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Effectiveness and tolerability of adjunctive perampanel in the treatment of pediatric patients with uncontrolled epilepsy: A retrospective, single-center, real-world study

Open AccessPublished:October 31, 2022DOI:https://doi.org/10.1016/j.yebeh.2022.108961

      Highlights

      • Perampanel therapy in pediatric patients remains understudied in China.
      • Perampanel showed good effectiveness and tolerability in pediatric patients.
      • Effectiveness of perampanel was not influenced by the etiology or type of epilepsy.
      • The superior efficacy of PER as early add-on therapy in pediatric patients was demonstrated for the first time.

      Abstract

      Objective

      The main aim of this study was to assess the efficacy, safety, and tolerability of adjunctive perampanel (PER) in the treatment of children and adolescents with epilepsy.

      Methods

      Pediatric patients who visited the pediatric epilepsy clinic of Henan Provincial People’s Hospital between May 2020 and December 2021 were recruited. All participants were treated with PER as adjunctive therapy and were seen routinely (minimum: a baseline and 12-week visit). The efficacy and tolerability of adjunctive PER for the treatment of epilepsy were investigated.

      Results

      One hundred and fourteen patients were enrolled, among whom 7 (6.1%) were lost to follow-up. At 12 weeks, the responder rate and the seizure-free rate were 56.1% (60/107) and 32.7% (35/107), respectively. The responder rate increased with the duration of PER administration and was significantly higher when PER was used as an early add-on (after ≤2 prior antiseizure medications (ASMs)) than a late add-on (after >2 prior ASMs). However, there was no significant difference in the treatment efficacy of adjunctive PER in patients with different epilepsy etiologies or types. Adverse events, including irritability, dizziness, somnolence, ataxic gait, weight gain, and tinnitus, were reported in thirty-two patients (29.9%).

      Conclusions

      In a routine clinical setting of pediatric patients with epilepsy, good effectiveness and tolerability of adjunctive PER were demonstrated. Notably, patients initiating PER as an early add-on showed a better seizure outcome than those initiating PER as a late add-on.

      Keywords

      1. Introduction

      Epilepsy is one of the most common neurological disorders. Approximately 75% of all epilepsy begins in childhood [

      Omran A, Elimam D, Yin F. MicroRNAs: new insights into chronic childhood diseases. Biomed Res Int. 2013;2013:291826. https://doi.org/10.1155/2013/291826.

      ]. The estimated prevalence of epilepsy among the pediatric population is 0.5–1% [
      • Iapadre G.
      • Balagura G.
      • Zagaroli L.
      • Striano P.
      • Verrotti A.
      Pharmacokinetics and drug interaction of antiepileptic drugs in children and adolescents.
      ]. Antiseizure medications (ASMs) are the mainstay of treatment. However, the epilepsy of 25–30% of pediatric patients remains refractory to medical therapy (refractory epilepsy, defined as the failure of two tolerated and appropriately chosen ASM schedules to achieve sustained seizure freedom) [
      • Verrotti A.
      • Loiacono G.
      • Coppola G.
      • Spalice A.
      • Mohn A.
      • Chiarelli F.
      Pharmacotherapy for children and adolescents with epilepsy.
      ,

      Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies [published correction appears in Epilepsia. 2010;51(9):1922]. Epilepsia. 2010;51(6):1069-1077. https://doi.org/10.1111/j.1528-1167.2009.02397.x.

      ]. Additionally, seizures that are still uncontrolled after one ASM is used have the potential to be refractory. Patients with uncontrolled epilepsy have an increased risk of disability, comorbidity, psychological and social dysfunction, and premature death [
      • Josephson C.B.
      • Patten S.B.
      • Bulloch A.
      • Williams J.V.A.
      • Lavorato D.
      • Fiest K.M.
      • et al.
      The impact of seizures on epilepsy outcomes: A national, community-based survey.
      ,
      • Thurman D.J.
      • Logroscino G.
      • Beghi E.
      • Hauser W.A.
      • Hesdorffer D.C.
      • Newton C.R.
      • et al.
      The burden of premature mortality of epilepsy in high-income countries: A systematic review from the Mortality Task Force of the International League Against Epilepsy.
      ]. Hence, it is essential to choose the appropriate ASMs to treat uncontrolled epilepsy. A comprehensive therapeutic strategy may be more effective than a second or third chance in ASM for patients with uncontrolled epilepsy [
      • Shorvon S.D.
      • Bermejo P.E.
      • Gibbs A.A.
      • Huberfeld G.
      • Kälviäinen R.
      Antiepileptic drug treatment of generalized tonic-clonic seizures: An evaluation of regulatory data and five criteria for drug selection.
      ,
      • Margolis J.M.
      • Chu B.-C.
      • Wang Z.J.
      • Copher R.
      • Cavazos J.E.
      Effectiveness of antiepileptic drug combination therapy for partial-onset seizures based on mechanisms of action.
      ].
      Perampanel (PER) is a highly selective, noncompetitive antagonist of the postsynaptic ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor [
      • Rogawski M.A.
      • Hanada T.
      Preclinical pharmacology of perampanel, a selective non-competitive AMPA receptor antagonist.
      ]. It depresses the excitability of neurons and controls seizures by inhibiting AMPA-induced Na+ and Ca2+ influx [
      • Rogawski M.A.
      • Hanada T.
      Preclinical pharmacology of perampanel, a selective non-competitive AMPA receptor antagonist.
      ,
      • Hanada T.
      • Hashizume Y.
      • Tokuhara N.
      • Takenaka O.
      • Kohmura N.
      • Ogasawara A.
      • et al.
      Perampanel: a novel, orally active, noncompetitive AMPA-receptor antagonist that reduces seizure activity in rodent models of epilepsy.
      ,
      • Tsai J.-J.
      • Wu T.
      • Leung H.
      • Desudchit T.
      • Tiamkao S.
      • Lim K.S.
      • et al.
      Perampanel, an AMPA receptor antagonist: From clinical research to practice in clinical settings.
      ]. In China, PER was first approved in 2019 as an adjunctive therapy for focal onset seizures (FOSs) with/without focal to bilateral tonic-clonic seizures (FBTCSs) in patients aged 12 years and older. Since July 2021, PER has been approved as monotherapy and adjunctive therapy for FOSs with/without FBTCSs in patients 4 years and older. It has also been approved as an adjunctive therapy for primary generalized tonic–clonic seizures (PGTCSs) in pediatric patients with epilepsy in the United States and the European Union. Perampanel is a potentially broad-spectrum ASM with a novel mechanism of action for patients with epilepsy with various seizure types [
      • Potschka H.
      • Trinka E.
      Perampanel: Does it have broad-spectrum potential?.
      ]. In previous studies, the efficacy of PER in the treatment of multiple generalized seizure types including myoclonic, absence, and tonic seizures has been demonstrated [
      • Trinka E.
      • Lattanzi S.
      • Carpenter K.
      • Corradetti T.
      • Nucera B.
      • Rinaldi F.
      • et al.
      Exploring the evidence for broad-spectrum effectiveness of perampanel: A systematic review of clinical data in generalised seizures.
      ]. Moreover, adjunctive PER was highly recommended for the treatment of refractory epilepsy by the American Academy of Neurology & American Epilepsy Society (AAN&AES) [
      • Kanner A.M.
      • Ashman E.
      • Gloss D.
      • Harden C.
      • Bourgeois B.
      • Bautista J.F.
      • et al.
      Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs II: Treatment-resistant epilepsy: Report of the American Epilepsy Society and the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.
      ]. However, adjunctive PER therapy in pediatric patients has been understudied, and there is a lack of large-sample studies in China. In the present study, we investigated the efficacy, safety, and tolerability of adjunctive PER in pediatric patients with epilepsy in real-world clinical settings.

      2. Materials and methods

      2.1 Patients

      For this retrospective, observational, single-center, real-world study, pediatric patients with epilepsy who visited the pediatric epilepsy clinic of Henan Provincial People's Hospital between May 2020 and December 2021 were recruited. The study was approved by the Ethics Committee of Henan Provincial People's Hospital. Written informed consent was received from a parent/legal guardian for each participant.
      Inclusion criteria: a diagnosis of epilepsy on the basis of symptoms, signs, or diagnostic examinations; a diagnosis of uncontrolled epilepsy (defined as the failure of at least one tolerated and appropriate ASM to achieve sustained seizure freedom); age 2–18 years; at least one seizure in the 4 weeks prior to enrollment; and follow-up after ≥12 weeks of PER as adjunctive therapy.
      Exclusion criteria: duration of PER as adjunctive therapy <12 weeks (except for patients for whom PER was discontinued due to poor seizure control or adverse events (AEs), a history of emotional or psychiatric disorders, poor compliance, and incomplete follow-up data.

      2.2 Treatment

      All patients were treated with PER once daily at bedtime. The initial dose was 1 mg/day or 0.03–0.05 mg/kg/day. The dose of PER was up-titrated every 2 weeks until the target dose or seizure-free status was reached. The target dose was 4–8 mg/day or 0.1–0.15 mg/kg/day.

      2.3 Data collection

      Data at baseline: Sex, age, the duration of epilepsy, the age of onset, the type of epilepsy, etiology, prior ASMs, concomitant ASMs, seizure frequency, and associated data were collected from patient’s clinical records. Seizure frequency at baseline was defined as the mean monthly seizure frequency over the last 12 weeks.
      Efficacy: Seizure frequency after adjunctive PER therapy was evaluated and recorded. Efficacy was evaluated according to the change in seizure frequency at the follow-up period relative to baseline. Responders were patients with a ≥50% seizure reduction from baseline. Responders other than seizure-free patients were called 50–99% responders.
      Tolerability: Adverse events were evaluated and recorded.

      2.4 Statistical analysis

      Normally distributed continuous variables are presented as the mean ± standard deviation (SD) and were analyzed by using a T-test or an analysis of variance. Skewed distributed continuous variables are presented as the median value and interquartile range (IQR). Categorical variables are presented as frequencies and percentages. Skewed distributed continuous variables and categorical variables were analyzed by using the chi-square test or Fisher’s exact test. The Kaplan–Meier method was performed to analyze the relationship between the responder rate and the duration of PER treatment.
      All statistical analyses were performed using SPSS version 23.0 (IBM corporation, Armonk, New York). The significance threshold was set to 0.05.

      3. Results

      3.1 Demographic and baseline characteristics of patients

      One hundred and fourteen patients were enrolled, among whom seven patients (6.1%) were lost to follow-up. The demographic and baseline characteristics of the one hundred and seven patients are shown in Table 1. Five patients in our study had undergone epilepsy surgery before initiating PER. They included surgery for moyamoya disease, surgery of the right lateral frontal lobe, surgery of the left frontal lobe, obstructive cerebral spinal ventriculoperitoneal shunt, and vagus nerve stimulation + deep brain stimulation (VNS + DBS). The previous ASMs before the enrollment and the concomitant ASMs at baseline are shown in Table 2.
      Table 1Demographic and baseline characteristics of patients.
      CharacteristicsData for patients receiving PER (n = 107)
      Male, n (%)70 (65.4%)
      Age, years (IQR)8.6 (5.8,10.7)
      Duration of epilepsy, years (IQR)3.8 (2.1, 6.5)
      Age of onset, years (IQR)4.0 (1.1, 6.5)
       ≤1 year25 (23.4%)
       >1 and ≤3 years18 (16.8%)
       >3 and ≤6 years32 (29.9%)
       >6 and ≤12 years30 (28.0%)
       >12 years2 (1.9%)
      Type of patients, n (%)
       Patients with refractory epilepsy91 (85.0%)
       Patients whose PER was the first concomitant ASM16 (15.0%)
      Type of epilepsy, n (%)
       Focal onset epilepsy
      Six patients with FBTCSs were included; SeLECTS, self-limited epilepsy with centrotemporal spikes.
      22 (20.6%)
       Generalized onset epilepsy56 (52.3%)
       Epileptic syndrome29 (27.1%)
        Dravet syndrome12 (11.2%)
        Infantile Epileptic Spasm Syndrome8 (7.5%)
        SeLECTS/variants of SeLECTS6 (5.6%)
        Doose syndrome2 (1.9%)
        Generalized epilepsy with febrile seizure1 (0.9%)
      Seizure frequency at baseline, 4 weeks (IQR)4.0 (1.0, 16.5)
      * Six patients with FBTCSs were included; SeLECTS, self-limited epilepsy with centrotemporal spikes.
      Table 2The prior ASMs and concomitant ASMs used in patients.
      Prior ASMs or concomitant ASMsPatients
      Number of prior (including current) ASMs, n (%)
       116 (15.0%)
       219 (17.8%)
       324 (22.4%)
       411 (10.3%)
       514 (13.1%)
       More than 523 (21.5%)
      Most common prior ASMs (≥10% of patients), n (%)
       Valproic acid89 (83.2%)
       Levetiracetam70 (65.4%)
       Oxcarbazepine49 (45.8%)
       Clonazepam45 (42.1%)
       Topiramate27 (25.2%)
       Lamotrigine26 (24.3%)
       Lacosamide21 (19.6%)
       Phenobarbital14 (13.1%)
      Number of concomitant ASMs associated with PER, n (%)
       127 (25.2%)
       240 (37.3%)
       329 (27.1%)
       49 (8.4%)
      Most common concomitant ASMs (≥10% of patients), n (%)
       Valproic acid73 (68.2%)
       Levetiracetam50 (46.7%)
       Clonazepam31 (29.0%)
       Oxcarbazepine27 (25.2%)
       Topiramate16 (15.0%)
       Lamotrigine15 (14.0%)
       Lacosamide11 (10.3%)
      Etiological characteristics: One hundred and seven patients underwent MRI. Structural brain abnormalities were observed in fifty-eight patients (54.2%). The most common structural abnormalities of these patients were brain atrophy (n = 22, 37.9%), encephalomalacia (n = 16, 27.6%), signal of brain metabolic abnormalities (n = 14, 24.1%), abnormalities of hippocampus (n = 12, 20.7%), and white matter demyelination (n = 9, 15.5%). Some patients (n = 25, 43.1%) suffered from ≥2 abnormalities. There was no significant difference in the incidence of structural brain abnormalities between patients with focal onset epilepsy and those with generalized onset epilepsy (54.6% versus 62.5%, P = 0.518). When patients with focal onset epilepsy and those with generalized onset epilepsy were compared with those with epileptic syndromes, a statistically significant difference was observed (37.9%, P = 0.039). In patients with structural abnormalities who had poor response to PER, 3 cases had indications for surgery based on the PET/MR results and MDT conclusion. The structural abnormalities of these patients were focal cortical dysplasia (FCD) in the left central region, FCD in the right parietal lobe, and FCD in the left frontal lobe. They continued PER after surgery and remained seizure-free up to the last visit. Genetic testing was performed for forty-three patients, and among them, positive results occurred in thirty-one patients (72.1%). The most common genetic abnormalities were associated with ion channels, accounting for 64.5% of positive cases (20/31). Eleven de novo mutations (55%) and 5 complex mutations (a combination of 3 or 4 mutations, 25%) were identified among the 20 mutations described above. The incidence of genetic abnormalities in epileptic syndrome was 79.0% (15/19), and all mutations were associated with ion channels. SCN1A mutations accounted for 80% of positive cases (12/15), including 10 de novo mutations and 3 heterozygous mutations (Table 3, Table 4).
      Table 3Etiological characteristics of the patients.
      Etiology (n/n)
      Positive patients/tested patients.
      Focal onset epilepsy, n (%)Generalized onset epilepsy, n (%)Epileptic syndrome, n (%)
      Structural (58/107)12 (20.7%)35 (60.3%)11 (19.0%)
      Genetic (31/43)3 (9.7%)13 (41.9%)15 (48.39%)
      Immune 41 (25.0%)3 (75.0%)0 (0.0%)
      Unknown 318 (25.8%)14 (45.2%)9 (29.0%)
      a Positive patients/tested patients.
      Table 4Mutation analysis of genetic epilepsy.
      Mutation (n/n)
      Positive patients/tested patients.
      Focal onset epilepsyGeneralized onset epilepsyEpileptic syndrome
      Genetic(31/43)3/2/17
      Positive patients/negative patients/untested patients.
      13/6/37
      Positive patients/negative patients/untested patients.
      15/4/10
      Positive patients/negative patients/untested patients.
      1 (CACNA1H)
      Ion channel.
      1 (SLC9A6)
      Ion channel.
      9 (SCN1A de novo)
      Ion channel.
      1(DEPDC5
      Unknown in OMIM.
      , NPRL3
      Enzyme modulator.
      )
      1 (SCN2A de novo)
      Ion channel.
      3 (SCN1A heterozygous mutations)
      Ion channel.
      1 (SPTBN5
      Regulator of cytoskeleton formation.
      , SETD1B
      Epigenetic regulator of gene transcription.
      )
      1 (GRIN2A)
      Receptor.
      1 (SCN2A de novo)
      Ion channel.
      2 (SCN8A)
      Ion channel.
      1 (KCNQ2)
      Ion channel.
      1 (PLEKHG2)
      Regulator of cytoskeleton formation.
      1 (KCNQ4)
      Ion channel.
      1 (GPR98 de novo)
      Receptor.
      1 (GABRD
      Neurotransmitter.
      , SLC2A1
      Glucose transporter.
      , CACNA1A
      Ion channel.
      , CHD2
      Chromatin remodeler.
      )
      1 (DLAPH3
      Regulator of cytoskeleton formation.
      , POLG2
      Mitochondrial polymerase.
      , GRIN3B
      Positive patients/negative patients/untested patients.
      )
      1 (NFIX)
      CCAAT-binding transcription factor.
      1 (TBC1D24
      Enzyme modulator.
      , PRRT2
      Neurotransmitter.
      )
      1 (GABRB2)
      Receptor.
      1 (PTPN23)
      Transporter.
      Total (n)31315
      a Positive patients/tested patients.
      b Positive patients/negative patients/untested patients.
      c Ion channel.
      d Receptor.
      e Enzyme modulator.
      f Regulator of cytoskeleton formation.
      g Neurotransmitter.
      h Glucose transporter.
      i Chromatin remodeler.
      j Mitochondrial polymerase.
      k Epigenetic regulator of gene transcription.
      l CCAAT-binding transcription factor.
      m Transporter.
      n Unknown in OMIM.

      3.2 Efficacy assessments

      The responder rate and the seizure-free rates were 56.1% (60/107) and 32.7% (35/107), respectively (Table 5), at 12 weeks. The responder rate increased with the duration of PER administration. At 48 weeks, the responder rate reached 77.1% (27/35). Kaplan–Meier analysis revealed similar results (Fig. 1). In twelve patients diagnosed with drug-resistant Dravet syndrome, the responder rate and the seizure-free rate were 50.0% (6/12) and 25.0% (3/12), respectively. Among sixteen patients for whom PER was the first concomitant ASM, thirteen patients were responders (82.8%), and ten patients became seizure-free (64.1%).
      Table 5Efficacy outcomes for different follow-up durations.
      Duration of follow-up, weeksPatients, nSeizure-free, n (%)50–99% responders, n (%)Non-responders, n (%)
      1210735 (32.7%)25 (23.4%)47 (43.9%)
      247120 (28.2%)25 (35.2%)26 (36.6%)
      48357 (20.0%)20 (57.1%)8 (22.9%)
      Figure thumbnail gr1
      Fig. 1Kaplan–Meier survival analysis of follow-up data.
      Etiology and type of epilepsy: At 24 weeks, the responder rate was 52.6% in patients with structural abnormalities (20/38) and 75.8% in patients without structural abnormalities (25/33); the difference was not statistically significant (P = 0.052). In patients in whom genetic abnormalities, ion channel-associated mutations, and SCN1A mutations were identified, the responder rates were 54.6% (12/22), 56.2% (9/16), and 66.7% (6/9), respectively. There was also no significant difference in the responder rates among the focal onset epilepsy, generalized onset epilepsy, and epileptic syndrome groups (P = 0.657) (Table 6).
      Table 6Efficacy analysis of different etiologies and types of epilepsy.
      Etiology or type of epilepsyPatients, nSeizure-free, n (%)50–99% responders, n (%)Non-responders, n (%)P value
      Structural abnormalities389 (23.7%)11 (28.9%)18 (47.4%)0.052
      Without structural abnormalities3311 (33.3%)14 (42.4%)8 (24.2%)
      Genetic abnormalities224 (18.2%)8 (36.4%)10 (45.5%)/
      Mutations associated with ion channels162 (12.5%)7 (43.8%)7 (43.8%)/
      SCN1A mutations90 (0.0%)6 (66.7%)3 (33.3%)/
      Focal onset epilepsy125 (41.7%)4 (33.3%)3 (25.0%)0.657
      Generalized onset epilepsy3610 (27.8%)12 (33.3%)14 (38.9%)
      Epileptic syndrome235 (21.7%)9 (39.1%)9 (39.1%)
      Early add-on versus late add-on: Perampanel was used as an early add-on (after ≤2 prior ASMs) in thirty-five patients and as a late add-on (after >2 prior ASMs) in seventy-two patients at 12 weeks. The responder rates were significantly higher in the early add-on group than in the late add-on group at 12 weeks and 24 weeks (P = 0.01 at 12 weeks, P = 0.004 at 24 weeks). At 48 weeks, the responder rate of the former was also higher, although the difference was not statistically significant (P = 0.073). The results are shown in Table 7.
      Table 7Comparison of efficacy between the early add-on group and the late add-on group.
      Duration of follow-up, weeksPatients, nPatients in different groups, nResponders, n (%)Non-responders, n (%)P value
      12107Early add-on n = 3528 (80.0%)7 (20.0%)0.01
      Late add-on n = 7232 (44.4%)40 (55.6%)
      2471Early add-on n = 2320 (87.0%)3 (13.0%)0.004
      Late add-on n = 4825 (52.1%)23 (47.9%)
      4835Early add-on n = 1010 (100.0%)0 (0.0%)0.073
      Late add-on n = 2517 (68.0%)8 (32.0%)

      3.3 Safety and tolerability assessments

      Thirty-two patients (29.9%) suffered from AEs, including irritability (14/32, 43.8%), dizziness (6/32, 18.8%), somnolence (5/32, 15.6%), ataxic gait (4/32, 12.5%), weight gain (2/32, 6.3%), and tinnitus (1/32, 3.1%) (Fig. 2). Most AEs were observed during the initial follow-up period. The severity of AEs gradually decreased with prolonged administration time. Patients taking topiramate (TPM) or levetiracetam (LEV) showed more obvious symptoms. After discontinuing TPM/LEV and controlling seizures, the AEs of these patients were alleviated.
      Figure thumbnail gr2
      Fig. 2Adverse events during the follow-up period.

      4. Discussion

      In this study, we explored the efficacy and safety of PER as adjunctive therapy in children and adolescents with epilepsy from real-world data. Our retrospective data analysis demonstrated that the responder rate and the seizure-free rates were 56.1% (60/107) and 32.7% (35/107), respectively, at 12 weeks. In a multicenter, randomized, double-blind, placebo-controlled, parallel-group study, 133 adolescents (12–17 years) on a regimen of 1–3 ASMs for FOSs were randomized [
      • Lagae L.
      • Villanueva V.
      • Meador K.J.
      • Bagul M.
      • Laurenza A.
      • Kumar D.
      • et al.
      Adjunctive perampanel in adolescents with inadequately controlled partial-onset seizures: A randomized study evaluating behavior, efficacy, and safety.
      ]. The 50% responder rate during the 13-week maintenance period was 37.0% in the placebo group versus 59.0% in the PER group (P = 0.0144) [
      • Lagae L.
      • Villanueva V.
      • Meador K.J.
      • Bagul M.
      • Laurenza A.
      • Kumar D.
      • et al.
      Adjunctive perampanel in adolescents with inadequately controlled partial-onset seizures: A randomized study evaluating behavior, efficacy, and safety.
      ]. In another study, twenty-two patients (3.1–11.4 years) with refractory epilepsy were included [
      • Yun Y.
      • Kim D.
      • Lee Y.J.
      • Kwon S.
      • Hwang S.K.
      Efficacy and tolerability of adjunctive perampanel treatment in children under 12 years of age with refractory epilepsy.
      ]. After an average of 9.2 months of follow-up, 68.2% of the patients showed a ≥50% reduction in seizure frequency, including 22.7% of patients who achieved seizure freedom [
      • Yun Y.
      • Kim D.
      • Lee Y.J.
      • Kwon S.
      • Hwang S.K.
      Efficacy and tolerability of adjunctive perampanel treatment in children under 12 years of age with refractory epilepsy.
      ]. Chang et al. reported that the responder rate and the seizure-free rates were 43.4% and 12.5%, respectively, after 6 months of PER treatment in young children with refractory epilepsy [
      • Chang F.M.
      • Fan P.C.
      • Weng W.C.
      • Chang C.H.
      • Lee W.T.
      The efficacy of perampanel in young children with drug-resistant epilepsy.
      ]. The results of the present study were concordant with those of previous studies with regard to the clinical efficacy of PER. This study provides strong evidence to support the application of PER in the adjunctive treatment of epilepsy in the pediatric population.
      Our series included twelve patients with Dravet syndrome; after PER treatment, the responder rate was 50.0% (6/12), and the seizure-free rate was 25.0% (3/12). In two previous studies, the responder rate was 67.0% and 80.0% in patients with Dravet syndrome [
      • Chang F.M.
      • Fan P.C.
      • Weng W.C.
      • Chang C.H.
      • Lee W.T.
      The efficacy of perampanel in young children with drug-resistant epilepsy.
      ,
      • Lin K.L.
      • Lin J.J.
      • Chou M.L.
      • Hung P.C.
      • Hsieh M.Y.
      • Chou I.J.
      • et al.
      Efficacy and tolerability of perampanel in children and adolescents with pharmacoresistant epilepsy: The first real-world evaluation in Asian pediatric neurology clinics.
      ]. These results indicated that PER may be efficacious for the treatment of seizures in patients with Dravet syndrome. SCN1A mutations were detected in nine patients. The responder rate in these patients reached 66.7% (6/9). SCN1A mutation represents the archetypal channelopathy associated with a wide phenotypic spectrum of epilepsies ranging from genetic epilepsy with febrile seizures plus to developmental and epileptic encephalopathies [
      • Scheffer I.E.
      • Nabbout R.
      SCN1A-related phenotypes: Epilepsy and beyond.
      ]. Ishikawa et al. described a female patient with early myoclonic encephalopathy due to an SCN1A mutation [
      • Ishikawa N.
      • Tateishi Y.
      • Tani H.
      • Kobayashi Y.
      • Itai T.
      • Miyatake S.
      • 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.
      ]. Her apneic seizures, which were refractory to many ASMs, were successfully treated with adjunctive PER [
      • Ishikawa N.
      • Tateishi Y.
      • Tani H.
      • Kobayashi Y.
      • Itai T.
      • Miyatake S.
      • 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.
      ]. Perampanel also showed good efficacy in patients with Lennox–Gastaut syndrome (LGS). Auvin et al. and Crespel et al. stated that the responder rate was 69.2% and 64.8% [
      • Auvin S.
      • Dozieres B.
      • Ilea A.
      Use of perampanel in children and adolescents with Lennox-Gastaut Syndrome.
      ,
      • Crespel A.
      • Tang N.P.L.
      • Macorig G.
      • Gelisse P.
      • Genton P.
      Open-label, uncontrolled retrospective study of perampanel in adults with Lennox-Gastaut syndrome.
      ]. Based on the evidence, we considered that PER could be used for a variety of types of pediatric epilepsy, especially for Dravet syndrome and other epileptic encephalopathies.
      The effectiveness of several emerging new treatment options in the treatment of Dravet syndrome or other encephalopathies has been demonstrated in previous studies. Lagae et al. and Knupp et al showed that the responder rates of fenfluramine (FF) (0.7 mg/kg) for the convulsive seizures in Dravet syndrome and the drop seizures in LGS were 68.0% and 25.3%, respectively [
      • Lagae L.
      • Sullivan J.
      • Knupp K.
      • Laux L.
      • Polster T.
      • Nikanorova M.
      • et al.
      Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial.
      ,
      • Knupp K.G.
      • Scheffer I.E.
      • Ceulemans B.
      • Sullivan J.E.
      • Nickels K.C.
      • Lagae L.
      • et al.
      Efficacy and safety of fenfluramine for the treatment of seizures associated with Lennox-Gastaut syndrome: A randomized clinical trial.
      ]. However, there is an association between FF and valvular heart disease and pulmonary arterial hypertension, which limits the use of FF [
      • Cannistra L.B.
      • Gaasch W.H.
      Appetite-suppressing drugs and valvular heart disease.
      ,
      • McGee M.
      • Whitehead N.
      • Martin J.
      • Collins N.
      Drug-associated pulmonary arterial hypertension.
      ]. In two Meta-Analysis associated with adjunctive cannabidiol (CBD), the responder rate for the convulsive seizures in Dravet syndrome and the drop seizures in LGS were 45.4% and 40.0%, respectively [
      • Lattanzi S.
      • Brigo F.
      • Trinka E.
      • Zaccara G.
      • Striano P.
      • Del Giovane C.
      • et al.
      Adjunctive cannabidiol in patients with Dravet syndrome: A systematic review and meta-analysis of efficacy and safety.
      ,
      • Lattanzi S.
      • Brigo F.
      • Cagnetti C.
      • Trinka E.
      • Silvestrini M.
      Efficacy and safety of adjunctive cannabidiol in patients with Lennox-Gastaut syndrome: A systematic review and meta-analysis.
      ]. Significantly, response to treatment with FF and CBD could be observed in patients with other epileptic conditions (e.g., CDKL5 deficiency disorder, SCN8A developmental and epileptic encephalopathy, and Aicardi, Dup15q, and Doose syndromes) as well [
      • Lattanzi S.
      • Trinka E.
      • Striano P.
      • Rocchi C.
      • Salvemini S.
      • Silvestrini M.
      • et al.
      Highly purified cannabidiol for epilepsy treatment: A systematic review of epileptic conditions beyond Dravet syndrome and Lennox-Gastaut syndrome.
      ,
      • Aledo-Serrano Á.
      • Cabal-Paz B.
      • Gardella E.
      • Gómez-Porro P.
      • Martínez-Múgica O.
      • Beltrán-Corbellini A.
      • et al.
      Effect of fenfluramine on seizures and comorbidities in SCN8A-developmental and epileptic encephalopathy: A case series.
      ]. In view of the comparative effectiveness, we considered that PER can be used as an option for the treatment of epileptic syndromes in clinical practice. Whereas, the efficacy of PER for epileptic syndromes needs to be verified by further research because of the small sample size of patients with epileptic syndromes in the previously performed studies. Besides, the comparison of the efficacy of PER, FF, and CBD should be investigated in future clinical trials.
      We also analyzed the primary factors affecting the efficacy of PER. No significant difference in efficacy was observed among patients with different etiologies and epilepsy types. This finding was consistent with those of other studies, indicating that PER was efficacious for the treatment of various types of epilepsy [
      • Yun Y.
      • Kim D.
      • Lee Y.J.
      • Kwon S.
      • Hwang S.K.
      Efficacy and tolerability of adjunctive perampanel treatment in children under 12 years of age with refractory epilepsy.
      ]. Additionally, PER was more effective in the early add-on setting than after 3 or more ASMs. Villanueva V et al. also showed that the seizure-free rate and the retention rate in idiopathic generalized epilepsy patients starting PER as an early add-on were markedly higher than those in patients starting PER as a late add-on (seizure-free rate, 71.7% vs 52.1%, P = 0.02; retention rate, 92.5% vs 78.1%, P = 0.038) [
      • Villanueva V.
      • Montoya J.
      • Castillo A.
      • Mauri-Llerda J.Á.
      • Giner P.
      • López-González F.J.
      • et al.
      Perampanel in routine clinical use in idiopathic generalized epilepsy: The 12-month GENERAL study.
      ]. Another multicenter, retrospective, observational study included One hundred and forty-nine patients who experienced inadequate seizure control on ASM monotherapy and tried ≤3 ASM monotherapies before initiating PER as a first add-on therapy [
      • Santamarina E.
      • Bertol V.
      • Garayoa V.
      • García-Gomara M.J.
      • Garamendi-Ruiz I.
      • Giner P.
      • et al.
      Efficacy and tolerability of perampanel as a first add-on therapy with different anti-seizure drugs.
      ]. The responder rate was 84.6% at 12 months [
      • Santamarina E.
      • Bertol V.
      • Garayoa V.
      • García-Gomara M.J.
      • Garamendi-Ruiz I.
      • Giner P.
      • et al.
      Efficacy and tolerability of perampanel as a first add-on therapy with different anti-seizure drugs.
      ]. Therefore, the use of PER as an early add-on was more appropriate than its use as a late add-on. To the best of our knowledge, the current study is the first to compare the efficacy of PER as an early add-on or late add-on in a pediatric population, and the result that higher efficacy was observed in the early add-on group is consistent with the results of previous studies in adults.
      The incidence of AEs in our study was 29.9% (32/107). No serious AEs were observed. In the study reported by Qu et al., the common AEs in Chinese patients (2–14 years) with refractory epilepsy included irritability (12.5%), somnolence (9.4%), dizziness (7.3%), and headache (5.2%) [
      • Qu R.
      • Dai Y.
      • Chen X.
      • Li R.
      • Liu M.
      • Zhu Y.
      Effectiveness and safety of perampanel in Chinese paediatric patients (2–14 years) with refractory epilepsy: a retrospective, observational study.
      ]. Perampanel was generally safe and well tolerated in the pediatric population based on these results. Several studies also investigated the safety and tolerability of PER in the adults or elderly [
      • Weiping L.
      • Dong Z.
      • Zhen H.
      • Patten A.
      • Dash A.
      • Malhotra M.
      Efficacy, safety, and tolerability of adjunctive perampanel in patients from China with focal seizures or generalized tonic-clonic seizures: Post hoc analysis of phase III double-blind and open-label extension studies.
      ,
      • Lattanzi S.
      • Cagnetti C.
      • Foschi N.
      • Ciuffini R.
      • Osanni E.
      • Chiesa V.
      • et al.
      Adjunctive perampanel in older patients with epilepsy: A multicenter study of clinical practice.
      ]. According to the results from our study and previous studies, the tolerability profile of PER in children, adults, and the elderly was similar while the proportion of these AEs was different. In general, the most common AEs of PER treatment were irritability, somnolence, and dizziness.
      The main limitations of this study are its retrospective design, lack of randomization, and lack of a control group. Furthermore, there may be some bias in the analysis of efficacy as a result of the heterogeneity of the recruited patients. Further follow-up studies are needed to evaluate the long-term efficacy and safety of adjunctive PER. However, there are several strengths of the study as well: the sample of patients included was relatively large, the real-world setting represents clinical practice, and the superior efficacy of PER as early add-on therapy in pediatric patients was demonstrated for the first time.

      5. Conclusion

      Data from real-world clinical settings were analyzed. Efficacy assessments revealed that adjunctive PER was efficacious for uncontrolled epilepsy in pediatric patients. The etiology and type of epilepsy did not influence the efficacy of adjunctive PER. In particular, PER was more effective in the early add-on setting than in the late add-on setting, which has not been reported in pediatric patients in previous studies. Safety assessments revealed that PER was well tolerated.

      Declaration of competing interest

      The authors declare that there are no conflicts of interest.

      Acknowledgments

      We would like to thank all the patients for participating in the study.

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