Perampanel reduces seizure frequency in patients with developmental and epileptic encephalopathy for a long term

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Perampanel (PER) is a novel antiseizure medication that non-competitively inhibits the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor and is expected to reduce seizure frequency not only for focal seizures and generalized tonic-clonic seizures (GTCS) but also for other seizure types. This study aimed to clarify the long-term therapeutic efficacy and tolerability of PER in patients with DEEs. We analyzed data regarding patients’ background characteristics, medication retention, trends in seizure frequency, and adverse events obtained from 16 patients with DEEs who had been on PER treatment for 60 months. The retention rates were 56.3% and 43.8% at 12 and 60 months, respectively. At 60 months after PER initiation, the rate of patients with > 50% seizure reduction was 38.5%, 38.5%, 36.4%, 60.0%, 40%, and 66.7% among patients with focal seizures, atypical absence seizures, tonic seizures, GTCS, atonic seizures, and myoclonic seizures, respectively. The frequency of adverse events was 75.0%. PER showed long-term efficacy in various seizure types. PER is a promising treatment option for patients with DEEs. Health sciences/Health care/Therapeutics/Drug therapy Health sciences/Neurology/Neurological disorders/Epilepsy perampanel Lennox-Gastaut syndrome epilepsy with myoclonic atonic seizures long-term efficacy & safety 1. Introduction Developmental and epileptic encephalopathies (DEEs) are a group of disorders characterized by epileptic seizures, electroencephalography (EEG) abnormalities, and developmental delays or regressions; further, they were proposed in the 2017 revision of the International League Against Epilepsy classification [ 1 , 2 ]. DEEs, being highly heterogeneous, can include various syndromes, such as Lennox-Gastaut syndrome (LGS), Dravet syndrome, West syndrome, and epilepsy with myoclonic atonic seizures (EMAtS) [ 2 – 5 ]. Patients with DEEs usually present various seizure types, including focal seizures, atypical absence seizures, tonic seizures, generalized tonic-clonic seizures (GTCS), atonic seizures, and myoclonic seizures [ 5 , 6 ]. Antiseizure medications (ASMs) often have limited efficacy, with some cases requiring multidrug therapy as well as ketogenic diets [ 7 ] or surgical procedures, including vagus nerve stimulation and/or corpus callosotomy [ 8 , 9 ]. Despite the various treatments, the risk of fatal outcomes due to epileptic seizures remains high [ 10 ]. Perampanel (PER) is an ASM with a unique mechanism of action that non-competitively inhibits the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor [ 11 ]. In Japan, PER was approved for marketing in 2016 for epilepsy patients ≥ 12 years of age with focal seizures and/or GTCS. From 2020, it has been used for focal seizures in patients ≥ 4 years of age [ 12 ]. Further, its efficacy and tolerability have been investigated in randomized clinical trials for patients ≥ 12 years of age with epilepsy, refractory focal seizures, or GTCS with 1–3 concomitant ASM at the start of the study [ 13 , 14 ] and numerous real-life clinical studies for patients with refractory epilepsy of various age groups and treatment histories [ 15 – 20 ]. Additionally, long-term outcomes within 3–5 years have been reported regarding patients who were investigated in randomized clinical trials [ 21 – 25 ]. Several reports have evaluated the therapeutic efficacy of PER for DEEs, including LGS [ 5 , 26 – 33 ]. However, the only long-term studies on PER treatment for patients with DEEs have been a 3-year study on patients with LGS [ 34 ], a 5-year follow-up case report on patients with Dravet syndrome [ 35 ], and a 3-year follow-up case report on a patient with GRIN-1 mutation [ 36 ]. The long-term outcomes of PER treatment of other DEEs, including EMAtS, remain unclear. This study aimed to examine the long-term efficacy and tolerability of PER for DEEs over a 60-month period. 2. Results 2 − 1. Characteristics of patients During the study period, twenty-six patients with DEEs were started on PER. Among them, we excluded two patients who were transferred, five patients who received additional ASMs after PER initiation, and three patients who restarted PER after discontinuation within the 60-month study period. Accordingly, we included sixteen patients, among them eleven patients with LGS, two with EMAtS, and one each with Dravet syndrome, SZT2 mutation, and tuberous sclerosis complex (TSC) (Table 1 , Suppl. table 1) Table 1 Characteristics of patients PER, perampanel; MRI, magnetic resonance imaging; DEE, developmental and epileptic encephalopathy; LGS, Lennox-Gastaut syndrome; EMAtS, epilepsy with myoclonic atonic seizures; TSC, Tuberous sclerosis complex; ASM, antiseizure medication; VNS, vagus nerve stimulation; GTCS, generalized tonic-clonic seizure n = 16 (%) Age at PER initiation 18years old 3 (18.8) Sex Male 9 (56.3) Age at seizure onset < 2 years old 9 (56.3) Structural abnormality on brain MRI 7 (43.8) Background disease Post cerebral infarction 2 (12.5) Gene mutation 2 (12.5) Cerebral palsy 1 (6.3) Cortical dysplasia 1 (6.3) Post anti-NMDA receptor encephalitis 1 (6.3) Post-acute encephalopathy 1 (6.3) Unknown 8 (50.0) DEE type LGS 11 (68.8) EMAtS 2 (12.5) Dravet syndrome 1 (6.3) SZT2 mutation 1 (6.3) TSC 1 (6.3) Intellectual ability Borderline to mild intellectual disability 4 (25.0) Moderate to severe intellectual disability 12 (75.0) Severely retarded 5 (31.3) Autism spectrum syndrome 10 (62.5) Number of previous ASMs before PER initiation < 10 drugs 9 (56.3) Post-operation VNS 1 (6.3) Corpus callosotomy 1 (6.3) Number of concomitant ASMs < 4 drugs 3 (18.8) With enzyme-induced ASM 8 (50.0) Seizure type at PER initiation Focal seizure 13 (81.3) Atypical absence seizure 13 (81.3) Tonic seizure 11 (68.8) Primary or secondary GTCS 10 (62.5) Atonic seizure 10 (62.5) Myoclonic seizure 9 (56.3) Titration schedule Every 2 weeks 6 (37.5) Every 4 weeks 9 (56.3) The case of SZT2 mutation was identified at 2 months of age with epilepsy. She had visual contact until onset, but it gradually disappeared, and at the initiation of PER, she was severely retarded and had an intellectual disability. Brain magnetic resonance imaging (MRI) showed a shortened and thickened corpus callosum. Whole exome analysis revealed a compound heterozygous mutation in SZT2 with the paternal allele c.3700_3716del:p.Asn1234Alafs*35 and maternal allele c.5482del:p.Gly1829Valfs*52 [ 37 ]. The case of TSC occurred at 7 months of age with West syndrome, and brain MRI showed subependymal nodules and multiple cortical nodules. Although genetic testing was not performed, the diagnostic criteria of TSC were satisfied [ 38 ]. At the start of PER, the patient had severe retarded and intellectual disability. Angiofibromas are clustered around the nose. There are multiple 1–3 cm angiomyolipomas on both kidneys. The median (range) age at initiation of PER was 9 years 8 months (4 years, 2 months to 35 years, 2 months); the age at onset was 2 years 1 month (0 months to 11 years, 1 month); the duration from DEE onset to PER initiation was 7 years and 8 months (2 years, 2 months to 24 years, 3 months); the number of ASMs used before PER initiation was 8 (5–13); and number of concomitant ASMs at PER initiation was 4 (2–8). The most common concomitant drugs were lamotrigine (n = 12, 75.0%), valproate (n = 11, 68.8%), and clonazepam (n = 10, 62.5%) (Suppl. table 2). 2–2. Retention rate During the 60-month study period, nine patients (56.3%) discontinued PER, including six (37.5%) patients due to inefficiency, one (6.3%) due to inefficiency and adverse events, one (6.3%) due to adverse events, and one (6.3%) due to seizure aggravation. Seven (43.8%) patients discontinued PER within the first 12 months. The retention rate at 60 months was 43.8% (Fig. 1). The patient who discontinued PER due to seizure aggravation was a 13-year-old boy with LGS due to cortical dysplasia, whose focal seizures and tonic seizure frequency increased immediately after PER initiation. Accordingly, PER was stopped 2 weeks after initiation, with the seizure frequency returning to baseline after PER was stopped. There was no relationship between the discontinuation of PER and the background factors of each case; it was due to poor efficacy of PER or adverse events (Suppl. table 3). 2–3. Efficiency At 60 months after PER initiation, the responder group comprised five (38.5%) patients with focal seizures, five (38.5%) with atypical absence seizures, four (36.4%) with tonic seizures, six (60.0%) with GTCS, four (40.0%) with atonic seizures, and eight (66.7%) with myoclonic seizures (Table 2 ). Table 2 Efficiency of perampanel on seizure types 12 months 24 months 36 months 48 months 60 months n (%) n (%) n (%) n (%) n (%) Focal seizure, Discontinued 5 (38.5) 6 (46.2) 6 (46.2) 6 (46.2) 7 (53.9) n = 13 No response 4 (30.8) 1 (7.7) 3 (23.1) 3 (23.1) 1 (7.7) 50% responder 2 (15.4) 4 (30.8) 2 (15.4) 2 (15.4) 3 (23.1) 75% responder 2 (15.4) 2 (15.4) 2 (15.4) 1 (7.7) 1 (7.7) Seizure free 0 (0.0) 0 (0.0) 0 (0.0) 1 (7.7) 1 (7.7) Responder group 4 (30.8) 6 (46.2) 4 (30.8) 4 (30.8) 5 (38.5) Atypical absence seizure, Discontinued 6 (46.2) 6 (46.2) 6 (46.2) 6 (46.2) 6 (46.2) n = 13 No response 2 (15.4) 1 (7.7) 2 (15.4) 2 (15.4) 2 (15.4) 50% responder 2 (15.4) 3 (23.1) 2 (15.4) 2 (15.4) 2 (15.4) 75% responder 3 (23.1) 3 (23.1) 3 (23.1) 0 (0.0) 0 (0.0) Seizure free 0 (0.0) 0 (0.0) 0 (0.0) 3 (23.1) 3 (23.1) Responder group 5 (38.5) 6 (46.2) 5 (38.5) 5 (38.5) 5 (38.5) Tonic seizure, Discontinued 6 (54.5) 6 (54.5) 6 (54.5) 6 (54.5) 6 (54.5) n = 11 No response 2 (18.2) 0 (0.0) 2 (18.2) 2 (18.2) 1 (9.1) 50% responder 2 (18.2) 4 (36.4) 2 (18.2) 2 (18.2) 3 (27.3) 75% responder 1 (9.1) 1 (9.1) 0 (0.0) 1 (9.1) 0 (0.0) Seizure free 0 (0.0) 0 (0.0) 1 (9.1) 0 (0.0) 1 (9.1) Responder group 3 (27.3) 5 (45.5) 3 (27.3) 3 (27.3) 4 (36.4) Primary or secondary GTCS, Discontinued 3 (30.0) 3 (30.0) 3 (30.0) 3 (30.0) 4 (40.0) No response 1 (10.0) 2 (20.0) 1 (10.0) 1 (10.0) 0 (0.0) n = 10 50% responder 2 (20.0) 1 (10.0) 2 (20.0) 2 (20.0) 2 (20.0) 75% responder 2 (20.0) 3 (30.0) 1 (10.0) 1 (10.0) 1 (10.0) Seizure free 2 (20.0) 1 (10.0) 3 (30.0) 3 (30.0) 3 (30.0) Responder group 6 (60.0) 5 (50.0) 6 (60.0) 6 (60.0) 6 (60.0) Atonic seizure, Discontinued 3 (30.0) 3 (30.0) 3 (30.0) 3 (30.0) 3 (30.0) n = 10 No response 0 (0.0) 2 (20.0) 2 (20.0) 3 (30.0) 3 (30.0) 50% responder 3 (30.0) 3 (30.0) 2 (20.0) 1 (10.0) 1 (10.0) 75% responder 2 (20.0) 2 (20.0) 2 (20.0) 1 (10.0) 1 (10.0) Seizure free 2 (20.0) 0 (0.0) 1 (10.0) 2 (20.0) 2 (20.0) Responder group 7 (70.0) 5 (50.0) 5 (50.0) 4 (40.0) 4 (40.0) Myoclonic seizure, Discontinued 2 (22.2) 3 (33.3) 3 (33.3) 3 (33.3) 3 (33.3) n = 9 No response 1 (11.1) 1 (11.1) 0 (0.0) 0 (0.0) 0 (0.0) 50% responder 2 (22.2) 1 (11.1) 2 (22.2) 2 (22.2) 2 (22.2) 75% responder 3 (33.3) 3 (33.3) 2 (22.2) 3 (33.3) 1 (11.1) Seizure free 1 (11.1) 1 (11.1) 2 (22.2) 1 (11.1) 3 (33.3) Responder group 6 (66.7) 5 (55.6) 6 (66.7) 6 (66.7) 6 (66.7) GTCS: generalized tonic-clonic seizure, Responder group: total of 50% responder, 75% responder and seizure free The median (range) PER dose among patients who could continue PER treatment was 6 mg/day (8–3 mg) at 12 months, 7 mg/day (3–8 mg) at 24 months, and 8 mg/day (3–10 mg) at 36, 48, and 60 months. The number of patients in the responder group with any seizure type was seven (43.8%) between 12 and 60 months. In addition, the number of patients in the responder group for all seizure types was four (25.0%) at 12 months, five (31.3%) at 24 months, four (25.0%) at 36 months, and three (18.8%) at 48 and 60 months (Suppl. table 4). Regarding the relationship between the profile of each patient and the proportion of the responder group at 60 months, there was a significantly higher proportion of responders among patients with tonic seizures when the seizure frequency group was higher before PER initiation (Table 3 ). Table 3 Relationship between the profile of each patient and the responder group at 60 months Focal seizure, n = 13 Atypical absence seizure, n = 13 Tonic seizure, n = 11 Primary or secondary GTCS, n = 10 Atonic seizure, n = 10 Myoclonic seizure, n = 9 Responder, n = 5 p-value Responder, n = 5 p-value Responder, n = 4 p-value Responder, n = 6 p-value Responder, n = 4 p-value Responder, n = 6 p-value Sex Male 3 > 0.999 2 0.592 3 0.546 3 0.571 3 > 0.999 4 > 0.999 Age at seizure onset 0.999 2 0.076 1 0.524 2 0.167 Structural abnormality on brain MRI 2 0.592 1 0.266 2 > 0.999 2 > 0.999 1 0.191 2 0.500 DEE type LGS 3 0.511 3 0.511 4 > 0.999 4 0.524 2 0.500 4 > 0.999 EMAtS 2 0.128 2 0.128 0 > 0.999 2 0.467 2 0.500 2 0.500 Dravet syndrome 0 > 0.999 0 0.110 0 > 0.999 0 0.400 0 > 0.999 0 0.333 SZT2 mutation 0 > 0.999 0 > 0.999 0 > 0.999 0 0.400 0 > 0.999 0 > 0.999 TSC 0 > 0.999 0 > 0.999 0 > 0.999 0 0.400 0 > 0.999 0 > 0.999 Intellectual ability Borderline to mild intellectual disability 1 > 0.999 2 > 0.999 0 0.236 2 0.467 1 > 0.999 1 > 0.999 Severely retarded 2 > 0.999 1 > 0.999 2 0.491 1 0.500 0 0.200 2 > 0.999 Autism spectrum disorder 2 0.592 3 > 0.999 2 0.491 4 > 0.999 3 > 0.999 3 > 0.999 Number of concomitant ASMs 0.999 0 0.333 With enzyme-induced ASM 2 0.293 2 > 0.999 1 > 0.999 3 0.571 2 > 0.999 2 > 0.999 Median seizure frequency (/month) 45 0.304 40 0.087 60 0.028* 7 0.235 12 0.665 30 0.692 Titration schedule Every 2 weeks 1 0.266 2 > 0.999 0 0.194 2 > 0.999 1 0.524 1 > 0.999 MRI, magnetic resonance imaging; DEE, developmental and epileptic encephalopathy; LGS, Lennox-Gastaut syndrome; EMAtS, epilepsy with myoclonic atonic seizures; TSC, Tuberous sclerosis complex; ASM, antiseizure medication *: p-value < 0.05 2–4. Safety During the study period, twelve (75.0%) patients experienced adverse events, including six (37.5%) patients with somnolence, five (31.3%) with emotional changes such as irritability or agitation (three with irritability, and two with agitation), two (12.5%) with dizziness, and one (6.3%) with athetosis. One (6.3%) patient experienced a combination of somnolence with emotional changes and dizziness with emotional changes. Except for two patients who discontinued PER due to adverse events (one with athetosis and one with dizziness and emotional changes), the others had mild symptoms. Almost all adverse events occurred gradually within two weeks after PER initiation or dose escalation; moreover, the adverse symptoms improved following adjustment of the PER dose or reduction of concomitant medications. Additionally, no patient complained of adverse reactions at 60 months after PER initiation. Regarding the relationship between adverse events and background characteristics, somnolence and dizziness were significantly more frequent among patients with severe retardation and borderline-to-mild intellectual disability, respectively (Table 4 ). Table 4 Relationship between adverse events and patients’ background characteristics Adverse events Somnolence, n = 6 Emotional change, n = 5 Dizziness, n = 2 Athetosis, n = 1 Total, n = 12 n p-value n p-value n p-value n p-value n p-value Sex Male 4 0.633 2 0.596 0 0.175 1 > 0.999 7 > 0.999 Age at seizure onset 0.999 0 0.438 6 0.585 Structural abnormality on brain MRI 3 > 0.999 1 0.301 2 0.175 1 0.438 6 0.585 DEE type LGS 4 > 0.999 5 0.119 2 > 0.999 1 > 0.999 10 0.063 EMAtS 1 > 0.999 0 > 0.999 0 > 0.999 0 > 0.999 1 0.450 Dravet syndrome 0 > 0.999 0 > 0.999 0 > 0.999 0 > 0.999 0 0.250 SZT2 mutation 0 > 0.999 0 > 0.999 0 > 0.999 0 > 0.999 0 0.250 TSC 1 0.438 0 > 0.999 0 > 0.999 0 > 0.999 1 > 0.999 Intellectual ability Borderline to mild intellectual disability 0 0.234 1 > 0.999 2 0.049* 1 0.25 3 > 0.999 Severely retarded 4 0.036* 1 > 0.999 0 > 0.999 0 > 0.999 4 > 0.999 Autism spectrum disorder 4 > 0.999 3 > 0.999 1 > 0.999 1 > 0.999 8 0.604 Number of concomitant ASMs 0.999 1 0.350 0 > 0.999 1 0.136 With enzyme-induced ASMs 2 0.608 1 0.282 1 > 0.999 1 > 0.999 5 0.569 Titration schedule Every 2 weeks 2 > 0.999 1 0.588 2 0.125 1 0.375 5 > 0.999 MRI, magnetic resonance imaging; DEE, developmental and epileptic encephalopathy; LGS, Lennox-Gastaut syndrome; EMAtS, epilepsy with myoclonic atonic seizures; TSC, Tuberous sclerosis complex; ASM, antiseizure medication *: p-value < 0.05 3. Discussion This study investigates the efficacy and tolerability of PER treatment for DEEs over 60 months. A five-year study of clobazam in patients with LGS reported 82%, 75%, and 85% seizure reduction from baseline at 3, 4, and 5 years, respectively [ 39 ]. High-purity cannabidiol reduced seizure frequency in patients with LGS by 53% from baseline at 145–156 weeks after initiation [ 40 ]. Valproate is recommended as the first-line drug for the treatment of EMAtS [ 41 ]. Recent studies on the treatment of epilepsy in patients with EMAtS have investigated the efficacy of felbamate [ 42 ] and cannabidiol [ 43 ]. However, there have been no reports of outcomes with long-term use of a specific drug. Regarding the treatment of Dravet syndrome with ASMs, 3-year outcomes have been reported for stiripentol (long-term outcomes for patients with > 50% seizure reduction; efficacy rates of 48% and 55% for GTCS and focal seizures, respectively) [ 44 ], fenfluramine (70% of patients remained seizure-free for a mean duration of 6 years and 7 months) [ 45 ], and cannabidiol (43% efficacy rate at 145–156 weeks after initiation) [ 46 ]. In this study, the 3-year efficacy rates of PER were 30.8% for focal seizure, 38.5% for atypical absence seizure, 27.3% for tonic seizure, 60.0% for primary or secondary GTCS, 50.0% for atonic seizure, and 66.7% for myoclonic seizure (Table 2 ). It is difficult to compare PER with other drugs due to differences in the evaluation methods across previous studies [ 39 – 41 , 44 – 47 ]. However, although PER is less effective than clobazam for LGS [ 39 ], it is likely to have similar long-term efficacy as cannabidiol for LGS and Dravet syndrome [ 40 , 41 ]. Although PER, like cannabidiol, does not have very high efficacy because DEEs are comorbid with very refractory epilepsy, it shows good potential to suppress seizures. Cannabidiol has yet to be approved in Japan as of March 2024; further, in Europe, it is only approved for patients with Dravet syndrome, LGS, and TSC [ 49 ]. PER has the advantage that it can be used in all patients with DEEs since it can be used regardless of the epilepsy syndrome (i.e., it is not limited to patients with Dravet syndrome, LGS, or TSC). Regarding PER, the short-term (3–12 months) efficacy rates for refractory epilepsy, including DEEs such as LGS and Dravet syndrome, range from 30–69% [ 26 , 27 , 29 – 33 ], which is consistent with our findings. Additionally, we confirmed that the efficacy rates at 12–24 months after PER initiation were maintained for up to 60 months for all seizure types. Regarding the efficacy against each syndrome, PER was highly effective for every seizure type in patients with EMAtS, without significant differences according to seizure type. To our knowledge, there have been no studies on the use of PER for EMAtS. EMAtS is an age-dependent syndrome in which seizures often disappear within 3 years of onset; however, it shows high drug resistance during the early stages of the onset [ 47 , 48 ]. In our study, one of the patients with EMAtS was 2 years 2 months from onset (the other patient was 6 years 4 months from onset), and the natural history of EMAtS may have affected the efficacy rate. In other words, the possibility cannot be ruled out that the decrease in seizures was not due to the effect of PER treatment but because the patient reached 3 years old during treatment. The responder rate of PER for myoclonic seizures in patients with idiopathic generalized epilepsy and juvenile myoclonic epilepsy is reported to be 85–89% [ 50 ]. Gamma-aminobutyric acid (GABA) receptor dysfunction has been associated with the onset of myoclonic seizures [ 51 ]. AMPA receptors are present in developing GABAergic terminals, and their activation inhibits GABAergic activity [ 52 , 53 ]. Inhibition of the AMPA receptor by PER may activate GABAergic function. Although the relationship between AMPA receptors and myoclonic seizures is unknown, the responder rate for myoclonic seizures in this study was high, especially in EMAtS cases, where myoclonic seizures were suppressed in 2 out of 2 cases (100%). PER is not targeted to a specific seizure type. However, when effective, it is often effective for all seizure types in an “all or nothing” manner [ 35 ], and the high sensitivity for myoclonic seizures may have influenced the high responder rate for EMAtS cases in this study. A variety of genetic mutations can cause DEEs. However, only three of the cases included in this study had genetic analysis, including one LGS case with tetrasomy 15q, one case with SCN1A mutation (Dravet syndrome), and one case with SZT2 mutation. The case with tetrasomy 15q was in the responder group, but the other cases had no efficacy for PER and discontinued it. It is reported that the efficacy of PER is high for cases with SCN1A , GNAO1 , PIGA , SYNGAP1 , CDKL5 , NEU1 , PCDH19 , POLG1 , and POLG2 mutations [ 54 ]. In addition, there are case reports of PER’s effectiveness, including epsilon sarcoglycan gene mutation [ 55 ] and GRIN1 mutation [ 36 ]. Tetrasomy 15q is known as a chromosomal abnormality that can cause LGS [ 56 ], and its epileptogenesis is said to be due to a rearrangement of the α5 and β3 GABA receptor subunit gene [ 57 ]. Although there are no reports of the use of PER for patients with Tetrasomy 15q, PER may be effective in epilepsy, a genetically abnormal disorder that results in the inhibition of GABAergic function [ 54 ]. Regarding Dravet syndrome, effectiveness for PER in cases with SCN1A c.2588 T > C, p.Leu863Ser or c.4547C > A, p.Ser1516* has been reported [ 35 , 58 ]. The mutation site of the SCN1A in the patient with Drave syndrome in this study was c.664C > T, p.Arg222*. PER for patients with SCN1A mutation is highly effective in suppressing epileptic seizures, but in 33–5% of cases, it has been reported to be less effective [ 31 , 54 ]. The reason may lie in the difference in amino acid mutation sites. Regarding EMAtS, genetic mutations such as SLC2A1 , SLC6A1 , CHD2 , SCN1A , and GABRG2 are known to cause it [ 59 ], but the genetic analysis was not performed in our patients with EMAtS. Therefore, we do not know whether the cases with EMAtS in this study were genetically highly effective for PER. If the genetic factors of the effective cases and their relationship to the AMPA receptor are found, the genetic information for each patient could help select PER as the ASM for the patient. On the other hand, in real-world clinical practice, genetic analysis is not performed in all cases of refractory epilepsy, including DEEs. We believe that the purpose and result of this report would not change even if the genetic variants of all the cases included in this study were revealed. The reported incidence of adverse events among patients with DEEs ranged from 22–70%, with 9–18%, 5–50%, 10–22%, and 32% for dizziness, somnolence, emotional changes, and behavioral disturbances, respectively [ 5 , 26 , 27 , 29 – 33 ]. The relationship between adverse events of PER and background characteristics in patients with DEEs remains unclear. Our findings indicated that somnolence and dizziness were significantly more frequent among patients with severe retardation and those with borderline-to-mild intellectual disability, respectively. However, most adverse events were mild, and we do not believe that PER should be excluded as a treatment option for patients with severe retardation or borderline-to-mild intellectual disability. This study has several limitations. First, this study had a small sample size. It was difficult to increase the sample size because this study focused on rare diseases. Due to the small number of cases, it is difficult to draw conclusions regarding the efficacy of PER based on the results of this study alone. Second, we could not perform long-term EEG monitoring or evaluate subclinical seizures. Third, since we could not perform routine monitoring of the blood concentration of PER, we could not evaluate the relationship between the blood concentration and efficacy or safety. Fourth, emotional changes in patients with severe retardation may have been overlooked in the absence of behavioral disorders such as violence. In addition, regarding somnolence, there is an objective indicator that even patients with severe retardation sleep longer; however, dizziness might have been underestimated since it is a subjective symptom. Moreover, in case of severe intellectual disability, the patient may not complain of dizziness, even if it was present. Conversely, the possibility cannot be ruled out that adverse events may have been overlooked due to the intellectual and motor abilities of each case. 4. Methods 4 − 1. Study design and patients This retrospective study included patients who visited the Department of Pediatrics, Tochigi Children’s Medical Center at Jichi Medical University. The inclusion criteria were as follows: (i) developmental delay or regression after onset, (ii) seizures not controlled after treatment with two or more drugs, (iii) multidrug treatment for ≥ 2 years after onset [ 60 ], and (iv) patients who started PER treatment between June 2016 and May 2018. The exclusion criteria were as follows: (i) patients who were transferred to a different hospital during the study period and could not be followed up, (ii) patients who received additional ASMs and/or underwent surgery for epilepsy after PER initiation, and (iii) patients who restarted PER after discontinuation. Patients who discontinued PER were also considered excluded cases if they had episodes that fit (i) or (ii) during the 60-month period after starting PER. The diagnostic criteria for LGS are as follows: (i) various types of seizures, including tonic seizures, atonic seizures, atypical absence seizures, and GTCS, and (ii) > 3 Hz slow spike and waves during awake state and rapid rhythms of 10–20 Hz during the sleep state on EEG [ 26 , 27 ]. The diagnostic criteria for EMAtS are as follows: (1) normal development and cognition before the onset of epilepsy; (2) onset of epilepsy between the ages of 6 months and 6 years (peak: 2–4 years); (3) mandatory presentation of myoclonic-atonic seizures; (4) presence of generalized spike-wave discharges at 2–3 Hz without persistent focal spike discharges [ 59 ]. The diagnostic criteria for Dravet syndrome are as follows: (i) onset of prolonged febrile or afebrile focal seizures or GTCS at ≥ 1 year of age, (ii) onset of myoclonic or atypical absence seizures at ≥ 1 year of age, (iii) status epilepticus induced by fever or bathing, and (iv) cognitive and behavioral disorders after onset [ 61 ]. 4 − 2. Data collection The following data were collected from electronic medical records: age at PER initiation, sex, age at onset, structural abnormalities on brain MRI, background disease, genetic abnormalities, DEE type, severity of intellectual disability, number of ASMs used prior to PER initiation, history of surgical therapy and/or ketone diet, ASMs used concomitantly upon PER initiation, seizure type, and PER titration schedule. The mean seizure frequencies of each seizure type within 3 months before PER initiation were compared with those at 12, 24, 36, 48, and 60 months after PER initiation. Patients with < 50%, 50–74%, 75–99%, and 100% seizure reduction were classified as no response, 50% responders, 75% responders, and seizure-free, respectively. Patients who discontinued PER and had no response were included in the non-responder group; moreover, 50% responders, 75% responders, and seizure-free patients were included in the responder group. 4 − 3. Statistical analysis All statistical analyses were performed using the R software program version 4.3.2 ( https://crane.r-project.org , accessed on 29 Dec 2023) (R Foundation for Statistical Computing, Vienna, Austria). The Fisher’s exact test was used to evaluate background factors related to the retention of PER. These factors included sex, age at onset (< 2 years vs. ≥2 years), structural abnormalities on MRI, DEE type, intellectual ability (borderline-to-mild vs. moderate-to-most severe intellectual disability), number of ASMs used before PER initiation (< 10 vs. ≥10), number of concomitant ASMs at PER initiation (< 4 vs. ≥4), use of enzyme-induced ASMs (carbamazepine, phenytoin, and phenobarbital), and the titration schedule. Similarly, the Fisher’s test was used to evaluate background factors related to the responder group and cases with adverse events regarding sex, age at onset (< 2 years vs. ≥2 years), structural abnormalities on MRI, DEE type, intellectual ability (borderline-to-mild vs. moderate-to-most severe intellectual disability), number of ASMs used before PER initiation (< 10 vs. ≥10), number of concomitant ASMs at PER initiation (< 4 vs. ≥4), use of enzyme-induced ASMs (carbamazepine, phenytoin, and phenobarbital), and the titration schedule. The Mann-Whitney U test was used to evaluate the relationship between age at PER initiation and PER discontinuation. Similarly, the Mann-Whitney U test was used to evaluate the relationship between age at PER initiation and the responder group, age at initiation and the cases with adverse events, and seizure frequency and the responder group. 4–4. Ethics This study was approved by the ethics committee of Jichi Medical University (Jichi Medical University 17–118). This study had been performed according to the Declaration of Helsinki. Upon PER initiation, informed consent was obtained from the patients and their parents. If patients had difficulty expressing their intention due to their intellectual ability or age, we only obtained informed consent from their parents. PER prescriptions for patients aged < 12 years were for off-label use at the time of the study initiation [ 12 ], which was explained to the patients or their parents. Declarations Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Author contribution H.Y. wrote the manuscript; H.O. and T.T. contributed to the conceptualization and design of this study; H.Y., H.O., K.M., K.K., Y.M., T.M., Y.A., K.W., and K.N. collected and analyzed data; H.O., K.M., and T.T. critically reviewed the manuscript and supervised the entire study process. All authors have read and approved the final manuscript. Data availability statement All data generated in this study are provided in the manuscript and Supplementary Information. Funding None. Acknowledgments Ms. Makiko Mieno, Associate Professor in the Department of Medical Informatics at the Center for Information, Jichi Medical University, supervised the statistical analysis. We express our gratitude to all the patients and their parents for their cooperation and participation in this study. We would also like to thank the medical colleagues of the Jichi Medical University Tochigi Children’s Medical Center, who are devoted to the treatment of patients with refractory epilepsy. 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International tuberous sclerosis complex consensus group. tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International tuberous sclerosis complex consensus conference. Pediatr Neurol . 49 , 243–254 (2013). Conry, J. A. et al. Stable dosages of clobazam for Lennox- Gastaut syndrome are associated with sustained drop-seizure and total-seizure improvements over 3 years. Epilepsia 55 , 558–567 (2014). Patel, A. D. et al. Long-term safety and efficacy of add-on cannabidiol in patients with Lennox-Gastaut syndrome: results of a long-term open-label extension trial. Epilepsia 62 , 2228–2239 (2021). Nickels, K. et al. How do we diagnose and treat epilepsy with myoclonic-atonic seizures (Doose syndrome)? Results of the pediatric epilepsy research consortium survey. Epilepsy Res . 144 , 14–19 (2018). Reed, L. al. Efficacy of felbamate in a cohort of patients with epilepsy with myoclonic atonic seizures (EMAtS). Epilepsy Res . 201 , 107314 (2024). Caraballo, R. H. et al. Cannabidiol in children with treatment-resistant epilepsy with myoclonic-atonic seizures. Epilepsy Behav. 143 , 109245 (2023). Myers, K. A., Lightfoot, P., Patil, S. G., Cross J. H. & Scheffer, I. E. Stiripentol efficacy and safety in Dravet syndrome: a 12-year observational study. Dev Med Child Neurol . 60 :574–578 (2018). Ceulemans, B. et al. Successful use of fenfluramine as an add-on treatment for Dravet syndrome. Epilepsia 53 , 1131–1139 (2012). Scheffer, I. E. et al. Add-on cannabidiol in patients with Dravet syndrome: results of a long-term open-label extension trial. Epilepsia 62 , 2505–2517 (2021). Oguni, H. et al. Treatment and long-term prognosis of myoclonic-astatic epilepsy of early childhood. Neuropediatrics 33 , 122–132 (2002). Trivisano, M. et al. Myoclonic astatic epilepsy: an age-dependent epileptic syndrome with favorable seizure outcome but variable cognitive evolution. Epilepsy Res. 97 , 133–141 (2011). Sills, G. J. Pharmacological diversity amongst approved and emerging antiseizure medications for the treatment of developmental and epileptic encephalopathies. Ther Adv Neurol Disord. 16 , 17562864231191000 (2023). D’Souza, W. et al. Perampanel for the treatment of patients with myoclonic seizures in clinical practice: evidence from the PERMIT study. Seizure 100 , 56–66 (2022) Hirose, S. Mutant GABA(A) receptor subunits in genetic (idiopathic) epilepsy. Prog Brain Res. 213 , 55–85 (2014). Satake, S., Saitow, F., Yamada, J. & Konishi, S. Synaptic activation of AMPA receptors inhibits GABA release from cerebellar interneurons. Nat Neurosci. 3 , 551–558 (2000). Fiszman, M. L., Erdélyi, F., Szabó, G. & Vicini, S. Presynaptic AMPA and kainate receptors increase the size of GABAergic terminals and enhance GABA release. Neuropharmacology 52 , 1631–1640 (2007). Nissenkorn A, Kluger G, Schubert-Bast S, Bayat A, Bobylova M, Bonanni P, et al. Perampanel as precision therapy in rare genetic epilepsies. Epilepsia (2023) 64:866-874. Belli, E. et al. Perampanel as a novel treatment for subcortical myoclonus in myoclonus-dystonia syndrome. Neurol Sci. 44, 2943–2945 (2023). Battaglia, A. et al. The inv dup(15) syndrome: a clinically recognizable syndrome with altered behaviour, mental retardation and epilepsy. Neurology 48 , 1081–1086 (1997). Battaglia, A. The inv dup (15) or idic (15) syndrome (Tetrasomy 15q). Orphanet J Rare Dis. 3 , 30 (2008). Ishikawa, N. et al. Successful treatment of intractable life-threatening seizures with perampanel in the first case of early myoclonic encephalopathy with a novel de novo SCN1A mutation. Seizure 71 , 20–23 (2019). Oguni, H. Epilepsy with myoclonic-atonic seizures, also known as Doose syndrome: Modification of the diagnostic criteria. Eur J Paediatr Neurol . 36 , 37–50 (2022). Kwan, P. et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE commission on therapeutic strategies. Epilepsia 51:1069–1077 (2010). Dravet C. Severe myoclonic epilepsy in infants and its related syndromes. Epilepsia 41 , 7 (2000). Additional Declarations No competing interests reported. Supplementary Files SFigure1.tif Supplementary Figure 1. The retention rate of perampanel. The retention rate was 62.5% at 6 months, 56.3% at 12 months, 50.0% at 24–48 months, and 43.8% at 60 months. Supplementarytable1.docx Supplementarytable2.docx Supplementarytable3.docx Supplementarytable4.docx Cite Share Download PDF Status: Published Journal Publication published 03 Dec, 2024 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 13 Nov, 2024 Reviews received at journal 12 Nov, 2024 Reviews received at journal 31 Oct, 2024 Reviews received at journal 21 Oct, 2024 Reviewers agreed at journal 21 Oct, 2024 Reviewers agreed at journal 21 Oct, 2024 Reviewers agreed at journal 21 Oct, 2024 Reviewers invited by journal 21 Oct, 2024 Editor assigned by journal 21 Oct, 2024 Editor invited by journal 18 Oct, 2024 Submission checks completed at journal 18 Oct, 2024 First submitted to journal 18 Oct, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5286706","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":367790302,"identity":"a3cf723c-0822-4917-a98f-8b4b16ed4176","order_by":0,"name":"Hirokazu Yamagishi","email":"","orcid":"","institution":"Jichi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hirokazu","middleName":"","lastName":"Yamagishi","suffix":""},{"id":367790303,"identity":"f78e450f-127e-42d2-b9ed-9eae34a90811","order_by":1,"name":"Hitoshi Osaka","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAz0lEQVRIiWNgGAWjYBACAyBmbGCwYWZj4GE4wADhEaUljXQth4EUD5EOM2dvf/hxRs15dj72swcPMNTYMTDPJmCNZc8ZY8kNx24zs/HkJRxgOJbMwDjnAAGH3chhkHzABtQiwWNwgIHtAAPjjARCWtIf/3zw7xxUyz+itCSYSW5sOwDRwthGjJYzZ8wsZ/YlA/2SY3AgsS+Zh7Bfjrc/vtnzzS5Zvv2M8YcP3+zkDAmFGAwkg0mgk3gMZxCng8EOzpKXIFLLKBgFo2AUjBgAAFm5Q76TA0ADAAAAAElFTkSuQmCC","orcid":"","institution":"Jichi Medical University","correspondingAuthor":true,"prefix":"","firstName":"Hitoshi","middleName":"","lastName":"Osaka","suffix":""},{"id":367790304,"identity":"e9bdfa6f-a571-45f2-9803-1271bdd83170","order_by":2,"name":"Kazuhiro Muramatsu","email":"","orcid":"","institution":"Jichi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Kazuhiro","middleName":"","lastName":"Muramatsu","suffix":""},{"id":367790305,"identity":"ae73c7ea-b523-4cdd-9e0f-2a8187815215","order_by":3,"name":"Karin Kojima","email":"","orcid":"","institution":"Jichi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Karin","middleName":"","lastName":"Kojima","suffix":""},{"id":367790306,"identity":"e6ed020b-e8c4-4b48-b55a-2647cc1ef286","order_by":4,"name":"Yukifumi Monden","email":"","orcid":"","institution":"Jichi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yukifumi","middleName":"","lastName":"Monden","suffix":""},{"id":367790307,"identity":"b697cd52-9d51-496d-8141-68419a0bf9bc","order_by":5,"name":"Tadahiro Mitani","email":"","orcid":"","institution":"Jichi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Tadahiro","middleName":"","lastName":"Mitani","suffix":""},{"id":367790308,"identity":"033c6db4-17a1-470d-a44f-a8f08b8ad139","order_by":6,"name":"Yuta Asakura","email":"","orcid":"","institution":"Jichi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yuta","middleName":"","lastName":"Asakura","suffix":""},{"id":367790309,"identity":"d7746e64-e81c-4006-bca2-1648aa32b792","order_by":7,"name":"Keizo Wakae","email":"","orcid":"","institution":"Jichi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Keizo","middleName":"","lastName":"Wakae","suffix":""},{"id":367790310,"identity":"fdc8c4ed-9c76-43e2-8f56-16aa2c55f37e","order_by":8,"name":"Kohei Nagai","email":"","orcid":"","institution":"Jichi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Kohei","middleName":"","lastName":"Nagai","suffix":""},{"id":367790311,"identity":"e5a780f5-329d-450a-a9a8-cf8c10fe14c5","order_by":9,"name":"Toshihiro Tajima","email":"","orcid":"","institution":"Jichi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Toshihiro","middleName":"","lastName":"Tajima","suffix":""}],"badges":[],"createdAt":"2024-10-18 05:53:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5286706/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5286706/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-024-82014-5","type":"published","date":"2024-12-03T15:57:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":70964594,"identity":"0f76c703-d278-46f3-a4a1-35047e4d8ec3","added_by":"auto","created_at":"2024-12-09 16:10:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1104897,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5286706/v1/636f2151-72a0-441f-b187-c0149653646f.pdf"},{"id":67187453,"identity":"2be417c0-2cd6-4a4f-b749-6b5a36ae20c9","added_by":"auto","created_at":"2024-10-22 07:32:33","extension":"tif","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":602444,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Figure 1. The retention rate of perampanel.\u003c/p\u003e\n\u003cp\u003eThe retention rate was 62.5% at 6 months, 56.3% at 12 months, 50.0% at 24–48 months, and 43.8% at 60 months.\u003c/p\u003e","description":"","filename":"SFigure1.tif","url":"https://assets-eu.researchsquare.com/files/rs-5286706/v1/3605f0be850d5cc430de3b4e.tif"},{"id":67187456,"identity":"f1c8f0cd-53c2-4fd6-9058-21a7f55ae325","added_by":"auto","created_at":"2024-10-22 07:32:34","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":21992,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarytable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-5286706/v1/23aaa3018320b96b3ab69960.docx"},{"id":67187455,"identity":"dfbfb889-d3d8-41a8-9ca8-a5d9e71518f2","added_by":"auto","created_at":"2024-10-22 07:32:33","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":16307,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarytable2.docx","url":"https://assets-eu.researchsquare.com/files/rs-5286706/v1/1af84ce661616dc30e952b9f.docx"},{"id":67187458,"identity":"b446a7e4-7936-4430-be79-c6eb14f5de5b","added_by":"auto","created_at":"2024-10-22 07:32:34","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":19154,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarytable3.docx","url":"https://assets-eu.researchsquare.com/files/rs-5286706/v1/f803d8bd9bfc9edcc53ef708.docx"},{"id":67187454,"identity":"74469a88-25fb-4060-b4bb-e4bf7de156a3","added_by":"auto","created_at":"2024-10-22 07:32:33","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":33601,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarytable4.docx","url":"https://assets-eu.researchsquare.com/files/rs-5286706/v1/6f617752c1df4097835af9f0.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Perampanel reduces seizure frequency in patients with developmental and epileptic encephalopathy for a long term","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eDevelopmental and epileptic encephalopathies (DEEs) are a group of disorders characterized by epileptic seizures, electroencephalography (EEG) abnormalities, and developmental delays or regressions; further, they were proposed in the 2017 revision of the International League Against Epilepsy classification [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDEEs, being highly heterogeneous, can include various syndromes, such as Lennox-Gastaut syndrome (LGS), Dravet syndrome, West syndrome, and epilepsy with myoclonic atonic seizures (EMAtS) [\u003cspan additionalcitationids=\"CR3 CR4\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePatients with DEEs usually present various seizure types, including focal seizures, atypical absence seizures, tonic seizures, generalized tonic-clonic seizures (GTCS), atonic seizures, and myoclonic seizures [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Antiseizure medications (ASMs) often have limited efficacy, with some cases requiring multidrug therapy as well as ketogenic diets [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] or surgical procedures, including vagus nerve stimulation and/or corpus callosotomy [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Despite the various treatments, the risk of fatal outcomes due to epileptic seizures remains high [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePerampanel (PER) is an ASM with a unique mechanism of action that non-competitively inhibits the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In Japan, PER was approved for marketing in 2016 for epilepsy patients\u0026thinsp;\u0026ge;\u0026thinsp;12 years of age with focal seizures and/or GTCS. From 2020, it has been used for focal seizures in patients\u0026thinsp;\u0026ge;\u0026thinsp;4 years of age [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Further, its efficacy and tolerability have been investigated in randomized clinical trials for patients\u0026thinsp;\u0026ge;\u0026thinsp;12 years of age with epilepsy, refractory focal seizures, or GTCS with 1\u0026ndash;3 concomitant ASM at the start of the study [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] and numerous real-life clinical studies for patients with refractory epilepsy of various age groups and treatment histories [\u003cspan additionalcitationids=\"CR16 CR17 CR18 CR19\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Additionally, long-term outcomes within 3\u0026ndash;5 years have been reported regarding patients who were investigated in randomized clinical trials [\u003cspan additionalcitationids=\"CR22 CR23 CR24\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSeveral reports have evaluated the therapeutic efficacy of PER for DEEs, including LGS [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan additionalcitationids=\"CR27 CR28 CR29 CR30 CR31 CR32\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. However, the only long-term studies on PER treatment for patients with DEEs have been a 3-year study on patients with LGS [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], a 5-year follow-up case report on patients with Dravet syndrome [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], and a 3-year follow-up case report on a patient with \u003cem\u003eGRIN-1\u003c/em\u003e mutation [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. The long-term outcomes of PER treatment of other DEEs, including EMAtS, remain unclear.\u003c/p\u003e \u003cp\u003eThis study aimed to examine the long-term efficacy and tolerability of PER for DEEs over a 60-month period.\u003c/p\u003e"},{"header":"2. Results","content":"\n\u003ch3\u003e2 − 1. Characteristics of patients\u003c/h3\u003e\n\u003cp\u003eDuring the study period, twenty-six patients with DEEs were started on PER. Among them, we excluded two patients who were transferred, five patients who received additional ASMs after PER initiation, and three patients who restarted PER after discontinuation within the 60-month study period. Accordingly, we included sixteen patients, among them eleven patients with LGS, two with EMAtS, and one each with Dravet syndrome, SZT2 mutation, and tuberous sclerosis complex (TSC) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, Suppl. table 1)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of patients PER, perampanel; MRI, magnetic resonance imaging; DEE, developmental and epileptic encephalopathy; LGS, Lennox-Gastaut syndrome; EMAtS, epilepsy with myoclonic atonic seizures; TSC, Tuberous sclerosis complex; ASM, antiseizure medication; VNS, vagus nerve stimulation; GTCS, generalized tonic-clonic seizure\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;16\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at PER initiation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;12 years old\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(43.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12\u0026ndash;18 years old\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(37.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;18years old\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(18.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(56.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at seizure onset\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;2 years old\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(56.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eStructural abnormality on brain MRI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(43.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBackground disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePost cerebral infarction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(12.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGene mutation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(12.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCerebral palsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(6.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCortical dysplasia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(6.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePost anti-NMDA receptor encephalitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(6.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePost-acute encephalopathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(6.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(50.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDEE type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLGS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(68.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEMAtS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(12.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDravet syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(6.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSZT2 mutation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(6.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTSC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(6.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntellectual ability\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBorderline to mild intellectual disability\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(25.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eModerate to severe intellectual disability\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(75.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSeverely retarded\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(31.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAutism spectrum syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(62.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of previous ASMs before PER initiation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;10 drugs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(56.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePost-operation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVNS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(6.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCorpus callosotomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(6.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of concomitant ASMs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;4 drugs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(18.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eWith enzyme-induced ASM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(50.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSeizure type at PER initiation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFocal seizure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(81.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAtypical absence seizure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(81.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTonic seizure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(68.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePrimary or secondary GTCS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(62.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAtonic seizure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(62.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMyoclonic seizure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(56.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTitration schedule\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEvery 2 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(37.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEvery 4 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(56.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe case of SZT2 mutation was identified at 2 months of age with epilepsy. She had visual contact until onset, but it gradually disappeared, and at the initiation of PER, she was severely retarded and had an intellectual disability. Brain magnetic resonance imaging (MRI) showed a shortened and thickened corpus callosum. Whole exome analysis revealed a compound heterozygous mutation in \u003cem\u003eSZT2\u003c/em\u003e with the paternal allele c.3700_3716del:p.Asn1234Alafs*35 and maternal allele c.5482del:p.Gly1829Valfs*52 [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. The case of TSC occurred at 7 months of age with West syndrome, and brain MRI showed subependymal nodules and multiple cortical nodules. Although genetic testing was not performed, the diagnostic criteria of TSC were satisfied [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. At the start of PER, the patient had severe retarded and intellectual disability. Angiofibromas are clustered around the nose. There are multiple 1\u0026ndash;3 cm angiomyolipomas on both kidneys.\u003c/p\u003e \u003cp\u003eThe median (range) age at initiation of PER was 9 years 8 months (4 years, 2 months to 35 years, 2 months); the age at onset was 2 years 1 month (0 months to 11 years, 1 month); the duration from DEE onset to PER initiation was 7 years and 8 months (2 years, 2 months to 24 years, 3 months); the number of ASMs used before PER initiation was 8 (5\u0026ndash;13); and number of concomitant ASMs at PER initiation was 4 (2\u0026ndash;8).\u003c/p\u003e \u003cp\u003eThe most common concomitant drugs were lamotrigine (n\u0026thinsp;=\u0026thinsp;12, 75.0%), valproate (n\u0026thinsp;=\u0026thinsp;11, 68.8%), and clonazepam (n\u0026thinsp;=\u0026thinsp;10, 62.5%) (Suppl. table 2).\u003c/p\u003e\n\u003ch3\u003e2–2. Retention rate\u003c/h3\u003e\n\u003cp\u003eDuring the 60-month study period, nine patients (56.3%) discontinued PER, including six (37.5%) patients due to inefficiency, one (6.3%) due to inefficiency and adverse events, one (6.3%) due to adverse events, and one (6.3%) due to seizure aggravation. Seven (43.8%) patients discontinued PER within the first 12 months. The retention rate at 60 months was 43.8% (Fig.\u0026nbsp;1).\u003c/p\u003e \u003cp\u003eThe patient who discontinued PER due to seizure aggravation was a 13-year-old boy with LGS due to cortical dysplasia, whose focal seizures and tonic seizure frequency increased immediately after PER initiation. Accordingly, PER was stopped 2 weeks after initiation, with the seizure frequency returning to baseline after PER was stopped.\u003c/p\u003e \u003cp\u003eThere was no relationship between the discontinuation of PER and the background factors of each case; it was due to poor efficacy of PER or adverse events (Suppl. table 3).\u003c/p\u003e\n\u003ch3\u003e2–3. Efficiency\u003c/h3\u003e\n\u003cp\u003eAt 60 months after PER initiation, the responder group comprised five (38.5%) patients with focal seizures, five (38.5%) with atypical absence seizures, four (36.4%) with tonic seizures, six (60.0%) with GTCS, four (40.0%) with atonic seizures, and eight (66.7%) with myoclonic seizures (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eEfficiency of perampanel on seizure types\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"12\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e12 months\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e24 months\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003e36 months\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003e48 months\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003e60 months\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFocal seizure,\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDiscontinued\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(38.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(46.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(46.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(46.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(53.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(30.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(7.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(23.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(23.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(7.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50% responder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(30.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(23.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e75% responder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(7.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(7.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSeizure free\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(7.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(7.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eResponder group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(30.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(46.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(30.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(30.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(38.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAtypical absence seizure,\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDiscontinued\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(46.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(46.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(46.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(46.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(46.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(7.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(15.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50% responder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(23.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(15.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e75% responder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(23.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(23.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(23.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSeizure free\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(23.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(23.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eResponder group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(38.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(46.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(38.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(38.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(38.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTonic seizure,\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDiscontinued\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(54.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(54.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(54.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(54.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(54.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(18.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(18.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(18.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(9.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50% responder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(18.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(36.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(18.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(18.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(27.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e75% responder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(9.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(9.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(9.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSeizure free\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(9.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(9.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eResponder group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(27.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(45.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(27.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(27.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(36.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePrimary or secondary\u003c/p\u003e \u003cp\u003eGTCS,\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDiscontinued\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(30.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(30.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(30.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(30.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(40.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(10.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(10.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(10.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50% responder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(10.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(20.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e75% responder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(30.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(10.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(10.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(10.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSeizure free\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(10.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(30.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(30.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(30.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eResponder group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(60.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(60.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(60.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(60.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAtonic seizure,\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDiscontinued\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(30.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(30.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(30.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(30.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(30.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(30.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(30.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50% responder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(30.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(30.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(10.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(10.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e75% responder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(10.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(10.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSeizure free\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(10.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(20.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eResponder group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(70.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(40.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(40.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMyoclonic seizure,\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDiscontinued\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(22.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(33.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(11.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(11.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50% responder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(22.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(11.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(22.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(22.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(22.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e75% responder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(22.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(11.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSeizure free\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(11.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(11.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(22.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(11.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(33.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eResponder group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(55.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(66.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003eGTCS: generalized tonic-clonic seizure, Responder group: total of 50% responder, 75% responder and seizure free\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe median (range) PER dose among patients who could continue PER treatment was 6 mg/day (8\u0026ndash;3 mg) at 12 months, 7 mg/day (3\u0026ndash;8 mg) at 24 months, and 8 mg/day (3\u0026ndash;10 mg) at 36, 48, and 60 months. The number of patients in the responder group with any seizure type was seven (43.8%) between 12 and 60 months. In addition, the number of patients in the responder group for all seizure types was four (25.0%) at 12 months, five (31.3%) at 24 months, four (25.0%) at 36 months, and three (18.8%) at 48 and 60 months (Suppl. table 4).\u003c/p\u003e \u003cp\u003eRegarding the relationship between the profile of each patient and the proportion of the responder group at 60 months, there was a significantly higher proportion of responders among patients with tonic seizures when the seizure frequency group was higher before PER initiation (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRelationship between the profile of each patient and the responder group at 60 months\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"14\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eFocal seizure, n\u0026thinsp;=\u0026thinsp;13\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eAtypical absence seizure, n\u0026thinsp;=\u0026thinsp;13\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eTonic seizure, n\u0026thinsp;=\u0026thinsp;11\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003ePrimary or secondary GTCS, n\u0026thinsp;=\u0026thinsp;10\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003eAtonic seizure,\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;10\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c14\" namest=\"c13\"\u003e \u003cp\u003eMyoclonic seizure,\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;9\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eResponder, n\u0026thinsp;=\u0026thinsp;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eResponder, n\u0026thinsp;=\u0026thinsp;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eResponder, n\u0026thinsp;=\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eResponder, n\u0026thinsp;=\u0026thinsp;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eResponder, n\u0026thinsp;=\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eResponder, n\u0026thinsp;=\u0026thinsp;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.592\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.546\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.571\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at seizure onset\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;2 years old\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.592\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.266\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.076\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.524\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.167\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eStructural abnormality on brain MRI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.592\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.266\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.191\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.500\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDEE type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLGS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.511\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.511\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.524\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.500\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEMAtS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.128\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.128\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.467\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.500\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.500\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDravet syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.110\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.400\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.333\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSZT2 mutation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.400\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTSC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.400\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntellectual ability\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBorderline to mild intellectual disability\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.236\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.467\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSeverely retarded\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.491\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.500\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.200\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAutism spectrum disorder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.592\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.491\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of concomitant ASMs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;4 drugs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.487\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.487\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.491\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.133\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.333\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eWith enzyme-induced ASM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.293\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.571\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eMedian seizure frequency (/month)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.304\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.087\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.028*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.235\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.665\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.692\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTitration schedule\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEvery 2 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.266\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.194\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.524\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"14\"\u003eMRI, magnetic resonance imaging; DEE, developmental and epileptic encephalopathy; LGS, Lennox-Gastaut syndrome; EMAtS, epilepsy with myoclonic atonic seizures; TSC, Tuberous sclerosis complex; ASM, antiseizure medication\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"14\"\u003e*: p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003e2–4. Safety\u003c/h3\u003e\n\u003cp\u003eDuring the study period, twelve (75.0%) patients experienced adverse events, including six (37.5%) patients with somnolence, five (31.3%) with emotional changes such as irritability or agitation (three with irritability, and two with agitation), two (12.5%) with dizziness, and one (6.3%) with athetosis. One (6.3%) patient experienced a combination of somnolence with emotional changes and dizziness with emotional changes.\u003c/p\u003e \u003cp\u003eExcept for two patients who discontinued PER due to adverse events (one with athetosis and one with dizziness and emotional changes), the others had mild symptoms. Almost all adverse events occurred gradually within two weeks after PER initiation or dose escalation; moreover, the adverse symptoms improved following adjustment of the PER dose or reduction of concomitant medications. Additionally, no patient complained of adverse reactions at 60 months after PER initiation.\u003c/p\u003e \u003cp\u003eRegarding the relationship between adverse events and background characteristics, somnolence and dizziness were significantly more frequent among patients with severe retardation and borderline-to-mild intellectual disability, respectively (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRelationship between adverse events and patients\u0026rsquo; background characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"12\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eAdverse events\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eSomnolence, n\u0026thinsp;=\u0026thinsp;6\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eEmotional change, n\u0026thinsp;=\u0026thinsp;5\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eDizziness,\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eAthetosis,\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003eTotal,\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;12\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.633\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.596\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.175\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at seizure onset\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;2 years old\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.633\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.596\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.438\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.585\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eStructural abnormality on brain MRI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.301\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.175\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.438\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.585\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDEE type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLGS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.119\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.063\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEMAtS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.450\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDravet syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.250\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eSZT2\u003c/em\u003e mutation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.250\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTSC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.438\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntellectual ability\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBorderline to mild intellectual disability\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.234\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.049*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSeverely retarded\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.036*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAutism spectrum disorder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.604\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of concomitant ASMs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;4 drugs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.250\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.350\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.136\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eWith enzyme-induced ASMs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.608\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.282\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.569\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTitration schedule\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEvery 2 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.588\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.375\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003eMRI, magnetic resonance imaging; DEE, developmental and epileptic encephalopathy; LGS, Lennox-Gastaut syndrome; EMAtS, epilepsy with myoclonic atonic seizures; TSC, Tuberous sclerosis complex; ASM, antiseizure medication\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003e*: p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"3. Discussion","content":"\u003cp\u003eThis study investigates the efficacy and tolerability of PER treatment for DEEs over 60 months.\u003c/p\u003e \u003cp\u003eA five-year study of clobazam in patients with LGS reported 82%, 75%, and 85% seizure reduction from baseline at 3, 4, and 5 years, respectively [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. High-purity cannabidiol reduced seizure frequency in patients with LGS by 53% from baseline at 145\u0026ndash;156 weeks after initiation [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Valproate is recommended as the first-line drug for the treatment of EMAtS [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Recent studies on the treatment of epilepsy in patients with EMAtS have investigated the efficacy of felbamate [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e] and cannabidiol [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. However, there have been no reports of outcomes with long-term use of a specific drug. Regarding the treatment of Dravet syndrome with ASMs, 3-year outcomes have been reported for stiripentol (long-term outcomes for patients with \u0026gt;\u0026thinsp;50% seizure reduction; efficacy rates of 48% and 55% for GTCS and focal seizures, respectively) [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e], fenfluramine (70% of patients remained seizure-free for a mean duration of 6 years and 7 months) [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e], and cannabidiol (43% efficacy rate at 145\u0026ndash;156 weeks after initiation) [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. In this study, the 3-year efficacy rates of PER were 30.8% for focal seizure, 38.5% for atypical absence seizure, 27.3% for tonic seizure, 60.0% for primary or secondary GTCS, 50.0% for atonic seizure, and 66.7% for myoclonic seizure (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). It is difficult to compare PER with other drugs due to differences in the evaluation methods across previous studies [\u003cspan additionalcitationids=\"CR40\" citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan additionalcitationids=\"CR45 CR46\" citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. However, although PER is less effective than clobazam for LGS [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e], it is likely to have similar long-term efficacy as cannabidiol for LGS and Dravet syndrome [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Although PER, like cannabidiol, does not have very high efficacy because DEEs are comorbid with very refractory epilepsy, it shows good potential to suppress seizures. Cannabidiol has yet to be approved in Japan as of March 2024; further, in Europe, it is only approved for patients with Dravet syndrome, LGS, and TSC [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. PER has the advantage that it can be used in all patients with DEEs since it can be used regardless of the epilepsy syndrome (i.e., it is not limited to patients with Dravet syndrome, LGS, or TSC).\u003c/p\u003e \u003cp\u003eRegarding PER, the short-term (3\u0026ndash;12 months) efficacy rates for refractory epilepsy, including DEEs such as LGS and Dravet syndrome, range from 30\u0026ndash;69% [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan additionalcitationids=\"CR30 CR31 CR32\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e], which is consistent with our findings. Additionally, we confirmed that the efficacy rates at 12\u0026ndash;24 months after PER initiation were maintained for up to 60 months for all seizure types.\u003c/p\u003e \u003cp\u003eRegarding the efficacy against each syndrome, PER was highly effective for every seizure type in patients with EMAtS, without significant differences according to seizure type. To our knowledge, there have been no studies on the use of PER for EMAtS. EMAtS is an age-dependent syndrome in which seizures often disappear within 3 years of onset; however, it shows high drug resistance during the early stages of the onset [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. In our study, one of the patients with EMAtS was 2 years 2 months from onset (the other patient was 6 years 4 months from onset), and the natural history of EMAtS may have affected the efficacy rate. In other words, the possibility cannot be ruled out that the decrease in seizures was not due to the effect of PER treatment but because the patient reached 3 years old during treatment. The responder rate of PER for myoclonic seizures in patients with idiopathic generalized epilepsy and juvenile myoclonic epilepsy is reported to be 85\u0026ndash;89% [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. Gamma-aminobutyric acid (GABA) receptor dysfunction has been associated with the onset of myoclonic seizures [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. AMPA receptors are present in developing GABAergic terminals, and their activation inhibits GABAergic activity [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. Inhibition of the AMPA receptor by PER may activate GABAergic function. Although the relationship between AMPA receptors and myoclonic seizures is unknown, the responder rate for myoclonic seizures in this study was high, especially in EMAtS cases, where myoclonic seizures were suppressed in 2 out of 2 cases (100%). PER is not targeted to a specific seizure type. However, when effective, it is often effective for all seizure types in an \u0026ldquo;all or nothing\u0026rdquo; manner [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], and the high sensitivity for myoclonic seizures may have influenced the high responder rate for EMAtS cases in this study.\u003c/p\u003e \u003cp\u003eA variety of genetic mutations can cause DEEs. However, only three of the cases included in this study had genetic analysis, including one LGS case with tetrasomy 15q, one case with \u003cem\u003eSCN1A\u003c/em\u003e mutation (Dravet syndrome), and one case with \u003cem\u003eSZT2\u003c/em\u003e mutation. The case with tetrasomy 15q was in the responder group, but the other cases had no efficacy for PER and discontinued it. It is reported that the efficacy of PER is high for cases with \u003cem\u003eSCN1A\u003c/em\u003e, \u003cem\u003eGNAO1\u003c/em\u003e, \u003cem\u003ePIGA\u003c/em\u003e, \u003cem\u003eSYNGAP1\u003c/em\u003e, \u003cem\u003eCDKL5\u003c/em\u003e, \u003cem\u003eNEU1\u003c/em\u003e, \u003cem\u003ePCDH19\u003c/em\u003e, \u003cem\u003ePOLG1\u003c/em\u003e, and \u003cem\u003ePOLG2\u003c/em\u003e mutations [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. In addition, there are case reports of PER\u0026rsquo;s effectiveness, including epsilon sarcoglycan gene mutation [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e] and \u003cem\u003eGRIN1\u003c/em\u003e mutation [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Tetrasomy 15q is known as a chromosomal abnormality that can cause LGS [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e], and its epileptogenesis is said to be due to a rearrangement of the α5 and β3 GABA receptor subunit gene [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]. Although there are no reports of the use of PER for patients with Tetrasomy 15q, PER may be effective in epilepsy, a genetically abnormal disorder that results in the inhibition of GABAergic function [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. Regarding Dravet syndrome, effectiveness for PER in cases with \u003cem\u003eSCN1A\u003c/em\u003e c.2588 T\u0026thinsp;\u0026gt;\u0026thinsp;C, p.Leu863Ser or c.4547C\u0026thinsp;\u0026gt;\u0026thinsp;A, p.Ser1516* has been reported [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e]. The mutation site of the \u003cem\u003eSCN1A\u003c/em\u003e in the patient with Drave syndrome in this study was c.664C\u0026thinsp;\u0026gt;\u0026thinsp;T, p.Arg222*. PER for patients with \u003cem\u003eSCN1A\u003c/em\u003e mutation is highly effective in suppressing epileptic seizures, but in 33\u0026ndash;5% of cases, it has been reported to be less effective [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. The reason may lie in the difference in amino acid mutation sites. Regarding EMAtS, genetic mutations such as \u003cem\u003eSLC2A1\u003c/em\u003e, \u003cem\u003eSLC6A1\u003c/em\u003e, \u003cem\u003eCHD2\u003c/em\u003e, \u003cem\u003eSCN1A\u003c/em\u003e, and \u003cem\u003eGABRG2\u003c/em\u003e are known to cause it [\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e], but the genetic analysis was not performed in our patients with EMAtS. Therefore, we do not know whether the cases with EMAtS in this study were genetically highly effective for PER. If the genetic factors of the effective cases and their relationship to the AMPA receptor are found, the genetic information for each patient could help select PER as the ASM for the patient. On the other hand, in real-world clinical practice, genetic analysis is not performed in all cases of refractory epilepsy, including DEEs. We believe that the purpose and result of this report would not change even if the genetic variants of all the cases included in this study were revealed.\u003c/p\u003e \u003cp\u003eThe reported incidence of adverse events among patients with DEEs ranged from 22\u0026ndash;70%, with 9\u0026ndash;18%, 5\u0026ndash;50%, 10\u0026ndash;22%, and 32% for dizziness, somnolence, emotional changes, and behavioral disturbances, respectively [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan additionalcitationids=\"CR30 CR31 CR32\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. The relationship between adverse events of PER and background characteristics in patients with DEEs remains unclear. Our findings indicated that somnolence and dizziness were significantly more frequent among patients with severe retardation and those with borderline-to-mild intellectual disability, respectively. However, most adverse events were mild, and we do not believe that PER should be excluded as a treatment option for patients with severe retardation or borderline-to-mild intellectual disability.\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, this study had a small sample size. It was difficult to increase the sample size because this study focused on rare diseases. Due to the small number of cases, it is difficult to draw conclusions regarding the efficacy of PER based on the results of this study alone. Second, we could not perform long-term EEG monitoring or evaluate subclinical seizures. Third, since we could not perform routine monitoring of the blood concentration of PER, we could not evaluate the relationship between the blood concentration and efficacy or safety. Fourth, emotional changes in patients with severe retardation may have been overlooked in the absence of behavioral disorders such as violence. In addition, regarding somnolence, there is an objective indicator that even patients with severe retardation sleep longer; however, dizziness might have been underestimated since it is a subjective symptom. Moreover, in case of severe intellectual disability, the patient may not complain of dizziness, even if it was present. Conversely, the possibility cannot be ruled out that adverse events may have been overlooked due to the intellectual and motor abilities of each case.\u003c/p\u003e"},{"header":"4. Methods","content":"\n\u003ch3\u003e4 − 1. Study design and patients\u003c/h3\u003e\n\u003cp\u003eThis retrospective study included patients who visited the Department of Pediatrics, Tochigi Children\u0026rsquo;s Medical Center at Jichi Medical University. The inclusion criteria were as follows: (i) developmental delay or regression after onset, (ii) seizures not controlled after treatment with two or more drugs, (iii) multidrug treatment for \u0026ge;\u0026thinsp;2 years after onset [\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e], and (iv) patients who started PER treatment between June 2016 and May 2018. The exclusion criteria were as follows: (i) patients who were transferred to a different hospital during the study period and could not be followed up, (ii) patients who received additional ASMs and/or underwent surgery for epilepsy after PER initiation, and (iii) patients who restarted PER after discontinuation. Patients who discontinued PER were also considered excluded cases if they had episodes that fit (i) or (ii) during the 60-month period after starting PER.\u003c/p\u003e \u003cp\u003eThe diagnostic criteria for LGS are as follows: (i) various types of seizures, including tonic seizures, atonic seizures, atypical absence seizures, and GTCS, and (ii)\u0026thinsp;\u0026gt;\u0026thinsp;3 Hz slow spike and waves during awake state and rapid rhythms of 10\u0026ndash;20 Hz during the sleep state on EEG [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. The diagnostic criteria for EMAtS are as follows: (1) normal development and cognition before the onset of epilepsy; (2) onset of epilepsy between the ages of 6 months and 6 years (peak: 2\u0026ndash;4 years); (3) mandatory presentation of myoclonic-atonic seizures; (4) presence of generalized spike-wave discharges at 2\u0026ndash;3 Hz without persistent focal spike discharges [\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e]. The diagnostic criteria for Dravet syndrome are as follows: (i) onset of prolonged febrile or afebrile focal seizures or GTCS at \u0026ge;\u0026thinsp;1 year of age, (ii) onset of myoclonic or atypical absence seizures at \u0026ge;\u0026thinsp;1 year of age, (iii) status epilepticus induced by fever or bathing, and (iv) cognitive and behavioral disorders after onset [\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003e4 − 2. Data collection\u003c/h3\u003e\n\u003cp\u003eThe following data were collected from electronic medical records: age at PER initiation, sex, age at onset, structural abnormalities on brain MRI, background disease, genetic abnormalities, DEE type, severity of intellectual disability, number of ASMs used prior to PER initiation, history of surgical therapy and/or ketone diet, ASMs used concomitantly upon PER initiation, seizure type, and PER titration schedule. The mean seizure frequencies of each seizure type within 3 months before PER initiation were compared with those at 12, 24, 36, 48, and 60 months after PER initiation. Patients with \u0026lt;\u0026thinsp;50%, 50\u0026ndash;74%, 75\u0026ndash;99%, and 100% seizure reduction were classified as no response, 50% responders, 75% responders, and seizure-free, respectively. Patients who discontinued PER and had no response were included in the non-responder group; moreover, 50% responders, 75% responders, and seizure-free patients were included in the responder group.\u003c/p\u003e\n\u003ch3\u003e4 − 3. Statistical analysis\u003c/h3\u003e\n\u003cp\u003eAll statistical analyses were performed using the R software program version 4.3.2 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://crane.r-project.org\u003c/span\u003e\u003cspan address=\"https://crane.r-project.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e, accessed on 29 Dec 2023) (R Foundation for Statistical Computing, Vienna, Austria). The Fisher\u0026rsquo;s exact test was used to evaluate background factors related to the retention of PER. These factors included sex, age at onset (\u0026lt;\u0026thinsp;2 years vs. \u0026ge;2 years), structural abnormalities on MRI, DEE type, intellectual ability (borderline-to-mild vs. moderate-to-most severe intellectual disability), number of ASMs used before PER initiation (\u0026lt;\u0026thinsp;10 vs. \u0026ge;10), number of concomitant ASMs at PER initiation (\u0026lt;\u0026thinsp;4 vs. \u0026ge;4), use of enzyme-induced ASMs (carbamazepine, phenytoin, and phenobarbital), and the titration schedule. Similarly, the Fisher\u0026rsquo;s test was used to evaluate background factors related to the responder group and cases with adverse events regarding sex, age at onset (\u0026lt;\u0026thinsp;2 years vs. \u0026ge;2 years), structural abnormalities on MRI, DEE type, intellectual ability (borderline-to-mild vs. moderate-to-most severe intellectual disability), number of ASMs used before PER initiation (\u0026lt;\u0026thinsp;10 vs. \u0026ge;10), number of concomitant ASMs at PER initiation (\u0026lt;\u0026thinsp;4 vs. \u0026ge;4), use of enzyme-induced ASMs (carbamazepine, phenytoin, and phenobarbital), and the titration schedule. The Mann-Whitney U test was used to evaluate the relationship between age at PER initiation and PER discontinuation. Similarly, the Mann-Whitney U test was used to evaluate the relationship between age at PER initiation and the responder group, age at initiation and the cases with adverse events, and seizure frequency and the responder group.\u003c/p\u003e\n\u003ch3\u003e4–4. Ethics\u003c/h3\u003e\n\u003cp\u003e This study was approved by the ethics committee of Jichi Medical University (Jichi Medical University 17\u0026ndash;118). This study had been performed according to the Declaration of Helsinki. Upon PER initiation, informed consent was obtained from the patients and their parents. If patients had difficulty expressing their intention due to their intellectual ability or age, we only obtained informed consent from their parents. PER prescriptions for patients aged\u0026thinsp;\u0026lt;\u0026thinsp;12 years were for off-label use at the time of the study initiation [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], which was explained to the patients or their parents.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eH.Y. wrote the manuscript; H.O. and T.T. contributed to the conceptualization and design of this study; H.Y., H.O., K.M., K.K., Y.M., T.M., Y.A., K.W., and K.N. collected and analyzed data; H.O., K.M., and T.T. critically reviewed the manuscript and supervised the entire study process. All authors have read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated in this study are provided in the manuscript and Supplementary Information.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMs. Makiko Mieno, Associate Professor in the Department of Medical Informatics at the Center for Information, Jichi Medical University, supervised the statistical analysis. We express our gratitude to all the patients and their parents for their cooperation and participation in this study. We would also like to thank the medical colleagues of the Jichi Medical University Tochigi Children\u0026rsquo;s Medical Center, who are devoted to the treatment of patients with refractory epilepsy.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eScheffer, I. E. et al. Classification of the epilepsies: New concepts for discussion and debate-Special report of the ILAE classification task force of the commission for classification and terminology. \u003cem\u003eEpilepsia Open\u003c/em\u003e\u003cstrong\u003e1\u003c/strong\u003e, 37\u0026ndash;44 (2016).\u003c/li\u003e\n\u003cli\u003eScheffer, I. E. et al. ILAE classification of the epilepsies: Position paper of the ILAE commission for classification and terminology. \u003cem\u003eEpilepsia\u003c/em\u003e\u003cstrong\u003e58\u003c/strong\u003e, 512\u0026ndash;521 (2017) \u003c/li\u003e\n\u003cli\u003eWirrell E, Tinuper P, Perucca E, Mosh\u0026eacute; SL. 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Severe myoclonic epilepsy in infants and its related syndromes. \u003cem\u003eEpilepsia\u003c/em\u003e\u003cstrong\u003e41\u003c/strong\u003e, 7 (2000). \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"perampanel, Lennox-Gastaut syndrome, epilepsy with myoclonic atonic seizures, long-term, efficacy \u0026 safety","lastPublishedDoi":"10.21203/rs.3.rs-5286706/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5286706/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eSeizures in patients with developmental and epileptic encephalopathies (DEEs) are often highly resistant to various antiseizure medications. Perampanel (PER) is a novel antiseizure medication that non-competitively inhibits the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor and is expected to reduce seizure frequency not only for focal seizures and generalized tonic-clonic seizures (GTCS) but also for other seizure types. This study aimed to clarify the long-term therapeutic efficacy and tolerability of PER in patients with DEEs. We analyzed data regarding patients\u0026rsquo; background characteristics, medication retention, trends in seizure frequency, and adverse events obtained from 16 patients with DEEs who had been on PER treatment for 60 months. The retention rates were 56.3% and 43.8% at 12 and 60 months, respectively. At 60 months after PER initiation, the rate of patients with \u0026gt;\u0026thinsp;50% seizure reduction was 38.5%, 38.5%, 36.4%, 60.0%, 40%, and 66.7% among patients with focal seizures, atypical absence seizures, tonic seizures, GTCS, atonic seizures, and myoclonic seizures, respectively. The frequency of adverse events was 75.0%. PER showed long-term efficacy in various seizure types. PER is a promising treatment option for patients with DEEs.\u003c/p\u003e","manuscriptTitle":"Perampanel reduces seizure frequency in patients with developmental and epileptic encephalopathy for a long term","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-22 07:32:28","doi":"10.21203/rs.3.rs-5286706/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-11-13T05:39:24+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-13T03:47:38+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-31T17:29:42+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-22T03:09:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"255281654728068725938089452184939554518","date":"2024-10-21T22:17:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"134149703343648438241882319351198618403","date":"2024-10-21T22:08:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"332117618775577279790991491564392422129","date":"2024-10-21T19:13:53+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-10-21T19:11:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-21T18:40:33+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-10-18T17:33:29+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-10-18T17:31:48+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-10-18T05:44:47+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b382056b-c851-46ed-970e-c26ca87e6c25","owner":[],"postedDate":"October 22nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":39140313,"name":"Health sciences/Health care/Therapeutics/Drug therapy"},{"id":39140314,"name":"Health sciences/Neurology/Neurological disorders/Epilepsy"}],"tags":[],"updatedAt":"2024-12-09T15:59:10+00:00","versionOfRecord":{"articleIdentity":"rs-5286706","link":"https://doi.org/10.1038/s41598-024-82014-5","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2024-12-03 15:57:00","publishedOnDateReadable":"December 3rd, 2024"},"versionCreatedAt":"2024-10-22 07:32:28","video":"","vorDoi":"10.1038/s41598-024-82014-5","vorDoiUrl":"https://doi.org/10.1038/s41598-024-82014-5","workflowStages":[]},"version":"v1","identity":"rs-5286706","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5286706","identity":"rs-5286706","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}