Emergency management of pediatric epileptic seizures in non-hospital settings in Japan

Objective: To assess the current management of pediatric epileptic seizures in non-hospital settings and the efficacy of early therapeutic intervention with rescue medication in Japan. Methods: This descriptive cross-sectional study was based on an online survey of caregivers of pediatric patients with epilepsy. The survey consisted of questions regarding seizure frequency and symptoms, the use of rescue medication, and emergency medical care. Statistical analyses were performed to evaluate the association be-tween the time to rescue medication administration and seizure resolution. Results: Responses were obtained from 1147 caregivers of pediatric patients with epilepsy. Of the patients described in the study, 98.5 % had been prescribed anti-seizure medication, 95.3 % had more than a few seizures per year, and 90.3 % used rescue medication. The time to seizure resolution was significantly reduced when rescue medication was administered early. Overall, 28.4 % of the patients required emergency transport to hospital, which increased disruption to the lives of caregivers, who returned to their normal activities after an average of 17.2 h. Conclusion: Emergency transport of patients places a significant burden on caregivers. Earlier administration of rescue medications is associated with a reduction in the need for emergency room visits, which reduces the burden on the patient as well as the caregiver.


Introduction
Recent advances in the diagnosis of epilepsy and its treatment with anti-seizure medications (ASMs) have resulted in many patients achieving seizure-free status, allowing them to lead normal, socially active lives.However, 20-30 % of patients with epilepsy continue to experience seizures [1].Research has demonstrated that seizures, especially those that are prolonged or occur several times a day, can have psychological, social, and economic impacts on both patients and their caregivers [2][3][4][5].Status epilepticus occurs when seizures are prolonged, and is associated with increased mortality; seizures lasting longer than 30 min increase the risk of neurological sequelae [6].
Several studies have examined the current management of epileptic seizures in non-hospital settings, including the use of rescue medications, as well as the clinical significance and economic benefits of early intervention [7][8][9].In Japan, 0.6-0.8% of the population has epilepsy [10,11].However, no studies have comprehensively examined the emergency response to epileptic seizures in non-hospital settings and the effects of rescue medication on seizure management in Asia.There is therefore a lack of information and understanding regarding the current status of epilepsy management.To determine the optimal treatment approaches for patients and caregivers in non-medical settings, we surveyed caregivers of pediatric patients with epilepsy.
The objectives of this study were to assess the current use of rescue medication in non-hospital settings and emergency transport to medical facilities, and identify any issues associated with these aspects of pediatric patient management, therefore assessing the efficacy of early therapeutic intervention.

Study design
This was a descriptive cross-sectional study based on an online survey of caregivers of pediatric patients with epilepsy.To enable the analysis of data stratified by the various types and frequencies of epileptic seizures, the target sample size was set at 1000, based on a prior study on the willingness of Japanese patients with epilepsy and their caregivers to pay for epilepsy treatment, in which the results were stratified by seizure type [12].The present study was approved by the MINS Research Ethics Review Committee (MINS-REC-230209, approved on 2023-03-01).

Study participants
Participants were recruited via the following four routes: 1) caregivers of patients receiving care at medical facilities where the study investigators work; 2) caregivers utilizing the "nanacara" smartphone app (Knock on the Door, Inc., Tokyo, Japan), which allows families of pediatric patients with epilepsy to easily record information on seizures to be recorded, manage daily information such as medication status and seizure frequency, and shared this information with family members and physicians; 3) caregivers belonging to patient support groups coordinated by the Japan Epilepsy Association (an affiliate of the International Bureau for Epilepsy) or Dravet Syndrome JP; and 4) caregivers belonging to patient support groups affiliated with Knock on the Door, Inc.
The survey was conducted between March and May 2023.An initial screening survey of caregivers of pediatric patients with epilepsy was conducted to identify and select study participants.Epilepsy diagnosis was self-reported by the participants.Caregivers aged < 18 years, caregivers of patients aged ≥ 18 years, and caregivers living alone were excluded from the study.The screening survey also contained a patient information document requesting consent to participate.Caregivers indicated that they fully understood the nature of the survey and voluntarily consented to participate.

Online survey
The online survey consisted of questions regarding the frequency and symptoms of epileptic seizures, use of rescue medication, and emergency medical care received (Table S1).The survey consisted of questions to be answered by a single caregiver, taking approximately min to complete.The survey was reviewed and validated by two medical specialists (S.O. and E.N.).Subsequently, the survey was tested by several caregivers of pediatric patients with epilepsy to ensure that the intent of the questions and their choices were clear.The survey invitation and URL for access were sent by post or e-mail to the caregivers recruited by each of the four previously described routes.The survey was administered to caregivers who accessed the survey website via the URL and provided their consent to participate in the study.

Data management
Prior to analysis, a data cleaning step excluded responses that exceeded defined thresholds for specific survey questions, including: time from seizure onset to use of rescue medication (≥60 min), time from calling the emergency services to the arrival of an ambulance at the scene (≥515 min), time between ambulance departure from the scene and arrival at the hospital (≥153 min), and time between initiating the seizure response and the patient returning to normal life (≥240 h).The criteria for excluding outliers from aggregation were established in consultation with medical specialists (S.O. and E.N.) after reviewing the distribution of the responses and considering responses in the nonclinically valid range to be errors; it was considered reasonable to treat them as outliers due to their impact on the mean.Data within these limits were considered valid and included in the analysis.

Statistical analysis
Continuous variables are expressed as mean ± standard deviation and categorical variables are expressed as proportions.To evaluate the association between the time to rescue medication administration following seizure onset and the time to seizure resolution, responses were categorized into three groups based on the interval between seizure onset and medication administration: ≤4, 5, and ≥6 min.The caregiver reported the time between seizure onset and medication use as an integer; as 5 min was the predominant response, the groups were based around this value.The definition of status epilepticus and the guidelines for the treatment of pediatric epilepsy also informed the selection of 5 min as the threshold for this classification [6,13].Statistical analysis was based on the multiple comparison method using a Wilcoxon rank sum test with the Bonferroni correction.Fisher's exact probability test was also used to assess the association between emergency transport and the prescription of rescue medication and between emergency transport and the time between seizure onset and the use of rescue medication.P < 0.05 was considered statistically significant.Statistical analyses were performed using R software version 4.3.1 (R Foundation for Statistical Computing, Vienna, Austria).

Respondent characteristics
A total of 1624 caregivers of patients diagnosed with pediatric epilepsy completed the initial screening survey; 1147 of these caregivers met the eligibility criteria and consented to participate (Fig. 1).The characteristics of caregivers and patients are presented in Table 1.Notably, 98.5 % of patients (n = 1129) were prescribed one or more ASMs, and 95.3 % of these patients (n = 1076) experienced more than a few seizures per year.

Rescue medication use
Rescue medications were used by 90.3 % of all patients.The most commonly prescribed medication in patients of all ages was diazepam (suppository), which was used for all types of seizures.Midazolam (oromucosal solution) was more frequently prescribed for patients aged ≤ 6 years than those in other age groups.Midazolam was also more frequently prescribed for patients receiving multiple ASMs and for those with motor seizures, including tonic-clonic seizures.Diazepam tended to be used by patients who had previously experienced a maximum of two or more seizures per day, whereas midazolam was typically used by patients who had previously experienced a seizure duration of ≥ 5 min (Table 2).Diazepam was often used prophylactically during episodes of fever, whereas other rescue medications were more often used for prolonged or repeated seizures.Compared to other medications, midazolam was used less frequently for recurrent seizures and more frequently for prolonged seizures (Table S2).
All rescue medications were predominantly taken at home.Compared to other rescue medications, midazolam was less frequently used in schools or nurseries, but more frequently used in other settings outside the home (Table S3).

Time from seizure onset to rescue medication use and seizure resolution
Most rescue medications were administered 5-9 min after seizure onset (Fig. S1).With the exception of midazolam, rescue medications were reported to take 10 min or longer to resolve seizure symptoms.Notably, drugs in suppository form mostly took 10-19 min to resolve the seizure, whereas the oromucosal solution and rectal kit achieved faster seizure resolution (Fig. S2).The mean time from rescue medication administration to seizure resolution was 11.8 ± 14.3 min for the ≤ 4 min group, 15.1 ± 8.4 min for the 5 min group, and 22.8 ± 15.8 min for the ≥ 6 min group.The time from rescue medication administration to seizure resolution was significantly lower in the ≤ 4 min group than in the 5 min group (P < 0.001), and significantly lower in the 5 min group than in the ≥ 6 min group (P < 0.001) (Fig. 2).

Emergency transport
Among all patients, 28.4 % required emergency transport due to seizures (Table 1).Patients who used emergency transport were more likely to use multiple ASMs, have convulsive seizures, experience longer seizures, be prescribed rescue medications, and wait more than 5 min between seizure onset and rescue medication administration than those who had not used emergency transport (Table S4).Fisher's exact probability test showed a significant association between the prescription of rescue medication (<1, ≥1) and number of emergency transports (none, ≥1) (P < 0.01) and between the time from seizure onset to rescue medication administration (≤4, 5, ≥6 min) and the number of emergency transports (none, ≥1) (P < 0.001).Patients who used emergency transport waited an average of 34.2 min from calling the emergency services to arrival at a medical facility, and 47.7 min from the emergency call to seizure resolution following admission to a medical facility (Table 3).
Caregivers were able to return to normal daily activities more quickly if epileptic seizures were treated in a non-hospital setting, such as at home (3.1 h) or school (4.7 h) than if seizures were treated after transport of the patient to a medical facility (17.2 h) (Table 4).

Satisfaction and rescue medication issues
Using a 7-point Likert scale ranging from "very satisfied" to "very dissatisfied," most caregivers rated their level of satisfaction with both rescue medications overall and suppositories alone as "somewhat satisfied" or "neither satisfied nor dissatisfied."The level of satisfaction with the use of oromucosal solution was higher than with other types of rescue medications (Fig. S3).
The issues raised by caregivers regarding the use of rescue medications are summarized in Table 5.Many caregivers found it difficult to determine if the seizure was severe enough to require rescue medication.Caregivers found suppositories challenging to administer because of the complicated procedure and specific anatomical site of administration.However, oromucosal solutions had the disadvantage of requiring emergency transport of patients following administration.The combination of suppositories and oromucosal solutions was challenging not only because of the aforementioned issues but also because seizures recurred on the day of medication administration.Additionally, this treatment combination cannot be administered outside the home.

Ideal rescue medicine
The characteristics that caregivers deemed essential in a rescue medication are shown in Fig. 3. Specifically, caregivers desired rescue medications that have fewer side effects and are fast-acting and easy to use.Additionally, many caregivers indicated a preference for long- acting rescue medications.

Discussion
The present study characterized the current status of rescue medication and emergency transport use in Japan, based on data collected through an online survey of caregivers of pediatric patients with epilepsy.We obtained more than 1000 completed surveys by providing access to the survey via the nanacara app, which is primarily used by caregivers of patients with refractory epilepsy, and patient support groups, rather than through the usual internet-based approaches.Notably, 95.3 % of patients whose caregivers completed the survey had more than a few seizures per year, despite the use of ASMs.The use of rescue medication was higher than that reported by previous studies [7], suggesting a higher proportion of refractory epilepsy cases in our population than in those of previous studies.
At the time of this study, the rescue medications approved for use in Japan were diazepam (suppository), chloral hydrate (suppository), chloral hydrate (rectal kit), midazolam (oromucosal solution), and phenobarbital sodium (suppository).Chloral hydrate (suppository) is a rectal capsule suppository and chloral hydrate (rectal kit) is a kit preparation containing a colorless liquid.
Diazepam was the most commonly prescribed rescue medication in all age groups, consistent with reports from other countries [7].In this study, midazolam was more frequently prescribed to patients aged ≤ 6 years, those receiving multiple ASMs, those with convulsive or motor seizures, and those with a possible history of status epilepticus, in which seizures last ≥ 5 min, and which frequently occurs in younger patients.Diazepam and midazolam were used more and less, respectively, in this study than in a study by Vigevano et al. [8], reflecting the wider use of diazepam in Japan than in the European Union.
In July 2022, the Ministry of Education, Culture, Sports, Science, and Technology, and the Ministry of Health, Labour and Welfare issued an administrative notice to prefectural and municipal governments regarding the administration of midazolam during epileptic seizures in schools, and prefectures and municipalities informed schools and nurseries.The administrative communication has made it no longer a violation of the Medical Practitioners Law to administer midazolam by nonmedical personnel.Despite this change, midazolam remains less widely used in schools, perhaps due to the limited availability of midazolam in school settings.The administrative communication was issued prior to the planning of the study and had no effect on the study procedures.
The time to seizure resolution for each rescue medication was likely influenced by differences in mechanism of action, formulation, and route of administration [14].In this study, midazolam and chloral hydrate (rectal kit) were the fastest acting rescue medications.The time to seizure resolution was also significantly associated with the interval between seizure onset and rescue medication administration, with earlier treatment resulting in faster seizure resolution.This significant association was present across all three groups (≤4, 5, and ≥ 6 min).This is consistent with the results of previous studies [15][16][17].However, it should be noted that these times were reported by caregivers and were therefore not objective accurate measurements.
There was also a significant association between the time from seizure onset to rescue medication administration and the use of emergency transport.This finding is consistent with those of previous studies, which have suggested that early intervention can reduce the occurrence of recurrent seizures [16], emergency calls, emergency department visits, and hospitalizations, and improve patient quality of life [6].The use of rescue medications in adults with epilepsy is associated with fewer emergency department visits [18].However, since rescue medications were prescribed to more than 90 % of the patients in this study, there was an inverse association between the prescription of rescue medication and emergency transport, in contrast to previous studies.The results of this study suggest that early rescue medication administration may relieve the burden on caregivers by avoiding transport to a medical facility and thus enabling a faster return to normal activities.
A survey conducted in six major cities in western Japan found that the average time to ambulance arrival at the scene ranged from 12.9 ± 6.8 to 21.7 ± 10.6 min [19].The Fire and Disaster Management Agency of the Japanese Ministry of Internal Affairs and Communications reported the national average time to ambulance arrival at the scene as approximately 10.3 min, and the national average time to hospital admittance as approximately 47.2 min [20].Similarly, in this study the average time to hospital admittance was more than 30 min.As the risk of neurological sequelae increases in seizures lasting longer than 30 min [6], the prescription of rescue medications that can be administered in non-hospital settings is essential to quickly resolve the seizure and minimize the risk of complications.
Caregivers who used oromucosal solutions expressed greater satisfaction with rescue medication than those who administered suppositories, likely due to the faster action and easier use of the oromucosal solution.The high satisfaction with midazolam is similar to that reported by a previous study conducted in the United Kingdom [21].Many   caregivers reported difficulties using suppository rescue medications outside the home or immediately after seizure onset, consistent with the findings of previous studies [22,23].However, caregivers also expressed dissatisfaction with oromucosal solutions because of the need for emergency transport following their use, with the package insert for midazolam stating: "In principle, emergency transport should be arranged after administration of this medication."An ideal rescue medication would therefore allow immediate use and not require emergency transport.
Many caregivers were unsure as to which seizures require rescue medication.The possibility of spontaneous seizure resolution may cause a caregiver to delay rescue medication administration, and it is therefore essential to clearly define the criteria for seizures that require intervention to encourage early intervention in these cases.Other countries use action plans that provide individualized guidance to help caregivers determine when intervention is required [24].The implementation of a seizure action plan and/or acute seizure action plan [25] in Japan may help to address this issue.
Each existing rescue medication is associated with specific challenges.For example, although oromucosal solutions are portable and can be used outside the home, the lack of midazolam use in schools continues to be an issue.The use of rescue medication in schools is also an issue in other countries, where barriers to the delegation of authority and a lack of training have resulted in its infrequent use [26].A previous survey found that few teachers (15 %) reported actively administered rescue medication [27].In Japan, it has been reported that some teachers lack knowledge of epileptic seizures and their treatment, and are concerned about their own response and responsibility [28].As midazolam use in schools was only approved in 2022, awareness and acceptance of this medication are likely to be limited.Thus, strategies are needed to enable widespread acceptance of in-school administration of oromucosal solutions.Furthermore, most caregivers desire rescue medications that have minimal side effects and are fast acting and easy to use.Therefore, new rescue medications with these characteristics are required to address the issues associated with existing medications.
This study has several limitations.Since the survey was administered online, participants were limited to caregivers with access to a computer or smartphone, and this selection bias may limit the generalizability of our study.In addition, information reported by caregivers may have been influenced by preconceived notions, leading to cognitive bias.As the survey asked about past experiences and thoughts, responses may have been inaccurate or incomplete, and the results of the study may therefore have been subject to recall bias.The diagnosis of epilepsy was reported by the caregiver, but because respondents were recruited from medical facilities, patient groups, and users of the "nanacara" app, we believe it is highly probable that all the patients did indeed have epilepsy.Additionally, 95.35 % of the study population experienced several seizures per year and the target sample consisted primarily of patients with uncontrolled refractory epilepsy.The results of the analysis were not classified according to rescue medication formulation, which may have been influenced by the drugs prescribed.Finally, it was not possible to draw conclusions about clinical efficacy and causation from the results of this observational study.

Conclusions
The results of this study suggest that patients who receive therapeutic intervention with rescue medication early after the onset of epileptic seizures experience faster seizure resolution than those who do not receive timely treatment.In addition, early intervention with rescue medication after seizure onset is associated with reduction the need for emergency transport to a medical facility.Early seizure resolution is clinically important, and preventing emergency room visits not only reduces the burden on the patient, but is also associated with reduction in the burden on the caregiver.Caregivers also expressed a desire for new rescue medications that address the issues associated with existing rescue medications.

Fig. 2 .
Fig. 2. Time to rescue medication administration and seizure resolution.Responses indicating > 60 min from seizure onset to rescue medication administration were considered outliers and were excluded from the analysis.*** P < 0.001.

Table 1
Characteristics of caregivers and patients.
S. Okazaki et al.

Table 2
Rescue medication use.
S. Okazaki et al.

Table 3
Timing of emergency transport, hospital arrival, and seizure resolution.

Table 4
Time from initial response to seizure to caregiver's return to normal life, by type and location of response (h).
S. Okazaki et al.

Table 5
Issues regarding the use of rescue medications.
Fig. 3. Rescue medication characteristics desired by caregivers.S. Okazaki et al.