UNASSIGNED: Neurologic circadian influences, including sleep/wake transitions, processes (e.g., hormonal variation), and behavioral patterns (e.g., consumption of food and oral medications), may affect seizure patterns. Specific circadian patterns of seizures have been reported depending on type, onset location, and severity; however, data on patterns for patients with seizure clusters and effectiveness of rescue therapy by time of day are limited.
UNASSIGNED: We conducted post hoc analyses using patient diary data from the phase 3 safety study of diazepam nasal spray, which is indicated for acute treatment of seizure clusters in patients with epilepsy aged ≥6 years. Patients were administered age- and weight-based doses; second doses could be administered if needed to control a seizure cluster. We assessed clock timing of seizure-cluster onset along with second-dose use as a proxy for effectiveness. Treatment-emergent adverse events were recorded.
UNASSIGNED: Seizure-cluster onset was observed to be generally highest during mornings and late evenings and lowest in the early evening and middle of the night. Second-dose use was not consistently associated with a specific time of day. The safety profile was consistent with that expected from previous studies of diazepam nasal spray.
UNASSIGNED: These results suggest that diazepam nasal spray can be effectively administered at any time of day.

BACKGROUND: Seizure clusters are underresearched and associated with adverse outcomes in patients with epilepsy. This study was a noninterventional, retrospective claims-based analysis using the Wisconsin Health Information Organization (WHIO) All-Payer Claims Database to characterize the epilepsy population in Wisconsin, with a focus on prevalence, treatment patterns, and healthcare resource utilization (HCRU) in patients with seizure clusters prior to the introduction of nasal spray rescue medications. This timeframe allows characterization of a historical baseline for future comparisons with newer treatments.
METHODS: Four cohorts were defined: (1) all-epilepsy (all patients with epilepsy); and subcohorts of: (2) patients receiving a monotherapy antiseizure medication (ASM); (3) patients receiving ASM polytherapy; and (4) patients treated for seizure clusters (ie, those taking rescue medications and ≥ 1 ASM). Primary outcomes were HCRU over a 12-month follow-up period, which were descriptively analyzed.
RESULTS: Between 2017 and 2019, 16,384 patients were included in the all-epilepsy cohort; 11,688 (71.3 %) were on monotherapy, 3,849 (23.5 %) were on polytherapy, and 526 (3.2 %) were treated for seizure clusters. Twelve-month retentions to the ASM treatments were 46.7 % (7,895/16,904) in the all-epilepsy cohort, and 40.0 % (4,679/11,688) and 40.1 % (1,544/3,849) in the monotherapy and polytherapy subcohorts, respectively. Rescue medication prescriptions were obtained 1,029 times by the 526 patients in the treated seizure cluster subcohort, with infrequent refill rates (mean 1.6-1.9 times/year). A higher proportion of patients in the treated seizure cluster subcohort had epilepsy-related outpatient visits (89.7 %), other visits (71.3 %), and hospitalizations (25.3 %) than patients in the monotherapy (72.2 %, 50.2 %, 19.3 %, respectively) and polytherapy (83.3 %, 63.3 %, 22.8 %, respectively) subcohorts. Mean (standard deviation) all-cause ($114,717 [$231,667]) and epilepsy-related ($76,134 [$204,930]) costs over 12 months were higher in the treated seizure cluster subcohort than the monotherapy ($89,324 [$220,181] and $30,745 [$145,977], respectively) and polytherapy ($101,506 [$152,931] and $49,383 [$96,285], respectively) subcohorts.
CONCLUSIONS: Patients treated for seizure clusters incurred higher all-cause and epilepsy-related costs and epilepsy-related HCRU than other subcohorts and had infrequent rescue medication refills. The findings of this analysis highlight the need for appropriate treatment for those patients with epilepsy experiencing seizure clusters. The effect of newer rescue medications to alter these findings will be explored in a follow-up study. Regardless, specialist providers with expertise in treating refractory epilepsy and seizure cluster patients may help to reduce the burden of seizure clusters.

Sex differences in drug pharmacokinetics include variations in the expression of the cytochrome P450 enzymes, which are involved in the metabolism of benzodiazepines. It is unclear whether sex influences outcomes associated with intranasally administered drugs. A post hoc analysis of sex differences was conducted to evaluate the effectiveness and safety of diazepam nasal spray, which included examining changes in the number of days between seizure clusters over time (SEIzure interVAL [SEIVAL]). Diazepam nasal spray is approved for acute treatment of seizure clusters in patients with epilepsy aged ≥6 years. Data from a phase 3 safety study were used to determine the proportion of second doses used within 24 h (ie, a proxy for effectiveness) and SEIVAL. Adverse events were recorded. Of 163 treated patients, 89 were female, and 74 were male. Approximately 16% of both sexes self-administered the study drug. A slightly higher proportion of seizure clusters was treated with a second dose in female (14.7%) than male (9.4%) patients. SEIVAL increased significantly and substantially over a year for all patients. The safety profile was generally similar between the sexes. These results suggest that potential sex differences in benzodiazepine pharmacokinetics do not meaningfully influence outcomes associated with diazepam nasal spray. PLAIN LANGUAGE SUMMARY: Some drugs may have differences in absorption and metabolism between genders that could translate into differences in safety and effectiveness. This safety study looked at diazepam nasal spray for treating seizure clusters in patients at least 6 years old. It found that safety was about the same for females and males. For both groups, most clusters stopped after only 1 dose of the drug, and the time between treated clusters got longer over a year.

Seizure clustering, is the most frequently reported adverse event in epilepsy monitoring unit (EMU) safety studies which, can also potentiate other adverse events, such as falls, status epilepticus, and increased length of stay. The purpose of this study is to determine variables associated with increased risk of seizure clustering among patients admitted to the EMU.
A retrospective review of patients admitted to the EMU over a two-year period was completed. Data collected included patient demographics, types of epilepsy, seizure frequency, anti-seizure medications (ASMs) and hospital and EMU course including incidence of seizure clustering.
Two hundred seven patients were included in our study; of these, ninety patients experienced two or more seizures in a 24-hour period (24SC), and 68 patients experienced two or more seizures in a 4-hour period (4SC). Logistic regression analysis associated the absence of long-acting ASM with increased clustering within the 4SC group (p = 0.038). For every additional ASM taken by a patient at home, the odds of seizure clustering increased by 81% in the 4SC group (p = 0.009) and by 61% in the 24SC group (p = 0.022). In addition, patients with a diagnosis of temporal lobe epilepsy had some association with clustering in the 24SC group (p = 0.061).
Our data showed that long-acting ASMs can be protective against seizure clustering. Furthermore, patients with temporal lobe epilepsy, and those on increased numbers of ASMs, were more likely to experience seizure clustering when undergoing medication withdrawal during an EMU evaluation.

Patients with epilepsy (PWE) may experience seizure emergencies including acute repetitive seizures despite chronic treatment with daily antiseizure medications. Seizures may adversely impact routine daily activities and/or healthcare utilization and may impair the quality of life of patients with epilepsy and their caregivers. Seizures often occur at home, school, or work in a community setting. Appropriate treatment that is readily accessible for patients with seizure urgencies and emergencies is essential outside the hospital setting. When determining the best acute antiseizure therapy for PWE, clinicians need to consider all of the available rescue medications and their routes of administration including the safety and efficacy profiles. Benzodiazepines are a standard of care as a rescue therapy, yet there are several misconceptions about their use and safety. Reevaluating potential misconceptions and formulating best practices are necessary to maximize usage for each available option of acute therapy. We examine common beliefs associated with traditional use of acute seizure therapies to refute or support them based on the current level of evidence in the published literature.

Limited acute home treatments are available for patients with prolonged (>5 minutes) or repetitive (≥2 in 24 hours) seizures. While this early seizure treatment may reduce the need for emergency care, intermittent intranasal benzodiazepine formulations are expensive and rectal diazepam administration is often socially unacceptable. We determined whether caregivers could use sublingual lorazepam oral concentrate solution effectively as acute treatment for adults with prolonged and repetitive seizures.
Patients prescribed sublingual lorazepam solution at the Johns Hopkins Epilepsy Center for acute seizure treatment during a 5-year period (2012-2017) were screened. We determined clinical history of seizure patterns and number of antiseizure medications (ASMs) through patient and caregiver surveys, and we verified this history in patients\' medical records and charts. During a 2-year span (2017-2018), patients and caregivers were surveyed on responses to their most recent use of sublingual lorazepam solution, including seizure cessation (prolonged seizure stopping <5 minutes or ≤1 repetitive seizure), presence of sedation and adverse events within 24 hours of administration, and whether refrigeration limited use.
In total, 52 patients used sublingual lorazepam for treatment of acute seizures during the study period (median dose 1 mg, range 0.5 to 2 mg). Of them, 48 patients participated in treatment survey interviews. Family caregivers usually administered lorazepam (88%); 3 self-administered. Patients were surveyed on responses to their most recent use of sublingual lorazepam treatment: 66% (23/35) of patients with repetitive seizures reported no further seizure activity after administering treatment; 70% (7/10) with prolonged seizures reported seizure activity ceased within 5 minutes of treatment. Three patients treated auras and had no seizures. There were no serious adverse events during most recent use: 31% of patients developed moderate/severe sedation. Of note, 98% refrigerated lorazepam, often with coolers; 44%, however, said this limited treatment access. There was high treatment satisfaction; 79% reported that having the emergency treatment available made them feel safer.
This patient survey and retrospective chart review demonstrates that home treatment with sublingual lorazepam solution may be effective for interrupting prolonged and repetitive seizures. No patients had sedation complications with home doses of 0.5 to 2 mg, and patients report high satisfaction with the treatment.

Epilepsy is a common neurological disorder in the United States, affecting approximately 1.2% of the population. Some people with epilepsy may experience seizure clusters, which are acute repetitive seizures that differ from the person\'s usual seizure pattern. Seizure clusters are unpredictable, are emotionally burdensome to patients and caregivers (including care partners), and require prompt treatment to prevent progression to serious outcomes, including status epilepticus and associated morbidity (e.g., lacerations, fractures due to falls) and mortality. Rescue medications for community use can be administered to terminate a seizure cluster, and benzodiazepines are the cornerstone of rescue treatment. Despite the effectiveness of benzodiazepines and the importance of a rapid treatment approach, as many as 80% of adult patients do not use rescue medication to treat seizure clusters. This narrative review provides an update on rescue medications used for treatment of seizure clusters, with an emphasis on clinical development and study programs for diazepam rectal gel, midazolam nasal spray, and diazepam nasal spray. Results from long-term clinical trials have shown that treatments for seizure clusters are effective. Intranasal benzodiazepines provide ease of use and patient and caregiver satisfaction in pediatric and adult patients. Adverse events attributed to acute rescue treatments have been characterized as mild to moderate, and no reports of respiratory depression have been attributed to treatment in long-term safety studies. The implementation of an acute seizure action plan to facilitate optimal use of rescue medications provides an opportunity for improved management of seizure clusters, allowing those affected to resume normal daily activities more quickly.
Some people with epilepsy who take antiseizure medications may still have seizures. These seizures might happen in clusters. Seizure clusters are emergencies that need to be treated quickly to lower the risk of status epilepticus and hospitalization. Also, these clusters can be stressful. Approved rescue medications are diazepam rectal gel, midazolam nasal spray, and diazepam nasal spray. They can all be used by family and other caregivers, and nasal sprays may be preferred in a public setting. All of these treatments can be used for adults, but each has a different age limit for children. Overall, these therapies are underused; however, all have been shown to work in stopping seizure clusters and have mild to moderate side effects. Nasal treatments offer ease of use and satisfaction for patients and caregivers (care partners). However, data for some effects and patient groups are not available for all treatments. Seizure action plans are designed to give step-by-step instructions about when and how to use rescue medication. Increased use of action plans may improve at-home treatment of seizure clusters and allow patients to perform their normal daily activities and avoid injury or hospitalizations.

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.

We assessed whether (1) women with statistical clustering of daily seizure counts (DSCs) or seizure intervals (SIs) also showed clinical clustering, defined separately by ≥2 (≥2-SC) and ≥3 (≥3-SC) seizures on any single day; and (2) how these classifiers might apply to catamenial epilepsy.
This is a retrospective case-control analysis of data from 50 women with epilepsy (WWE). We assessed the relationships of the four classifiers to each other and to catamenial versus noncatamenial epilepsy using chi-squared, correlation, logistic regression, and receiver operating characteristic (ROC) analyses.
≥3-SC, not ≥2-SC, was more frequent in WWE who had statistical DSC clustering versus those who did not (21/25 [84.0%] vs. 11/25 [44.0%], p = .007). Logistic regression (p = .006) and ROC (p = .015) identified ≥3-SC, not ≥2-SC, as a predictor of statistical DSC clustering, but ≥4-SC was more accurate. ≥3-SC correlated with the average daily seizure frequencies (ADSFs) of the subjects (p = .01). ROC optimal sensitivity-specificity cut-point for ADSF prediction of ≥3-SC (.372) was 64.6% higher than for ≥2-SC (.226). SI clustering was more common in WWE who had catamenial versus noncatamenial epilepsy (p = .013). Logistic regression identified statistical SI clustering as the only significant classifier (p = .043). ROC analysis offered only marginal support (p = .056), because specificity was low (42.1%).
The findings lend statistical support for (1) the utility of clinical ≥3-SC as a predictor of convulsive status epilepticus, (2) consideration of ADSFs in defining clustering, and (3) ≥4-SC as a more accurate clinical predictor of statistical DSC clustering. Statistical SI clustering occurred more frequently in women with catamenial than noncatamenial epilepsy (90.3% vs. 57.9%, p = .013). Although sensitivity was high (90.3%, 28/31), specificity was only 42.1% (8/19). Algorithms that test patterns and periodicities of clusters are more applicable.

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.