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Perampanel, a selective, non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, is a once-daily oral anti-seizure medication (ASM) for focal-onset seizures (FOS) and generalized tonic-clonic seizures (GTCS). In the US, perampanel is approved for the treatment of FOS (adjunctive and monotherapy), with or without focal to bilateral tonic-clonic seizures (FBTCS), in patients aged ≥4 years, and as adjunctive treatment of GTCS in patients aged ≥12 years. The monotherapy approvals in the US were based on the Food and Drug Administration's (FDA's) policy allowing extrapolation of adjunctive data to the monotherapy setting in the absence of randomized controlled monotherapy trials; since then, perampanel monotherapy has received approvals in approximately 48 countries. As there are key differences in clinical evidence of perampanel as adjunctive therapy vs monotherapy, we review the clinical outcomes of perampanel when administered as primary or secondary monotherapy. Eight publications reporting the efficacy and safety outcomes of perampanel monotherapy in clinical trial and real-world settings were selected during our literature search and are included; these comprise three Eisai-sponsored studies in patients with epilepsy: one prospective, open-label, Phase III clinical trial of patients with newly diagnosed epilepsy (Study 342 [FREEDOM]) and two retrospective, real-world Phase IV studies of patients with epilepsy who received perampanel during routine clinical care (Studies 504 and 506 [PROVE]); and five retrospective, real-world studies in patients with epilepsy who were prescribed perampanel during routine clinical care. Results from these studies demonstrated that seizure freedom may be achieved following treatment with perampanel monotherapy (either primary or secondary), with favorable retention rates and safety profiles. Overall, the clinical evidence supports the use of perampanel monotherapy both in newly diagnosed patients and in those who have been unable to control their seizures with other ASMs., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Ideal rescue treatments for acute treatment of seizure clusters should be easy to administer, so it is important to assess user perceptions of these treatments. Diazepam nasal spray is designed to have a rapid, noninvasive, and socially acceptable route of administration. Patient and caregiver (including care partner) responses to surveys from a phase 3 safety study of diazepam nasal spray are reported., Methods: The study enrolled patients aged 6-65 years with seizure clusters. Surveys distributed to patients and caregivers at study end, completion, or discontinuation collected data on comfort using diazepam nasal spray outside the home, timing of administration and return to their usual selves, and comfort of use compared with rectal diazepam. Safety was assessed., Results: Of 175 patients enrolled at the October 31, 2019, interim cutoff, 158 received diazepam nasal spray. Sixty-seven (42.4%) patients and 84 (53.2%) caregivers responded to the surveys (including 35 matched pairs). Most patients (78.8%, 52/66) responded that they were very comfortable doing activities outside the home with diazepam nasal spray available; 59.4% of patients returned to their usual selves within an hour of administration. Twenty-seven (40.3%) of these patients reported self-administration, 48% doing so at the first sign of a seizure. Administration of diazepam nasal spray was rated extremely or very easy by 93.8% of caregivers. Safety profile was consistent with diazepam rectal gel; no patient discontinued owing to treatment-emergent adverse events. Nasal discomfort was typically mild and transient. Among patients who had used diazepam rectal gel, most were not at all comfortable using it outside the home (86.7%) or at home (64.5%) compared with diazepam nasal spray, whereas caregivers reported that diazepam rectal gel was not at all easy to use compared with diazepam nasal spray., Conclusions: This survey from the phase 3 safety study of diazepam nasal spray shows that patients and caregivers were satisfied with, and more comfortable using, diazepam nasal spray than rectal diazepam in public. NCT02721069., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Tolerance is a known consideration for maintenance use of benzodiazepines and other antiseizure drugs; however, clinical experience suggests that tolerance may not be anticipated with long-term intermittent use of benzodiazepines as rescue therapy. Diazepam nasal spray (Valtoco®) is a proprietary intranasal formulation approved for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) in patients with epilepsy aged ≥6 years. Reported here are exploratory analyses investigating whether there was evidence of development of tolerance in an interim analysis of a long-term, phase 3, open-label safety study of diazepam nasal spray., Methods: Patients and care partners were trained to administer 5, 10, 15, or 20 mg of diazepam nasal spray (age- and weight-based dosing), with a second dose administered 4-12 hours later if needed. A series of analyses were performed to assess evidence of tolerance using 2 equal, adjacent time periods and data for each patient to compare the proportion of events for which second doses of diazepam nasal spray (as a proxy for effectiveness) were administered in period 1 compared with period 2., Results: A total of 175 patients were enrolled at interim cutoff, and 158 were treated with diazepam nasal spray for 3370 seizure-cluster events. For 73.4% of patients, duration of exposure to diazepam nasal spray was ≥12 months. A total of 191 analyses were conducted; the proportion of analyses in which second doses in period 2 were lower than in period 1 was 72.8%. Only 5 analyses showed nominally statistically significant changes (P < 0.05); this is fewer than expected by chance, and these differences were not directionally consistent. There was no safety signal with continued use., Conclusions: These analyses found no statistical evidence of tolerance with the use of diazepam nasal spray over time based on use of a second dose in an initial period of the study compared with a subsequent period for each patient. These results are in agreement with prior studies of benzodiazepine rescue therapy., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Irritability is a adverse effect of many antiseizure medications (ASMs), but there are no validated measures currently available to characterize this behavioral risk. We examined both child and parent/guardian versions of the Affective Reactivity Index (ARI), a validated measure developed for application in adolescent psychiatry, to determine its sensitivity to ASM-related irritability. We hypothesized irritability increases associated with levetiracetam (LEV) but not lamotrigine (LTG) or oxcarbazepine (OXC)., Method: The ARI was administered to 71 child and parent/guardian pairs randomized to one of three common ASMs (LEV, LTG, OXC) used to treat new-onset focal (localization-related) epilepsy. Subjects were recruited as part of a prospective multicenter, randomized, open-label, parallel group design. The ARI was administered at baseline prior to treatment initiation and again at 3 months after ASM initiation., Results: There was a significant increase in ARI ratings for both child and parent/guardian ratings for LEV but not LTG or OXC when assessed 3 months after treatment initiation. When examined on the individual subject level using a criterion of at least a 3-point ARI increase, there was an increase associated with LEV for child ratings but not parent/guardian scores., Conclusion: Both child and parent/guardian versions of the ARI appear sensitive to medication-induced irritability associated with LEV on both the group and individual levels. The findings extend the applicability of ARI from characterizing the presence of clinical irritability as a psychiatric diagnostic feature to a more modifiable aspect of behavior change related to medication management and support its use in clinical trial applications., (Copyright © 2019. Published by Elsevier Inc.)

Objective: We studied spatiotemporal dynamics of electrocorticographic (ECoG) high-gamma modulation (HGM) during visual naming., Methods: In 8 patients, aged 4-19 years, with left hemisphere subdural electrodes, propagation of ECoG HGM during overt visual naming was mapped with trial-averaged time-frequency analysis. Group-level synthesis was performed by transforming all electrodes to a standard space and assigning cortical parcels based on a reference atlas., Results: After image display following cortical parcels were activated: inferior occipital, caudal angular, fusiform, and middle temporal gyri, and superior temporal sulcus [0-400 ms]; rostral pars triangularis (A45r), inferior frontal sulcus, caudal dorsolateral premotor cortex (A6cdl) [300-600 ms]; caudal ventrolateral premotor cortex (A6cvl), caudal pars triangularis (A45c), pars opercularis (A44) [400-800 ms]; primary sensorimotor cortex [600-1400 ms], with most prominent HGM in glossolaryngeal region (A4tl). Lastly, auditory cortex (A41/A42) and superior temporal gyrus (A22) were activated [900 ms-1.4 s]. After 1.5 s, HGM decreased globally, except in ventrolateral premotor cortex., Conclusions: During visual naming, ECoG HGM shows a sequential but overlapping spatiotemporal course through cortical regions. We provide neurophysiologic validation for a model of visual naming incorporating both modular and distributed cortical processing. This may explain cognitive deficits seen in some patients after surgery involving HGM naming sites outside perisylvian language cortex., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Epilepsy affects millions of people worldwide. Approximately one-third have pharmacoresistant epilepsy, and of these, the majority are not candidates for epilepsy surgery. Vagus nerve stimulation (VNS) therapy has been an option to treat pharmacoresistant seizures for 30 years. In this update, we will review the clinical data that support the device's efficacy in children, adolescents, and adults. We will also review its side-effect profile, quality of life and cost benefits, and the impact the device has on sudden unexpected death in epilepsy (SUDEP). We will then discuss candidate selection and provide guidance on dosing and future models. Vagus nerve stimulation therapy is an effective treatment for many seizure types and epilepsy syndromes with a predictable and benign side-effect profile that supports its role as the most commonly prescribed device to treat pharmacoresistant epilepsy. "This article is part of the Supplement issue Neurostimulation for Epilepsy.", (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Once-daily extended-release (XR) antiepileptic drugs (AEDs) offer potential adherence and tolerability advantages over their BID immediate-release (IR) counterparts. However, patients with epilepsy will inevitably be at least occasionally nonadherent with a prescribed dosing regimen, regardless of formulation. Although perturbations in plasma concentrations due to dosing irregularities may have clinical consequences for AEDs with concentration-response relationships, clinical studies that deliberately expose patients to specific dosing irregularities in order to assess the effect on plasma concentrations and determine appropriate corrective actions would be unethical., Methods: Computer simulation was used to assess the impact of irregular dosing on topiramate (TPM) concentrations in noninduced (monotherapy/neutral cotherapy) and induced (adjunctive therapy with enzyme-inducing AEDs) states using a population pharmacokinetic (PK) model developed to predict steady-state plasma concentration-time profiles produced by once-daily Trokendi XR (extended-release topiramate capsules, Supernus Pharmaceuticals) and BID TPM-IR., Results: Computer simulations predicted that, relative to adherent dosing, delaying a dose 4 to 24h in noninduced patients would decrease trough (Cmin) levels 9% to 31% in the case of TPM-IR and 6% to 27% with Trokendi XR; a single omitted dose would reduce Cmin by 21% (TPM-IR) and 27% (Trokendi XR). After dose recovery to correct for a delayed or omitted dose, simulated peak concentration (Cmax) was higher than steady-state Cmax, regardless of formulation, although the magnitude of "overshoot" was consistently lower with Trokendi XR vs. TPM-IR. Doubling of a dose would increase Cmax by 26% and 28%, respectively. Predicted changes for nonadherent vs. adherent dosing were greater in the induced vs. noninduced state but were generally comparable for the two TPM formulations. Because the long half-life of TPM has been cited as a justification for QD dosing of TPM-IR, simulations also compared steady-state PK profiles of once-daily Trokendi XR and QD TPM-IR. Predicted TPM plasma concentration-time profiles were markedly different, as demonstrated by peak-trough fluctuation (QD TPM-IR, 64%; QD Trokendi XR, 18%) and 34% lower Cmin with QD TPM-IR., Conclusions: Based on these simulations, dosing irregularities with once-daily Trokendi XR should pose no greater risk than with BID TPM-IR. In the event of a delayed or omitted Trokendi XR dose, TPM concentrations can be restored in noninduced and induced states by administering the delayed/omitted dose at any time during the next dosing interval or by adding the missed dose to the next scheduled dose., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Lennox-Gastaut syndrome (LGS) severity varies considerably, so the potential impact of differences in baseline severity on patient outcome following treatment is clinically informative. Here, two surrogate indicators of LGS severity (baseline seizure frequency and vagus nerve stimulation [VNS] use) were used in post hoc analyses of both short- and long-term clobazam trials (Phase III OV-1012 [CONTAIN] and open-label extension [OLE] OV-1004). In CONTAIN, 217 patients comprised the modified, intention-to-treat population. Each baseline seizure-frequency quartile had ~40 patients, and baseline weekly drop-seizure frequency ranges were as follows: <10 (Quartile 1), 10-30 (Quartile 2), 32-86 (Quartile 3), and 86-1077 (Quartile 4). Mean percentage decreases in average weekly drop and total seizures were similar for all quartiles. More than 50% of patients in all 4 quartiles demonstrated ≥ 50% decreases in weekly drop- and total-seizure frequency. The percentage of patients achieving 100% reduction in drop seizures was 33% for clobazam-treated patients (vs. 7% for placebo) in Quartile 1. Five percent of clobazam-treated patients in Quartile 4 (most severe LGS) vs. 0% for placebo achieved 100% reduction in drop seizures. A total of 267 of 306 possible patients entered the OLE (61/68 from a Phase II study and 206/238 from Phase III CONTAIN). Each quartile had ~66 patients, and baseline weekly drop-seizure ranges were as follows: <10 (Quartile 1), 10-31 (Quartile 2), 32-110 (Quartile 3), and 111-1147 (Quartile 4). Median percentage decreases in average weekly drop and total seizures were similar between quartiles. Through 5 years of therapy, >50% of patients in all 4 quartiles demonstrated ≥ 50% decreases in weekly frequency for drop seizures. More than 12% of patients in Quartile 4 achieved 100% reduction in drop seizures from Month 3 through Year 5. For the VNS analyses in CONTAIN, the least-squares mean decreases in average weekly rate of drop seizures (mITT population) were 52% for VNS patients receiving clobazam vs. -22% for placebo (p < 0.01). For non-VNS patients, these percentages were 53% for clobazam and 26% for placebo (p < 0.01). Moreover, 50% and 54% of clobazam-treated patients in the VNS and non-VNS groups demonstrated ≥ 50% decreases in average weekly drop- and total-seizure frequencies, and 11% and 14% in the two groups achieved drop-seizure freedom, respectively. Analyses using baseline seizure frequency and VNS use as surrogates for disease severity showed that clobazam treatment of patients with less severe or severe LGS was equally efficacious., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Guidance for seizure emergency plans exists, although their impact and extent of use in patients with epilepsy are undetermined. This study's primary purpose was to measure the estimated use and content of seizure emergency plans. Secondary objectives included measuring: disease severity, quality of life, productivity, and adherence among patients with and without a plan. An online survey was conducted among 408 patients with epilepsy (ages 18-64) who took one or more antiepileptic drugs. Only 30% of patients reported having a plan, which included avoiding injury, notifying a physician, resting/relaxing, and seeking emergency assistance. Those with a plan were more likely to have experienced more seizures in the past year, to have missed school/work, to have incurred injury, to have visited the ER, to have been hospitalized, to fear additional seizures, and to have lost a job. Seizure emergency plans appear to be reserved for adults with more severe disease, but there may be clinical benefits to developing a plan for all adult patients with epilepsy.

Non-adherence to epilepsy medications can interfere with treatment and may adversely affect clinical outcomes, although few studies have examined this relationship. This study assessed barriers and drivers to adherence, its impact on quality of life, and the importance of the patient-physician relationship to adherence. Two cross-sectional online surveys were conducted among 408 adult patients with epilepsy and 175 neurologists who treat epilepsy patients. Twenty-nine percent of patients self-reported being non-adherent to antiepileptic medications in the prior month. Non-adherence was found to be associated with reduced seizure control, lowered quality of life, decreased productivity, seizure-related job loss, and seizure-related motor vehicle accidents. Patient-oriented epilepsy treatment programs and clear communication strategies to promote self-management and patients' understanding of epilepsy are essential to maximizing treatment and quality of life outcomes while also minimizing economic costs.

The social and health consequences associated with epilepsy are often magnified among patients with refractory epilepsy. Despite recent advances in the treatment of seizure disorders, many people with epilepsy continue to suffer from uncontrolled seizures and adverse side effects from medical therapy. This survey is the first to focus solely on the experiences, attitudes, and quality of life of a refractory epilepsy population, both those with the condition and their caregivers. To participate in this survey, respondents had to currently be experiencing seizures or troubling treatment side effects and had to have tried at least two different epilepsy medications. These survey data represent three groups of participants (n = 903): those with epilepsy who self-reported on their condition (Group 1, n = 503), the caregivers of those with refractory epilepsy (Group 2, n = 200), and those with epilepsy who had their condition reported on by a caregiver (Group 3, n = 200). This survey revealed that the negative consequences associated with epilepsy tend to be greater among those experiencing treatment side effects and a greater number of seizures. Physicians must take into account medication side effects and quality-of-life issues when treating patients with epilepsy.

This study investigates the frequency of symptoms of panic attack in a sample of adults (n = 18) and adolescents (n = 21) who were evaluated for intractable seizure disorder and diagnosed with psychogenic nonepileptic seizures (PNES). Medical records were retrospectively reviewed for symptoms associated with their typical seizure events as documented by the attending epileptologist. Adolescents, as a group, reported significantly more symptoms of panic attack than adults. Three adolescents met the full criteria for a panic attack, while no adults met these criteria. In addition, while numerous adults endorsed no panic symptoms associated with their PNES episodes, all adolescents endorsed at least one symptom. Implications of results are discussed in terms of the diagnosis and treatment of PNES in the different age groups.

Considerable evidence supports the idea of magnetoencephalography (MEG) being a valuable noninvasive tool for presurgical mapping of sensory and motor functions. In this study, we test the validity and replicability of a new experimental paradigm for simultaneous sensory and motor mapping using MEG recordings. This comprehensive sensorimotor protocol (CSSMP), where external mechanic stimulation serves as a cue for voluntary movements, allows the recording of sensory and motor cortical responses during a single activation task. The stability and replicability of MEG-derived recordings during this paradigm were tested in a group of eight neurologically normal volunteers and six patients with perirolandic lesions. We found that a common sensorimotor cortical network, engaging sensory (S1, S2) and motor (M1) areas, was reliably activated in all subjects and patients and that the results remained exceptionally stable over time. Additionally, the clinical validity of the MEG-derived maps of activation was tested through intraoperative electrocortical stimulation mapping in the group of patients. The MEG-derived anatomical maps for specific sensory (S1) and motor (M1) responses were verified, by direct cortical mapping, and confirmed with the patient's surgical outcome. The results of this validation study show that the so-called CSSMP is a reliable and reproducible method for assessing simultaneously sensory and motor areas. This method minimizes methodological problems and improves our knowledge of the spatiotemporal organization of the sensorimotor cortical network and helps to optimize the surgical management of patients with perirolandic lesions.