Carrazana, Enrique

Abstract Emotional experiences during focal seizures are often misinterpreted as psychiatric disorders. We aimed to evaluate symptoms involving affective symptoms at seizure onset. We aimed to identify the most prevalent affective symptoms at seizure onset and characterize their localizing and lateralizing value. We performed a scoping review based on Preferred Reporting Items for Systematic reviews and Meta‐Analyses–extension for Scoping Reviews guidelines. A systematic search identified records from 4 databases: PubMed, Embase, CINAHL (via EBSCOhost), and Web of Science. Two reviewers independently screened titles/abstracts and full texts; discrepancies were resolved by consensus. This review focused on patients with focal seizures, as affective symptoms may occur in generalized epilepsies. The affective symptoms: fear, anxiety, panic, sadness, mystic, ecstatic, sexual, and mirth were identified, and semiology was evaluated in accordance with ILAE guidelines. Symptom onset, frequency, brain localization, and video‐EEG monitoring technique were evaluated to assess localization and lateralization of regional networks. Scalp EEG, invasive EEG recordings, and electrical stimulation were analyzed. A total of 1276 documents were identified, with 98 studies included for review. Fear was the most frequently reported ictal emotion, identified in 274 patients (66%), predominantly in temporal lobe epilepsy. Sadness and sexual, ecstatic symptoms were also consistently associated with temporal networks. Mirth was more frequently reported with frontal onset seizures. Evidence, primarily from Class IV studies, reported right hemispheric predominance for ecstasy, mystic, and sexual symptoms at seizure onset. Ictal affective symptoms at seizure onset yield localizing information. The limbic system, especially the temporal lobe, followed by the frontal lobe, was the most common site of origin. Fear was the most common spontaneous and electrically elicited symptom, followed by anxiety. While bi‐hemispheric lateralization occurred, right lateralization predominated. Recognizing paroxysmal affective symptoms as ictal phenomena may reduce misdiagnosis and aid presurgical evaluation in drug‐resistant focal epilepsy.

AbstractObjectiveCurrent diazepam nasal spray labeling requires waiting 4 h before administering a second dose. The objective of the current analyses was to examine safety and pharmacokinetic profiles of second doses of diazepam nasal spray given 0−4 h after the first dose.MethodsTwo datasets were analyzed. The first, a long‐term, repeat‐dose safety study of diazepam nasal spray, compared rates of treatment‐emergent adverse events (TEAEs), serious TEAEs, and treatment‐related TEAEs for patients receiving ≥1 second dose ≤4 h versus all second doses >4 h after the first. The second was a population pharmacokinetic analysis using data from three phase 1 studies to model drug exposure when a second dose of diazepam nasal spray was administered across multiple time points (1 min−4 h) following the first dose.ResultsIn the repeat‐dose safety study, a second dose of diazepam nasal spray was administered ≤24 h after the first to treat 485 seizure clusters in 79 patients. Rates of TEAEs were similar between patients receiving ≥1 second dose in ≤4 h (89.5%, n = 38) compared with >4–24 h only (80.5%, n = 41). The most common treatment‐related TEAEs were associated with nasal discomfort, which was mild or moderate and transient. There were no reports of respiratory or cardiac depression. The pharmacokinetic simulations of second doses predicted comparable elevations of plasma diazepam concentrations with administrations across a range of intervals after the first dose (1 min−4 h).SignificanceThese data indicate that the safety and pharmacokinetic profiles of a second dose of diazepam nasal spray administered within 4 h of the first dose are consistent with those associated with current labeling. This is potentially important for patients with seizure clusters who have a recurrent seizure within 4 h of first treatment and might benefit from immediate retreatment to reduce the risk of progression to status epilepticus.

Abstract Objective An exploratory analysis from a long‐term, phase 3, open‐label, repeat‐dose safety study of diazepam nasal spray for acute treatment of seizure clusters assessed the use of a second dose up to 24 hours after the initial dose and effectiveness in potentially reducing the number of seizures. Methods Seizures and doses were recorded in diaries. Results Of 175 patients enrolled, 163 received ≥1 dose of diazepam nasal spray and were included in the safety population; those patients received a total of 4390 doses for a total of 3853 seizure clusters. Less than half of these patients used a second dose a least once during the study (79 patients [48.5%]), with a total of 485 second doses for seizure clusters (12.6% of all seizure clusters). Among these 79 patients, 33 (41.8%) used only one second dose during the study (range: 1–82). The proportion of seizure clusters treated with a second dose over time was consistently low across 24 h: 0–4 h, 152 (3.9%); 4–6 h, 72 (1.9%); 6–8 h, 39 (1.0%); 8–12 h, 55 (1.4%); 12–16 h, 42 (1.1%); 16–20 h, 42 (1.1%); 20–24 h, 83 (2.2%). Rates of treatment‐emergent adverse events (TEAEs) and treatment‐related TEAEs occurring within 1 day of a second dose were low (15.2% and 5.1%, respectively). Significance Patients with epilepsy may experience seizure clusters lasting up to 24 hours, and little is known about the effectiveness of rescue therapies for that duration. The current labeling of the US Food and Drug Administration (FDA)–approved outpatient treatments for seizure clusters (rectal diazepam, intranasal midazolam, and diazepam nasal spray) allows for a second dose, if needed, for control. These findings support the safety profile of second doses, and the low use supports the effectiveness of diazepam nasal spray across 24 hours.

Abstract Objective A Phase 3 open‐label safety study (NCT02721069) evaluated long‐term safety of diazepam nasal spray (Valtoco) in patients with epilepsy and frequent seizure clusters. Methods Patients were 6–65 years old with diagnosed epilepsy and seizure clusters despite stable antiseizure medications. The treatment period was 12 months, with study visits at Day 30 and every 60 days thereafter, after which patients could elect to continue. Doses were based on age and weight. Seizure and treatment information was recorded in diaries. Treatment‐emergent adverse events (TEAEs), nasal irritation, and olfactory changes were recorded. Results Of 163 patients in the safety population, 117 (71.8%) completed the study. Duration of exposure was ≥12 months for 81.6% of patients. There was one death (sudden unexpected death in epilepsy) and one withdrawal owing to a TEAE (major depression), both considered unlikely to be related to treatment. Diazepam nasal spray was administered 4390 times for 3853 seizure clusters, with 485 clusters treated with a second dose within 24 h; 53.4% of patients had monthly average usage of one to two doses, 41.7% two to five doses, and 4.9% more than five doses. No serious TEAEs were considered to be treatment related. TEAEs possibly or probably related to treatment ( n = 30) were most commonly nasal discomfort (6.1%); headache (2.5%); and dysgeusia, epistaxis, and somnolence (1.8% each). Only 13 patients (7.9%) showed nasal irritation, and there were no relevant olfactory changes. The safety profile of diazepam nasal spray was generally similar across subgroups based on age, monthly usage, concomitant benzodiazepine therapy, or seasonal allergy/rhinitis. Significance In this large open‐label safety study, the safety profile of diazepam nasal spray was consistent with the established profile of rectal diazepam, and the high retention rate supports effectiveness in this population. A second dose was used in only 12.6% of seizure clusters.