Outpatient management of prolonged seizures and seizure clusters to prevent progression to a higher-level emergency: Consensus recommendations of an expert working group

1 INTRODUCTION

While there have been significant advances in the treatment of epilepsy and, in particular, the expanded number of chronic anti-seizure medications (ASMs), 30%–40% of patients are not seizure-free,¹ placing them at risk of a seizure emergency.² Seizure emergencies occur when self-regulating mechanisms of spontaneous seizure termination fail, resulting in abnormally long seizures or repetitive seizures within minutes to hours.^{3, 4} Uncontrolled seizures negatively impact patient and caregiver quality of life and increase the risk of injury, seizure recurrence, and progression to status epilepticus (SE), which is associated with a high risk of long-term serious consequences such as neuronal cell death, irreversible brain damage, and mortality.^2-11

SE has a widely accepted definition proposed by the International League Against Epilepsy (ILAE), with thresholds of ≥5 min for tonic-clonic convulsions and ≥ 10 min for focal seizures with impaired consciousness.^{3, 4} SE is a medical emergency that requires treatment with parenteral benzodiazepines and ASMs administered by medically trained professionals, which often necessitates hospitalization for stabilization.^{3, 12, 13} Seizure clusters (also referred to as acute repetitive seizures) are associated with a negative impact on quality of life and a range of adverse clinical outcomes, including an increased risk of progressing to SE.^14-16 While the objective of treatment to delay or prevent the next seizure is generally accepted, optimal management is impeded by the lack of an accepted definition and evidence-based guidelines.^{6, 17, 18} Seizures that have failed to self-terminate in a typical timeframe but have not yet progressed to SE or a seizure cluster lack both standardized, uniform definitions, and clinical guidance.³ For example, the term “prolonged seizure” is not well defined and is frequently used synonymously with SE, despite the ILAE definition.

Preclinical data and evidence from patients who experience SE suggests that seizure duration is clinically meaningful and that terminating an ongoing seizure as early as possible, ideally prior to hospitalization, could translate into improved clinical outcomes and reduced healthcare resource utilization.^{8, 19-27} The effective treatment of seizure emergencies prior to hospitalization is hampered by the fact that most patients with epilepsy do not have a seizure action plan in place,²⁸ and often rely on the administration of injected benzodiazepines by emergency personnel. One factor contributing to the low uptake of seizure action plans to date may be the lack of approved and effective benzodiazepine formulations suitable for outpatient use that have a sufficiently rapid onset of action to terminate an ongoing seizure before it progresses to a tonic-clonic phase, or SE, and can be easily administered by patients and caregivers.^{28, 29}

Rapid epileptic seizure termination (REST), with treatment administered in an outpatient setting at or near the time of seizure onset (<5 min), has been recently proposed as a therapeutic goal for ongoing seizures in patients at risk of progressing to a more severe seizure or seizure emergency.³ In this paper, we will explain why we recommend that “REST” should evolve to “rapid and early seizure termination” to more accurately reflect the management goal. While REST medications are not currently available, ongoing advances in the development of rapidly acting treatments mean that interventions with the potential to achieve this goal may become available. The Seizure Termination Project was established to develop expert consensus recommendations for the definition and management of certain prolonged epileptic seizures and clusters in the outpatient setting to prevent progression to a higher-level emergency.

2 METHODS

2.3 The modified Delphi approach

The consensus recommendations were developed using a multi-step modified Delphi approach. This method provides a structured, systematic way to formulate consensus recommendations that harness the collective knowledge and experience of the expert working group with iterative rounds of anonymous voting to remove any potential bias that could be introduced by a dominant member(s). The process consisted of three online questionnaires with a hybrid face-to-face/online meeting between questionnaires 2 and 3 (Figure 1). Literature findings were reviewed to identify key management gaps, and the working group completed questionnaire 1 to provide further insights. During subsequent questionnaires and at the meeting, working group members voted on statements and provided commentary on their thought processes with the aim of identifying areas of preferred clinical practice where consensus could be found. All expert group members were blinded to individual questionnaire responses and votes. At each round of voting, experts could select from five options: “strongly agree,” “agree,” “disagree,” “strongly disagree,” or “unable to answer.” Consensus was considered to have been achieved when at least 75% (9/12) of the working group voted “strongly agree” or “agree.” Statements that did not reach consensus or that group members felt could be improved were adapted based on discussion and feedback and then revoted on.

3 RESULTS

4 DISCUSSION

This working group brought together a diverse panel of experts in the field of epilepsy from across Europe and the United States to develop definitions of prolonged seizures and seizure clusters and treatment recommendations to terminate an ongoing seizure or prevent the next or further seizures in a cluster. With the definitions of prolonged seizures and seizure clusters as seizure events that could benefit from early intervention, new terminologies are needed to clearly distinguish between treatments for terminating ongoing seizures versus treatments intended to prevent subsequent seizures in a cluster. We propose REST medication and ACT, respectively, to replace the previously used “rescue treatment” with more specific terms that describe the aim of the treatment and are likely to be more widely understood. Termination of an ongoing seizure in as short a time as possible is the primary goal of REST medication. The working group came to a consensus that an ideal REST medication would need to start acting within 2 min of administration to terminate seizures before they progressed to a more severe seizure, including SE. Currently available formulations of “rescue medications” that are suitable for administration by patients and their caregivers are not known to achieve this goal because they likely have onsets of effect of 2 min or later.²⁹ Future clinical trials of potential REST medications should focus on time to seizure termination as a primary outcome measure, rather than the number of seizures over a given time period.

While further studies are needed, prolonged seizures, seizure clusters, and status epilepticus may be considered to result from related underlying mechanisms. The significant association between the occurrence of seizure clusters and convulsive status epilepticus found in one study leads the authors to suggest that seizure clusters may indicate a pathophysiology that also predisposes to status epilepticus.³⁵ Another hypothesis is that the occurrence of seizures over time may persistently lower the seizure threshold, leading to both seizure clusters and status epilepticus.³⁶ Based on available evidence, the working group believes that rapid and early seizure termination and the consequent reduction in risk of progression to SE, should lead to clear outcome-related benefits, including reduced use of emergency services, reduced risk of hospitalization and mortality, and increased overall quality of life. Seizure duration is an independent adverse predictor of outcome,^{3, 5, 6, 8, 19, 20} and a reduction in total time from seizure onset to seizure termination (i.e. time to administration plus time to seizure cessation) correlates with improved outcomes.^{3, 5, 6, 19} Several studies, in both adult and pediatric patient cohorts, have shown that early treatment of SE, prior to hospital admission, is associated with an increased likelihood of seizure termination, and a decreased risk of prolonged hospitalization, the need for further treatment, and death.^{22-27, 37} Further research will be needed to clearly demonstrate the benefits of rapid termination of an ongoing seizure with respect to prevention of SE, healthcare resource utilization, and patient/caregiver quality of life. One potential outcome-related benefit that will require further research is a reduction in the risk of cumulative neuronal damage, including the possible worsening of epilepsy.

To facilitate the identification of patient groups who may benefit from REST medication or ACT, we have proposed clear terminology defining different types of prolonged seizures and seizure clusters. Our proposed 2-minute threshold for defining prolonged bilateral tonic-clonic seizures is supported by data from several electroencephalographic telemetry studies showing that the majority of such seizures terminate within 2 min, with the convulsive phase lasting on average 62–74 s.^{20, 32, 38, 39}

The 2-minute threshold for generalized absence seizures was largely based on the varied individual experiences of the experts, given the lack of published data to support the recommendation. The analysis published by Meritam Larsen PM et al. (2022), shortly after the working group session, reported that typical absence seizures rarely have a duration that exceeds 30 s and atypical absence seizures last up to 100 s, suggesting that this threshold could be revised to 1 min.³⁸ On the other hand, the authors acknowledge that the risk of adverse consequences from prolonged absence seizures is very low.

For seizure clusters, it was noted that, for some patients, clusters are their typical pattern. They, therefore, may not experience an increase in their usual pattern but still experience clusters. Although some were in favor of including a timeframe for the seizure cluster definition, it was ultimately agreed that this should not be included in the consensus definition; however, in clinical practice, ≥2 or 3 seizures within 6, 12, or 24 h may be a useful threshold when considering if a patient requires ACT, and the number of seizures within the same timeframe may be useful for quantifying treatment outcomes. In addition to seizure frequency, it may also be important to consider the inter-seizure interval when assessing a patient's risk of progressing to SE. A recent study found that in SE, the interval between seizures was less than 120 s. This suggests there may be an inter-seizure interval below which the development of SE is more likely, although further studies are needed to determine this.⁴⁰

We aimed not to over complicate the statements regarding who should be offered treatment, since this could lead to confusion and possible underuse. Thus, the first recommendations are that all patients who have experienced a prolonged seizure should be offered a REST medication, and all patients who have experienced a seizure cluster should be offered an ACT. While there is limited evidence showing that experiencing a first prolonged seizure or seizure cluster increases a patient's risk of a similar subsequent event, offering REST or ACT medication would provide a degree of reassurance, reducing seizure worry. In the case that a pattern of prolonged seizure or seizure cluster does not emerge, the medication can be withdrawn. In many cases, the appropriate use of REST medication and ACT will be driven by a clear understanding of each patient's seizure history.

There is an ongoing discussion around the use of REST medication in patients with serious post-ictal symptoms. Most patients with seizures will experience some form of post-ictal symptoms, including confusion, fear, exhaustion, headache, emotional reactivity, memory problems, and behavioral changes that can last for some time.^41-44 The most dramatic after effect of seizures is probably postictal psychosis, which is reported to occur in around 2% of patients with epilepsy,⁴² and which the ILAE suggests should be treated with benzodiazepines and early administration of anti-psychotic medication.⁴⁵ The construction of clear recommendations for treatment during the post-ictal phase is complicated by the fact that post-ictal symptoms can be difficult to distinguish from ictal symptoms. In some patients, ictal activity continues, often in an occult fashion, as a type of nonconvulsive status epilepticus.⁴⁶ Furthermore, the severity and duration of post-ictal symptoms are not necessarily dependent on the duration of the seizure; in this case, recommending REST medication based on a history of prolonged post-ictal symptoms irrespective of the duration of the seizure may be too broad. The recommendation specifies that REST medication “may be offered” to those with a history of “debilitating” post-ictal symptoms; however, further research is needed to confirm the benefits of rapid seizure termination in reducing the impact of debilitating post-ictal symptoms.

The recommendation of offering a REST medication for patients whose ASM regime is being simplified or discontinued generated debate before consensus was reached. While there may be a risk that such a broad recommendation could lead to overuse of REST medication, it was felt that the availability of a rapidly effective treatment could provide a sense of security for patients who feel worried/anxious about coming off chronic ASM. This clinical scenario should be considered on a case-by-case basis. Research investigating the potential benefits of a REST medication in reducing the seizure duration in patients reducing or discontinuing their ASM would be of value to further inform this recommendation.

Available ACTs and investigational REST medications are generally based on benzodiazepine formulations delivered via various routes of administration.^{3, 5, 29} As such, patients can experience adverse events related to both the drug (typically somnolence, sedation, and drowsiness) and the route (e.g. injection site pain, nasal discomfort, and abnormal taste).^{5, 29} While benzodiazepines can lead to respiratory depression when administered in high doses and dependence through misuse or long-term intake,²⁹ the controlled dose delivered by drug–device combinations may mitigate against these risks.

For patients and their caregivers, these recommendations will represent a major change in the way they view the management of seizures and will require careful explanation and education. In most cases, patients without a history of prolonged seizure do not receive emergency medication within 5 min of seizure onset since even a seizure meeting the definition of prolonged would be over before currently available treatments would likely have their onset of effect.²⁹ The earlier treatment proposed in our recommendations should be presented as an ideal scenario, with acceptance that this may not always be possible in real-world settings.

Effective early administration of a REST medication or ACT will rely on the prior establishment of a viable seizure action plan discussed with and clearly explained to the patient and their caregiver.¹⁶ Currently, most adult patients with epilepsy do not have a seizure action plan in place, with only 30% of patients (n = 259) with seizure clusters reporting having one in place in a survey conducted in the United States.^{28, 47} However, support for the provision of seizure action plans is increasing, and electronic customizable templates are available to help establish a standardized and widespread approach to developing seizure action plans for all patients with epilepsy.^{16, 28} Other potential barriers to the effective implementation of our recommendations may include a lack of awareness of future REST medications and ACTs as they become available, a lack of adequate insurance coverage, and a lack of clear legal frameworks covering liability for the administration of medications in community settings (e.g., schools).⁴⁸

This consensus report has some limitations. The working group was selected by the co-chairs based on their evaluation of experience and expertise and could have been subject to some selection bias; however, the group aimed to include both pediatric and adult experts and to have representatives from a broad international community. Similarly, there is a possibility of bias in the selection of topics for research and discussion by the co-chairs and the formulation of survey questions to address these topics. Nevertheless, this working group believes that the recommendations proposed herein will complement the existing guidance for SE, providing a robust framework for further development of clear definitions and recommendations supporting the possibility of treating earlier to rapidly terminate ongoing seizures and avoid progression to SE and the associated consequences such as use of emergency services, brain damage, long-term hospitalization, and mortality.^{4, 7, 9, 49} These recommendations will require ongoing adaptation as new data and new treatments become available.

5 CONCLUSIONS

Lack of clarity regarding the ideal timing of intervention is an important barrier to the effective use of seizure termination and prevention treatment. The consensus statements proposed here should provide a clearer picture for clinicians, patients, and caregivers, and facilitate the establishment of REST as a new paradigm for the management of acute, ongoing seizures. The availability of REST medications supported by adequately controlled clinical trials is needed to accomplish this goal.

AUTHOR CONTRIBUTIONS

Jesus Eric Pina-Garza and Eugen Trinka conceptualized and designed the consensus methodology and supervised data collection. All authors were involved in the analysis and interpretation of the literature review, contributed to the voting data, and reviewed and critically revised the manuscript. All authors approved the final manuscript for submission.

FUNDING INFORMATION

The Seizure Termination Project is funded by UCB Pharma. Project management, data collation, and editorial assistance, provided by Ogilvy Health UK, were funded by UCB Pharma. UCB Pharma reviewed the outputs of the project for scientific accuracy but was not directly involved in any stage of the formulation of recommendations and was blinded to all stages of expert working group voting.

CONFLICT OF INTEREST STATEMENT

All authors received honoraria from UCB Pharma for participating in the Seizure Termination Project. Jesus Eric Pina-Garza has received book royalties from Elsevier; received consulting fees as an advisor to Eisai, Jazz Pharmaceuticals, Marinus, Neurelis, SK Life Science, UCB Pharma, and Zogenix; and received payment or honoraria for speaker bureaus for Eisai, Jazz Pharmaceuticals, Marinus, Neurelis, SK Life Science, UCB Pharma, and Zogenix. Michael Chez has received honoraria as a consultant and speaker for Marinus, UCB Pharma; as a speaker for Catalyst and Neurelis; and as an advisory board member for SK Life Science. James Cloyd has received consulting fees from Neurelis, Solievo, UCB Pharma, and West Therapeutics; royalty payments through the University of Minnesota from Ligand; and research funding through the University of Minnesota from PrevEp. Lawrence Hirsch has received consultation fees for advising from Accure, Ceribell, Eisai, Gilead, Marinus, Neurelis, Neuropace, Rafa Laboratories, UCB Pharma & Vial Health Technology; Royalties from Wolters-Kluwer for authoring chapters for UpToDate-Neurology, and from Wiley for co-authoring the book “Atlas of EEG in Critical Care,” 1st and 2nd editions; and honoraria for speaking from Neuropace, Natus, and UCB Pharma. Reetta Kälviäinen reports personal fees from Angelini Pharma, Lundbeck, Marinus, Orion Pharma, Eisai, UCB Pharma, OmaMedical, Takeda, and Jazz Pharmaceuticals; her institution received grants from the European Union, the Academy of Finland, Finnish Government Research Funding, the Saastamoinen Foundation, the Vaajasalo Foundation, and the Jane and Aatos Erkko Foundation. Pavel Klein has served as a consultant, advisory board member, or speaker for Abbott, Angelini, Aquestive, Arvelle Therapeutics, Aucta Pharmaceuticals, Dr. Reddy's, Eisai, Jazz Pharmaceuticals, Neurelis, Neurona, SK Life Science, Sunovion, UCB Pharma, UNEEG, UniQure, is a member of the Medical Advisory Board of Stratus and of the Scientific Advisory Board of OB Pharma, is the CEO of PrevEp, Inc., and has received research support from CURE/Department of Defense and from the NIH/SBIR. Lieven Lagae has received grants, and is a consultant and/or speaker for Zogenix (now a part of UCB Pharma), LivaNova, UCB Pharma, Shire, Eisai, Novartis, Takeda/Ovid, NEL, and Epihunter en. Raman Sankar has received grants or contracts from DoD and NINDS; has received book royalties from Cambridge University Press and Demos; has received consulting fees from Aquestive, Eisai, and UCB Pharma; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Aquestive, BioMarin, Jazz Pharmaceuticals, Neurelis, SK Life Science, UCB Pharma, and Zogenix; and has participated on a Data Safety Monitoring Board for Takeda. Nicola Specchio has served on scientific advisory boards for GW Pharma, BioMarin, Arvelle, Marinus, and Takeda; has received speaker honoraria from Arvelle, Jazz Pharmaceuticals, Biocodex, UCB Pharma, Zogenix, Takeda, Eisai, Biomarin, Livanova, Sanofi; and has served as an investigator for Zogenix, Marinus, Biomarin, UCB Pharma, Roche, Takeda, GRIN Therapeutics, Jazz Pharmaceuticals, and Livanova. Adam Strzelczyk received personal fees and grants from Angelini Pharma, Biocodex, Desitin Arzneimittel, Eisai, Jazz (GW) Pharmaceuticals, Marinus Pharma, Precisis, Takeda, UCB Pharma (Zogenix), and UNEEG medical. Manuel Toledo declares consulting honoraria and research fundings from Arvelle, Angelini, UCB Pharma, Eisai Inc., Bial, Takeda, Jazz Pharma, GW Pharmaceuticals, Esteve, Neuraxpharm, and Neuroelectrics. Eugen Trinka reports paid consultancy from Arvelle, Argenx, Angelini, Clexio, UCB Pharma, Eisai, Epilog, Bial, Medtronic, Everpharma, Biogen, Biocodex, Takeda, Jazz, Liva-Nova, Newbridge, Sunovion, GW Pharmaceuticals/Jazz, and Marinus; Research funding (directly or to an institution) from GSK, Biogen, Eisai, Novartis, Red Bull, Bayer, and UCB Pharma; Speaker's honoraria from Arvelle, Angelini, GSK, GW Pharmaceuticals, Biocodex, Böhringer Ingelheim, Eisai, Epilog, Bial, Everpharma, UCB Pharma, Liva-Nova, Newbridge, Hikma, Novartis, and Sanofi. He is CEO of Neuroconsult Ges.m.b.H. Grants from the Austrian Science Fund (FWF), the Österreichische Nationalbank, and the European Union.