Diazepam is a cornerstone immediate-use antiseizure rescue therapy that may extend the duration between seizure clusters in people living with epilepsy. However, our mechanistic understanding of intermittent rescue therapy on disease progression is limited by the lack of suitable preclinical models. Specifically, the pharmacokinetics of diazepam varies widely between humans and laboratory animals. Here, we developed a novel repeat rescue therapy dosing paradigm in rats to maintain prolonged therapeutic concentrations seen in humans. Rats received three diazepam doses separated by 1 h (0.75, 1.5, or 3 mg/kg, intraperitoneal); plasma and brains were collected at 10 min and 1, 3, or 6 h following the last dose. Plasma and brain concentrations followed a dose-dependent increase with peak concentrations following the repeat 3 mg/kg paradigm (180 ng/mL) being equivalent to plasma levels observed in human studies with diazepam nasal spray. Increased brain-to-plasma ratios in this paradigm indicate that diazepam accumulation in the brain may be long-acting at the site of action. Overall, our repeat diazepam dosing paradigm mimics drug concentrations and accumulation seen in humans, offering a preclinical tool to study the impact of benzodiazepine rescue therapy on seizure-cluster biology in rodent models of epilepsy. PLAIN LANGUAGE SUMMARY: There is more to learn about how diazepam works in the brains of people who use it only when they have two or more seizures in 24 h (this is called a seizure cluster). Ethical studies in animals can be used to learn more about medicines in the body. In this study, we showed that three doses of diazepam in rats give about the same amount of the drug as one dose for a person. We can now test rats with epilepsy to see how the drug might work in people who take it when needed for seizure clusters.

Previous studies suggested that patients with epilepsy might be able to forecast their own seizures. This study aimed to assess the relationships between premonitory symptoms, perceived seizure risk, and future and recent self-reported and electroencephalographically (EEG)-confirmed seizures in ambulatory patients with epilepsy in their natural home environments.
Long-term e-surveys were collected from patients with and without concurrent EEG recordings. Information obtained from the e-surveys included medication adherence, sleep quality, mood, stress, perceived seizure risk, and seizure occurrences preceding the survey. EEG seizures were identified. Univariate and multivariate generalized linear mixed-effect regression models were used to estimate odds ratios (ORs) for the assessment of the relationships. Results were compared with the seizure forecasting classifiers and device forecasting literature using a mathematical formula converting OR to equivalent area under the curve (AUC).
Fifty-four subjects returned 10 269 e-survey entries, with four subjects acquiring concurrent EEG recordings. Univariate analysis revealed that increased stress (OR = 2.01, 95% confidence interval [CI] = 1.12-3.61, AUC = .61, p = .02) was associated with increased relative odds of future self-reported seizures. Multivariate analysis showed that previous self-reported seizures (OR = 5.37, 95% CI = 3.53-8.16, AUC = .76, p < .001) were most strongly associated with future self-reported seizures, and high perceived seizure risk (OR = 3.34, 95% CI = 1.87-5.95, AUC = .69, p < .001) remained significant when prior self-reported seizures were added to the model. No correlation with medication adherence was found. No significant association was found between e-survey responses and subsequent EEG seizures.
Our results suggest that patients may tend to self-forecast seizures that occur in sequential groupings and that low mood and increased stress may be the result of previous seizures rather than independent premonitory symptoms. Patients in the small cohort with concurrent EEG showed no ability to self-predict EEG seizures. The conversion from OR to AUC values facilitates direct comparison of performance between survey and device studies involving survey premonition and forecasting.

UNASSIGNED: Acute repetitive seizures (ARSs) are one of the few commonly encountered neurological emergencies in children. There is a need for an appropriate timeline-based treatment protocol, which will be shown to be safe and efficacious in a clinical study.
UNASSIGNED: This was a retrospective chart review to determine the efficacy of a pre-specified treatment protocol for the management of ARSs in children aged 1-18 years. The treatment protocol was specifically applied in children with a diagnosis of epilepsy and not critically ill, who met the criteria for ARSs, with the exemption of new onset of ARSs. The first tier of treatment protocol focused on intravenous lorazepam, optimization of dose of existing anti-seizure medications (ASMs), and control of triggers like acute febrile illness, while second-tier focused on adding one or two additional ASMs, commonly used in cases with seizure clusters or status epilepticus.
UNASSIGNED: We included the first 100 consecutive patients (7.6 ± 3.2 years, 63% boys). Our treatment protocol was successful in 89 patients (58 and 31 required first-tier and second-tier treatment). The absence of pre-existing drug-resistant epilepsy and the presence of acute febrile illness as a triggering factor (P = 0.02 and 0.03) were associated with the success of the first tier of the treatment protocol. Excessive sedation (n = 29), incoordination (n = 14), transient gait instability (n = 11), and excessive irritability (n = 5) were the most common adverse effects observed during the initial 1 week.
UNASSIGNED: This pre-specified treatment protocol is safe and efficacious in controlling ARSs in cases with established epilepsy who are not critically sick. External validation from other parts of the world/centers and a more diverse epilepsy population are required before generalizing the protocol into clinical practice.

Acute seizure therapies given out of the hospital are important for interrupting acute repetitive and prolonged seizures and preventing hospitalization. These vary in their administration routes, indications for children and adults, pharmacologic profiles, and efficacy. We reviewed and compared the uses of current formulations available to treat acute seizures, including newly released intranasal (IN) benzodiazepines and older formulations which are widely used for interrupting seizures.

Midazolam nasal spray (MDZ-NS) is a new emerging rescue medication that suppresses epileptic seizures. Until now, few studies, pharmacokinetic (PK) and pharmacodynamic (PD) profiles, and clinical trials have shown that midazolam nasal spray could become an effective and promising alternative to conventional routes (intravenous {IV}/rectal). Therefore, we thought of conducting a systematic review and meta-analysis of midazolam (MDZ) to assess its potential outcomes. The analysis was also evaluated based on the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of midazolam nasal spray. A systematic literature search was carried out through various databases to identify studies of accounted outcomes of midazolam nasal spray (MDZ-NS). Randomized and other studies of patients (12 years or older) with seizure clusters (SCs) were included. A total of three full-text articles were considered for systematic review and meta-analysis as per the inclusion and exclusion criteria. The 5 mg MDZ-NS was observed to be equally safe as a placebo, and the risk ratio (RR) was 1.01 (95% confidence interval (CI): 0.67-1.53). After the administration of MDZ-NS, either the patients remained seizure-free for six hours or more or the seizure was terminated within 10 minutes and had no recurrence between 10 minutes and six hours. The risk ratio (RR) obtained was 1.54 (95% CI: 1.25-1.91). The result was statistically significant as a higher success rate was observed with the use of 5 mg midazolam nasal spray compared to placebo (p < 0.0001). Heterogeneity was not observed in the results of the included studies (inconsistency index {I2}: 0%). The present systematic review and meta-analysis demonstrated that 5 mg midazolam nasal spray was efficacious in treating patients with seizure clusters and is well-tolerated. Also, its use is relatively safe.

Purpose: This retrospective observational study aimed to investigate the self-reported prevalence of seizure clusters (SCs) in patients with epilepsy (PWE) and its relationship with clinical characteristics. Methods: We retrospectively analyzed data from consecutive PWE from our hospital in northeastern China. Data were collected from the databank of a tertiary epilepsy center. Logistic regression models were employed to investigate the relationships between the individual patient demographic/clinical variables and the occurrence of SC. Results: In total, 606 consecutive PWE were included in the final analysis, and 268 (44.2%) patients experienced at least one seizure cluster. In multivariate logistic regression models, age (OR: 1.014; 95% CI: 1.002-1.027; p = 0.02), seizure frequency (OR: 2.08; 95% CI: 1.555-2.783; p < 0.001), multiple seizure types (OR: 5.111; 95% CI: 1.737-15.043; p = 0.003), number of current anti-seizure medications (ASM) (OR: 1.533; 95% CI: 1.15-2.042; p = 0.004), drug-resistant epilepsy (OR: 1.987; 95% CI: 1.159-3.407; p = 0.013), and a history of status epilepticus (OR: 1.903; 95% CI: 1.24-2.922; p = 0.003) were independent variables associated with a history of SC in PWE. Conclusion: Seizure clusters (SCs) are common occurrences at our study center. The occurrence of SC in individuals with epilepsy, to some extent, is determined by the epilepsy severity.

Disease-related treatment action plans for acute exacerbations providing information that may be helpful for self-management for patients and caregivers are commonly used for chronic conditions such as asthma and diabetes. However, among patients with epilepsy, a review of the literature suggested that the majority did not have an action plan in place for acute seizure treatment.
Currently, there is a lack of unified guidance on seizure action plans (SAPs) in the literature. In the authors\' opinion, available formats have limitations for practical use and may not be easily customizable to individual patients, and they are not often designed to provide simple-to-follow steps for rapid immediate steps to determine and initiate appropriate treatment of seizure emergencies. Our group reviewed current examples of SAPs and provided guidance on the development of acute seizure action plans (ASAPs) designed to facilitate rapid, appropriate acute care in the community and to be as useful as possible for a wide range of care partners, including those with limited experience.
This paper provides agreed upon expert opinion recommendations and considerations for goals, development process, types of content, and format for an ASAP.

BACKGROUND: Seizure emergencies-status epilepticus and seizure clusters-require rapid evaluation and treatment. Several consensus-based guidelines support a prompt use of intravenous benzodiazepines as the first-line therapy in seizure emergencies. However, most seizure emergencies start outside the hospital settings. Until recently, approved prehospital rescue therapies were limited to rectal diazepam and buccal midazolam (Europe only).
METHODS: The author provides a narrative review of rescue therapies for seizure emergencies based on a comprehensive literature review (PubMed and OvidSP vendors with appropriate keywords to incorporate recent evidence) to highlight the changing landscape of seizure recue therapies.
RESULTS: A commercial version of intranasal midazolam was approved by the FDA in 2019 for 12 ≥ years old with seizure clusters. In 2020, the FDA also approved a proprietary vitamin E solution-based diazepam nose spray to abort seizure clusters in ≥ 6 years old subjects. Other than these two new options, the author discussed two previously approved therapies: rectal diazepam and buccal midazolam. The review also includes the use of intramuscular diazepam and midazolam, clonazepam wafer, sublingual and intranasal lorazepam in seizure emergencies. Besides the availability of new therapies from successful trials in controlled settings, the real-world challenges of using rescue medicines in community settings are slowly emerging.
CONCLUSIONS: With multiple options, a more robust and updated cost-effective analysis of different rescue medicines needs to be performed using effectiveness data from the literature and cost data from publicly available market prices. Further research is also ongoing to develop alternative non-intravenous treatment options for outpatient settings. Lastly, several other non-benzodiazepine drugs, such as allopregnanolone, propofol, and brivaracetam, are also currently under development for seizure emergencies.

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.
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.
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.
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.

Intranasal formulations are commonly used for drug delivery, and the literature has shown that seasonal allergies do not affect nasal administration of some agents. Diazepam nasal spray (Valtoco®) is a proprietary intranasal formulation with n-dodecyl-beta-d-maltoside (Intravail® A3) that is indicated for acute treatment of seizure clusters in patients with epilepsy aged 6 years and older. The analysis presented here is from an interim cutoff of a phase 3 open-label study evaluating the safety and tolerability of diazepam nasal spray. This analysis assessed whether seasonal allergies alter control of seizures with an intranasal formulation, using administration of a second dose as a surrogate efficacy endpoint. Of 158 evaluated patients with epilepsy having seizures despite a stable anti-seizure regimen, 62 patients had medical histories that included seasonal allergies or rhinitis. The results of this analysis show that seasonal allergies did not appear to influence use of a second dose; the groups of patients with and without a history of seasonal allergies both presented with low rates of seizure episodes for which a second dose was used, which suggests that there is not a major difference in pattern of use. Diazepam nasal spray demonstrated a similar safety and tolerability profile in patients with and without a history of seasonal allergies.