Short-Term Impact of Seizures and Mitigation Opportunities

Purpose of Review The burden of epilepsy is complex and consists of elements directly related to acute seizures as well as those associated with living with a chronic neurologic disorder. The purpose of this systematic review was to characterize short-term burdens of seizures and to explore the potential value of acute treatments to mitigate these burdens apart from reducing the risk of status epilepticus. Recent Findings A systematic literature search was conducted using PubMed to identify articles published from January 1, 2017, to June 22, 2023, that described short-term burdens and acute treatments of seizures. Primary outcomes included those related to short-term burdens of seizures and the benefits of acute treatments to reduce short-term burdens. Of the 1332 articles identified through PubMed and 17 through other sources, 27 had relevant outcomes and were included in the qualitative synthesis. Seizure emergencies negatively affected short-term quality of life and the ability to conduct normal daily living activities and were associated with physical (injury) and financial (emergency transport, hospitalization) burdens. The use of acute treatment was associated with a rapid return (≤ 1 h) to normal function/self for both patients and caregivers and potentially lower healthcare utilization and costs. Seizure action plans may improve knowledge and comfort with seizure care, empowering patients and caregivers. Summary The short-term burden of seizures can create a substantial negative impact on patients and caregivers. Acute treatments may reduce the short-term burdens of seizures in addition to their well-described role to reduce seizure activity and the risk for status epilepticus.


Introduction
The burdens of epilepsy are complex and diffuse, affecting patients, family members, and other caregivers.Burdens of epilepsy include those directly related to seizures (e.g., disability, injury, mortality, healthcare costs) [1][2][3], as well as those related to the challenges of living with or caring for those with an unpredictable neurologic disorder (e.g., quality of life) [4][5][6].Additionally, burdens of epilepsy can be further categorized as those associated with the short-term, immediate effects of seizures, as well as those associated with the long-term impact of epilepsy [4].In the context of mitigating short-term burdens directly related to seizures [7], acute treatments may reduce the risk of potential prolonged seizure activity and status epilepticus [8].
Epilepsy's expression varies from person to person.The variable severity of the expression affects the perception of risk for serious outcomes associated with discrete seizures, ultimately influencing patient and caregiver decisions on appropriate treatment.Regardless of perceived risk of status epilepticus, people with epilepsy, family members, and caregivers must navigate through the respective short-and long-term burdens (psychosocial, medical, financial) that acute seizures and epilepsy present [6].Benzodiazepines, the cornerstone of rescue treatment, have shown effectiveness in attenuating seizure activity in hospital and community settings, and play an important role in decreasing risks associated with status epilepticus [8][9][10].The potential for rescue medications to attenuate short-term seizure burden aside from the prevention of status epilepticus may be underrecognized.The objective of this systematic review of recent literature is to characterize the various shortterm burdens of seizures beyond status epilepticus, and to describe the role of acute treatment as well as its availability in helping ameliorate seizure impact.

Methods
A systematic literature search was conducted to identify studies indexed on PubMed and published from January 1, 2017, to June 22, 2023, that examined the short-term burden of seizure emergencies or the potential value of acute treatment for any seizure, apart from reducing the risk for status epilepticus.Search terms included the following: ((((epilepsy AND seizure) AND (acute OR rescue)) AND (treatment)) AND (burden OR quality of life OR control OR hospitalization OR injury OR cognitive function OR mood OR cost OR anxiety OR fear OR depression OR worry)).The following article types were excluded: review (systematic, narrative), letter to the editor, correspondence, editorial, and opinion articles that did not present original data.Additionally, articles related to the general burden of epilepsy (e.g., depression) were excluded, as were articles that pertained to certain consequences of acute seizures (e.g., drowning) for which the impact might not be expected to be modified through the use of acute treatments.Primary outcomes were those related to the short-term burden of seizures, including quality of life and physical and financial burdens, as well as the benefits of acute (rescue) treatments to reduce seizure burden.

Quality of Life/Daily Activities
Seizure severity, of which seizure duration is a key component, constitutes a substantial aspect of seizure burden [4].In addition to negative outcomes directly related to the seizure (e.g., injuries, emergency services), the acute burden of seizures includes the interruption of activities or normal routines as well as managing the emotional and social aftermath of a seizure (e.g., cleaning up, trauma to others, embarrassment) [4].In a survey of patients with seizure clusters, 71% reported lowered expectations to conduct daily activities, and 68% believed that these seizure emergencies got in the way of performing their daily responsibilities [5].70% of patients felt that seizure clusters had a moderate to major negative impact on quality of life, 54% reported that they worry about a loss of seizure control in public, and 75% somewhat or strongly agreed that they live in fear that a seizure will occur at any time.68% of patients worry about a loss of independence, and more than half of the patients indicated that seizure clusters make them feel exhausted (76%), stressed (63%), or depressed (62%).Additionally, seizure clusters affected employment and school attendance/ performance for 69% and 32% of patients, respectively.A majority of patients indicated negative impacts of seizure clusters on the ability to participate in extracurricular (58%) or social activities (57%), and 59% felt that clusters negatively affected their ability to travel [5].
In a cross-sectional study, health-related quality of life assessed with the EuroQoL-5D instrument was very low in children and adolescents who experienced prolonged acute convulsive seizures (PACS) compared with adults (mean scores of children/adolescents with PACS rated by clinicians [0.52], parents [0.51], and patients [0.74] vs. adult population norm [0.86]) [13].Seizure-related injuries also can negatively affect quality of life [18,19].In a retrospective study conducted at an epilepsy outpatient clinic, injured patients had decreased overall quality-of-life scores compared with uninjured patients (mean QOLIE-31 T-score; 38.9 vs. 49.2,respectively; P < 0.001), including greater seizure worry (P ≤ 0.001) and reduced social function (P < 0.001) [18].In a separate retrospective study, injured patients had reduced quality of life compared with uninjured patients (mean QOLIE-31 score; 36.5 vs. 55.6, respectively; P = 0.002), as well as greater levels of seizure worry (Cambridge Worry Scale; 5.3 vs. 4.3, P = 0.008) [19].

Physical Burden
Acute seizures can lead to accidents and injuries, such as fractures, head trauma, joint dislocations/sprains, and burns [2,11,14,18].In a retrospective, single-center study that examined seizure-related injuries, the most common injury type was fracture (49%), followed by head trauma (27%) and soft tissue injuries (24%) such as lacerations, joint dislocations, and sprains; 29% of patients required intensive care [2].In a retrospective study that evaluated patients at epilepsy centers in controlled conditions who were monitored with video and electroencephalography, serious adverse events (e.g., fractures, joint dislocation, eye abrasions, tooth loosening) associated with generalized convulsive seizures occurred in 13 patients (3%); 1 had a fall-related serious adverse event [17].Additionally, 12% of patients experienced minor physical injuries (e.g., tongue/lip biting, lacerations) [17].A prospective study found that 16% of patients from a comprehensive epilepsy center outpatient clinic experienced a seizure-related injury over a 1-year follow-up [33].In another study conducted at an epilepsy outpatient clinic, 14% of patients had injuries attributed to epilepsy during a 3-month period, and 7% of patients were hospitalized as a result of injury [18].In a retrospective study of women with epilepsy, 13% experienced injuries related to epilepsy during the 3-month study period [19].The most commonly reported injuries were laceration; abrasion, cut, bruise or hematoma; burns; fracture; and severe tongue bites.Predominant seizure type (focal tonic or clonic, generalized tonic-clonic, or only automotor seizures) was not associated with injury [19].Shoulder dislocation can occur during a seizure, and chronic dislocation can lead to damage of articular cartilage, bone, and neurovascular structures, resulting in persistent pain, stiffness, and reduced range of motion [11,14].In a retrospective study conducted at a university hospital (neurology and surgery/orthopedics departments), 1% of patients over an 8-year period who experienced an acute bilateral tonic-clonic seizure also had an acute shoulder dislocation, and these patients constituted 5% of all patients (any etiology) treated for acute shoulder dislocations [14].
Fig. 1 PRISMA chart.*The following article types were excluded: review (systematic, narrative), letter to the editor, correspondence, editorial, and opinion articles that did not present original data.Additionally, articles related to the general burden of epilepsy (e.g., depression) were excluded, as were articles that pertained to certain consequences of acute seizures (e.g., drowning) for which the impact might not be expected to be modified through the use of acute treatments were $9837 and $19,577, respectively [3].In a separate study using US commercial and Medicaid data from 2010 to 2015, the average cost per seizure event (as determined through International Classification of Diseases codes, 9th Revision [ICD-9] for epilepsy or convulsion; recorded upon admission to the ED or inpatient clinic that originated in the ED) ranged from $8147 to $14,759 in patients with Lennox-Gastaut syndrome, $4637 to $8751 for those with Dravet syndrome, and $5335 to $9672 for those with tuberous sclerosis complex [15].Additionally, absenteeism from work could contribute to the financial burden of acute seizures [5].In a survey of patients with seizure clusters, among the 69% who reported that seizure emergencies negatively affected their job/career or ability to work, 62% of patients reported having experienced a seizure at work, 53% reported having to stop working completely at some point due to seizures, and 33% felt that their job performance was more closely monitored [5].Almost half (48%) reported lost employment due to seizure clusters.In a survey of caregivers, 48% indicated that seizure clusters negatively affected their job or career; among caregivers reporting an effect on work, 49% had to reduce time at work, 43% had to stop working for a period of time, and 35% had to disclose the patient's condition to their employer [5].

Financial Burden
Patients might seek professional medical care (e.g., emergency medical services, emergency department [ED] visit) for treatment of acute seizures, in part, because of a lack of education (e.g., have not had a discussion about home management as outlined by an individualized seizure action plan) to manage the episode [5].In a survey of patients with seizure clusters, most patients (24%) indicated that they would visit the ED for treatment compared to taking rescue medication (20%) or calling their doctor (20%) [5].In some school settings, however, administrative policies may require a call for emergency services even if rescue medication was administered [32].In a prospective study of patients with epilepsy, 17% reported seizure-related ED visits over a 1-year period [33].
One regional study of emergency calls for convulsions/ seizures in the United Kingdom estimated that total costs in England for prehospital ambulance care of acute seizures could be as high as £9.8 million per year in 2012 (~$15.5 million USD) [16].In a retrospective cohort study that used commercial and federal (United States, Medicare/Medicaid) claims data from 2013/4 to 2017/8, the median cost for an epilepsy-related hospitalization in commercially insured patients was $22,305, and the median length of stay was 4 days (in patients of working age [19-64 y]) [3].Median costs for epilepsy-related hospitalizations for Medicaid-and Medicare (with supplemental insurance)-insured patients administer rescue medication improved from 52% before training to 81% after training [20].

Acute Treatment to Reduce Short-Term Burden of Seizures
Acute treatment for seizure emergencies typically includes a benzodiazepine [8] formulated according to the route of administration.Injectable diazepam, lorazepam (both intramuscular and intravenous), and midazolam (intramuscular) are approved by the US Food and Drug Administration (FDA) for status epilepticus [35].FDA-approved treatments for seizure clusters are diazepam rectal gel (approved in patients with epilepsy ≥ 2 years of age), diazepam nasal spray (≥ 6 years), diazepam buccal film (2-5 years), and midazolam nasal spray (≥ 12 years) [36][37][38][39].Seizure patterns associated with clusters are distinguishable from a patient's usual pattern and typically can be recognized by a caregiver [40].In the European Union, an oromucosal midazolam solution (buccal) is approved by the European Medicines Agency for acute treatment of PACS [35].Other benzodiazepine formulations (e.g., oral) may be used offlabel to treat seizure emergencies [41].
In a survey of patients and caregivers from a long-term safety study of diazepam nasal spray, 38% of patients returned to their usual self within 30 min of receiving diazepam nasal spray, and by 1 h, 59% had done so [31].This suggested that acute treatment reduced any lingering mental or physical consequences from the seizure emergency for the majority of patients.59% of caregivers indicated that they themselves were able to return to normal daily activities within an hour of administration [31].The rate of somnolence, which has been associated with benzodiazepines [8,37], was 7%, and treatment-related somnolence was low (2%) and consistent with a return to normal self/activity [42].Rates of somnolence reported in long-term safety studies of midazolam nasal spray and diazepam rectal gel were 9% and 17%, respectively [29,43]; for diazepam rectal gel, the rate of somnolence attributed to treatment was 9% [29].Whether treating the seizure actually contributes to the reduction of seizure-associated somnolence by reducing the progression and intensity of the seizure is an area for future study.Short-term data related to quality of life are not available for midazolam nasal spray, but longer-term data for nasal formulations of both midazolam and diazepam have reported beneficial effects on measures of quality of life [44,45].
Formal cost analyses for rescue medication are lacking [46]; however, there is evidence to suggest that the use of rescue medication may reduce medical costs associated with seizures [12,28,29,33].The use of rescue medication to treat a seizure emergency has been associated with

Potential Role for Seizure Action Plans
Seizure action plans (SAPs) that detail overall seizure management (daily and rescue medications and use, first aid, special instructions, contact information), as well as acute seizure action plans (ASAPs) that focus specifically on acute management of seizure emergencies, may reduce the short-term burden of seizures [23,34].SAPs may increase caregiver knowledge [21,22] and comfort with seizure care [24] and can educate and empower patients, family members, and caregivers to self-manage seizure emergencies (standard first aid, when and how to administer rescue medication, when emergency services should be called).There are no studies that directly examine whether SAPs specifically reduce healthcare resource utilization; there is some indirect evidence from 2 studies of pediatric patients with epilepsy [24,25].In these studies, pediatric patients who received an SAP either had more follow-up clinic visits [25] or were less likely to miss a clinic visit [24] than patients without an SAP.In a separate study of pediatric patients, the completion of an SAP and availability of rescue medication at school in addition to the implementation of 5 other interventions were associated with a reduction in ED visits from 13% to 10% per 1000 patients over a 4-year period from project initiation [30].
An ASAP is designed to provide easy-to-understand instructions to care for seizure emergencies and to reinforce the proper use of therapy.This allows family members and other caregivers to manage a seizure in the community setting.This potentially reduces the need for emergency transport and hospitalization and possibly then reduces healthcare costs associated with single seizures [23].The ASAP (Fig. 2) format combines succinct instructions along with graphics to aid in its use during seizure emergencies [23].Although there are no studies that examine the effectiveness of an ASAP to reduce the short-term burden of seizures, the potential value of an ASAP is supported by evidence associated with the use of action plans in other therapeutic areas (e.g., asthma, COPD), which incorporate similar structural elements (concise wording, color coding, graphics, flow charts) and have demonstrated success to reduce healthcare utilization [26,27].Additionally, structured educational programs may be effective to improve acute seizure treatment in home and community settings.One study described the effects of an educational program to improve participant (teachers, social workers) knowledge and attitudes related to acute seizure treatment [20].After the program, which included training meetings and educational materials (slides, simulations, videos), participant knowledge of how to best manage epileptic seizures improved from 8% before training to 67% after training.Importantly, confidence to 1 3 [5].Acute treatments might potentially alleviate concerns (worry, anxiety) about seizure emergencies and instill confidence for people who experience the seizure as well as for their supervisors and coworkers.
Although data are limited and formal analyses are lacking [46], healthcare costs would be expected to be lower for those who use emergency benzodiazepine treatment for seizure emergencies.The reduction in costs might also indirectly influence the emotional burden by alleviating the stress of additional medical costs and hospitalization/ length of hospitalization.The potential for acute treatment to reduce risk of physical injury is not yet fully understood.Injuries may occur during a seizure or the postictal period.Benzodiazepines inhibit seizure activity, and benzodiazepine treatment theoretically may reduce the risk of injury by reducing seizure duration (i.e., the time period when a seizure-related injury would occur) or severity, such as progression of a focal seizure to a secondary generalized seizure.This is an area for further research.A potential consideration for prompt treatment of any seizure is the associated risk-to-benefit assessment of unnecessary treatment.Although these agents have favorable safety and tolerability profiles, their potential effectiveness, cost, and upper limits of use (i.e., number of times permitted per seizure emergency, per month) may vary by agent.The fact that some seizure emergencies, such as seizure clusters, have distinguishing characteristics or patterns and are recognizable [40] might aid caregivers in their treatment decisions, including the necessity of prompt treatment.In all, these results suggest that acute treatment has value in reducing the short-term burden of seizures to the patient, caregiver, family, and community.

Conclusions
Acute antiseizure treatments, from a clinical standpoint, are important to reduce seizure duration and the risk to progress to status epilepticus.For patients, families, and caregivers, acute seizures present a daily burden, limiting daily activities and reducing quality of life.The potential to easily and conveniently administer newer benzodiazepine formulations to attenuate seizure activity has the potential to address multiple facets of seizure burden, improving the day-to-day lives of patients, caregivers, and family members.a lower likelihood of visiting the ED [28].In a long-term, open-label study of diazepam rectal gel, the requirement for ED visits was calculated to be reduced by more than half in those who received diazepam rectal gel when compared with placebo control from a related randomized controlled trial [29].In an analysis from a prospective study that examined a subset of patients (n = 26) who had used rescue medication for acute seizure treatment at least once during the study, the use of rescue medication for seizure events was associated with fewer injuries (2% vs. 92%; P < 0.0001) and ED visits (5% vs. 17%; P < 0.0239) per event compared with no rescue medication [33].Finally, in a retrospective cost-of-illness study in Germany, children and adolescents treated with a benzodiazepine (unspecified) for status epilepticus before hospital admission had substantially shorter length of stay (6.2 vs. 12.2 d; P < 0.001) and lower inpatient treatment costs (€4372 vs. €7015; P < 0.005) than those who did not receive prehospital benzodiazepine treatment [12].

Discussion
This review characterized the short-term burden of seizures and the potential value of acute treatment to mitigate short-term burdens apart from reducing the risk of status epilepticus.Short-term burdens consisted of quality-of-life outcomes associated with a seizure, physical injuries, and costs related to seizure care.There was evidence that use of acute treatment in the form of rescue medication was effective at reducing short-term burdens of seizures.Continuous seizure activity including seizure clusters can evolve into status epilepticus, which is associated with morbidity and mortality [8].However, the majority of seizures will terminate on their own [47], which might potentially influence how patients and caregivers perceive the need to treat acute seizures.The results of this systematic review suggest that the use and availability of acute treatments for any seizure may be of value apart from reducing the risk of status epilepticus.
The use of acute treatments, such as rescue medications, can provide a level of confidence to engage in or resume normal daily activities.For seizure clusters, providing a level of confidence that the seizure cluster will be terminated after administration can address the unpredictability aspect of seizure clusters, which weighs heavily on quality of life, influencing how the patient and caregiver plan for the rest of their day.This is important not only for working adults with epilepsy, who may fear that their seizure emergency may negatively influence employment (e.g., lost employment, responsibilities reduced), but also children and adolescents, who may be concerned over the potential negative impacts of seizures on school attendance and performance

Table 1 (
seizure action plan; ASM, antiseizure medication; COPD, chronic obstructive pulmonary disease; DS, Dravet syndrome; ED, emergency department; LGS, Lennox-Gastaut syndrome; N/A, not applicable; PACS, prolonged acute convulsive seizure; QOL, quality of life; RCT, randomized controlled trial; SAP, seizure action plan; sZAP, standardized seizure action plan; TSC, tuberous sclerosis complex a LGS and DS cohorts were identified indirectly, using a combination of other diagnosis and medication codes as well as patient demographic and clinical characteristics continued)