Efficacy and safety of perampanel monotherapy in Chinese children with newly diagnosed focal epilepsy: a single-center prospective study

Introduction

Epilepsy is a chronic brain disease caused by abnormal excessive discharge of brain neurons. Children are the age group where epilepsy is most commonly observed (1). Globally, the incidence rate of childhood epilepsy reached 61.0 per 100,000 (2). Notably, focal epilepsy is the most common type of childhood epilepsy, accounting for two-thirds of all cases (3). Antiseizure medications (ASMs) are the main treatment methods for most children with focal epilepsy. Perampanel (PER), a α-amino-3-hydroxyl-5-methyl-4-isoxazole propionate (AMPA) competitive antagonists of glutamate receptor, has been used in treatment of patients with focal epilepsy, which can inhibit glutamate-mediated excitatory neurotransmission by acting on the postsynaptic membrane AMPA receptor, thereby effectively preventing seizure (4).

In recent years, PER has been approved for adjunctive treatment in patients with focal epilepsy for patients (≥12 years) in more than 40 countries including the United States and Europe. Pascarella et al. (5) enrolled 485 patients in 2025, and Gasparini et al. (6) included 503 patients in 2022. The results indicated that PER monotherapy exhibits favorable efficacy and tolerability in real-world settings, establishing its potential as a valuable early treatment option. To date, most studies have focused on populations aged 12 years of age, leaving a significant gap in the evidence for children under 12 years of age. There is an urgent need for studies to evaluate the safety and effectiveness of PER monotherapy in Chinese pediatric patients aged 4–12 years. The aim of this study was to analyze the efficacy and safety of PER in the treatment of Chinese children aged from 2 to 12 years with focal epilepsy. We present this article in accordance with the TREND reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-396/rc).

Methods

This single-center prospective study was conducted in Hangzhou Children’s Hospital in China. One hundred and three patients who diagnosed with focal epilepsy were enrolled from May 2021 to June 2024. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Hangzhou Children’s Hospital [(2023) Ethical Approval (Clinical Trial) No. 60, No. 2023-062-01] and informed consent was obtained from all individual participants’ legal guardians.

Inclusion and exclusion criteria

Here are the inclusion criteria: (I) all patients were diagnosed and recruited referred to the diagnostic and classification criteria of ILAE focal epilepsy; (II) we divided focal epilepsy patients into seven groups based on the anatomical origin of seizure onset, including frontal lobe epilepsy, temporal lobe epilepsy, parietal lobe epilepsy, occipital lobe epilepsy, and multilobar epilepsy. Additionally, we included focal to bilateral tonic-clonic seizures (FBTCS) and self-limited epilepsy with centrotemporal spikes (SeLECTS) as distinct subtypes for analysis (7); (III) no other ASMs were used before treatment.

Here are the exclusion criteria: (I) patients hadn’t diagnosed focal epilepsy; (II) patients had contraindications for orally PER treatment; (III) patients had clinically significant medical or psychiatric conditions, severe liver or kidney diseases, other organ or immune dysfunction diseases, suicide attempts, significant electrocardiography abnormality and drug dependence; (IV) patients received other ASMs before using PER.

Treatment regimen

All patients took the PER once a day before sleeping. For children aged from 4 to 12 years, 2 mg/day was given for patients weighing >30 kg as the initial dose, 1 mg/day was given for patients weighing 20–30 kg as the initial dose; for children under 4 years of age or under 20 kg, the initial oral dose was 0.5 mg/d. The dose of PER was increased by one starting dose per 2-week until a maintenance dose of 2–8 mg/day. The maintenance dose was determined at the investigator’s discretion based on patients’ clinical responses and tolerability. After the maintenance dose was established, no further modifications were made to the dosing regimen.

Data collection

We recorded the seizure data and other laboratory examinations before treatment as study baseline. At 12 and 24 weeks during the PER treatment period, we recorded the data of patients, which including seizure status, seizure frequency, seizure duration, PER concentration, blood routine, liver and kidney function, electrolytes, myocardial enzymes, head magnetic resonance and head computed tomography (CT). Additionally, we performed 16-hour-long-term electroencephalogram (EEG) monitoring prior to initiating treatment and at 3- and 6-month follow-ups post-treatment to evaluate the impact of PER on EEG by analyzing the frequency of epileptiform discharges. Epileptiform discharges were defined as interictal spikes, sharp waves, and other similar waveforms detected during EEG recordings. Six 10-min segments were selected from both interictal awake and sleep periods, totaling 60 min. The percentage of time occupied by abnormal electrical activity within each segment was recorded to calculate the interictal discharge indices. A reduction of exceeding 50% in the discharge index was considered clinically meaningful. Seizures were recorded daily in a patient epilepsy diary, and AEs of PER monotherapy were monitored throughout the studies. The seizure diaries utilized were the standardized template developed by the China Association Against Epilepsy, with caregivers providing entries in either written or video format. Pediatric neurologists conducted scheduled follow-ups to systematically analyze and synthesize the collected data. Cognitive and behavioral assessments of patients were administered using standardized assessment scales (Achenbach Child Behavior Checklist, Social Anxiety Scale for Children, Adverse Drug Reaction Scale, and so on) by the pediatric health care department. The efficacy of PER was evaluated by comparing it with the baseline.

The primary efficacy endpoint was seizure-freedom rates and ≥50% responder rates (proportion of patients with ≥50% reduction from baseline in seizure frequency over 28 days during maintenance period) (8). Safety endpoints of AEs and reasons for discontinuation were assessed according to the records of their caregivers. The classification and grading of AEs were classified and graded according to the Common Terminology Criteria for Adverse Events (CTCAE), and all assessments were performed under blinded conditions to ensure objectivity and minimize bias.

Statistical analysis

We used SPSS 22.0 statistics program for statistical analysis (IBM Corp., Armonk, NY, USA). Demographic characteristics were summarized using mean and standard deviation (SD) or percentages. Statistical analyses included chi-squared analyses, Fisher’s exact test, and logistic regression to analyze the data of this study. To evaluate differences in treatment efficacy at the study endpoint, univariate and multivariate analyses were conducted to examine the associations of four prespecified variables: epilepsy type, sex, age, and body weight with treatment outcomes. The significance level was ≤0.05.

Results

In total, 103 patients aged from 2 to 12 years met the inclusion criteria were enrolled. Among them, 95 children with focal epilepsy completed the 24-week follow-up study. All 95 patients who completed the study successfully reached their target maintenance doses. Three patients discontinued and switched to other ASMs due to AEs, and two patients withdrew because of inadequate therapeutic response to PER. The caregivers of three patients refused to follow up due to their personal reasons. Among the 95 patients, it included 57.9% (55/95) males and 42.1% (40/95) females. The average maintenance dose of PER was 4.23±1.38 mg. According to the classification of focal epilepsy, there were 18.9% (18/95) cases of frontal lobe epilepsy, 11.6% (11/95) cases of temporal lobe epilepsy, 5.3% (5/95) cases of parietal lobe epilepsy, 7.4% (7/95) cases of occipital lobe epilepsy, 12.6% (12/95) cases of multilobar epilepsy, 21.1% (20/95) cases of FBTCS and 23.1% (22/95) cases of SeLECTS. Patient demographics characteristics are listed in Table 1.

Compared with the baseline, the overall seizure-free rates at 12 and 24 weeks were 64.2% [61/95, 95% confidence interval (CI): 54.6% to 73.8%] and 53.7% (51/95, 95% CI: 43.7% to 63.7%), respectively. The overall responder rates at 12 and 24 weeks were 82.1% (78/95, 95% CI: 74.4% to 89.8%) and 77.9% (74/95, 95% CI: 69.6% to 86.2%), respectively. The retention at 12 and 24 weeks were 93.2% (96/103) and 99.0% (95/96), respectively.

The responder rates of different types of epilepsy at 24 weeks were 50.0% (frontal lobe epilepsy), 63.6% (temporal lobe epilepsy), 80.0% (parietal lobe epilepsy), 85.7% (occipital lobe epilepsy), 83.3% (multilobar epilepsy), 85.0% (FBTCS) and 95.5% (SeLECTS), respectively (Figure 1). The P value of 0.023 indicates statistically significant variability in PER’s efficacy across epilepsy subtypes. Specifically, among focal epilepsy with different onset regions, frontal lobe epilepsy exhibited comparatively lower response rates, while focal epilepsies originating from the parietal lobe, occipital lobe, and multiple lobes demonstrated higher efficacy. Notably, PER maintained consistently favorable efficacy in both FBTCS and SeLECTS groups, with particularly pronounced effectiveness observed in the SeLECTS patients (Table 1).

Figure 1 Efficacy of different types of focal epilepsy at 24 weeks endpoint. FBTCS, focal to bilateral tonic-clonic seizures; SeLECTS, self-limited epilepsy with centrotemporal spikes.

To access factors that may affect PER efficacy, multivariate regression and univariate analysis was made. There was no statistically significant difference for age (P=0.36) and weight (P=0.45). The P value of 0.02 for the gender variable indicates a statistically significant association between patient sex and PER treatment efficacy, with female patients demonstrating generally higher response rates than male patients.

EEG was examined in 95 children at 12 and 24 weeks. At 12 and 24 weeks, the rates of complete suppression of epileptiform discharges on EEG were 57.9% (55/95) and 48.4% (46/95), respectively, while the percentages of EEG improvement (including complete control) were 85% (81/95) and 79% (75/95), respectively (P=0.26). These findings demonstrate that PER effectively reduces the frequency of interictal epileptiform discharges in pediatric patients. However, the magnitude of this reduction does was not significantly correlated with treatment duration indicating that EEG improvements may plateau within the early maintenance period (Table 2).

During the 24-week maintenance period, 24 patients occurred AEs, included dizziness (12/95, 12.6%), irritability (11/95, 11.6%), fall prone (2/95, 2,1%), somnolence (3/95, 3.2%), hypomnesia (2/95, 2.1%) and headache (2/95, 2.1%). According to the CTCAE, all observed AEs were classified as Grade 1, indicating they were mild, generally well-tolerated, and did not require specific medical intervention. Notably, among the three patients who withdrew from the study prematurely, two occurred Grade 2 irritability and one presented with Grade 1 headache. Although clinical assessments determined that these events did not necessitate targeted therapeutic management, caregivers opted to withdraw their children from the study due to safety concerns and perceived discomfort. Among 25.3% (24/95) patients who occurred AEs, the drug plasma concentrations were higher. The average drug plasma concentrations of patients who occurred AEs was 429.26±212.82 ng/mL, with 231.54±115.64 ng/mL of patients who hadn’t occurred AEs. The results showed that the incidence of AEs will be higher within the higher blood concentration. It indicated that PER monotherapy has good tolerance.

Discussion

Since National Medical Products Administration of China approved PER for the adjunctive treatment of focal seizures in adults and children aged 12 years and older on September 2019, the clinical research of PER for the treatment of focal epilepsy in patients younger than 12 years old in China is relatively few. In a real-world study of PER adjunctive therapy in refractory epilepsy children aged 4 years or older with epilepsy in the South Korea, the overall responder rate was 43.6%, and the seizure-freedom rate was 17.7%, this study indicated that adjunctive treatment with PER was efficacious and tolerated in pediatric patients aged 4 years or older with epilepsy (9). In another efficacy and tolerability of adjunctive PER in pediatric patients (aged 4–12 years) with refractory epilepsy in China, the observed responder rates in at 4, 8, 12, 24, 36 and 48 weeks were 37.50%, 43.75%, 53.13%, 59.37%, 59.37% and 62.07%, respectively (10). In the open-label, Phase III 342 study of PER monotherapy found that 54 (74.0%, n=54/73) patients aged ≥12 years with newly diagnosed focal epilepsy or recurrence of epilepsy were seizure free at the last evaluated dose of 4 or 8 mg/d (11). Nissenkorn et al. (12) enrolled 137 patients with epilepsy, aged 2 to 61 years, representing a heterogeneous spectrum of etiologies. After a mean treatment duration of 2 years, the cohort exhibited a mean seizure frequency reduction of 56.61%±34.36%. Remarkably, 60 patients (43.5%) achieved a sustained reduction in seizure frequency exceeding 75%, with 38 patients (27.5%) achieving a reduction greater than 90%, indicating a substantial proportion of patients derived robust and clinically meaningful benefit. Our study showed the responder rate (77.9%) of PER monotherapy was higher in Chinese children aged from 2 to 12 years. In which indicated PER monotherapy is effective in the treatment of focal epilepsy in children. The higher observed efficacy in our cohort may be partially attributable to the inclusion of SeLECTS patients.

SeLECTS is a self-limiting pediatric epilepsy syndrome characterized by centrotemporal spikes on EEG and seizures that typically remit spontaneously during adolescence (7). This study enrolled newly diagnosed patients receiving PER monotherapy, were followed for 24 weeks, a duration shorter than the expected natural remission period of SeLECTS. Consequently, while the findings provide preliminary evidence of PER’s efficacy in this subgroup, they must be interpreted with caution. However, future placebo-controlled trials specifically targeting SeLECTS patients would be more valuable for understanding its therapeutic role in this distinct population. Given the relatively favorable prognosis of SeLECTs patients, which may have contributed to the higher overall response rate and seizure-free rate observed in this study. To accurately delineate the therapeutic impact of PER in SeLECTS, future placebo-controlled trials with extended follow-up are warranted to comprehensively evaluate both efficacy and safety in this distinct pediatric population.

Two studies showed that 8 mg/d was the most appropriate dose (13,14). PER dose and plasma concentration showed a close linear correlation (15). The pharmacokinetic/pharmacodynamics (PK/PD) analysis showed a significant decrease in seizure frequency and significant increased probability of being a responder, as PER concentration increased (16). In a prospective study, PER plasma concentrations were obtained from 194 patients younger than 18 years, the effective range predicted from plasma concentration data in responders was 215–862 µg/L (17). There was a significant difference in the plasma concentration of PER between the responders, whether in children or adults. Another research included 92 adult patients suggested that the differences between plasma levels of responders and non-responders were not statistically significant (15). However, the effective blood concentration range of PER is still inconclusive. The results of our study showed that the incidence of AEs will be higher with the higher blood concentration. Therefore, we suggest that timely adjustment of medication by monitoring blood drug concentration and body weight may improve the retention rate and responder rate of children.

In recent years, the impact of ASMs on cognitive and behavioral functions become a prominent focus in pediatric epilepsy research. Scorrano et al. (18) reported that PER generally does not impair cognitive functions, including visual-spatial skills, and may even enhance verbal memory; however, mild declines in attention have been observed in some patients. In our study, 11.6% of patients exhibited irritability, while 2.1% demonstrated memory decline, with no other cognitive or behavioral impairments identified. These findings underscore the necessity of employing standardized neuropsychological assessments to rigorously and systematically evaluate the potential cognitive and behavioral effects of PER.

Conclusions

PER have a significant efficacy on different types of focal epilepsy in Chinese children aged 2–12 years, especially in children with self-limited epilepsy with centrotemporal spikes. PER can also significantly reduce the frequency of discharges, especially in the sleeping period. The common AEs of PER monotherapy in children with focal epilepsy were dizziness and irritability. Appropriate blood drug concentration can help to efficiently control seizures in pediatric patients with focal epilepsy.

Acknowledgments

The authors would like to thank The Fourth School of Clinical Medicine, Graduate School, Zhejiang Chinese Medical University, and Hangzhou Children’s Hospital for the support of research. The authors also would like to thank all the patients, their guardians, all the doctors and nurses who helped in this research.

Footnote

Reporting Checklist: The authors have completed the TREND reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-396/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-396/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-396/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-396/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Hangzhou Children’s Hospital [(2023) Ethical Approval (Clinical Trial) No. 60, No. 2023-062-01] and informed consent was obtained from all individual participants’ legal guardians.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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