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Change of centrotemporal spikes from onset to remission in self-limited epilepsy with centrotemporal spikes (SLECTS)
Brain & Development xxx (2019) xxx–xxx www.elsevier.com/locate/braindev
Original article
Change of centrotemporal spikes from onset to remission in self-limited epilepsy with centrotemporal spikes (SLECTS) Ji Yeon Han a, Sun Ah Choi b,c, Yoon Gi Chung d, Young Kyu Shim a,e, Woo Joong Kim a,e, Soo Yeon Kim a,e, Hunmin Kim b,⇑, Byung Chan Lim a,e, Hee Hwang b, Jong-Hee Chae a,e, Jieun Choi f, Ki Joong Kim a,e a Department of Pediatrics, Seoul National University Children’s Hospital, Seoul, South Korea Department of Pediatrics, Seoul National University Bundang Hospital, Gyeonggi-do, South Korea c Department of Pediatrics, Dankook University Hospital, Dankook University College of Medicine, Cheonan, South Korea d Healthcare ICT Research Center, Seoul National University Bundang Hospital, Gyeonggi-do, South Korea e Pediatric Clinical Neuroscience Center, Seoul National University Children’s Hospital, Seoul, South Korea f Department of Pediatrics, SMG-SNU Boramae Hospital, Seoul, South Korea b
Received 17 September 2019; received in revised form 5 November 2019; accepted 19 November 2019
Abstract Objective: To reveal the changes of centrotemporal spikes that occur during the disease course of self-limited epilepsy with centrotemporal spikes (SLECTS). Method: We retrospectively reviewed the serial EEGs of 63 patients with SLECTS from initial diagnosis to remission. There were 32 patients who did not undergo treatment and 31 patients who underwent treatment with oxcarbazepine (OXC). The change of occurrence or abundance, voltage, and location of centrotemporal spikes of serial EEGs were analyzed and compared between the two groups. Clinical seizure evidenced and reported was counted. The time gap between seizure remission and EEG remission was measured in the two groups. Result: Changes of occurrence or abundance of the centrotemporal spikes were either abrupt (sudden disappearance of the frequent spikes on following EEG) or gradual (decline in number over 2 or more serial EEGs). Pattern of spike disappearance was not significantly different between the medication naı¨ve group and OXC treated group. The spike voltage or the location of centrotemporal spikes did not change during the disease course in most cases. Delay between seizure remission and EEG normalization was 3.34 ± 1.75 (mean ± standard deviation, range: 0.77–7.97) years in untreated patients and 3.03 ± 1.41 (0.95–6.61) years in OXCtreated group. Conclusion: Pattern of spike disappearance in SLECTS was either abrupt or gradual. Treatment with OXC had no effect in the disappearance pattern. Precise data regarding the pattern of disappearance and delay between seizure remission and EEG normalization can help to understand the evolution of spike in SLECTS and to predict the timing of normalization of EEG after seizure remission. Ó 2019 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Epilepsy; Spike; Self-limited epilepsy with centrotemporal spikes; Natural course
⇑ Corresponding author at: Department of Pediatrics, Seoul National University Bundang Hospital, 166 Gumi-ro Bundang-gu, Seongnam-si, Gyeonggi-do 13620, South Korea. E-mail address: [email protected] (H. Kim).
https://doi.org/10.1016/j.braindev.2019.11.005 0387-7604/Ó 2019 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Han JY et al. Change of centrotemporal spikes from onset to remission in self-limited epilepsy with centrotemporal spikes (SLECTS). Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.11.005
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J.Y. Han et al. / Brain & Development xxx (2019) xxx–xxx
1. Introduction Benign epilepsy with centrotemporal spikes (BECTS) is the most common epilepsy syndrome among childhood idiopathic focal epilepsy [1]. It is very well known for its self-limiting course and the new term self-limited epilepsy with centrotemporal spike (SLECTS) was coined with the emphasis of this [2]. Extensive studies of the past have revealed its self-limiting and benign natural course that the seizures are well controlled with anti-epileptic drugs (AEDs) and the centrotemporal spikes will eventually disappear before adulthood [3– 6]. It is one of the epilepsy syndromes with typical features that can be grouped as benign childhood seizure susceptibility syndromes. While its benign course has been extensively studied in the past, the etiology of SLECTS is not fully understood. The exact mechanism underlying its agespecificity that it starts in school-aged children and it spontaneously remits before adulthood is not well understood. There are recent studies that analyzed serial EEGs during the disease [7–9] and these studies were focused on predicting further seizure or prognosis of SLECTS. Studies that assessed serial EEGs on children with centrotemporal spikes with seizures only analyzed few patients with SLECTS in their cohort [10]. The purpose of this study is to describe in detail about the change in centrotemporal spikes from serial EEGs of SLECTS patients from onset to remission without treatment. We also assessed the change in patients who underwent treatment and compared the change with those without treatment. We tried to precisely answer the delay between seizure remission and EEG remission, which we already know by observation that seizure remits before spike normalization. 2. Methods 2.1. Patient selection Patients who were diagnosed with SLECTS at Seoul National University Children’s Hospital (SNUCH) and Seoul National University Bundang Hospital (SNUBH) from January 2004 to December 2018 were identified by using clinical data warehouse (CDW) program. Medical records were reviewed retrospectively to confirm the diagnosis. Patients who met the diagnostic criteria of SLECTS according to International League Against Epilepsy (ILAE) criteria were included [11]. Only the patients who showed the typical benign course of seizure and EEG outcome were included to select the patients that showed typical benign nature and selflimited natural course that has been recently proposed [2]. To select the cohort of patients with typical SLECTS with sufficient information including seizures and consecutive EEG data from onset to remission, exclusion
criteria were as follow: patients with atypical progression [12], patient who were still on treatment, patients who were diagnosed and treated before visiting study institutions, insufficient EEG data, and loss to followup. To investigate the effect of an AED on serial EEG changes and other features of interest, we identified 31 patients that received oxcarbazepine (OXC) for treatment. The final decision to treat was made after discussion with parents or caregivers at the clinic as needed. We suggested treatment for SLECTS if they have very frequent seizures, seizures during waking, or prolonged seizures. 2.2. Data collection Demographic and clinical characteristics of the patients including sex, age at the first, subsequent, and last seizure, follow-up duration, and usage of an AED were collected. Seizures recognized by parents or caregivers and reported at the outpatient visit were analyzed. Routine EEGs were recorded with a 32-channel digital EEG system (Grass Telefactor Inc.) using international 10–20 system electrode placement. Both sleep and waking EEGs were recorded. Sleep EEG was achieved without sedation if possible, and chloral hydrate was used as a sedative medication if needed (50 mg/kg, maximum 1000 mg). Detailed EEG reports were reviewed for the evaluation of epileptiform abnormalities by epileptologists. Serial EEGs from initial diagnosis to remission were obtained, and variable parameters of centrotemporal spikes; (i) occurrence or abundance (ii) voltage, and (iii) location were analyzed longitudinally. Serial EEGs were obtained from the beginning of SLECTS until EEG normalization was confirmed in at least two consecutive EEG exams. EEG evaluations were repeated as needed regarding the seizure control within a regular yearly follow-up. Centrotemporal spikes were visually quantified on each sleep EEG recordings and occurrence during non-rapid-eye-movement (non-REM) sleep stage 1 and 2 (N1 and N2) was assessed to measure frequency of centrotemporal spikes and expressed as frequent, occasional, a few, or no spikes [13]. The location of the spike peak was determined using the phase reversal of the peaks in bipolar montages. For the electrodes that were at the end of a chain, the electrode with the maximum amplitude from average reference montage was used to identify the peak. Presence of epileptiform foci other than the centrotemporal region and generalized epileptiform discharges were also assessed. Regarding the serial change of occurrence or abundance of centrotemporal spikes, we classified the pattern as abrupt or gradual based on whether the number of spikes declined consecutively toward remission or abruptly disappeared and achieved remission without a serial decrease in the number of spikes. Description of the EEG findings was
Please cite this article in press as: Han JY et al. Change of centrotemporal spikes from onset to remission in self-limited epilepsy with centrotemporal spikes (SLECTS). Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.11.005
J.Y. Han et al. / Brain & Development xxx (2019) xxx–xxx
based on revised terminology guideline [13] and American Clinical Neurophysiology Society (ACNS) guideline [14]. The age of EEG normalization was defined as when the disappearance of the centrotemporal spike was first noted from serial EEG recordings. 2.3. Serial EEG analysis We aimed to reveal the pattern of disappearance of centrotemporal spikes as abrupt disappearance if frequent centrotemporal spikes completely disappeared on the following EEGs or gradual disappearance if the number of spikes decreased for two or more serial EEGs. An additional question that we tried to answer was whether the location or voltage of centrotemporal spikes changes following the course of the disease. We also measured the duration between the patient’s last seizure to spike disappearance to find the delay between seizure remission and EEG normalization. To exclude the effect of treatment and solely reveal the EEG changes along the natural course of SLECTS, a detailed description of EEG change was only performed in untreated patients. The pattern of disappearance of spikes until EEG normalization was compared between OXC-treated group and the group without treatment and the delay of EEG normalization from seizure remission was assessed in both groups. 2.4. Statistical analysis Statistical analysis was performed using IBM SPSS Statistics 25. A normal distribution of variables was evaluated using the Kolmogorov-Smirnov test and Shapiro-Wilk test. Continuous data were presented as the mean ± standard deviation (SD). Student’s t-test and the Chi-square test were used in comparisons between untreated group and OXC-treated group. A P value below 0.05 was defined as statistically significant. 2.5. Ethics committee and informed consent The institutional review board (IRB) of the Seoul National University Hospital and Seoul National Bundang Hospital approved this retrospective review of medical records and relevant EEG data (IRB No. B1902/520-109). The IRB approved the waiver of informed consent, due to the retrospective review of medical records and EEG data. 3. Results 3.1. Patients Two hundred and six patients who visited SNUCH (n = 72) and SNUBH (n = 134) from January 2004 to December 2018 was confirmed with the diagnosis of
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SLECTS. Number of patients and the reason for exclusion were: patients who were still on treatment and before remission (87 patients), lost to follow-up (22 patients), treatment initiated before visiting our institutions (12 patients), treatment with AED other than OXC (13 patients), and atypical progression (9 patients). After the exclusion, there were 32 patients that did not receive treatment (untreated group) and 31 patients that were treated with OXC (OXC-treated group) who had sufficient data from onset to remission. The overall clinical profiles of the two groups are described in Table 1. 3.2. Seizure and centrotemporal spikes during the disease (untreated patients) Detailed seizure history and changes in the occurrence of centrotemporal spikes from onset to remission of untreated patients is shown in Fig. 1 and treatment duration added information of OXC-treated patients is shown in Fig. 2. Interestingly there was one patient whose EEG was normal at the onset and showed centrotemporal spikes on subsequent EEGs. Three patients had an EEG without spikes in between the EEGs with frequent centrotemporal spikes. Most of the seizures occurred with abnormal EEG with centrotemporal spikes, but two patients had seizures while there were no centrotemporal spikes (Fig. 1). 3.3. Changes in centrotemporal spikes in both untreated and treated groups Overall when both medication naı¨ve group and OXCtreated groups were analyzed, 31/63 patients showed an abrupt disappearance on serial EEGs whereas 32/63 patients showed a gradual decline in the number of centrotemporal spikes over more than two serial EEGs (Table 2). The decrease in the voltage of centrotemporal spikes was observed in 13 patients (21%). Location of the centrotemporal spikes changed in 8 patients (13%) and in most of the cases the location of spikes moved to the temporal region (7/8), and there was one patient that the spike location moved to frontal lobe on the course of the disease (Table 2). The pattern of disappearance between the untreated group and OXCtreated group was not significantly different. 3.4. Delay from seizure remission to EEG remission Although the primary purpose of this study was the precise description of EEG changes following the disease course, there were some noticeable differences between the two groups. The number of seizures was higher in patients who underwent treatment, and the number of EEGs performed was also higher. Onset age and sex ratio did not show a significant difference between the two groups (Table 1). Years of spike disap-
Please cite this article in press as: Han JY et al. Change of centrotemporal spikes from onset to remission in self-limited epilepsy with centrotemporal spikes (SLECTS). Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.11.005
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Table 1 Demographics and clinical characteristics of patients without treatment and OXC-treated patients.
Sex (M:F) Age at onset of seizure Follow-up duration (years) Number of seizures Number of serial EEGs Mean interval of EEG (months)
Untreated (n = 32)
OXC-treated (n = 31)
19:13 7.50 ± 1.99 (3.6–11.0) 4.05 ± 1.29 (2.2–7.5) 2.5 ± 2.2 (1–8) 5.5 ± 1.76 (3–9) 9.6
19:12 7.94 ± 5.06 ± 3.74 ± 6.29 ± 11.76
2.06 (4.7–11.4) 1.13 (2.9–7.5) 2.31 (1–14) 1.4 (3–9)
M, male; F, female.
Fig. 1. Diagram showing clinical seizures, serial EEG findings (occurrence or abundance of centrotemporal spikes) along the natural course of the SLECTS patients without treatment. (X: Reported seizures, filled circle indicate result of occurrence and abundance of CT spikes as red filled circle: frequent spikes, purple filled circle: occasional spikes, light purple filled circle: a few spikes, green filled circle: no spikes). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
pearance and seizure remission were evaluated and compared between medication naı¨ve group and OXC-
treated group. The mean delay time between seizure remission and EEG normalization was 3.19 ± 1.58
Please cite this article in press as: Han JY et al. Change of centrotemporal spikes from onset to remission in self-limited epilepsy with centrotemporal spikes (SLECTS). Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.11.005
J.Y. Han et al. / Brain & Development xxx (2019) xxx–xxx
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Fig. 2. Diagram showing clinical seizures, treatment duration, serial EEG findings (occurrence or abundance of centrotemporal spikes) along the natural course of the SLECTS patients who were treated with OXC. (X: Reported seizures, filled circle indicate result of occurrence and abundance of CT spikes as red filled circle: frequent spikes, purple filled circle: occasional spikes, light purple filled circle: a few spikes, green filled circle: no spikes, closed arrow indicate the duration of OXC treatment). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Table 2 Changes in serial EEGs, and EEG features of patients without treatment and OXC-treated patients.
Pattern of change Decrease in occurrence (Abrupt:Gradual) Decrease in voltage Change in location Generalized epileptiform discharges Spike location other than centrotemporal region
Untreated (n = 32)
OXC-treated (n = 31)
13:19 8/32 5/32 (CT ? T) 5/32 3/32
18:13 5/31 3/31 (CT ? T(2), CT ? F(1)) 2/31 2/31
CT, centrotemporal region; F, frontal region; T, temporal region.
Please cite this article in press as: Han JY et al. Change of centrotemporal spikes from onset to remission in self-limited epilepsy with centrotemporal spikes (SLECTS). Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.11.005
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(range 0.77–7.97) years in all patients. It was 3.34 ± 1.75 (0.77–7.97) years in untreated group and 3.03 ± 1.41 (0.95–6.61) years in OXC-treated group. The ratio of abrupt disappearance group per gradual disappearance group did not show a significant difference between the untreated group and OXC-treated group. 3.5. Epileptiform discharges other than centrotemporal spikes Generalized epileptiform discharges (mostly generalized spike-wave discharges) were present in 7 patients (11%). Focal epileptiform discharges other than centrotemporal spike were noted in 5 patients (8%) (Table 2). Occipital focal spike was noted in 4 patients and frontal focal spike was noted in 1 patient. 4. Discussion The pattern of EEG normalization or centrotemporal spike disappearance in SLECTS varied when we performed extensive review from SLECTS patients. Although it seemed gradual pattern of disappearance was more common in medication naı¨ve group, the ratio between gradual and abrupt disappearance did not differ when both groups were compared. Some patients revealed a decrease in the voltage of centrotemporal spikes or change in location of the spikes near remission. However, in most patients, location or voltage of the centrotemporal spikes did not change and their spikes disappeared from frequent to none in serial yearly follow-up EEGs. This information provides the precise clinical feature and EEG changes which occur during the natural course of SLECTS. In spite of the wellknown benign nature of the disease [5,6], the understanding of age-specificity and the etiology of SLECTS is still limited [15]. Most of the studies of serial EEGs focused on predicting subsequent seizure in SLECTS [7,8] rather than understanding the EEG changes that occur during SLECTS. Identifying the precise change that occurs during SLECTS can help understand the etiology and guide with further basic research questions on revealing the mechanism of benign epilepsy susceptibility syndrome. Although SLECTS is well-known for its excellent outcomes, parents or caregivers are worried about unpredictable seizures and they look forward to remission of the disease. As more detailed information regarding what happened during the disease are gathered, we can provide them with helpful information regarding the course of the disease. SLECTS is known to remit by the age of 18 [3,4] and our recent study identified that the mean age of spike normalization was 11.9 years [9]. Our finding that half of the overall patients showed a gradual decline in the number of the centrotemporal spikes during the disease could be of
use in counseling to inform parents or caregivers if serial EEGs of patents show the same finding. Data of certain cases that showed decreased voltage and change in location to the temporal region can also be helpful in interpreting the change in serial EEGs. It is well known that EEG normalized after the seizure remission in SLECTS [3,6]. However, the precise lag between seizure remission and EEG normalization was not available. Recently, one prospective cohort study [16] and two retrospective studies [17,18] assessed duration of seizure and EEG disorder in patients with SLECTS. Those studies showed seizure remission ahead of EEG remission which is consistent with our findings. Datta et al [17] evaluated time lag between seizure remission and EEG normalization in patients with typical SLECTS which were 2.75 years. The time lag was similar in our study and it was 3.19 years. We showed that this lag varied widely ranging from 9 months to 6– 7 years. As pharmacologic treatments were heterogeneous in theses previous studies, this may affect the time of seizure and EEG remission. To our knowledge, this is the first study to explore temporal difference between seizure and EEG remission in untreated SLECTS patients. This is useful information that we can provide when their EEG is still abnormal several years after their last seizure. It has been shown in the previous studies that AED treatment does not have an effect on EEG normalization except clonazepam [19]. This finding adds to the evidence that the AED treatment is to control seizure [20,21] and it is not useful for shortening the delay of spike disappearance in SLECTS. The frequency of generalized epileptiform discharges and focal spikes other than centrotemporal spikes were similar to the previous reports. There were similar studies that reported brief generalized bursts of epileptiform discharges in about 4% to 14.6% of patients with SLECTS [22,23]. Focal spike focus other than the centrotemporal region was detected from occipital, parietal, frontal, and midline focus [24]. In our series, there were mainly occipital and one frontal focus in about 8% of patients and this was concordant with the study that reported 9% from 130 patients [25]. In conclusion, we observed the pattern of centrotemporal spikes disappearance from both medication naı¨ve patients and OXC-treated patients with SLECTS. The pattern varied regarding the decrease in the number of the spikes. Decreased in voltage and change in location was not frequently observed. Precise information regarding the course of SLECTS can be of help in patient care and further research in understanding the basic mechanisms underlying SLECTS. There are limitations to this study from the retrospective design of the research. Patients were not prospectively randomized to either treatment or non-treatment group. Serial EEGs were from clinical practice and their irregular interval and yearly follow-up could not accurately detect
Please cite this article in press as: Han JY et al. Change of centrotemporal spikes from onset to remission in self-limited epilepsy with centrotemporal spikes (SLECTS). Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.11.005
J.Y. Han et al. / Brain & Development xxx (2019) xxx–xxx
the timing of the disappearance. Further research should be done in prospective study design and detail spike analysis using quantitative analysis and source localization.
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Please cite this article in press as: Han JY et al. Change of centrotemporal spikes from onset to remission in self-limited epilepsy with centrotemporal spikes (SLECTS). Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.11.005
Original article
Change of centrotemporal spikes from onset to remission in self-limited epilepsy with centrotemporal spikes (SLECTS) Ji Yeon Han a, Sun Ah Choi b,c, Yoon Gi Chung d, Young Kyu Shim a,e, Woo Joong Kim a,e, Soo Yeon Kim a,e, Hunmin Kim b,⇑, Byung Chan Lim a,e, Hee Hwang b, Jong-Hee Chae a,e, Jieun Choi f, Ki Joong Kim a,e a Department of Pediatrics, Seoul National University Children’s Hospital, Seoul, South Korea Department of Pediatrics, Seoul National University Bundang Hospital, Gyeonggi-do, South Korea c Department of Pediatrics, Dankook University Hospital, Dankook University College of Medicine, Cheonan, South Korea d Healthcare ICT Research Center, Seoul National University Bundang Hospital, Gyeonggi-do, South Korea e Pediatric Clinical Neuroscience Center, Seoul National University Children’s Hospital, Seoul, South Korea f Department of Pediatrics, SMG-SNU Boramae Hospital, Seoul, South Korea b
Received 17 September 2019; received in revised form 5 November 2019; accepted 19 November 2019
Abstract Objective: To reveal the changes of centrotemporal spikes that occur during the disease course of self-limited epilepsy with centrotemporal spikes (SLECTS). Method: We retrospectively reviewed the serial EEGs of 63 patients with SLECTS from initial diagnosis to remission. There were 32 patients who did not undergo treatment and 31 patients who underwent treatment with oxcarbazepine (OXC). The change of occurrence or abundance, voltage, and location of centrotemporal spikes of serial EEGs were analyzed and compared between the two groups. Clinical seizure evidenced and reported was counted. The time gap between seizure remission and EEG remission was measured in the two groups. Result: Changes of occurrence or abundance of the centrotemporal spikes were either abrupt (sudden disappearance of the frequent spikes on following EEG) or gradual (decline in number over 2 or more serial EEGs). Pattern of spike disappearance was not significantly different between the medication naı¨ve group and OXC treated group. The spike voltage or the location of centrotemporal spikes did not change during the disease course in most cases. Delay between seizure remission and EEG normalization was 3.34 ± 1.75 (mean ± standard deviation, range: 0.77–7.97) years in untreated patients and 3.03 ± 1.41 (0.95–6.61) years in OXCtreated group. Conclusion: Pattern of spike disappearance in SLECTS was either abrupt or gradual. Treatment with OXC had no effect in the disappearance pattern. Precise data regarding the pattern of disappearance and delay between seizure remission and EEG normalization can help to understand the evolution of spike in SLECTS and to predict the timing of normalization of EEG after seizure remission. Ó 2019 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Epilepsy; Spike; Self-limited epilepsy with centrotemporal spikes; Natural course
⇑ Corresponding author at: Department of Pediatrics, Seoul National University Bundang Hospital, 166 Gumi-ro Bundang-gu, Seongnam-si, Gyeonggi-do 13620, South Korea. E-mail address: [email protected] (H. Kim).
https://doi.org/10.1016/j.braindev.2019.11.005 0387-7604/Ó 2019 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Han JY et al. Change of centrotemporal spikes from onset to remission in self-limited epilepsy with centrotemporal spikes (SLECTS). Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.11.005
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J.Y. Han et al. / Brain & Development xxx (2019) xxx–xxx
1. Introduction Benign epilepsy with centrotemporal spikes (BECTS) is the most common epilepsy syndrome among childhood idiopathic focal epilepsy [1]. It is very well known for its self-limiting course and the new term self-limited epilepsy with centrotemporal spike (SLECTS) was coined with the emphasis of this [2]. Extensive studies of the past have revealed its self-limiting and benign natural course that the seizures are well controlled with anti-epileptic drugs (AEDs) and the centrotemporal spikes will eventually disappear before adulthood [3– 6]. It is one of the epilepsy syndromes with typical features that can be grouped as benign childhood seizure susceptibility syndromes. While its benign course has been extensively studied in the past, the etiology of SLECTS is not fully understood. The exact mechanism underlying its agespecificity that it starts in school-aged children and it spontaneously remits before adulthood is not well understood. There are recent studies that analyzed serial EEGs during the disease [7–9] and these studies were focused on predicting further seizure or prognosis of SLECTS. Studies that assessed serial EEGs on children with centrotemporal spikes with seizures only analyzed few patients with SLECTS in their cohort [10]. The purpose of this study is to describe in detail about the change in centrotemporal spikes from serial EEGs of SLECTS patients from onset to remission without treatment. We also assessed the change in patients who underwent treatment and compared the change with those without treatment. We tried to precisely answer the delay between seizure remission and EEG remission, which we already know by observation that seizure remits before spike normalization. 2. Methods 2.1. Patient selection Patients who were diagnosed with SLECTS at Seoul National University Children’s Hospital (SNUCH) and Seoul National University Bundang Hospital (SNUBH) from January 2004 to December 2018 were identified by using clinical data warehouse (CDW) program. Medical records were reviewed retrospectively to confirm the diagnosis. Patients who met the diagnostic criteria of SLECTS according to International League Against Epilepsy (ILAE) criteria were included [11]. Only the patients who showed the typical benign course of seizure and EEG outcome were included to select the patients that showed typical benign nature and selflimited natural course that has been recently proposed [2]. To select the cohort of patients with typical SLECTS with sufficient information including seizures and consecutive EEG data from onset to remission, exclusion
criteria were as follow: patients with atypical progression [12], patient who were still on treatment, patients who were diagnosed and treated before visiting study institutions, insufficient EEG data, and loss to followup. To investigate the effect of an AED on serial EEG changes and other features of interest, we identified 31 patients that received oxcarbazepine (OXC) for treatment. The final decision to treat was made after discussion with parents or caregivers at the clinic as needed. We suggested treatment for SLECTS if they have very frequent seizures, seizures during waking, or prolonged seizures. 2.2. Data collection Demographic and clinical characteristics of the patients including sex, age at the first, subsequent, and last seizure, follow-up duration, and usage of an AED were collected. Seizures recognized by parents or caregivers and reported at the outpatient visit were analyzed. Routine EEGs were recorded with a 32-channel digital EEG system (Grass Telefactor Inc.) using international 10–20 system electrode placement. Both sleep and waking EEGs were recorded. Sleep EEG was achieved without sedation if possible, and chloral hydrate was used as a sedative medication if needed (50 mg/kg, maximum 1000 mg). Detailed EEG reports were reviewed for the evaluation of epileptiform abnormalities by epileptologists. Serial EEGs from initial diagnosis to remission were obtained, and variable parameters of centrotemporal spikes; (i) occurrence or abundance (ii) voltage, and (iii) location were analyzed longitudinally. Serial EEGs were obtained from the beginning of SLECTS until EEG normalization was confirmed in at least two consecutive EEG exams. EEG evaluations were repeated as needed regarding the seizure control within a regular yearly follow-up. Centrotemporal spikes were visually quantified on each sleep EEG recordings and occurrence during non-rapid-eye-movement (non-REM) sleep stage 1 and 2 (N1 and N2) was assessed to measure frequency of centrotemporal spikes and expressed as frequent, occasional, a few, or no spikes [13]. The location of the spike peak was determined using the phase reversal of the peaks in bipolar montages. For the electrodes that were at the end of a chain, the electrode with the maximum amplitude from average reference montage was used to identify the peak. Presence of epileptiform foci other than the centrotemporal region and generalized epileptiform discharges were also assessed. Regarding the serial change of occurrence or abundance of centrotemporal spikes, we classified the pattern as abrupt or gradual based on whether the number of spikes declined consecutively toward remission or abruptly disappeared and achieved remission without a serial decrease in the number of spikes. Description of the EEG findings was
Please cite this article in press as: Han JY et al. Change of centrotemporal spikes from onset to remission in self-limited epilepsy with centrotemporal spikes (SLECTS). Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.11.005
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based on revised terminology guideline [13] and American Clinical Neurophysiology Society (ACNS) guideline [14]. The age of EEG normalization was defined as when the disappearance of the centrotemporal spike was first noted from serial EEG recordings. 2.3. Serial EEG analysis We aimed to reveal the pattern of disappearance of centrotemporal spikes as abrupt disappearance if frequent centrotemporal spikes completely disappeared on the following EEGs or gradual disappearance if the number of spikes decreased for two or more serial EEGs. An additional question that we tried to answer was whether the location or voltage of centrotemporal spikes changes following the course of the disease. We also measured the duration between the patient’s last seizure to spike disappearance to find the delay between seizure remission and EEG normalization. To exclude the effect of treatment and solely reveal the EEG changes along the natural course of SLECTS, a detailed description of EEG change was only performed in untreated patients. The pattern of disappearance of spikes until EEG normalization was compared between OXC-treated group and the group without treatment and the delay of EEG normalization from seizure remission was assessed in both groups. 2.4. Statistical analysis Statistical analysis was performed using IBM SPSS Statistics 25. A normal distribution of variables was evaluated using the Kolmogorov-Smirnov test and Shapiro-Wilk test. Continuous data were presented as the mean ± standard deviation (SD). Student’s t-test and the Chi-square test were used in comparisons between untreated group and OXC-treated group. A P value below 0.05 was defined as statistically significant. 2.5. Ethics committee and informed consent The institutional review board (IRB) of the Seoul National University Hospital and Seoul National Bundang Hospital approved this retrospective review of medical records and relevant EEG data (IRB No. B1902/520-109). The IRB approved the waiver of informed consent, due to the retrospective review of medical records and EEG data. 3. Results 3.1. Patients Two hundred and six patients who visited SNUCH (n = 72) and SNUBH (n = 134) from January 2004 to December 2018 was confirmed with the diagnosis of
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SLECTS. Number of patients and the reason for exclusion were: patients who were still on treatment and before remission (87 patients), lost to follow-up (22 patients), treatment initiated before visiting our institutions (12 patients), treatment with AED other than OXC (13 patients), and atypical progression (9 patients). After the exclusion, there were 32 patients that did not receive treatment (untreated group) and 31 patients that were treated with OXC (OXC-treated group) who had sufficient data from onset to remission. The overall clinical profiles of the two groups are described in Table 1. 3.2. Seizure and centrotemporal spikes during the disease (untreated patients) Detailed seizure history and changes in the occurrence of centrotemporal spikes from onset to remission of untreated patients is shown in Fig. 1 and treatment duration added information of OXC-treated patients is shown in Fig. 2. Interestingly there was one patient whose EEG was normal at the onset and showed centrotemporal spikes on subsequent EEGs. Three patients had an EEG without spikes in between the EEGs with frequent centrotemporal spikes. Most of the seizures occurred with abnormal EEG with centrotemporal spikes, but two patients had seizures while there were no centrotemporal spikes (Fig. 1). 3.3. Changes in centrotemporal spikes in both untreated and treated groups Overall when both medication naı¨ve group and OXCtreated groups were analyzed, 31/63 patients showed an abrupt disappearance on serial EEGs whereas 32/63 patients showed a gradual decline in the number of centrotemporal spikes over more than two serial EEGs (Table 2). The decrease in the voltage of centrotemporal spikes was observed in 13 patients (21%). Location of the centrotemporal spikes changed in 8 patients (13%) and in most of the cases the location of spikes moved to the temporal region (7/8), and there was one patient that the spike location moved to frontal lobe on the course of the disease (Table 2). The pattern of disappearance between the untreated group and OXCtreated group was not significantly different. 3.4. Delay from seizure remission to EEG remission Although the primary purpose of this study was the precise description of EEG changes following the disease course, there were some noticeable differences between the two groups. The number of seizures was higher in patients who underwent treatment, and the number of EEGs performed was also higher. Onset age and sex ratio did not show a significant difference between the two groups (Table 1). Years of spike disap-
Please cite this article in press as: Han JY et al. Change of centrotemporal spikes from onset to remission in self-limited epilepsy with centrotemporal spikes (SLECTS). Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.11.005
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Table 1 Demographics and clinical characteristics of patients without treatment and OXC-treated patients.
Sex (M:F) Age at onset of seizure Follow-up duration (years) Number of seizures Number of serial EEGs Mean interval of EEG (months)
Untreated (n = 32)
OXC-treated (n = 31)
19:13 7.50 ± 1.99 (3.6–11.0) 4.05 ± 1.29 (2.2–7.5) 2.5 ± 2.2 (1–8) 5.5 ± 1.76 (3–9) 9.6
19:12 7.94 ± 5.06 ± 3.74 ± 6.29 ± 11.76
2.06 (4.7–11.4) 1.13 (2.9–7.5) 2.31 (1–14) 1.4 (3–9)
M, male; F, female.
Fig. 1. Diagram showing clinical seizures, serial EEG findings (occurrence or abundance of centrotemporal spikes) along the natural course of the SLECTS patients without treatment. (X: Reported seizures, filled circle indicate result of occurrence and abundance of CT spikes as red filled circle: frequent spikes, purple filled circle: occasional spikes, light purple filled circle: a few spikes, green filled circle: no spikes). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
pearance and seizure remission were evaluated and compared between medication naı¨ve group and OXC-
treated group. The mean delay time between seizure remission and EEG normalization was 3.19 ± 1.58
Please cite this article in press as: Han JY et al. Change of centrotemporal spikes from onset to remission in self-limited epilepsy with centrotemporal spikes (SLECTS). Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.11.005
J.Y. Han et al. / Brain & Development xxx (2019) xxx–xxx
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Fig. 2. Diagram showing clinical seizures, treatment duration, serial EEG findings (occurrence or abundance of centrotemporal spikes) along the natural course of the SLECTS patients who were treated with OXC. (X: Reported seizures, filled circle indicate result of occurrence and abundance of CT spikes as red filled circle: frequent spikes, purple filled circle: occasional spikes, light purple filled circle: a few spikes, green filled circle: no spikes, closed arrow indicate the duration of OXC treatment). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Table 2 Changes in serial EEGs, and EEG features of patients without treatment and OXC-treated patients.
Pattern of change Decrease in occurrence (Abrupt:Gradual) Decrease in voltage Change in location Generalized epileptiform discharges Spike location other than centrotemporal region
Untreated (n = 32)
OXC-treated (n = 31)
13:19 8/32 5/32 (CT ? T) 5/32 3/32
18:13 5/31 3/31 (CT ? T(2), CT ? F(1)) 2/31 2/31
CT, centrotemporal region; F, frontal region; T, temporal region.
Please cite this article in press as: Han JY et al. Change of centrotemporal spikes from onset to remission in self-limited epilepsy with centrotemporal spikes (SLECTS). Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.11.005
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(range 0.77–7.97) years in all patients. It was 3.34 ± 1.75 (0.77–7.97) years in untreated group and 3.03 ± 1.41 (0.95–6.61) years in OXC-treated group. The ratio of abrupt disappearance group per gradual disappearance group did not show a significant difference between the untreated group and OXC-treated group. 3.5. Epileptiform discharges other than centrotemporal spikes Generalized epileptiform discharges (mostly generalized spike-wave discharges) were present in 7 patients (11%). Focal epileptiform discharges other than centrotemporal spike were noted in 5 patients (8%) (Table 2). Occipital focal spike was noted in 4 patients and frontal focal spike was noted in 1 patient. 4. Discussion The pattern of EEG normalization or centrotemporal spike disappearance in SLECTS varied when we performed extensive review from SLECTS patients. Although it seemed gradual pattern of disappearance was more common in medication naı¨ve group, the ratio between gradual and abrupt disappearance did not differ when both groups were compared. Some patients revealed a decrease in the voltage of centrotemporal spikes or change in location of the spikes near remission. However, in most patients, location or voltage of the centrotemporal spikes did not change and their spikes disappeared from frequent to none in serial yearly follow-up EEGs. This information provides the precise clinical feature and EEG changes which occur during the natural course of SLECTS. In spite of the wellknown benign nature of the disease [5,6], the understanding of age-specificity and the etiology of SLECTS is still limited [15]. Most of the studies of serial EEGs focused on predicting subsequent seizure in SLECTS [7,8] rather than understanding the EEG changes that occur during SLECTS. Identifying the precise change that occurs during SLECTS can help understand the etiology and guide with further basic research questions on revealing the mechanism of benign epilepsy susceptibility syndrome. Although SLECTS is well-known for its excellent outcomes, parents or caregivers are worried about unpredictable seizures and they look forward to remission of the disease. As more detailed information regarding what happened during the disease are gathered, we can provide them with helpful information regarding the course of the disease. SLECTS is known to remit by the age of 18 [3,4] and our recent study identified that the mean age of spike normalization was 11.9 years [9]. Our finding that half of the overall patients showed a gradual decline in the number of the centrotemporal spikes during the disease could be of
use in counseling to inform parents or caregivers if serial EEGs of patents show the same finding. Data of certain cases that showed decreased voltage and change in location to the temporal region can also be helpful in interpreting the change in serial EEGs. It is well known that EEG normalized after the seizure remission in SLECTS [3,6]. However, the precise lag between seizure remission and EEG normalization was not available. Recently, one prospective cohort study [16] and two retrospective studies [17,18] assessed duration of seizure and EEG disorder in patients with SLECTS. Those studies showed seizure remission ahead of EEG remission which is consistent with our findings. Datta et al [17] evaluated time lag between seizure remission and EEG normalization in patients with typical SLECTS which were 2.75 years. The time lag was similar in our study and it was 3.19 years. We showed that this lag varied widely ranging from 9 months to 6– 7 years. As pharmacologic treatments were heterogeneous in theses previous studies, this may affect the time of seizure and EEG remission. To our knowledge, this is the first study to explore temporal difference between seizure and EEG remission in untreated SLECTS patients. This is useful information that we can provide when their EEG is still abnormal several years after their last seizure. It has been shown in the previous studies that AED treatment does not have an effect on EEG normalization except clonazepam [19]. This finding adds to the evidence that the AED treatment is to control seizure [20,21] and it is not useful for shortening the delay of spike disappearance in SLECTS. The frequency of generalized epileptiform discharges and focal spikes other than centrotemporal spikes were similar to the previous reports. There were similar studies that reported brief generalized bursts of epileptiform discharges in about 4% to 14.6% of patients with SLECTS [22,23]. Focal spike focus other than the centrotemporal region was detected from occipital, parietal, frontal, and midline focus [24]. In our series, there were mainly occipital and one frontal focus in about 8% of patients and this was concordant with the study that reported 9% from 130 patients [25]. In conclusion, we observed the pattern of centrotemporal spikes disappearance from both medication naı¨ve patients and OXC-treated patients with SLECTS. The pattern varied regarding the decrease in the number of the spikes. Decreased in voltage and change in location was not frequently observed. Precise information regarding the course of SLECTS can be of help in patient care and further research in understanding the basic mechanisms underlying SLECTS. There are limitations to this study from the retrospective design of the research. Patients were not prospectively randomized to either treatment or non-treatment group. Serial EEGs were from clinical practice and their irregular interval and yearly follow-up could not accurately detect
Please cite this article in press as: Han JY et al. Change of centrotemporal spikes from onset to remission in self-limited epilepsy with centrotemporal spikes (SLECTS). Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.11.005
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the timing of the disappearance. Further research should be done in prospective study design and detail spike analysis using quantitative analysis and source localization.
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Please cite this article in press as: Han JY et al. Change of centrotemporal spikes from onset to remission in self-limited epilepsy with centrotemporal spikes (SLECTS). Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.11.005