The international 10/20 electrode placement system was used. The openeclosed eye test and hyperventilation were involved in every video-EEG test. The patients were divided into idiopathic and symptomatic groups according to etiology. The new International League Against Epilepsy report proposes to replace the terms “idiopathic,” “symptomatic,” and “cryptogenic” with “genetic,” “structuralemetabolic,” and “unknown,” respectively. In this study, the previous terms were maintained. The efficacy of levetiracetam in the monotherapy and add-on therapy groups was also observed in this study. Patients in the monotherapy group were treated using levetiracetam as an independent drug, whereas those in the add-on therapy group were treated by adding levetiracetam to the antiepileptic drugs that the patients previously received. Patients
All patients met the following inclusion criteria: (1) onset of focal seizures or focal EEG discharges; (2) further occurrence of new clinical manifestations, such as atypical absences, atonic, myoclonic, and negative myoclonic seizures; and (3) characterized epileptic activity of ESES according to video-EEG; during nonrapid eye movement, the focal or diffuse spikes and waves became continuous with SWI 50%. The SWI was confirmed by two physicians trained in electrophysiological images. The exclusion criteria were as follows: (1) Lennox-Gastaut syndrome and West syndrome that do not fulfill the criteria for ESES and (2) patients who had previously received levetiracetam. Assessment
Throughout the study, the patients’ parents or legal caregivers kept diaries to record seizure types and frequencies. The efficacy of levetiracetam was measured by seizure frequency and the reduction in SWI that were compared with data gathered during the baseline period. Clinical response to therapy was graded as seizure-free, significant reduction in seizures, and no change or increase in seizures. EEG response to therapy was divided into three categories: 50% reduction in SWI, <50% reduction in SWI, and with no change or increase in SWI. Statistical analysis
Mann-Whitney U test was used to compare the efficacy between the idiopathic and symptomatic groups with a 0.05 two-sided significance level.
Results Materials and Methods Study design
This research was designed as a multicenter, retrospective, openlabel study. Between 2009 and 2013, 73 patients were diagnosed with ESES at seven pediatric centers in China. The trial was conducted in accordance with the international rules of good clinical practice and was by the Ethical Committee of the Chinese PLA General Hospital. Informed consent was obtained from each patient’s parents before the initiation of the trial-related procedures. The first month before the patients’ arrival at the research clinics was considered the baseline period. After being diagnosed with ESES, all patients underwent videoEEG, cerebral magnetic resonance imaging, urine analysis, complete
Demographics and baseline clinical characteristics
The clinical and EEG outcomes of 73 patients with ESES were analyzed in this study. The median follow-up duration was 19 months (range: 6 to 24 months). The 73 patients comprised 45 males and 28 females. All urine analysis, complete blood count, and biochemical test results were normal during the follow-up period. The median age of the patients was 8 years. The age at onset of focal epilepsy was 4 months to 10 years and 3 months, with a median age of 2 years. The age at onset of ESES was 1 year and 1 month to 11 years and 8 months, with a median age
X.-Q. Chen et al. / Pediatric Neurology 50 (2014) 243e249 TABLE 1. Demographics and baseline characteristics of the 73 patients
Number of Patients (n ¼ 73) Gender Male/female (n, %) Median age Age at onset of epilepsy Age at onset of ESES Seizure types before ESES Complex focal seizures (n, %) Myoclonic seizures (n, %) Atypical absences (n, %) Focal seizures with secondary generalization (n, %) Epilepsy syndromes ABECT (n, %) CSWS (n, %) LKS (n, %) Psychomotor impairment (n, %)
45 (61.6)/28 (38.4) 8 yrs. 2 yr (4 mo to 10 yr, 3 mo) 5.5 yr (1 yr, 1 mo to 11 yr, 8 mo) 45 12 9 7
(61.6) (16.4) (12.3) (9.6)
38 19 4 39
(52.1) (26.0) (5.5) (53.4)
Abbreviations: ABECT ¼ Atypical benign childhood epilepsy with centrotemporal spikes CSWS ¼ Continuous spikes and waves during sleep LKS ¼ Landau Kleffner syndrome
of 5.5 years. The median time between the onset of first seizures and onset of ESES was 3.5 years. Before the onset of ESES, 45 patients experienced complex focal seizures, 12 had myoclonic seizures, nine had atypical absences, and seven had focal seizures with secondary generalization. Fifty-five patients experienced seizures during sleep. After the onset of ESES, 59 of the 73 patients exhibited new types of seizures, including negative myoclonus, positive myoclonus, atypical absences, and atonic seizures. Then, 39 (53.4%) of the 73 patients exhibited cognitive delays, of whom 28 exhibited delays on all the three aspects of motor, language, and cognition. Two patients had expressive language disturbances and learning difficulties. Seven patients exhibited intellectual deterioration, whereas one patient showed only motor impairment. Attention deficit hyperactivity disorder was detected in two children. In addition, two children exhibited autistic behavior (Table 1). According to the etiology, 42 patients were classified into the idiopathic group, among whom atypical benign childhood
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epilepsy with centrotemporal spikes was diagnosed in 38 children, and Landau-Kleffner syndrome was diagnosed in four. Conversely, 31 patients were in the symptomatic group. Among the 31 patients, six had cerebral palsy, five had perinatal hypoxia-ischemia encephalopathy, five had hydrocephalus, four had polymicrogyria, two had autism, two had encephalitis, and one had schizencephaly according to magnetic resonance imaging (Fig 1). Six patients were identified as either “cryptogenic” or “unknown.” They were reported to have normal magnetic resonance imaging scans and no definite signs of lesions in neurological examinations; their etiology was undetermined. These six patients were included in the analysis of the symptomatic group results. In addition, 21 patients were in the monotherapy group and 52 patients were in the add-on therapy group (Table 2). Efficacy Clinical and EEG efficacy of levetiracetam in idiopathic and symptomatic groups
During the baseline period, 21 patients had no seizure and only exhibited abnormal EEG discharges. Eleven of these patients were in the idiopathic group and 10 were in the symptomatic group. Of the 52 patients who exhibited clinical manifestations and returned for evaluation visits during months 1 to 24, 11 were seizure free (21.2%) and 22 (42.3%) showed significantly reduced seizures. In addition, 19 patients (36.5%) experienced no change or increase in seizures. The total clinical response rate of the 52 patients was 63.5%. Of the 31 patients in the idiopathic group, seven (22.6%) were seizure free, 14 (45.2%) showed significantly reduced seizures, and 10 (32.6%) showed no change or increase in seizures. Of the 21 patients in the symptomatic group, four (19.1%) were seizure free, eight (38.1%) showed significantly reduced seizures, and nine (42.9%) had no change or increase in seizures. The response rates of the idiopathic and symptomatic groups were 67.7% and 57.1%, respectively (Table 3A, Fig 2A). No significant difference was found in the clinical efficacy of levetiracetam between the idiopathic and symptomatic groups (Z ¼ 0.691, P ¼ 0.489 > 0.05).
FIGURE 1. (A) Sleep electroencephalogram demonstrating continuous spikes and waves during slow sleep. (B) Axial T2-weighted magnetic resonance image showing schizencephaly of the left parietal lobe (arrow) and dysplastic gray matter lining the cleft.
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TABLE 2. Group distribution of the 73 patients
Grouping Method
Group Name
Number of Patients (n)
Etiology
Idiopathic group Symptomatic group Monotherapy group Add-on therapy group
42 31 21 52
Therapy strategy of levetiracetam
For EEG efficacy, of the 73 patients who were evaluated during months 1 through 24, 15 (20.6%) exhibited 50% reduction in SWI, 26 (35.6%) exhibited <50% reduction in SWI, and 32 (43.8%) exhibited no change or increase in SWI. The total EEG response rate was 56.2%. When analyzed separately, 50% reduction in SWI was observed in 10 (23.8%) of the 42 patients in the idiopathic group and in five (16.1%) of the 31 patients in the symptomatic group. The EEG of six patients in the idiopathic group even normalized during months 1 to 6. A <50% reduction in SWI in the EEG was observed in 17 patients (40.9%) in the idiopathic group and in nine (29.0%) in the symptomatic group. No change or increase in SWI was observed in 15 (35.7%) and 17 (54.8%) patients in the idiopathic and symptomatic groups, respectively. The response rates of the idiopathic and symptomatic groups were 64.3% and 45.2%, respectively (Table 3B, Fig 2B). Similarly, no significant difference was found in the EEG efficacy of levetiracetam between the idiopathic and symptomatic groups (Z ¼ 1.527, P ¼ 0.127 > 0.05). Clinical and EEG efficacy of levetiracetam as monotherapy and addon therapy
Fifty-two patients received levetiracetam as add-on therapy. The main concomitant antiepileptic drugs were valproate, oxcarbazepine, topiramate, lamotrigine, carbamazepine, clonazepam, nitrazepam, and corticosteroid (four patients). Twenty-one patients received levetiracetam as monotherapy. During the baseline period, 21 patients had no seizure and only exhibited abnormal EEG discharges. Among the 21 patients, eight were in the monotherapy group and 13 were in the add-on therapy group. Of the 52 patients who exhibited clinical manifestations, five (38.5%) of the 13 monotherapy patients and six (15.4%) of the 39 add-on therapy patients were seizure-free. A significant reduction in seizures was observed in four patients (30.8%) in the monotherapy group and in 18 patients (46.2%) in the add-on therapy group. No change or increase in seizures was observed in four patients (30.8%) in the monotherapy group and in 15 patients (38.5%) in the add-on therapy group. The response rates of the monotherapy and add-on
therapy groups were 69.2% and 61.5%, respectively (Table 3C, Fig 2C). For the respective EEG efficacies of levetiracetam in the monotherapy and the add-on therapy groups, 50% reduction in SWI was observed in six (28.6%) of the 21 patients in the monotherapy group and in nine (17.3%) of the 52 patients in the add-on therapy group. A <50% reduction in SWI on the EEG was found in seven patients (33.3%) in the monotherapy group and in 19 patients (36.5%) in the add-on therapy group. SWI did not change or increase in eight (38.1%) and 24 (46.2%) patients of the monotherapy and add-on therapy groups, respectively. The response rates of the monotherapy and the add-on therapy groups were 61.9% and 53.9%, respectively (Table 3D, Fig 2D). Notably, 18 patients relapsed during follow-up, of which eight relapsed clinically and electroencephalographically, eight relapsed electroencephalographically, and two relapsed clinically only. Among the eight patients who relapsed electroencephalographically, one had no clinical response after levetiracetam was introduced and four had no seizure during the baseline period and follow-up. The two patients who relapsed clinically had no EEG response toward levetiracetam. Discussion
We analyzed the efficacy of levetiracetam in 73 patients with ESES. The follow-up period was 6 months to 2 years. Levetiracetam has good efficacy for clinical manifestations and EEG epileptiform discharges of children with ESES. To date, no ESES treatment protocol has been published. The absence of seizures, normalized EEG discharges, and improvement of neuropsychological impairment are the most important goals to achieve in treating patients with ESES. Previous studies have reported different ESES treatment options. Among the traditional antiepileptic drugs, valproate combined with ethosuximide and benzodiazepines are reportedly effective for ESES.13 However, some reports have suggested that the efficacy of these antiepileptic drugs is transient and partial.23 In a prospective, longterm, follow-up trial, a combination of valproate and ethosuximide was reported to be effective in the treatment of ESES.24 Several studies have demonstrated that antiepileptic drugs such as carbamazepine and phenobarbital may even induce or worsen ESES.25 Oxcarbazepine was reported to have caused electroclinical deterioration in three patients with benign childhood epilepsy with centrotemporal spikes, among whom two patients manifested atypical absences, neuropsychological disturbances, and generalized spikeand-wave discharges in their EEGs that became continuous during sleep.26 In the current study, two patients had ESES
TABLE 3A. Clinical efficacy of levetiracetam in idiopathic and symptomatic groups (n, %)
Idiopathic Symptomatic Total
Seizure-Free
Significant Reduction
No Change or Increase
Total
Response Rate (%)
7 (22.6%) 4 (19.1%) 11 (21.2%)
14 (45.2%) 8 (38.1%) 22 (42.3%)
10 (32.3%) 9 (42.9%) 19 (36.5%)
31 21 52
67.7 57.1 63.5
Twenty-one patients had no seizure during the baseline period, 11 were in the idiopathic group and 10 in the symptomatic group. Mann-Whitney U: Z ¼ 0.691, P ¼ 0.489 > 0.05.
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FIGURE 2. (A) Efficacy of levetiracetam treatment in the idiopathic group (black columns) and symptomatic group (white columns). Numbers of patients without seizures, with significant reduction in seizures, and with no change or with increase in seizures are shown. (B) Efficacy of levetiracetam treatment in the idiopathic (black columns) and symptomatic (white columns) groups. Numbers of patients with 50% reduction in spikeewave index (SWI), with <50% reduction in SWI, and with no change or increase in SWI are shown. (C) Efficacy of levetiracetam treatment given as monotherapy (black columns) and addon therapy (white columns). Numbers of patients without seizures, with significant reduction in seizures and with no change or increase in seizures are shown. (D) Efficacy of levetiracetam treatment given as monotherapy (black columns) and add-on therapy (white columns). Numbers of patients with 50% reduction in SWI, with <50% reduction in SWI, and with no change or with increase in SWI are shown.
after the independent introduction of oxcarbazepine and carbamazepine. Reports indicate that “new” antiepileptic drugs, such as topiramate,27 have some efficacy in the control of ESES. However, most of these reports are anecdotal
and involved a limited number of patients. Most of the patients in the present study had received several antiepileptic drugs, such as valproate, lamotrigine, topiramate, carbamazepine, and oxcarbazepine, before levetiracetam was
TABLE 3B. EEG efficacy of levetiracetam in idiopathic and symptomatic groups (n, %)
Idiopathic Symptomatic Total
Reduction of SWI 50%
Reduction of SWI <50%
No Change or Increase
Total
Response Rate (%)
10 (23.8%) 5 (16.1%) 15 (20.6%)
17 (40.5%) 9 (29.0%) 26 (35.6%)
15 (35.7%) 17 (54.8%) 32 (43.8%)
42 31 73
64.3 45.2 56.2
Mann-Whitney U: Z ¼ 1.527, P ¼ 0.127 > 0.05.
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TABLE 3C. Clinical efficacy of levetiracetam in monotherapy and add-on therapy groups (n, %)
Monotherapy Add-on therapy Total
Seizure-Free
Significant Reduction
No Change or Increase
Total
Response Rate (%)
5 (38.5%) 6 (15.4%) 11 (21.2%)
4 (30.8%) 18 (46.2%) 22 (42.3%)
4 (30.8%) 15 (38.5%) 19 (36.5%)
13 39 52
69.2 61.5 63.5
Twenty-one patients had no seizure during the baseline period: eight were in the monotherapy group and 13 were in the add-on therapy group.
introduced. Despite the transient efficacy in the beginning, these drugs could not prevent the onset of ESES and persistent EEG epileptiform discharges. Steroids or adrenocorticotropic hormone are other alternative therapeutic options for ESES,9 particularly for refractory cases. However, many patients may relapse on termination of the steroids or adrenocorticotropic hormone or experience severe side effects of long-term hormone therapies. In this study, four patients received steroids before levetiracetam was administered. ESES disappeared in one patient after levetiracetam was given as add-on therapy; however, the patient relapsed 1 month after the steroids was stopped. Levetiracetam can reduce the incidence of seizures and interictal epileptiform complexes in patients who have idiopathic generalized and focal epilepsy.28,29 Kramer et al. evaluated the efficacy of several antiepileptic drugs in ESES. Results showed that levetiracetam had a positive response rate of 41%. The response rates of clobazam, steroids, diazepam, and sulthiame are 31%, 65%, and 37%, respectively. Meanwhile, valproate, lamotrigine, and topiramate did not show any efficacy.30 A prospective open-labeled study suggested that CSWS patients with two of three responders, 50% seizure free, and no aggravation are targets of levetiracetam.22 A recent placebo-controlled, doubleblind crossover study has demonstrated that levetiracetam can efficiently reduce the SWI of patients with ESES. The study revealed that 50% of the patients have >50% reduction in SWI.31 In the present study, 33 of 52 patients who had clinical manifestations before inclusion exhibited positive clinical response to levetiracetam, with a clinical response rate of 63.5%. Furthermore, 41 (56.2%) of the 73 patients with an EEG pattern of ESES had an EEG-positive response to levetiracetam. Hence, the results of the present study are consistent with those of previous reports. Interestingly, levetiracetam was more effective in controlling seizures than in reducing SWI. However, this discovery needs to be confirmed by further studies and statistical analysis. Regarding the efficacy of levetiracetam in patients with ESES of different etiologies, a retrospective study about ESES showed that the outcome depends on etiology. The idiopathic group had an excellent prognosis.32 The
present study show that the clinical (67.7%) and EEG response rates (64.3%) of the idiopathic group were better than those of the symptomatic group (57.1% and 45.2%, respectively) and that the EEG of six patients in the idiopathic group normalized after levetiracetam treatment. However, no significant difference was found through the Mann-Whitney U test. This result may be attributed to the limited number of patients in this study. In addition, during follow-up, 18 patients relapsed, a concern that can be solved using levetiracetam to treat ESES. Moreover, the inclusion of 38 atypical benign childhood epilepsy with centrotemporal spike patients may result in a higher response rate. Despite this deficiency, levetiracetam was revealed to be an efficient therapeutic intervention for ESES. Levetiracetam has an acceptable safety profile and has no significant drugedrug interaction with other antiepileptic drugs because of its unique mechanism of action and favorable pharmacokinetics.16 The most common adverse effects are somnolence, asthenia, dizziness, accidental injury, hostility, nervousness, and nausea.33 This study demonstrated the positive safety profile of levetiracetam; no patient discontinued the trial because of intolerable side effects. The main side effects reported were somnolence (six patients), anorexia (five patients), and nausea (three patients), which usually appear early after initiation of levetiracetam therapy and were generally resolved without medication withdrawal. ESES syndrome is characterized by neuropsychological and motor impairment. Reports have indicated that levetiracetam is not associated with cognitive impairment19 and that it specifically acts to protect against neurobiological changes.34 The trial conducted in this study focused on the clinical and EEG efficacy of levetiracetam in ESES. Further research can evaluate the efficacy of levetiracetam in improving behavior and cognition. Overall, this retrospective study suggests that levetiracetam has good efficacy in ESES. With its safety profile, little interaction with other antiepileptic drugs, and neuroprotective ability, levetiracetam is considered a good choice for patients with ESES. More randomized controlled trials should be encouraged to
TABLE 3D. EEG efficacy of levetiracetam in monotherapy and add-on therapy groups (n, %)
Monotherapy Add-on therapy Total
Reduction of SWI 50%
Reduction of SWI <50%
No Change or Increase
Total
Response Rate (%)
6 (28.6%) 9 (17.3%) 15 (20.6%)
7 (33.3%) 19 (36.5%) 26 (35.6%)
8 (38.1%) 24 (46.2%) 32 (43.8%)
21 52 73
61.9 53.9 56.2
Abbreviations: EEG ¼ Electroencephalograph SWI ¼ Spike wave index
X.-Q. Chen et al. / Pediatric Neurology 50 (2014) 243e249
explore the efficacy and usage of levetiracetam in patients with ESES. The authors thank all physicians, children, and families of the children who provided clinical information. This study was funded by the National Natural Science Foundation of China (grant nos. 30801249, 30770747, and 81071055), the Natural Science Foundation of Beijing (grant nos. 7042024 and 7081002), the National Basic Research Program of China (973) (no. 2012CB517903), and the Peking-Tsinghua Center for Life Sciences and Center of Epilepsy, Beijing Institute for Brain Disorders (BIBD-PXM2013_014226_07_000084).
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