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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.)

Objective: The aim of this study was to evaluate long-term safety, efficacy, and quality of life (QOL) of ≤400-mg/day USL255, Qudexy® XR (topiramate) extended-release capsules, as adjunctive therapy for partial-onset seizures (POS) in adults., Methods: Patients who completed the 11-week double-blind treatment phase of the phase 3 PREVAIL study were eligible to enroll in this 1-year open-label extension (OLE) study (PREVAIL OLE). The primary objective was to evaluate the safety and tolerability of USL255 (including treatment-emergent adverse events [TEAEs]). The secondary objective was to assess seizure frequency in patients (e.g., median percent reduction from baseline in weekly POS frequency, responder rate [proportion of patients with ≥25%, ≥50%, ≥75%, or 100% reduction from baseline in POS frequency], and seizure-free intervals [proportion of patients who were seizure-free for 4, 12, 24, 36, or 48weeks]). Exploratory clinical-status endpoints included the Global Impression of Change (CGI-C) and Quality of Life in Epilepsy-Problems (QOLIE-31-P) questionnaires. Post hoc analyses evaluated neurocognitive TEAE incidences during the first 11 and entire 55weeks of treatment and efficacy by patient age and drug-resistant status., Results: Of the 217 patients who completed PREVAIL (USL255, n=103; placebo, n=114), 210 (97%) enrolled in PREVAIL OLE and were included in the ITT population. Across the entire 55-week treatment period, USL255 was generally safe and well tolerated, with low individual neurocognitive TEAE incidences. Seizure reduction was sustained across the year-long study and observed in patient subgroups, including those with highly drug-resistant seizures and those ≥50years of age. Improvements in CGI-C and QOLIE-31-P were also observed., Significance: The results of PREVAIL OLE are consistent with those from PREVAIL and demonstrate that adjunctive treatment with up to 400mg/day of USL255 may be a safe and effective treatment option for a variety of adult patients with refractory POS., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Results from a previously conducted global phase III study (PREVAIL; NCT01142193) demonstrate the safety and efficacy of once-daily USL255, Qudexy™ XR (topiramate) extended-release capsules, as adjunctive treatment of drug-resistant partial-onset seizures (POSs). In this study, we report a post hoc analysis of PREVAIL data according to patient level of treatment resistance (based upon the number of concomitant antiepileptic drugs [AEDs] and lifetime AEDs) at baseline, with patients defined as either having "highly" drug-resistant seizures (≥ 2 concurrent AEDs and ≥ 4 lifetime AEDs) or having "less" drug-resistant seizures (1 concurrent AED or <4 lifetime AEDs) at baseline. For each subgroup, median percent reduction in POS frequency (primary endpoint), responder rate, Clinical Global Impression of Change (CGI-C), and Quality of Life in Epilepsy--Problems (QOLIE-31-P) survey were assessed. Of 249 PREVAIL patients, 115 were classified as having highly drug-resistant seizures (USL255: n = 52, placebo: n = 63), and 134 were classified as having less drug-resistant seizures (USL255: n = 72, placebo: n = 62) at baseline. For the primary endpoint, USL255 resulted in significantly better seizure outcomes compared with placebo regardless of drug-resistant status (P = .004 and P = .040 for "highly" and "less", respectively). Responder rate was also significantly improved in patients with highly drug-resistant group (P = .023). The CGI-C scores indicated significant improvement in both subgroups (P = .003 and P = .013 for "highly" and "less", respectively). On the QOLIE-31-P, a significant improvement on the seizure worry subscale for the group with less drug-resistant seizures was noted in USL255-treated patients compared with placebo-treated patients (P = .003); the overall score and all other subscales were not significantly different for both subgroups. We conclude that USL255 led to significant improvements across multiple outcomes compared with placebo, including in those classified as having highly drug-resistant seizures to prior treatment, making it a valuable treatment option for patients with epilepsy., (Copyright © 2014. Published by Elsevier Inc.)

Objective: Selective amygdalohippocampectomy (AHC) has evolved to encompass a variety of techniques to resect the mesial temporal lobe. To date, there have been few large-scale evaluations of trans-middle temporal gyrus selective AHC. The authors examine a large series of patients who have undergone the trans-middle temporal gyrus AHC and assess its clinical and neuropsychological impact., Methods: A series of 76 adult patients underwent selective AHC via the trans-middle temporal gyrus approach over a 10-year period, 19 of whom underwent pre- and postoperative neuropsychological evaluations., Results: Favorable seizure response rates were achieved (92% Engel class I or II), with very low surgical morbidity and no mortality. Postoperative neuropsychological assessment revealed a decline in verbal memory for the left AHC group. No postoperative memory decline was identified for the right AHC group, but rather some improvements were noted within this group., Conclusions: The trans-middle temporal gyrus selective AHC is a safe and effective choice for management of medically refractory epilepsy in adults., (Copyright © 2013 Elsevier Inc. All rights reserved.)

From studies of epilepsy, Hughlings-Jackson proposed a model of brain function including levels of consciousness, a hierarchy of nervous centers, and a sensory-motor relationship. Hughlings-Jackson's ideas influenced Wilder Penfield, a pioneer of electrical stimulation for mapping of the human cerebral cortex. From his work with electrocortical stimulation in patients with epilepsy, Penfield observed what he referred to as a "record of the stream of consciousness," similar to Hughlings-Jackson's "subject consciousness." Penfield expanded upon Hughlings-Jackson's work and suggested that although higher and lower centers explained reflex movements, another separate unaccounted for force controlled voluntary movements. These two functional units he termed the "computer (or automatic sensory-motor mechanism)" and the "mind's mechanism (or highest brain mechanism)." The ideas of John Hughlings-Jackson and Wilder Penfield represent a continuum of thought about the relationship of epilepsy and brain function and continue to be relevant to our current understanding of memory function and the mind-brain relationship., (Copyright © 2012 Elsevier Inc. All rights reserved.)

With advances in technological innovation, electroencephalography has remained the gold standard for classification and localization of epileptic seizures. Like other diagnostic modalities, technological advances have opened new avenues for assessment of data, and hold great promise to improve interpretive capabilities. However, proper overall interpretation and application of electroencephalographic findings relies on valid correlations of associated clinical semiology. This article addresses interpretation of clinical signs and symptoms in the context of the diagnostic predictive value of electroencephalographic, clinical, and electrographic definitions of seizures, and upcoming challenges of interpreting intracranial high-frequency electroencephalographic data. This article is part of a Supplemental Special Issue entitled The Future of Automated Seizure Detection and Prediction., (Copyright © 2011 Elsevier Inc. All rights reserved.)