Predictors for and use of rescue medication in adults with epilepsy: A multicentre cross-sectional study from Germany

Background

Background: Seizure clusters, prolonged seizures, and status epilepticus are life-threatening neurological emergencies leading to irreversible neuronal damage.Benzodiazepines are current evidence-based rescue therapy options; however, recent investigations indicated the prescription of mainly unsuitable benzodiazepines and inappropriate use of rescue medication.Objective: To examine current use, satisfaction, and adverse events concerning rescue medication in patients with epilepsy in Germany.
Patients and Methods: The study was conducted at epilepsy centres in Frankfurt am Main, Greifswald, Marburg, and Münster between 10/2020 and 12/2020.Patients with an epilepsy diagnosis were assessed based on a questionnaire examining a 12-month period.Results: In total, 486 patients (mean age: 40.5, range 18-83, 58.2 % female) participated in this study, of which 125 (25.7 %) reported the use of rescue medication.The most frequently prescribed rescue medications were lorazepam tablets (56.8 %, n = 71 out of 125), buccal midazolam (19.2 %, n = 24), and rectal diazepam (10.4 %, n = 13).Seizures continuing for over several minutes (43.2 %, n = 54), seizure clusters (28.0 %, n = 35), and epileptic auras (28.0 %, n = 35) were named as indications, while 28.0 % (n = 35) stated they administered the rescue medication for every seizure.Of those continuing to have seizures, 46.0 % did not receive rescue medication.On average, rescue medication prescription occurred 7.1 years (SD 12.7, range 0-66) after an epilepsy diagnosis.Conclusions: Unsuitable oral benzodiazepines remain widely prescribed for epilepsy patients as rescue medication.Patients also reported inappropriate use of medication.A substantial proportion of patients who were not seizure-free did not receive rescue medication prescriptions.Offering each patient at risk for prolonged seizures or clusters of seizures an individual rescue treatment with instructions on using it may decrease mortality and morbidity and increase quality of life. .

Introduction
Despite adequate therapy with antiseizure medication (ASM), onethird of patients continue to have seizures, which may evolve into seizure emergencies, including seizure clusters, prolonged seizures, and status epilepticus, which represent life-threatening neurological emergencies with serious cerebral and systemic sequelae [1,2].Rescue medications are given as needed to disrupt the progression of a seizure and forestall what would otherwise be a more prolonged or severe clinical event [3,4].Benzodiazepines, such as diazepam, lorazepam, and midazolam, are positive allosteric modulators of GABAA receptors, whose activation leads to an increase in intracellular chloride, hyperpolarization of the cell membrane, and reduced excitation [5].The preferential intravenous administration of benzodiazepines has proven effective in treating prolonged seizures and status epilepticus [6], but this cannot be practised by laypersons in an out-of-hospital setting.Seizure clusters typically occur in out-of-hospital settings, where a more portable product that can be easily administered by non-medical caregivers is required [7,8].Current indications include 1. a prolonged seizure exceeding 5 min (in generalized convulsions exceeding 2 min); 2. a history of status epilepticus; 3. a history of seizure clusters; and 4. a patient being able to identify a specific trigger [9,10].Less restrictive indications may involve seizure occurrence in a different than usual type or pattern, or the occurence at high-risk timesfor example, during medicine changes or illness [11].Yet, no consensus definition of seizure clusters is available, while status epilepticus is more precisely defined, leaving room for interpretation on actual indications.Hence, comparing literature studies about drug efficacy on seizure clusters and measuring the extent of neuronal injury is challenging [12].Moreover, prescription patterns vary widely and might involve inappropriate administration pathways.In order to formulate recommendations, data on the current prescribing and use patterns of rescue medication in patients with epilepsy in Germany, as well as predictors of rescue medication use is needed, to improve understanding of use and access to rescue medication, satisfaction with the application, predictors for prescription, and any adverse events.

Study setting and design
This non-interventional, multicentre cohort Epi2020 study focused on different healthcare aspects of adult patients with epilepsy in Germany, details of the study design was published by Willems et al. [13,14].The study was conducted at epilepsy centres in Frankfurt am Main, Greifswald, Marburg, and Münster between 10/2020 and 12/2020.During this time period, patients attending the epilepsy clinics of the participating centers were recruited to complete a questionnaire covering general patient and epilepsy-specific characteristics.All participating patients provided written informed consent.The diagnosis and syndrome classification was based on the latest definitions proposed by the International League Against Epilepsy [15].Patients with an uncertain epilepsy diagnosis were excluded from data analysis to increase data quality and reliability.Inclusion criterion was a diagnosis of epilepsy and a minimum age of 18 years.The Epi2020 questionnaire was either completed by the patients alone or with help from family members in cases of mild intellectual or physical disability.Data on access to rescue medication, its use, adverse events and prescription details, current ASM, and healthcare resource use were assessed based on a questionnaire examining a 12-month period.Quality of Life in Epilepsy (QOLIE-31), HADS-A/D, and EQ-5D were used to estimate quality of life, depression and anxiety symptoms [16,17].Outcome measures regarding satisfaction with using rescue medication and side effects were assessed using a four-level Likert scale.The study was approved by the ethics committee of Goethe University (reference 19-440) and registered with the German Clinical Trials Register (DRKS00022024; Universal Trial Number: U1111-1252-5331).The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines were closely followed during study planning, execution, and data analysis [18].

Data entry and statistical analysis
Statistical analyses were performed using IBM SPSS Statistics 29 (SPSS Inc., Chicago, IL, USA).Data are presented as mean ± standard deviation (SD); minimum, maximum, and median or percentages; and 95 % confidence intervals (CI) where appropriate.All p-values <0.05 were regarded as statistically significant.The Pearson correlation coefficient was calculated to compare variables with normal distributions and the Mann-Whitney U test conducted to compare ordinal ranked variables with non-normal distributions.Chi-square analyses were performed to assess the prediction of nominal variables with and without the use of rescue medication.

Characteristics of patients and predictors for use of rescue medication
In total, 125 patients (25.7 %) reported receiving prescriptions for or using rescue medication.On average, prescription was 7.1 years (SD 12.7, range 0-66) after being diagnosed with epilepsy.Table 1 provides the characteristics of patients receiving and not receiving rescue medication.
Overall, patients receiving rescue medication were younger (r = 0.087, p = 0.054, Pearson correlation), had a significantly lower age of epilepsy onset (r = 0.173, p < 0.001, Pearson correlation), a higher seizure frequency (p < 0.001), or were taking more ASMs (p < 0.001).Gender and age did not significantly influence the prescription of rescue medication.In a chi-square analysis, significantly more patients receiving rescue medication used a seizure calendar (p < 0.001), were more likely to have had an inpatient stay due to epilepsy in the past 12 months (p < 0.001), and were more likely to require an emergency medical service in the past 12 months (p = 0.017).Of those 361 patients who did not receive rescue medication, 46.0 % (n = 166) continued to have seizures.
A majority of patients (68.8 %, n = 86) reported that the rescue medication was administered by relatives.In 44.8 %, the rescue medication was administered by themselves (n = 56).Friends or colleagues (16.0 %, n = 20) and formal caregivers (15.2 %, n = 19) were also reported to administer the medication.Considering self-application, oral lorazepam was administered independently by 23 (18.4 %) patients, while this was the case for buccal midazolam and rectal diazepam in three and two patients, respectively.
The majority of patients (92.0 %, n = 115) reported having access more than 8 h a day to the rescue medication, 19 patients (15.2 %) indicated access from 4 to 8 h per day, four patients (3.2 %) reported up to 4 h per day, and 14 patients (11.2 %) indicated only having access at night.Rescue medication was usually kept at home (90.4 %, n = 113) and was carried on their person or in a bag (80.0 %, n = 100).Fewer patients reported storing the medication at work or school (22.4 %, n = 28), with relatives (2.4 %, n = 3), or in the car (0.8 %, n = 1).
Seizures continuing for more than several minutes (43.2 %, n = 54), seizure clusters (28.0 %, n = 35), and epileptic auras (28.0 %, n = 35) were named as indications to administer rescue medication.Almost onethird (28.0 %, n = 35) stated they administered the rescue medication for every seizure, either during seizure activity or shortly afterwards.Other single-case reasons for taking the rescue medication were status epilepticus, excessive sleeplessness, seizure prevention, stressful situations, uncomfortable auras, or the day after a seizure.
Regarding adverse events associated with rescue medication, sleepiness was named as a major (n = 32) or moderate (n = 32) problem by one-third of patients.Dizziness, anxiety, and discomfort were less frequently reported as a problem; please refer to Fig. 1 for details.Other problems such as nausea/vomiting (n = 4), headache (n = 4), anger/ aggression (n = 2), confusion and visions/hallucinations (n = 3), and concentration problems (n = 3) were reported occasionally.
In total, 110 patients reported regarding the efficacy of their rescue medication.Most patients assessed the efficacy of their rescue medication as good (58.4 %, n = 73) or very good (24.0 %, n = 30), whereas 5.6 % (n = 7) evaluated its efficacy as low.

Quality of life, anxiety and depression symptoms, and health status among patients receiving and not receiving rescue medication
Quality of life in our patient cohort was assessed with QOLIE-31 and scored significantly lower in patients with rescue medication (mean 55.6 ± 19.6 vs 63.8 ± 17.5, p < 0.001).Again, a lower score among patients with rescue medication was observed in QOLIE-31 subscales seizure worry (mean 55.4,SD 29.0, p < 0.001) and social function (mean 58.0, SD 28.2, p < 0.001).The HADS-A/D subscale for depression showed significantly higher values (mean 7.3 ± 2.9 vs 6.5 ± 2.9, SD 2.9, p = 0.013) for patients taking rescue medication; however, this was not the case for the anxiety subscale.Additionally, the epilepsy stigma scale showed a significantly higher influence in patients taking rescue medication (mean 2.9 ± 2.8 vs 1.7 ± 2.4, p < 0.001).The EQ-5D questionnaire, which assesses health status based on five dimensions of health, did not show significant differences.Table 3 provides the detailed scores.

Discussion
This multicentre study examined rescue medication in adult patients with epilepsy in Germany regarding the use of rescue medication, application, adverse events, and patient satisfaction.
In our study, 25.7 % of the respondents took rescue medication to treat seizure emergencies, which is consistent with other studies between 2016 and 2023 [19][20][21].Of the 361 patients without rescue medication, 166 (46.0 %) continued to experience seizures.There might be an unmet medical need regarding the supply of rescue medication in this subpopulation.However, our data is not granular enough to indicate which patients continue to suffer from prolonged tonic-clonic seizures or seizure clusters that might result in higher morbidity and mortality risks.On average, rescue medication was prescribed more than 7 years after the initial diagnosis.Oral lorazepam, buccal midazolam, and rectal diazepam were the most commonly taken medications.The quality of life based on the QOLIE-31 overall, social function, and seizure worry score was lower in these patients; however, no correlation was shown based on the QOLIE-31 score and type of rescue medication.
A previous survey conducted in 2016 by the Epilepsy Centers Frankfurt and Marburg (Germany) found that 134 of 481 patients (27.9 %) reported being prescribed a rescue medication during the previous year [22].In most cases at that time, unsuitable benzodiazepines with slow absorption due to oral administration were prescribed, or buccal midazolam solution was used off-label in adults.Furthermore, inappropriate use of rescue medication at every seizure was reported by a substantial number of participating patients [22].Chen et al. reviewed the medical records of 4116 adult outpatients with epilepsy, of which 28.9 % took oral lorazepam, 7.8 % rectal diazepam, 7 % oral diazepam, 6.9 % midazolam, and 5.4 % oral clonazepam [23].It is remarkable that, despite emerging literature during this period of more than 6 years, unsuitable oral benzodiazepines remain widely used.
Lorazepam, if swallowed or melted in the mouth, has a slow absorption rate.The only scenario where this administration path could be beneficial would involve patients experiencing seizure clusters [8].This, again, highlights the need for concrete definitions to enable investigation of treatment efficacy.Buccal midazolam is not approved for use in adult patients.Available options on the market currently vary between intranasal, buccal, intramuscular, and rectal application [4,[24][25][26].Approved medications for acute seizure treatment differ between the North American and European market.Various prescription surveys indicate a preference for buccal or nasal administration routes, since these are less stigmatized than the rectal route [27][28][29].A meta-analysis performed by Arya et al. evaluating the efficacy of rescue medications showed that intramuscular and intranasal midazolam are the most efficacious options for aborting prolonged seizures or seizure clusters

Fig. 1.
Adverse events reported with the use of rescue medication, colours representing grading of severity.(Four-level Likert scale; y-axis: adverse event; x-axis: percentage of patients).[30].Intranasal application avoids the first-pass metabolism [31].Its use is considered safe, well-accepted, and well-tolerated; [32,33] compared to rectal diazepam, its use is also more cost-effective [34,35].Another potential benzodiazepine is clonazepam as orally disintegrating tablets, which is only approved in the US and Canada.However, it is subject to the same problems as orally disintegrating lorazepam if swallowed or melted in the mouth, which should be considered.An oral solution, which is available for lorazepam, could be an alternative, although it can only be used if a patient does not have copious secretions or emesis during the seizure.Additionally, the need for refrigeration makes it less practical for settings outside home or work situations [36].
The majority of our study population, 82.4 %, assessed the efficacy of their rescue medication as at least good, indicating that demands on medication might differ between patients and physicians.This raises the question of whether patients feel a deceptive safety by taking unsuitable medication.Another potential explanation might be a type of response or recall bias due to the survey characteristic of this study.
In a paediatric study, Wallace et al. analyzed different patient groups in the US based on age and developmental delay.They found that over two-thirds (69 %) of healthcare professionals prescribed intranasal midazolam for those aged 16.The likelihood of recommending rectal diazepam increased as the patient's age decreased.For those aged 7, clonazepam, as orally disintegrating tablets, was mainly prescribed.Rectal diazepam appeared more acceptable in patients with developmental delay and remained the primary option for young school-aged children.In our study population, 17 patients (13.6 %) had a severe disability, indicating inability to manage their lives independently; this is too small a sample to derive potential trends.Indeed, it remains unclear why rectal application in these patients is favoured.The most compelling reasons for the choice of rescue medication were the medication's ability to preserve patient dignity and ease of use [27].Furthermore, rescue medication prescription tends to be higher in the paediatric patient cohort.This could explain the lower age of patients with rescue medication in our study cohort, since prescription may continue during a patient's transition from a paediatric to an adult healthcare provider.
While multiple benzodiazepines abort seizures with similar efficacy, seizures reoccur less frequently with lorazepam than with diazepam due to its decreased volume of distribution and long-lasting central nervous system levels reaching 12 h [37].In January 2022, the European Medicines Agency approved another intranasal midazolam preparation (Nasolam®) as another option [38].Inhaled alprazolam is currently in phase 3 clinical trial; [39] a phase 2a study in 2019 confirmed the suppression of epileptiform activity in photosensitive epilepsy [40].
In 2019, the Epilepsy Foundation established the "Rescue Therapy Project in Epilepsy" to understand the gaps, needs, and barriers facing people with epilepsy who use or may benefit from rescue therapy.High expert agreement (83.9 %) was reached on using the term "seizure clusters" to refer to a change in the number or pattern of seizures within a certain period that does not differ from the person's typical event(s) [9].A multi-stakeholder approach reached a consensus on the need for everyone with epilepsy to be assessed for use of rescue therapy (95.4 %).No established stepwise plan was available.Instead, rescue therapy should be individualized by the treating physician [9].This physician should be a trained epileptologist who is familiar with the potential advantages and disadvantages of different rescue medications, who regularly evaluates their overuse, and also monitors and adjusts concomitant ASM therapy.Potential hazards are observed in separating epilepsy treatment between different non-specialized physicians, although the prescribing source was not assessed in our study.
In our study, almost one-third (28.0 %, n = 35) of participants reported inappropriate use in administering rescue medication for every seizure.In a survey-based cross-sectional study, Gainza-Lein et al. found that one-third of the caregivers did not know the recommended time interval for medication administration [21].Thus, implementing a seizure action plan or providing training opportunities on administering the medication for patients and caregivers could be beneficial, particularly, since administration devices are not always intuitive [41,42].This could decrease mortality, morbidity, and trauma risk.Fewer events creating an emotional burden, such as visits to the emergency department or the need for an ambulance, can also improve quality of life and decrease stigmatization.
The overall scores of the QOLIE-31 were assessed to address quality of life in this patient sample.Importantly, subscales involving "seizure worry" and "social functioning", which were hypothesized to be most relevant to using rescue treatment, showed significantly lower scores in patients with rescue treatment.As a possible confounder, disease severity should be considered, indicated by a higher number of ASMs, epilepsy duration, and seizure frequency in patients with rescue medication.In support of this, significantly higher scores for the HADS-D and epilepsy stigma scales were shown.Cramer et al. assessed quality of life in epilepsy in a phase 3 open-label safety study of diazepam nasal spray using the QOLIE-31.Conversely, the subscores mentioned above showed clinically meaningful improvements during the study, indirectly suggesting a potential reduction in the burden of seizure clusters [43].Penovich et al. conducted an online survey with 861 adult patients with epilepsy or a seizure disorder who had experienced seizure clusters in the past year.A majority of all respondent groups felt seizure clusters had a moderate/major negative impact on patients' and caregivers' quality of life, including emotional, financial, and social components.They also indicated possible overuse of emergency room services and underuse of rescue treatment [19].This is consistent with our study; patients with rescue medication were more likely to have required an ambulance, intensive care unit, or emergency room treatment in the past 12 months.The main limitation of this study is the survey characteristic, which may result in report and selection bias.Moreover, interpretation and response of the questionnaire solely relied on the participating patient and was not supervised by any health care professionals.

Conclusions
Despite emerging evidence, oral benzodiazepines with unsuitable pharmacokinetics remain widely used in seizure emergencies.Moreover, a substantial proportion of patients reports inappropriate use after every seizure.In conclusion, everyone with epilepsy and prolonged seizures, seizure clusters, or episodes of status epilepticus [10,44] should be offered an individualized rescue treatment plan.Physicians must examine potential indications for each patient and provide instructions on using the medication for patients and caregivers.In the future, the availability of intranasal midazolam in further regions and approval of inhaled alprazolam might significantly improve the situation.The mode of administration should be chosen carefully to preserve patient dignity.Improving rescue therapy options could reduce hospital admissions, reduce morbidity and mortality, and improve overall quality of life.

Table 1
Characteristics of patients receiving and not receiving rescue medication.

Table 2
Details of rescue medication prescriptions and administration .

Table 3
Quality of life, anxiety and depression symptoms, and health status among patients receiving and not receiving emergency medication.Mean ± standard deviation; HADS, Hospital Anxiety and Depression Scale; QOLIE-31, Quality of Life in Epilepsy; EQ-5D, a questionnaire assessing health status based on five dimensions of health.