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Division of Epilepsy and Neurophysiology, Department of Neurology, Boston Children’s Hospital, Boston, MA, United StatesFacultad de Medicina, Universidad Austral de Chile, Valdivia, Chile
Seizure clusters are common in patients with refractory epilepsy.
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There is no agreed upon definition for seizure clusters.
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Rescue medications are underutilized in seizure clusters.
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Non-rectal, non-IV benzodiazepines are safe and effective in the outpatient management of seizure clusters.
Abstract
Purpose
To summarize definitions, prevalence, risk factors, consequences, and acute management of seizure clusters using rescue medications.
Methods
We searched MEDLINE for studies that assessed definitions, clinical characteristics, outcomes, and use of rescue medication for aborting seizure clusters.
Results
Different clinical and statistical definitions for seizure clusters have been proposed, including: ≥3 seizures in 24 h, ≥2 seizures in 24 h, and ≥2 seizures in 6 h. Most studies of seizure clusters have been conducted in tertiary epilepsy centers, with refractory epilepsy patients. Patients with severe and poorly controlled epilepsy are more likely to experience seizure clusters.
Seizure clusters can result in increased health care utilization and have negative impact on the quality of life of patients and caregivers. Use of benzodiazepine rescue medications in acute management of seizure clusters can help avoid progression to status epilepticus and reduce emergency room visits. Rescue medications are underutilized in seizure clusters. Currently, rectal diazepam gel is the only FDA approved rescue medication for seizure clusters. In addition, buccal midazolam is approved in European countries for treatment of prolonged seizures. However, various non-rectal non-IV benzodiazepines are safe and effective in treating acute seizures and clusters. Most patients and caregivers preferred non-rectal routes.
Conclusion
Identifying patients that are at high risk for seizure clusters, providing them with formal action plans and educating them about use of rescue medication for seizure clusters can help ameliorate the outcomes in this group of epilepsy patients.
Patients with epilepsy often experience acute repetitive seizures or seizure clusters. Surveys of patients and caregivers suggested that seizure clusters have negative impact on quality of life, emotional wellbeing, daily function, and productivity of the patients and their caregivers [
There is no consensus in terms of definition of seizure clusters. Patients, caregivers and providers use different definitions for seizure clusters. There is a gap in communication among the providers and the patients or caregivers in identifying seizure clusters [
]. Lack of rescue plan and underutilization of rescue medication could result in unnecessary emergency room visits. Better definitions of seizure clusters may help better characterize them, and identify the patients that would benefit from intervening with rescue medications [
Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009.
]. It could be defined as a series of grouped seizures that have short interictal periods; however, the number of seizures and the interictal period is a subject of controversy [
]. Different studies and authors have proposed various definitions, some using a clinical approach and some based on a statistical approach.
2.1 Clinical definitions
Several studies propose clinical definitions that define a number of seizures during a limited time interval. It is assumed that if seizures occur within 8 h it is more likely that they arise from a concordant focus and thus not actually “independent” [
]. A study showed that seizures with interictal period of less than 8 h were more likely to come from the ipsilateral hemisphere than seizures with longer interictal intervals [
Efficacy of Nayzilam™ (USL261; midazolam nasal spray) in subjects with acute repetitive seizures: results from the randomized, phase 3 ARTEMIS-1 clinical trial.
in: American Epilepsy Society Annual Meeting, Washington, DC2017
]. A randomized controlled trial of rectal diazepam in the treatment of acute of repetitive seizures used the following operational definition: “An episode of multiple complex partial or generalized (tonic, clonic, tonic clonic, atypical absence, or myoclonic) seizures occurring within a 24-h period in adults or a 12-h period in children, with a pattern distinguishable from the patient’s usual seizure pattern, and with onset readily recognizable by a caregiver, such as a parent” [
Some studies have proposed statistical definitions that describe an increase in seizure occurrence compared with what is expected based on the patient’s average seizure frequency [
]. A more sophisticated statistical approach can be based on a Poisson (random) distribution, where the events occur randomly within independent time intervals. A deviation from this model can reflect seizure clusters, and also indicate periodic patterns or regularity [
]. Deviations could include negative dependence of seizures (having too many seizures in the prior day decreases the chance of having seizure in the following day), and positive dependence (occurrence of seizure in the prior day increases the chance of having seizure) [
]. Departure from a random model can be observed in many patients with refractory epilepsy. In a study of 24 patients with epilepsy who maintained a seizure diary, 10 out of 22 had seizures that were not randomly distributed [
]. In another study of 13 patients with intractable epilepsy who self-reported their seizures using a seizure diary, in almost all the patients studied, seizures did not follow a random pattern [
The clinical definitions do not account for the variability in the baseline seizure frequency among different patients, and tend to overestimate the occurrence of seizure clusters in patients who regularly have high frequencies of seizures [
]. However, these definitions could be easier to use clinically and probably more relevant in the acute settings in terms of using rescue medications to prevent status epilepticus. On the other hand, the statistical approach could be useful to identify “false positives”. In addition, the statistical definitions can be utilized in seizure detection and prediction algorithms [
]. Forty-three percent of patients who were keeping a seizure diary met the clinical definition of 3 or more seizures in 24 h, whereas only 22% met the statistical definition [
≥3/24 h (or 3 times the daily average for patients with daily seizures)
Symptomatic Generalized Epilepsy History of CNS infection Cortical dysplasia Complex partial seizure Status epilepticus Age at seizure onset Absence of 1-year seizure freedom Having failed 2 or more AEDs
Prevalence is also dependent on the study population. Most studies on seizure clusters have been conducted in tertiary epilepsy centers, where patients with refractory epilepsy are more prevalent [
]. Therefore, the reported prevalence might be an overestimation. The prevalence of seizure clusters ranges from 13 to 76% in the outpatient setting and 18 to 83% for the inpatient setting (epilepsy monitoring unit) [
]. In a study of adult patients in the outpatient setting, the prevalence of clusters (3 or more seizures in 24 h or 3 times the baseline frequency) was 14.9% [
]. In the inpatient setting the prevalence has been reported to be 50% or higher. In addition to the selection bias and more severe epilepsy patients in the inpatient setting, in the long-term monitoring units, anti-seizure medications are often temporarily withdrawn, which can trigger seizure clusters [
]. In another population based study in UK, which used the general practice research database, the prevalence of seizure clusters was 2.5/10,000 population (Confidence Interval: 2.3–2.7) using the definition of 3 or more seizures in 24 h. The prevalence was lower than many other studies (only 3% of patients with epilepsy) [
]. However, in the retrospective chart review studies, lack of structured interviews to identify seizure clusters might underestimate the prevalence of seizure clusters.
4. Patients at risk for seizure clusters
Some patients with epilepsy are at higher risk to develop seizure clusters than others. Several studies have looked into factors that are associated with seizure clusters (Table 1). Some studies have suggested that patients with extratemporal epilepsy [
]. However, as mentioned above in the definitions section, having a high baseline seizure frequency might result in an overestimation of prevalence of seizure clusters defined clinically. The higher number of seizures per day, the more likely they fall into the clinical definition of clusters (3 or more seizures in 24 h) [
Rather than identifying the risk factors for “being a clusterer”, it could also be clinically relevant to identify “periods of vulnerability” to seizure clusters [
]. In a study of patients with intractable localization-related epilepsy, convulsive status epilepticus had occurred in 44% of patients who typically had seizure clusters and 12.5% of patients without seizure clustering (p < 0.002). Typically clusterers were patients who had more than half of their seizures in clusters of 3 or more seizures in 24 h [
]. Intra-cluster seizures are relatively shorter in duration compared to isolated seizures or the terminal seizure in a cluster. It is hypothesized that the intra-cluster seizures are not long enough to activate the self-regulatory inhibitory mechanism that normally limits seizures [
]. Another hypothesized mechanism is the persistent lowering of seizure threshold by the seizures. Both of these mechanisms could contribute to status epilepticus or seizure cluster. Thus, patients with either condition are predisposed to the other [
The association of seizure clusters with mortality is not well stablished. In a prospective population-based study with a long term follow up of 37 years on average, an increased risk of mortality was observed in patients who started to have clusters (defined as 3 or more seizures in 24 h) during treatment, but no increased mortality in patients with clusters prior to treatment compared to patients without clusters [
]. Confounding factors such as severity of epilepsy and the underlying etiology should be taken into account while interpreting these results.
Interestingly, having seizure clusters could be associated with better outcome after epilepsy surgery. In a retrospective study of 681 patients with temporal lobe epilepsy who underwent surgical resection, those who had a history of seizure clusters had a better post-surgical outcome [
Seizure-related injury in patients with seizure clusters has not been well studied. In a study of 141 epilepsy patients including 41 (29%) with a history of seizure clusters, there was no association between seizure-related injuries and history of seizure clusters defined as 3 or more seizures in 24 h [
Use of benzodiazepine rescue medications is the cornerstone in acute management of seizure clusters that can help to abort clusters and reduce emergency room visits [
]. However, studies have shown that benzodiazepines are largely underutilized in patients with seizure clusters. A study of adult patients with seizure clusters showed that fewer than half of them were prescribed at least one benzodiazepine rescue medication [
]. The most common rescue medications used were oral lorazepam (28.9%), followed by rectal diazepam (7.8%), oral diazepam (7.0%), and intranasal midazolam (6.9%) [
Rectal diazepam is the only U.S. Food and Drug Administration (FDA) approved rescue medication for bouts of increased seizure activity. It has been shown to be effective and safe in treating acute repetitive seizures [
]. Other medications and different routes of administration have also been investigated. Buccal, intramuscular and intranasal midazolam, intramuscular and intranasal diazepam are among the alternatives to the rectal diazepam that have been studied for safety and efficacy. In addition to safety and efficacy of non-rectal routes, there is superiority in terms of ease of administration. Non-rectal non-IV routes were more rapidly administered than rectal route [
Oral clonazepam is widely use in the United States, Europe, and Latin America for seizure clusters. However, there is a gap in the literature in terms of its effectiveness in acute treatment of seizure clusters. IV clonazepam is an effective alternative to lorazepam and midazolam in treating status epilepticus [
]. There is a need to formally evaluate the effectiveness of oral clonazepam as a rescue medication for seizure clusters. Intranasal midazolam has shown effectiveness in aborting seizure clusters [
]. It has a rapid onset of action, reaching the peak concentration at 10–12 min, and likely reaching therapeutic levels significantly faster. The elimination half-life is between 3.6 and 3.8 h, which is shorter than diazepam (50 h) [
Safety and efficacy of intranasal midazolam USL261/Nayzilam in outpatient treatment of seizure clusters has been investigated in a phase 3 double-blind controlled clinical trial (NCT 01390220). Two hundred and one patients with seizure clusters (defined as 2 or more seizures within 6 h) were included. Based on the results presented at the American Epilepsy Society meeting, of patients in the midazolam arm, 53.7% achieved success (seizures terminated within 10 min and maintained seizure freedom from 10 min to 6 h after administration), compared with 34.4% in the placebo group [
Efficacy of Nayzilam™ (USL261; midazolam nasal spray) in subjects with acute repetitive seizures: results from the randomized, phase 3 ARTEMIS-1 clinical trial.
in: American Epilepsy Society Annual Meeting, Washington, DC2017
]. Mucosal irritation, lethargy, lacrimation, and abnormal taste were the most frequently reported treatment-related side effects for intranasal midazolam in this study [
Safety and tolerability of Nayzilam™ (USL261; midazolam nasal spray) in subjects with acute repetitive seizures: results from the randomized, phase 3 ARTEMIS-1 clinical trial.
in: American Epilepsy Sociaety Annaul Meeting, Washington, DC2017
]. However, the bioavailability of an intranasal diazepam formulation in patients with epilepsy was shown to be suboptimal in a recent clinical trial. The phase 3 clinical trial (NCT 02316847)[
] investigating the long-term safety and tolerability of diazepam intranasal spray in adolescents and adults with seizure clusters was terminated due to unexpectedly low nasal mucosal absorption of the diazepam preparation and its failure to demonstrate its bioequivalence to Diastat® rectal gel [
]. Another phase 3 clinical trial is currently ongoing to assess the safety of repeat doses of intranasal diazepam (NRL-1) administered to epilepsy patients who experience frequent breakthrough seizures or seizure clusters [
Midazolam can be successfully administered intramuscularly. Intramuscular midazolam had superior effectiveness in stopping convulsive status epilepticus compared with intravenous lorazepam when administered via an autoinjector by paramedics prior to hospital arrival [
]. In a small prospective randomized clinical trial in children with prolonged seizure, intramuscular midazolam resulted in more rapid cessation of seizures than intravenous diazepam (7.8 min vs 11.2 min, P = 0.047) [
Safety and effectiveness of long-term treatment with diazepam auto-injector administered by caregivers in an outpatient setting for the treatment of acute repetitive seizures.
A double-blind, randomized, placebo-controlled trial of a diazepam auto-injector administered by caregivers to patients with epilepsy who require intermittent intervention for acute repetitive seizures.
]. Because of the relatively high volume of solution that needs to be injected (3 ml), and the time of up to 10 s during which the injected site may not move or be moved, intramuscular application of diazepam does not seem to have the potential for acceptance by patients in caregivers. The drug company Pfizer that had sponsored a phase 3 trial for intramuscular diazepam administered by an autoinjector61 is no longer pursuing this project.
In a recent placebo controlled clinical trial, the Staccato® alprazolam showed promise in reduction of epileptic activity in photosensitive epilepsy [
]. The Staccato® system is a novel method for fast drug delivery which comprises the vaporization of drug and rapid generation of drug aerosols that the patient inhales in a single breath. The rapid absorption and onset of action (T max of 2 min) [
]. Nevertheless, rectal diazepam did not cause serious events such as respiratory or cardiac problems, even when multiple doses were administered due to inadequate efficacy of the initial standard dose in acute repetitive seizures [
]. In addition, it should be pointed out that in patients with convulsive status epilepticus en route to the hospital, IV benzodiazepines lead to lower rates (about half) of respiratory failure than placebo; stopping the seizures is the way to minimize respiratory issues [
]. Thus, the much anticipated alternatives to the rectal route would likely be widely accepted and adopted by the patients once approved and commercialized [
]. Currently, although not commercially available, intranasal midazolam is already in use off-label as a rescue medication in many institutions (including ours) by using an IV midazolam solution placed in a metered-dose nasal sprayer or a small syringe with an atomizer [
Intranasal midazolam during presurgical epilepsy monitoring is well tolerated: delays seizure recurrence, and protects from generalized tonic-clonic seizures.
In addition to benzodiazepines, other treatments are available for seizure clusters. Oral clobazam has been used for aborting seizure clusters when oral therapy is possible [
] and is often utilized in patients with seizure clusters via patient or caregiver swiping of a magnet to provide additional stimulation. Its efficacy in aborting seizure clusters has not been well studied [
Data on seizure frequencies are often obtained through self-report by patients and/or by parents or care givers. However, this method is suboptimal and subject to error and underestimation [
]. Although objective data have shown that epileptic seizures are generally equally distributed among day and night, in a survey of 170 patients with epilepsy, patients reported a three-fold higher frequency of seizures during daytime, which indicates the possibility of under-reporting the nighttime seizures [
]. In a study of 31 patients with epilepsy who were admitted to an epilepsy monitoring unit, only 26% of patients were always aware of their seizures, and 30% were never aware of their seizures [
]. In another study of 91 adult patients with focal epilepsy admitted for video-EEG monitoring, 55% of all recorded seizures went undocumented by the patients [
]. Similarly in pediatric patients, a retrospective review of clinical record of children admitted to the epilepsy monitoring unit showed that the parents/caregivers under-reported 50% of seizures [
]. In addition, in pediatric patients different caregivers might be observing patients in different settings (school/home), resulting in inconsistency in reporting seizures and difficulty in maintaining a comprehensive diary [
] (including electronic seizure diaries). Keeping logs of seizures might not be feasible for patients that have a high seizure frequency. Seizure detection devices could provide an objective mean of detecting and keeping track of seizures. However, the currently available devices have some limitations including questionable utility in different seizure types other than tonic-clonic seizures, and have high rates of false detections [
In addition to the inaccuracy of patient self-report, there are other factors that contribute to suboptimal addressing of seizure clusters during the patient-physician encounter. One of the most important factors is the gap in communication between patients/caregivers and physicians. Since there is no standard definition for seizure clusters, the patients and physicians might be referring to different entities by using the word “clusters” which might result in confusion. A survey of patient opinions based on internet forums revealed that sometimes patients felt lack of understanding and acknowledgement by their physician regarding their concern about seizure clusters [
It is important to raise the clinical awareness among the healthcare providers and encourage them to investigate specifically about seizure clusters during their patient encounter. Identifying patients that are at high risk for seizure clusters, providing them with formal action plans and educating them about use of rescue medication for seizure clusters can help ameliorate the outcomes in this group of epilepsy patients (Fig. 1). We will soon have additional approved options for treating clusters. Hopefully this will lead to fewer emergency room visits, fewer injuries, a lower prevalence of status epilepticus, more willingness to participate in activities away from home, and overall better quality of life for our patients with persistent seizures.
Fig. 1Steps towards improving seizure cluster outcome.
Seizure clusters are common in patients with refractory epilepsy, and can be associated with adverse outcomes. Rescue medications can help ameliorate the outcomes, but are generally underutilized in patients with seizure clusters. Non-rectal, non-IV benzodiazepines are safe and effective in the outpatient management of seizure clusters
Disclosure
Dr. Hirsch has received:
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Research support to Yale University for investigator-initiated studies from Eisai, Monteris, and Upsher-Smith.
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Consultation fees for advising from Ceribell, Eisai, Monteris, Sun Pharma, and Engage Therapeutics
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Royalties for authoring chapters for UpToDate-Neurology, chapters for Medlink—Neurology, and from Wiley for co-authoring the book “Atlas of EEG in Critical Care”, by Hirsch and Brenner.
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Honoraria for speaking from Neuropace.
Dr. Kellinghaus has received speaker’s honoraria from UCB, Cerbomed and Eisai. He has served on advisory boards for UCB and Eisai. He has acted as paid consultant for NrSign Inc, Vancouver, Canada.
Dr. Detyniecki has received Research support to Yale University for investigator-initiated studies from Eisai, Sunovion, Acorda and Upsher-Smith.
Dr. Jafarpour and Dr. Gaínza-Lein have received research support to Boston Children’s Hospital for an investigator-initiated study from Upsher-Smith Laboratories.
References
Penovich P.E.
Buelow J.
Steinberg K.
Sirven J.
Wheless J.
Burden of seizure clusters on patients with epilepsy and caregivers: survey of patient, caregiver, and clinician perspectives.
Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009.
Efficacy of Nayzilam™ (USL261; midazolam nasal spray) in subjects with acute repetitive seizures: results from the randomized, phase 3 ARTEMIS-1 clinical trial.
in: American Epilepsy Society Annual Meeting, Washington, DC2017 (Available from: https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/349298)
Safety and tolerability of Nayzilam™ (USL261; midazolam nasal spray) in subjects with acute repetitive seizures: results from the randomized, phase 3 ARTEMIS-1 clinical trial.
Safety and effectiveness of long-term treatment with diazepam auto-injector administered by caregivers in an outpatient setting for the treatment of acute repetitive seizures.
A double-blind, randomized, placebo-controlled trial of a diazepam auto-injector administered by caregivers to patients with epilepsy who require intermittent intervention for acute repetitive seizures.
Intranasal midazolam during presurgical epilepsy monitoring is well tolerated: delays seizure recurrence, and protects from generalized tonic-clonic seizures.
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