Search Results (42)

Background/Objectives: This study aimed to investigate whether therapy with perampanel is associated with the development of psychosis or psychosis-like symptoms in patients with epilepsy. Methods: We conducted systematic electronic searches in PubMed, Google Scholar, ScienceDirect, and Scindex databases. We included articles published as case reports/case series, as well as conference abstracts and letters from the editor, if they contained enough data for analysis and quality assessment. The main inclusion criteria relate to patients who experienced psychosis or psychosis-like symptoms described by the authors during perampanel therapy or during its recent use. Results: Publications (n = 17) describing a total of 33 patients who met the inclusion criteria were included. Patient ages ranged from 11 to 70 years, and the majority of them were female (66.67%). A confirmed personal psychiatric history was identified in 60.61% of patients. The time interval between the initiation of perampanel and the onset of adverse events varied significantly across cases. The most frequently reported symptom was aggression (75.75%), followed by irritability (30.30%), while delusions or hallucinations were observed in 8 patients (24.24%). Conclusions: Clinicians should be aware that psychosis or psychosis-like symptoms may represent dose-dependent adverse effects of perampanel with a satisfactory prognosis. Identified risk factors for these developments were positive personal psychiatric history, antiseizure polytherapy at high doses, women’s gender, and focal epilepsies with secondary generalization, mainly manifested as tonic–clonic seizures. Early recognition of symptoms, followed by drug discontinuation, dose reduction, symptomatic treatment, or a combination of the mentioned strategies, is crucial for achieving better outcomes. Full article

Gliomas are the most common malignant primary brain tumors in adults. The treatment of high-grade gliomas is very limited due to their diffuse infiltration, high plasticity, and resistance to conventional therapies. Although they were long considered passive massive lesions, they are now regarded as functionally integrated components of neural circuits, as they form authentic electrochemical synapses with neurons. This allows them to mimic neuronal activity to drive tumor growth and invasion. Ultrastructural studies show presynaptic vesicles in neurons and postsynaptic densities in glioma cell membranes, while electrophysiological recordings detect postsynaptic currents in tumor cells. Tumor microtubules (TMs), dynamic cytoplasmic protrusions enriched in AMPA receptors, are the structures responsible for glioma–glioma and glioma–neuron connectivity, also contributing to treatment resistance and tumor network integration. In these connections, neurons release glutamate that mainly activates their AMPA receptors in glioma cells, while gliomas release excess glutamate, causing excitotoxicity, altering the local excitatory-inhibitory balance, and promoting a hyperexcitable and pro-tumorigenic microenvironment. In addition, certain gliomas, such as diffuse midline gliomas, have altered chloride homeostasis, which makes GABAergic signaling depolarizing and growth promoting. Synaptogenic factors, such as neuroligin-3 and BDNF, further enhance glioma proliferation and synapse formation. These synaptic and paracrine interactions contribute to cognitive impairment, epileptogenesis, and resistance to surgical and pharmacological interventions. High functional connectivity within gliomas correlates with shorter patient survival. Therapies such as AMPA receptor antagonists (perampanel), glutamate release modulators (riluzole or sulfasalazine), and chloride cotransporter inhibitors (NKCC1 blockers) aim to improve outcomes for patients. Full article

Background/Objectives: Interpersonal violence is an increasing public health concern, and its prediction and prevention remain global challenges. This study aimed to identify prescribed medications associated with interpersonal violence in Spain. Methods: A descriptive, longitudinal and retrospective study and case-non case study of spontaneous reports of adverse drug reactions corresponding to interpersonal violence recorded in the Spanish Pharmacovigilance Database (FEDRA^®) from 1984 to 31 March 2021. Results: 533 cases were reported in the study period. The mean age was 46.70 years with ages ranging from 1 to 99 years. There were no sex differences except in child and adolescent age group where most reports were from male. Main therapeutic groups involved were nervous system (62.3%), anti-infectives for systemic use (10%) and respiratory system (8.6%). Mostly drugs reported were montelukast, levetiracetam, bupropion, donepezil, perampanel, quetiapine, fluoxetine, and lorazepam. A statistically significant association/disproportion in the notification has been found in the reporting of interpersonal violence and different drugs according to the literature, notably atomoxetine, perampanel, memantine, donepezil, montelukast and methylphenidate. Conclusions: The results highlight that interpersonal violence, while rare, could occur as a clinically relevant adverse reaction to a small subset of medications. They underscore the importance of careful prescribing, especially in vulnerable populations and in individuals with a history of psychiatric disorders. Full article

Glutamate receptors represent a potential target for neuroprotection in neurodegenerative neurological conditions. Perampanel, a non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR) antagonist, is clinically approved for the management of epilepsy. Perampanel’s neuroprotective effects have been reported in global and focal cerebral ischemia models, but the cellular mechanisms remain incompletely understood. Therefore, we studied the potential neuroprotective effects of perampanel in rats using the pial vessel disruption (PVD) stroke model, an established focal cortical non-reperfusion ischemic stroke model. Perampanel was given once intraperitoneally (3 mg/kg body weight) 1 h after PVD surgery and repeated on days 2–3 post-surgery. On the fourth day post PVD, animal behavioral assays and imaging, biochemical, and electrophysiological analyses were performed. Compared to vehicle control, perampanel in PVD-treated rats significantly inhibited hippocampal neurodegeneration and long-term potentiation deficits. Perampanel also attenuated PVD-induced motor deficits, depressive/anxiety-like behaviors, and hippocampal-dependent cognitive impairment. In addition, perampanel prevented the PVD-induced downregulation of surface-expressed GluA1 and GluA2 AMPARs and increased phosphorylation of GluA1 at S831 and S845. Molecular docking analysis revealed perampanel binding to transmembrane regions M1, M3 and M4 of GluA1 and GluA2 subunits. Together, our results show that perampanel attenuated PVD-induced neurodegeneration and behavioral deficits by blocking AMPARs and decreasing GluA1 and GluA2 internalization. In addition, this study shows the neuroprotective potential of perampanel through the inhibition of neuroinflammation mediated by activated microglia and astrocytes following cerebral ischemia. This study is the first to evaluate perampanel in the pial vessel disruption model of ischemia without reperfusion, a clinically relevant stroke paradigm that differs fundamentally from middle cerebral carotid artery occlusion and photothrombosis stroke models. Full article

Background: Lennox–Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by treatment-resistant seizures and significant morbidity. Despite multiple approved anti-seizure medications (ASMs), optimal seizure control remains elusive. This has led to ongoing interest in newer ASMs, including those not specifically approved for LGS. This review evaluates the emerging evidence on the use of these agents in LGS management. Methods: We conducted a comprehensive literature search of PubMed, Web of Science, and Embase to identify studies examining perampanel, brivaracetam, cenobamate, ganaxolone, and stiripentol in LGS populations. Both randomized controlled trials and observational studies were included. Results: Perampanel was studied in approximately 300 patients across one Phase 3 trial and seven observational studies, showing responder rates of 26–69% with particular efficacy for generalized tonic–clonic and myoclonic seizures, though behavioral side effects (irritability, aggression) were dose-related concerns. Brivaracetam demonstrated inconsistent efficacy in 59 patients across six studies (0–61.5% responder rates) but offered better behavioral tolerability than levetiracetam. Cenobamate showed exceptional promise in 223 patients across seven studies with 50–85% responder rates and significant polypharmacy reduction, though requiring careful titration. Ganaxolone demonstrated efficacy in LGS-like CDKL5 deficiency phenotypes with 28.2% drop seizure reduction versus placebo. Stiripentol showed potential benefit for generalized seizures in limited LGS data. Conclusions: Several newer ASMs show therapeutic promise in LGS. Perampanel offers the most extensive evidence base, cenobamate demonstrates exceptional efficacy potential, while brivaracetam provides an alternative for levetiracetam-intolerant patients. Further controlled studies are needed to define optimal treatment algorithms. Full article

Epilepsy remains a major therapeutic challenge, with approximately one-third of patients experiencing drug-resistant epilepsy (DRE) despite the availability of multiple antiseizure medications (ASMs). This review aims to evaluate emerging ASMs—cenobamate, fenfluramine, ganaxolone, ezogabine (retigabine), and perampanel—with a focus on their mechanisms of action, pharmacological profiles, and potential role in precision medicine. A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science to identify preclinical and clinical studies evaluating the pharmacodynamics, pharmacokinetics, efficacy, and safety of the selected ASMs. Relevant trials, reviews, and mechanistic studies were reviewed to synthesize the current understanding of their application in DRE and specific epilepsy syndromes. Each ASM demonstrated unique mechanisms targeting hyperexcitability, including the modulation of γ-aminobutyric acid receptor A (GABA-A) receptors, sodium and potassium channels, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptors), and serotonin systems. These mechanisms correspond with specific pathophysiological features in syndromes such as Dravet and Lennox–Gastaut. Evidence from clinical trials supports their use as adjunctive therapies with generally favorable tolerability, though adverse events and variable efficacy profiles were noted. The mechanistic diversity of these emerging ASMs supports their value in personalized epilepsy management, particularly in treatment-resistant cases. While the promise of precision medicine is evident, further studies are required to address challenges related to long-term safety, cost, and equitable access. Full article

Epilepsy is a common brain function disorder. The present study aims to evaluate the long-term effect of perampanel (PRM) and lacosamide (LCM), administered singly in a high-dose or in a low-dose combination of both, on comorbid anxiety, cognitive impairment, BDNF, and Cyclin D1 hippocampal expression in an experimental model of temporal lobe epilepsy with lithium–pilocarpine. PRM (3 mg/kg, p.o.)/LCM (30 mg/kg, p.o.) or PRM+LCM (0.5 mg/kg + 3 mg/kg, p.o.) treatments were administered three hours after the lithium–pilocarpine-induced status epilepticus and continued for up to ten weeks in adult Wistar rats. Our study demonstrated that perampanel and lacosamide administered singly in high doses improved epilepsy-associated cognitive impairment through ameliorating anxiety and facilitating passive learning and memory, with spatial and recognition memory measured in the elevated plus maze, step-through, Y-maze, and object recognition tests, respectively. In addition, the combination of both drugs in low doses demonstrated similar anxiolytic and cognitive-improving effects compared to the singly administered drugs. Moreover, the three experimental groups enhanced the hippocampal expression of the neurotrophic factor BDNF and mitigated the increased levels of the apoptotic factor Cyclin D1. These beneficial effects could be essential mechanisms through which administered anticonvulsants preserve neuronal survival and homeostasis in the CNS and especially in the hippocampus. Full article

Background: Post-stroke epilepsy can reduce patients’ abilities to carry out various activities of daily living. Despite their importance in preventing the onset of post-stroke epilepsy, the prophylactic administration of antiepileptic drugs is controversial due to a lack of high-level clinical research. In this study, we initiated a prospective interventional study of prophylactic antiepileptic drug administration in patients with a subcortical hemorrhage, who are at the highest risk of developing epilepsy after experiencing a stroke. Methods: The study was conducted in a single-center setting and was a single-arm study with no control group; the case entry period started in November 2023 and is due to end in March 2025. Only cases with a subcortical hemorrhage will be included. The treatment regimen used in this study is 2 mg of perampanel per day. Perampanel will be administered for one year, followed by two years of follow-up, for a total study period of three years. The primary endpoint will be the development of epilepsy. Results: Perampanel administration is expected to reduce the incidence of post-stroke epilepsy in comparison to the results of previous reports on the use of alternative treatments. Conclusions: The results of this study will provide new insights into the prevention of post-stroke epilepsy. The relatively small size of this study makes it difficult to provide strong evidence of the efficacy of perampanel, but it may serve as a basis for larger clinical trials. Full article

Perampanel, a novel α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, is registered for the adjunctive treatment of patients (aged ≥ 12 years) with refractory partial-onset seizures. A simple high-performance liquid chromatographic method fluorescence detection (HPLC-FLD) was developed to analyze perampanel in rats’ plasma and validated for bioanalytical purposes. Rats’ plasma (50 µL) was processed by microextraction packed sorbent (MEPS). The analytes were separated using a Hypersil Gold octadecyl silane column (250 × 4.6 mm internal diameter, 5 μm particle size) with isocratic elution. A mobile phase consisting of acetonitrile–methanol–water (275:275:450, v/v/v; containing 50 µL triethylamine and pH adjusted to 3.25 with orthophosphoric acid) was used in this analysis. The flow rate was 1.25 mL/min. Analytes were monitored at an excitation wavelength of 285 nm and an emission wavelength of 430 nm. The linearity range for this validated method was from 3.75 to 300 ng/mL. No endogenous peaks were found in the elution of analytes in drug-free rats’ plasma. Intra- and inter-batch reproducibility studies demonstrated accuracy and precision within the acceptance criteria. The results indicate that the present method is simple, selective, reproducible, and suitable for the analysis of perampanel in small volume samples. The robustness of the method was accessed using MODDE^® design of experiments software version 12.5. Full article

Back ground: Children with epilepsy are affected by several factors, including clinical and social variables. Among these variables, cognitive decline and behavioral disturbances, perceptions of stigma, and fatigue can lead to reductions in quality of life (QOL). Epileptic activities, including seizure severity, frequent seizures, and status epilepticus (SE), have been identified as important predictors of QOL. In addition, the frequency of interictal epileptiform discharges (IEDs) on electroencephalogram (EEG) may also be an important predictor of QOL, because IEDs can lead to cognitive decline and behavioral disturbances. Moreover, frequent seizures and/or IEDs may play a role in emotional mediators, such as stigma and fatigue, in childhood epilepsy. Seizure severity and/or IEDs are, therefore, important QOL-related factors in childhood epilepsy. Seizure severity as a QOL-related factor: Frontal lobe dysfunctions, such as cognitive decline and behavioral disturbances, can result in reduced QOL for both the child and their family. Frontal and prefrontal lobe growth disturbances can be present during active-phase epilepsy in some children with neuropsychological impairments. Recovery from prefrontal lobe growth disturbances may depend on the active seizure period. Children with a shorter active seizure period can recover from disturbances in prefrontal lobe growth more rapidly. In contrast, recovery may be delayed in children with a longer active seizure period. Moreover, frequent seizures can lead to seizure-associated headaches, perceptions of self-stigma and parental stigma, and fatigue. Accordingly, severe seizures can lead to neuropsychological impairments in association with prefrontal lobe growth disturbances in children with epilepsy. EEG abnormalities as QOL-related factors: IEDs on EEG, representing persistent pathological neuronal discharges, may be associated with several pathological aspects. Frontal IEDs can be a risk factor for recurrent seizures, cognitive decline, and behavioral disturbances, and they may also play a role as emotional mediators similar to stigma. In addition, behavioral disturbances may result in the presence of secondary bilateral synchrony (SBS) on EEG. Behavioral disturbances can be improved in association with a reduction in IEDs in children with frontal IEDs and SBS. Therefore, EEG abnormalities, such as frontal IEDs and SBS, can also lead to neuropsychological impairments in children with epilepsy. Therapeutic strategies in children with epilepsy: Seizure severity and IEDs on EEG may be associated with neuropsychological impairments, leading to QOL reduction. Therapeutic management may be desirable to reduce seizures and EEG abnormalities, such as frontal IEDs and SBS, as early as possible to improve QOL in children with epilepsy. During antiseizure medication (ASM) selection and adjustment, physicians should strategize the therapeutic approach to controlling seizures and suppressing EEG abnormalities in children with epilepsy. Among various ASMs, novel ASMs, such as levetiracetam and perampanel, may suppress both clinical seizures and IEDs on EEG; thus, these novel ASMs may represent an important addition to the treatments available for epileptic children presenting with frontal IEDs and SBS. Full article

In children and adolescents with epilepsy, neurodevelopmental comorbidities can impair the quality of life more than seizures. The aim of this review was to evaluate the cognitive and behavioural effects of perampanel (PER) in the paediatric population. We performed a systematic search of the literature, selecting studies published in English including children and adolescents with epilepsy treated with PER. Cognitive and behavioural outcomes were assessed through validated neuropsychological standardised scales. Eighteen studies involving 3563 paediatric patients were included. Perampanel did not impair general cognitive functions and visuospatial skills, whereas a slight improvement in verbal memory and a decline in attentional power were detected. In adolescents with refractory epilepsies, high doses and/or rapid titration of PER and an underlying psychiatric disorder were risk factors for developing or worsening psychiatric outcomes such as anger, aggressiveness, and irritability. Data on children and adolescents treated with new antiseizure medications are scant, and neuropsychiatric effects are tricky to be detected during developmental age. According to the currently available evidence, PER showed an overall favourable risk–benefit profile. Pharmacodynamics, co-administration of other antiseizure medications, and family and personal history of neuropsychiatric disorders should be considered before PER treatment. Full article

(1) Background: Increasing evidence supports the anti-inflammatory and neuroprotective role of perampanel (PER), mediated by decreased expression of pro-inflammatory cytokines and by interference with apoptosis processes. Therefore, the use of PER to treat status epilepticus (SE) with suspected inflammatory etiology is appealing and deserves further investigation. (2) Methods: We retrospectively analyzed seven patients (five F, two M; median age: 62 years) with refractory and super-refractory SE due to a probable or defined inflammatory etiology and treated with PER. (3) Results: PER was administered as the third (4/7) or fourth drug (3/7), with a median loading dose of 32 mg/day (range: 16–36 mg/day) and a median maintenance dose of 10 mg/day (range: 4–12 mg/day). In five cases, SE was focal, while in two patients, it was generalized. SE was caused by systemic inflammation in three patients, while in the other four subjects, it was recognized to have an autoimmune etiology. SE resolution was observed after PER administration in all cases, particularly within 24 h in the majority of patients (4/7, 57.1%). (4) Conclusions: Our data support the efficacy of PER in treating SE when first- and second-line ASMs have failed and suggest a possible earlier use in SE cases that are due to inflammatory/autoimmune etiology. Full article

SERS, a clinical practice where medical doctors can monitor the drug concentration in biological fluids, has been proposed as a viable approach to therapeutic drug monitoring (TDM) of the antiepileptic drug Perampanel. The adoption of an acidic environment during the SERS experiments was found to be effective in enhancing the spectroscopic signal. In this work, we combine SERS experiments, conducted with a custom spinning cell in controlled acidic conditions, with DFT calculations aimed at investigating the possible protonated forms of Perampanel. The DFT-simulated Raman spectra of protonated Perampanel accounts for most of the observed SERS signals, thus explaining the effective role of protonation of the analyte. Our results suggest protonation as a viable approach to fostering SERS of alkaline drugs. Full article

The objective of this study was to validate a novel assay using the volumetric absorptive microsampling (VAMS) technique combined with liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) for the determination of the antiseizure medication perampanel in saliva and its clinical applicability in patients with epilepsy. VAMS tips were loaded with 30 μL of saliva and dried for 60 min. Analytes were extracted with methanol. The supernatant was evaporated under a gentle stream of nitrogen and reconstituted with 60 μL of methanol. Separation and quantification were achieved on a monolithic column connected to a mass spectrometer. Calibration curves were linear between 0.5 and 300 ng/mL. Intra- and inter-day accuracy was within 85.6–103.2% and intra-day and inter-day precision did not exceed 12.1%. Perampanel was stable in samples collected by VAMS and stored under different storage conditions. The VAMS-LC-MS/MS method was validated according to internationally accepted criteria and tested in patients with epilepsy who were receiving a combination of perampanel and other antiseizure medications. The method showed adequate bioanalytical performances, holding great potential as an alternative strategy to support domiciliary TDM in patients with epilepsy treated with perampanel according to the simplicity of sample collection. Full article

Background: Epilepsy is one of the most common neurological disorders. Existing antiseizure medications (ASMs) are still unable to control seizures in one-third of these patients, making the discovery of antiseizure therapies with novel mechanisms of action a necessity. Aim of the Study: This study aimed to determine the safety and efficacy of perampanel (PER) as an adjuvant treatment for children with drug-resistant focal-onset seizures with or without focal to bilateral tonic-clonic seizures. Patients and methods: This is a single-center retrospective study of 38 epileptic pediatric patients, aged 2 to 14, at King Faisal Specialist Hospital and Research Center whose seizures were pharmaco-resistant to more than two antiseizure medications and followed for at least three months after PER adjuvant therapy initiation. Efficacy was assessed by the PER response rate at 3-, 6-, and 12-month follow-up evaluations, and side effects were also reported. Results: Multiple seizure types were reported. Myoclonic seizures were the predominant type of epilepsy in 17 children (44.7%). At 3 months, 6 months, and 12 months of follow-up, approximately 23.4%, 23.4%, and 18.4% of the patients were seizure-free at these time points, respectively. Adverse events were documented in 14 patients (35.7%) and led to the discontinuation of PER in 26.3%, 31.6%, and 36.8% of the studied group at the 3-, 6-, and 12-month follow-ups, respectively. The most common adverse events included dizziness or drowsiness, irritability, gait disturbance, and confusion; however, all were transient, and no serious adverse effects occurred. Conclusion: Our findings confirm the therapeutic efficacy of adjunctive PER in the treatment of drug-resistant epilepsy in children. As an adjunctive treatment for epilepsy, perampanel demonstrated sufficient effectiveness and tolerability. Full article