A multicenter, retrospective study of patients with developmental and epileptic encephalopathy (DEEs) [702] found that 51.7% of patients had signicant improve­ment in at least one seizure type. Seizure freedom for each specic type of seizure at 12months was signicantly achieved by 35% of patients with generalized tonic– clonic seizures (GTCS, p<0.001), 17% with tonic seizures (TS) (p=0.016) and 37% with seizure clusters (p<0.001). Patients achieved seizure freedom from other seizure types but with no statistical signicance: 7% freedom from focal onset sei­zures (FOSs), 28% freedom from atypical absences (AAs), 6% freedom from atonic seizures (ATSs), and 18% freedom from myoclonic seizures (MSs). Twenty-nine patients discontinued perampanel: 18 (21%) due to AEs, 8 (9%) due to lack of ef­cacy, and 3 (3%) due to seizure aggravation. Adverse events, mostly mild or moder­ate, were reported in 53% of patients, and irritability/mood changes (22%) and somnolence (17%) were the most frequent.

A multicenter retrospective analysis of the long-term efcacy of adding PER treatment for patients with Lennox–Gastaut syndrome (LGS) found that 52 subjects (59.8%) experienced treatment failure at a median time of 12months. Treatment failure was due to lack of efcacy in 27 patients (52.0%), lack of tolerance in 14 (27.0%), and both reasons in 11 (21.0%). Slower titration times compared to faster titration times are associated with a risk of PER failure, while the occurrence of adverse events increases the risk of treatment failure. At a median follow-up time of 11months, 36 patients (41.4%) were responders. After a median of 21months, 13/36 patients (36.1%) had seizure recurrence; the overall rate of seizure responders was 23 of 87 patients (26.4%) at the end of follow-up [703].

Belousova et al. [706] also conducted an observational study on pediatric patients, in which 47% of the enrolled patients had focal seizures, 65% had focal seizures converted to bilateral tonic–clonic seizures, and 65% had primary general­ized tonic–clonic seizures. Seizure cessation occurred in 12%, 19%, and 55% of patients, respectively, after treatment. The most common side effects were fatigue (26%), nasopharyngitis (19%), dizziness (13%), irritability (13%), fever (13%), and vomiting (11%).

−50.0% for motor focal seizures with conscious retention, −73.3% for nonmotor focal seizures with conscious retention, −28.6% for focal seizures with disturbance of consciousness, and −62.6% for focal to bilateral tonic seizures. Generalized tonic seizures were changed at a rate of −20.0%. These results suggest that PER is well-tolerated and effective in reducing seizure frequency in adolescent patients. No unexpected safety concerns were observed, and slow titration may reduce the inci­dence of adverse effects.

An observational study in Chinese patients showed good efcacy, safety, and tolerability of PER in children (aged 4–12years) with intractable epilepsy. The 50% response rates at 4, 8, 12, 24, 36, and 48weeks after the addition of PER were

Nuno Canas etal. [711] analyzed the efcacy and safety of PER in 60 patients after the failures of three antiseizure drugs and compared the efcacy of patients treated with PER as the preferred additional treatment (n=21). At 12months, there was no signicant difference in retention between the preferred add-on therapy group and the last-add-on therapy group (93.8% vs. 66.7%); however, freedom from seizures among patients in the rst group who preferred add-on therapy (81.2% vs. 27.8%; p=0.002) and response rate (93.8% vs. 44.4%; p=0.002) were signicantly higher. There was no signicant difference in tolerability between the two groups. Adverse events were reported in 54.3% of patients; most of these were mild or moderate, and dizziness was the most common.

Labate etal. [713] investigated the efcacy of PER in patients with medial tem­poral lobe epilepsy in real-world conditions. A total of 37 patients with medial tem­poral lobe epilepsy older than 12years of age were enrolled. The patients were divided into two groups: Group 1 (20/37 patients) was treated with PER after failure of the rst antiseizure drug, and Group 2 (17/37 patients) was treated with PER after the failure of ≥2 antiseizure drugs. At 3months, 70% of patients in the rst group

29.4% in the second. The authors speculate that PER has better efcacy as a pre­ferred add-on therapy in patients with medial temporal lobe epilepsy.

A post hoc analysis of the open-label extension (OLEx) study by Trevor Resnick etal. [715] found that 53.8% of patients who received PER treatment during the double-blinded study and did not have FBTCS remained seizure-free for up to 24months during Study 307. In contrast, 31.6% (6/19) of patients without GTCS in the double-blinded phase of Study 332 remained seizure-free for up to 24months in the OLEx phase. More than 40% of patients were seizure-free for at least six con­secutive months. Multivariate analysis showed that the best predictors of achieving FBTCS seizure freedom for at least 6months were a lower baseline seizure fre­quency (p=0.0014) and a lack of enzyme-induced antiseizure drug use at baseline (p =0.0056). In addition, PER was well-tolerated, and no new safety indicator issues were identied. The most common TEAE was dizziness. Based on the Study 332 open-label extension study, a phase study evaluating the long-term efcacy and safety of adjuvant PER treatment (up to 12mg/day) in patients aged over 12years with generalized tonic–clonic seizures found a median reduction in GTC episodes per 28days of 77% (weeks 1–13) and 90% (weeks 40–52), respectively. Retention rates were 88% (6months) and 75% (12months), respectively. Freedom from sei­zures was maintained for at least 2years regardless of the treatment received during the core study period. The most common pattern daily dose was >4–8mg/day, indi­cating that PER is generally well-tolerated and provides a long-term treatment option for patients ≥12years of age [716].

A systematic review including 21 studies aimed to assess the role of PER in ter­minating status epilepticus. It was found that PER was administered in 324 cases and started at a dose of 2–36mg between 30min and 59days after the onset of SE.SE was halted between 1h and 4weeks after the initiation of PER.A total of 119 patients (36.6%) were considered PER responders. However, according to the GRADE methodology, the quality of evidence for all outcomes was very low, and further clinical studies are needed to determine the appropriate timing, dosage, and titration methods for safe and effective termination of SE [719].

Lanzone etal. [720] studied QEEG changes in patients undergoing adjunctive treatment of epilepsy with PER, analyzed EEG changes in 25 patients with epilepsy before and after medication, and evaluated the correlation of their clinical character­istics. The results showed that θ power increased signicantly on QEEG after the use of PER, but there was no signicant change in EEG connectivity. Patients who responded to PER treatment had greater α power at T0 and T1, indicating that this parameter can predict the response to treatment. Therefore, the authors suggest that treatment-EEG is a viable tool for studying the neurophysiological changes induced by antiseizure drugs, emphasizing that α power changes can be used as a marker of response to antiseizure drugs.

0.9–2.7mg/kg PER, and the authors suggest that while the efcacy of these drugs against neonatal seizures may be limited, their efcacy increases with postnatal development. Vazquez etal. [727] studied the developmental effects of PER in preg­nant rats and rabbits and found that PER may be associated with postimplantation failure and/or some specic delays in physical development, but not with fertility and early embryonic development.

PER is a selective noncompetitive AMPA antagonist that slows the progression of the amyotrophic lateral sclerosis phenotype and increases anterior horn cell num­bers in transgenic mice. Hotait et al. [730] conducted a study in six patients to understand the safety of PER in patients with amyotrophic lateral sclerosis. Subjects were started on 2mg/day PER with weekly increases of 2mg/day to a maximum dose of 8mg/day. It was found that all six volunteers recruited had side effects to varying degrees; these mainly included mental and behavioral abnormalities. Two of the patients completed the trial and the other four withdrew due to the incidence of adverse events. All participants reported resolution of these events after discon­tinuation of the study regimen. The authors speculate that the use of PER in this amyotrophic lateral sclerosis study was limited by its poor tolerability. Another sys­tematic review and meta-analysis of PER in the treatment of amyotrophic lateral sclerosis found signicant improvements in cortical motor hyperexcitability with PER compared to placebo, but not according to the revised ALS Functional Rating Scale score. PER was associated with adverse events, such as irritability, somno­lence, anger, and dysarthria [731].

Recent studies have shown that PER can play a neuroprotective role in hemor­rhagic and ischemic stroke models by regulating blood–brain barrier function. To understand the neuroprotective effects of PER in neurovascular unit and traumatic brain injury models invitro, Chen etal. [732] used cultured neurons and found that PER protected the cells from traumatic and excitotoxic damage, and treatment with PER attenuated lipid peroxidation and expression of inammatory cytokines. In addition, PER increased Sirt3 protein expression, enhanced the activities of mito­chondrial enzymes IDH2 and SOD2, and preserved blood–brain barrier (BBB) function invitro. Sirt3 expression knockdown with a specic siRNA (si-Sirt3) par­tially preserved the effects of PER on neuronal injury and blood–brain barrier func­tion. The authors suggested that PER could protect neurons and reduce brain damage after TBI by activating the Sirt3 signaling cascade.

Characteristics oftheDrug

partial- onset seizures in patients 1month of age and older with epilepsy.

Tablets: 10mg, 25mg, 50mg, 75mg, and 100mg Oral solution: 10mg/mL Injection: 50mg/5mL single-dose vial

To understand the clinical efcacy and tolerability of BRV in patients with epilepsy, Stefanatou etal. [738] performed a retrospective observational multicenter study. Patients were 16years of age or older with various types of epilepsy and at least one follow-up after dose titration. The 156 enrolled patients had a mean age of 40years (16–84years), a mean duration of seizures of 21years, 81% diagnosed with focal