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Seizure clusters, rescue treatments, seizure action plans: Unmet needs and emerging formulations

Open AccessPublished:September 05, 2020DOI:https://doi.org/10.1016/j.yebeh.2020.107391

      Highlights

      • Up to 46% of patients treated for epilepsy experience seizure clusters.
      • Only about half of patients experiencing seizure clusters have seizure action plans.
      • Fewer than half of patients who experience seizure clusters receive rescue treatment.
      • Published guidelines for use of rescue therapies and management of seizure clusters are urgently needed.
      • Also needed are better rescue treatment options in this setting.

      Abstract

      Purpose of review

      The aim of the study was to provide an overview of the prevalence, risk factors, burden, and current and emerging pharmacologic treatments for seizure clusters in patients with epilepsy.

      Recent findings

      Close to half of patients with active epilepsy experience seizure clusters, and the clinical, social, and financial burdens of seizure clusters are high. However, there is no widely accepted definition of seizure clusters; their prevalence is underappreciated, contingencies for addressing them (seizure action plans) are often lacking, and their effects are not well-studied. These issues have resulted in an insufficient number of investigations and approved medications for this condition. Novel formulations are in late-stage development to meet this unmet need.

      Keywords

      1. Introduction

      An estimated 30% of patients with epilepsy experience uncontrolled or poorly controlled seizures, despite treatment with antiepileptic drugs (AEDs) [
      • Brodie M.J.
      Road to refractory epilepsy: the Glasgow story.
      ]. In some patients, on-treatment seizures appear to occur in clusters—2 or more within a relatively short time period, with return to baseline alertness in between. Terms such as seizure clusters, serial seizures, seizure flurries, and acute repetitive seizures (ARS) have been used, often interchangeably, to describe bouts of frequent seizures in patients with epilepsy [
      • Mitchell W.G.
      Status epilepticus and acute repetitive seizures in children, adolescents, and young adults: etiology, outcome, and treatment.
      ,
      • Haut S.R.
      Seizure clusters: characteristics and treatment.
      ,
      • Buelow J.M.
      • Shafer P.
      • Shinnar R.
      • Austin J.
      • Dewar S.
      • Long L.
      • et al.
      Perspectives on seizure clusters: gaps in lexicon, awareness, and treatment.
      ,
      • Cereghino J.J.
      Identification and treatment of acute repetitive seizures in children and adults.
      ,
      • Detyniecki K.
      • O'Bryan J.
      • Choezom T.
      • Rak G.
      • Ma C.
      • Zhang S.
      • et al.
      Prevalence and predictors of seizure clusters: a prospective observational study of adult patients with epilepsy.
      ,
      • Jafarpour S.
      • Hirsch L.J.
      • Gainza-Lein M.
      • Kellinghaus C.
      • Detyniecki K.
      Seizure cluster: definition, prevalence, consequences, and management.
      ,
      • Komaragiri A.
      • Detyniecki K.
      • Hirsch L.J.
      Seizure clusters: a common, understudied and undertreated phenomenon in refractory epilepsy.
      ]. However, despite the efforts of national and international health care agencies and epilepsy-focused advocacy groups, standardized terminology is yet to be defined and widely accepted.
      In the mid-1990s, the National Institutes of Health (NIH) Epilepsy Advisory Committee and the US Food and Drug Administration (FDA) Peripheral and Central Nervous System Drugs Advisory Committee offered a standardized definition in response to the need to define the condition (they termed it “acute repetitive seizures”) and to facilitate evaluation of potential treatments [
      • Haut S.R.
      Seizure clusters: characteristics and treatment.
      ,
      • Buelow J.M.
      • Shafer P.
      • Shinnar R.
      • Austin J.
      • Dewar S.
      • Long L.
      • et al.
      Perspectives on seizure clusters: gaps in lexicon, awareness, and treatment.
      ,
      • Cereghino J.J.
      Identification and treatment of acute repetitive seizures in children and adults.
      ]. The defining features of ARS, according to these committees, included the occurrence of multiple seizures within a defined period, despite optimal/maximal therapy with antiseizure drug(s); severe complex partial or generalized seizures; a seizure pattern distinguishable from a patient's “normal” pattern with respect to type, duration, frequency, and/or severity; onset clearly distinguishable (by patient, caregiver, or healthcare professional) from the patient's “typical” seizures; and recovery between seizures [
      • Buelow J.M.
      • Shafer P.
      • Shinnar R.
      • Austin J.
      • Dewar S.
      • Long L.
      • et al.
      Perspectives on seizure clusters: gaps in lexicon, awareness, and treatment.
      ,
      • Cereghino J.J.
      Identification and treatment of acute repetitive seizures in children and adults.
      ,
      • Detyniecki K.
      • O'Bryan J.
      • Choezom T.
      • Rak G.
      • Ma C.
      • Zhang S.
      • et al.
      Prevalence and predictors of seizure clusters: a prospective observational study of adult patients with epilepsy.
      ]. These features, in various combinations, have been used to define populations in clinical studies of rescue therapies for patients experiencing seizure clusters [
      • Detyniecki K.
      • O'Bryan J.
      • Choezom T.
      • Rak G.
      • Ma C.
      • Zhang S.
      • et al.
      Prevalence and predictors of seizure clusters: a prospective observational study of adult patients with epilepsy.
      ].
      The pathogenic mechanisms underlying seizure clusters remain unclear [
      • Komaragiri A.
      • Detyniecki K.
      • Hirsch L.J.
      Seizure clusters: a common, understudied and undertreated phenomenon in refractory epilepsy.
      ,
      • Haut S.R.
      Seizure clustering.
      ], and this knowledge gap represents a critical unmet need for this condition. It is not yet understood whether the mechanisms involved in drug-refractory epilepsy (e.g., overexpression of drug efflux pumps, altered structure/function of voltage-gated ion channels) are the same as those in seizure clusters [
      • Kwan P.
      • Schachter S.C.
      • Brodie M.J.
      Drug-resistant epilepsy.
      ]. Potential pathogenic factors include failure of seizure-terminating mechanisms and increased focal neuronal excitability [
      • Jafarpour S.
      • Hirsch L.J.
      • Gainza-Lein M.
      • Kellinghaus C.
      • Detyniecki K.
      Seizure cluster: definition, prevalence, consequences, and management.
      ,
      • Haut S.R.
      Seizure clustering.
      ,
      • Haut S.R.
      • Shinnar S.
      • Moshe S.L.
      • O'Dell C.
      • Legatt A.D.
      The association between seizure clustering and convulsive status epilepticus in patients with intractable complex partial seizures.
      ]. It has also been hypothesized that seizure clusters may represent a “self-triggering” mechanism and that shorter seizures are less likely than longer seizures to sufficiently activate seizure-termination mechanisms [
      • Ferastraoaru V.
      • Schulze-Bonhage A.
      • Lipton R.B.
      • Dumpelmann M.
      • Legatt A.D.
      • Blumberg J.
      • et al.
      Termination of seizure clusters is related to the duration of focal seizures.
      ].
      This review provides an overview of seizure cluster prevalence, risk factors, burden, and associated risks for progression in patients with epilepsy and examines the current and emerging pharmacologic rescue treatment landscape.

      2. Prevalence, risk factors, and disease burden of seizure clusters

      2.1 Prevalence

      Estimates regarding prevalence of seizure clusters among patients with epilepsy vary widely and depend on the definition applied and the study population [
      • Detyniecki K.
      • O'Bryan J.
      • Choezom T.
      • Rak G.
      • Ma C.
      • Zhang S.
      • et al.
      Prevalence and predictors of seizure clusters: a prospective observational study of adult patients with epilepsy.
      ,
      • Jafarpour S.
      • Hirsch L.J.
      • Gainza-Lein M.
      • Kellinghaus C.
      • Detyniecki K.
      Seizure cluster: definition, prevalence, consequences, and management.
      ]. Clustering has been defined on the basis of both seizure frequency (x seizures within y hours) and, as determined with statistical methods, timing patterns that differ from the patient's normal on-treatment seizure patterns; statistical methods typically generate lower prevalence estimates than frequency-based methods [
      • Buelow J.M.
      • Shafer P.
      • Shinnar R.
      • Austin J.
      • Dewar S.
      • Long L.
      • et al.
      Perspectives on seizure clusters: gaps in lexicon, awareness, and treatment.
      ]. Using data from epilepsy specialty practices may lead to overestimates of clustering prevalence, because these data sets typically include patients with more severe or intractable epilepsy versus the overall population of patients with epilepsy [
      • Haut S.R.
      • Shinnar S.
      • Moshe S.L.
      Seizure clustering: risks and outcomes.
      ]. A 2015 review reported that the prevalence of seizure clusters ranged from 13% to 76% for outpatient studies and from 18% to 61% for inpatient monitoring studies [
      • Haut S.R.
      Seizure clusters: characteristics and treatment.
      ]. Estimates of seizure cluster prevalence reported in recent studies are summarized in Table 1. In a recent prospective study designed to determine the prevalence of clusters, defined as ≥2 seizures within a 6-hour period, 46% of patients with active epilepsy (≥1 seizure within prior year) had ≥1 cluster within the observation year [
      • Detyniecki K.
      • O'Bryan J.
      • Choezom T.
      • Rak G.
      • Ma C.
      • Zhang S.
      • et al.
      Prevalence and predictors of seizure clusters: a prospective observational study of adult patients with epilepsy.
      ]. This included a cluster prevalence of 30% in those who reported never having had a day with >1 seizure within the year prior to enrollment, and 63% in those who reported a day with ≥1 seizure within that prior year. Six-hour clusters occurred in 71% of patients who reported having >4 seizures within the prior year.
      Table 1Studies of prevalence of seizure clusters.
      StudyPopulationNDefinition of seizure clustersPrevalence
      Haut et al., 2005 [
      • Haut S.R.
      • Shinnar S.
      • Moshe S.L.
      Seizure clustering: risks and outcomes.
      ]
      Patients treated at epilepsy monitoring unit and neurology clinic1413 seizures within 24 h29% at baseline
      Sillanpää & Schmidt, 2008 [
      • Sillanpää M.
      • Schmidt D.
      Seizure clustering during drug treatment affects seizure outcome and mortality of childhood-onset epilepsy.
      ]
      37-Year follow-up of 245 patients (≤15 years old) treated at hospital epilepsy clinic, 1961–19641203 seizures within 24 h22%
      Martinez et al., 2009 [
      • Martinez C.
      • Sullivan T.
      • Hauser W.A.
      Prevalence of acute repetitive seizures (ARS) in the United Kingdom.
      ]
      Patients with records in General Practice Research Database, a United Kingdom-wide repository2,936,2793 seizures within ~24 h
      Seizure definition included some flexibility, especially with respect to time window for multiple seizures.
      Epilepsy: 6.7/1000
      Age-adjusted prevalence estimate.


      (95% CI, 6.6–6.8)



      Seizure clusters: 2.5/10,000
      Age-adjusted prevalence estimate.


      (95% CI, 2.3–2.7)
      Asadi-Pooya et al., 2016 [
      • Asadi-Pooya A.A.
      • Nei M.
      • Sharan A.
      • Sperling M.R.
      Seizure clusters in drug-resistant focal epilepsy.
      ]
      Presurgical patients with drug-resistant focal epilepsy who underwent epilepsy surgery, 1986–2015978



      TLE: n = 681

      ETLE: n = 83

      Other: n=214
      Patients classified as other, including those undergoing corpus callosotomy, vagus nerve stimulation, or multilobar resections, were included in analysis in both groups (TLE, ETLE).
      2 seizures within 2 days (before surgery)TLE: 23.6%

      ETLE: 16.9%
      Chen et al., 2017 [
      • Chen B.
      • Choi H.
      • Hirsch L.J.
      • Katz A.
      • Legge A.
      • Wong R.A.
      • et al.
      Prevalence and risk factors of seizure clusters in adult patients with epilepsy.
      ]
      Outpatients (≥16 years old) treated at comprehensive epilepsy centers with ≥1-year follow-up, 2005–201541163 seizures within 24 h, or



      3× daily average (patients with daily seizures), or



      Determined by treating clinician
      Overall: 14.9%

      Focal epilepsy: 16.3%

      IGE: 7.4%

      SGE: 27.1%
      Detyniecki et al., 2018 [
      • Detyniecki K.
      • O'Bryan J.
      • Choezom T.
      • Rak G.
      • Ma C.
      • Zhang S.
      • et al.
      Prevalence and predictors of seizure clusters: a prospective observational study of adult patients with epilepsy.
      ]
      Outpatients (≥12 years old) treated at comprehensive epilepsy center; prospective study with 1-year follow-up2472 seizures within 6 h29%

      Active epilepsy (≥1 seizure within prior year): 46%
      CI, confidence interval; ETLE, extratemporal lobe epilepsy; IGE, idiopathic generalized epilepsy; SGE, symptomatic generalized epilepsy; TLE, temporal lobe epilepsy.
      a Seizure definition included some flexibility, especially with respect to time window for multiple seizures.
      b Age-adjusted prevalence estimate.
      c Patients classified as other, including those undergoing corpus callosotomy, vagus nerve stimulation, or multilobar resections, were included in analysis in both groups (TLE, ETLE).

      2.2 Risk factors

      Several prospective studies have attempted to identify risk factors for seizure clusters, typically based on assessment of demographic and clinical factors, as well as seizure history, at baseline [
      • Haut S.R.
      Seizure clusters: characteristics and treatment.
      ,
      • Detyniecki K.
      • O'Bryan J.
      • Choezom T.
      • Rak G.
      • Ma C.
      • Zhang S.
      • et al.
      Prevalence and predictors of seizure clusters: a prospective observational study of adult patients with epilepsy.
      ,
      • Komaragiri A.
      • Detyniecki K.
      • Hirsch L.J.
      Seizure clusters: a common, understudied and undertreated phenomenon in refractory epilepsy.
      ,
      • Haut S.R.
      • Shinnar S.
      • Moshe S.L.
      Seizure clustering: risks and outcomes.
      ,
      • Sillanpää M.
      • Schmidt D.
      Seizure clustering during drug treatment affects seizure outcome and mortality of childhood-onset epilepsy.
      ,
      • Chen B.
      • Choi H.
      • Hirsch L.J.
      • Katz A.
      • Legge A.
      • Wong R.A.
      • et al.
      Prevalence and risk factors of seizure clusters in adult patients with epilepsy.
      ,
      • Asadi-Pooya A.A.
      • Nei M.
      • Sharan A.
      • Sperling M.R.
      Seizure clusters in drug-resistant focal epilepsy.
      ]. Reported risk factors include previous head trauma, extratemporal seizure localization, extratemporal spikes and/or slow-wave abnormalities on electroencephalogram, mean number of prior-month seizures, history of convulsive status epilepticus or of nonstatus epilepticus seizure hospitalizations [
      • Haut S.R.
      Seizure clusters: characteristics and treatment.
      ,
      • Komaragiri A.
      • Detyniecki K.
      • Hirsch L.J.
      Seizure clusters: a common, understudied and undertreated phenomenon in refractory epilepsy.
      ,
      • Haut S.R.
      • Shinnar S.
      • Moshe S.L.
      Seizure clustering: risks and outcomes.
      ], higher frequency of seizures at diagnosis [
      • Sillanpää M.
      • Schmidt D.
      Seizure clustering during drug treatment affects seizure outcome and mortality of childhood-onset epilepsy.
      ] or during follow-up [
      • Detyniecki K.
      • O'Bryan J.
      • Choezom T.
      • Rak G.
      • Ma C.
      • Zhang S.
      • et al.
      Prevalence and predictors of seizure clusters: a prospective observational study of adult patients with epilepsy.
      ], intractable epilepsy (failure of ≥2 AEDs, lack of 1-year seizure-free periods), symptomatic generalized epilepsy, focal epilepsy (vs idiopathic generalized epilepsy), history of central nervous system infection, status epilepticus, early age at epilepsy onset [
      • Chen B.
      • Choi H.
      • Hirsch L.J.
      • Katz A.
      • Legge A.
      • Wong R.A.
      • et al.
      Prevalence and risk factors of seizure clusters in adult patients with epilepsy.
      ], longer epilepsy duration, poor seizure control or more severe epilepsy, and history of seizure clusters [
      • Haut S.R.
      Seizure clusters: characteristics and treatment.
      ,
      • Komaragiri A.
      • Detyniecki K.
      • Hirsch L.J.
      Seizure clusters: a common, understudied and undertreated phenomenon in refractory epilepsy.
      ].
      The wide range of reported risk factors reflects, in part, the use of various seizure cluster definitions and study populations, as well as inclusion of patients with varying degrees of severity of epilepsy. For some of the smaller studies, relatively small variations in the reported incidence of seizure clusters may have influenced the statistical significance of results. However, more severe epilepsy (greater severity/frequency of seizures), poor seizure control, history of status epilepticus and/or epilepsy-related hospitalizations, and inadequate response to AEDs—all features of severe, refractory epilepsy—appear to be consistently associated with increased risk for seizure clusters.

      2.3 Disease burden

      In 1996, Mitchell was the first to note the importance of effective rescue treatment in attenuating the risk for progression from seizure clusters to status epilepticus [
      • Mitchell W.G.
      Status epilepticus and acute repetitive seizures in children, adolescents, and young adults: etiology, outcome, and treatment.
      ]. In 2006, Haut emphasized the need to promptly treat seizure clusters to reduce the risk for disease progression and called out the potential for seizure clusters to confound the ability to properly localize epileptogenic foci in presurgical monitoring units [
      • Haut S.R.
      Seizure clustering.
      ].
      In 2007, in a comprehensive discussion of the personal and financial burdens of repetitive and prolonged seizures, O'Dell and colleagues highlighted several areas of specific concern [
      • O'Dell C.
      • Wheless J.W.
      • Cloyd J.
      The personal and financial impact of repetitive or prolonged seizures on the patient and family.
      ]. Health-related quality of life is negatively affected by seizure severity and frequency, degree of disability, family dynamics, and an overarching sense of worry and loss of control over one's situation. Seizure-related self-injury risk, which generally correlates with increased seizure frequency and severity, may also be elevated in patients with seizure clusters. Financial burdens include reduced income potential and increased risk for unemployment/underemployment, as well as higher direct and indirect costs of medical care [
      • O'Dell C.
      • Wheless J.W.
      • Cloyd J.
      The personal and financial impact of repetitive or prolonged seizures on the patient and family.
      ].
      In a long-term Finnish prospective observational study, patients newly diagnosed with epilepsy (N = 120) were followed up for a mean of 37 years (median, 40 years; range, 11–42 years). During that time, those with seizure clusters were significantly less likely than those without seizure clusters to achieve remission during treatment and were more likely to have drug-resistant epilepsy; they also had a higher mortality rate [
      • Sillanpää M.
      • Schmidt D.
      Seizure clustering during drug treatment affects seizure outcome and mortality of childhood-onset epilepsy.
      ]. More recently, a US survey-based study of disease burden in 861 respondents (259 adult patients with seizure clusters, 263 caregivers, 339 clinicians) [
      • 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.
      ] found that the perceived impact of seizure clusters was greater among patients and caregivers than clinicians. Almost 70% of patients with seizure clusters reported an association with negative career effects, and most patients also reported that seizure clusters led to exhaustion, mental slowness/confusion, stress, and a sense of helplessness and fear. Most respondents reported that seizure clusters had made patients' lives miserable. Moreover, the majority of caregivers reported that patient care had a negative effect on their own health and quality of life [
      • 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.
      ]. It should be noted that a prospective study of patients with epilepsy (N = 247) found that those with seizure clusters were not at increased risk for injuries or emergency department (ED) visits. In this study, isolated seizures versus seizure clusters were found to be more strongly associated with seizure-related injuries (88% vs 12%, respectively) and ED visits (76% vs 24%), though the associations between seizure type and injuries or ED visits were not significant (P = 0.137 and P = 0.272, respectively) [
      • Detyniecki K.
      • O'Bryan J.
      • Choezom T.
      • Rak G.
      • Ma C.
      • Zhang S.
      • et al.
      Prevalence and predictors of seizure clusters: a prospective observational study of adult patients with epilepsy.
      ].
      In summary, although estimates vary widely, seizure clusters are highly prevalent among patients undergoing medical treatment for epilepsy. Seizure clusters appear to be associated with more severe disease and are associated with substantial burdens across multiple domains, including clinical (potential for disease progression/premature mortality), health-related quality of life, and financial. These observations strongly suggest that an outpatient rescue strategy, including acute rescue treatments for seizure clusters, is essential and should be introduced as part of a management plan upon diagnosis of epilepsy [
      • Cereghino J.J.
      Identification and treatment of acute repetitive seizures in children and adults.
      ,
      • Jafarpour S.
      • Hirsch L.J.
      • Gainza-Lein M.
      • Kellinghaus C.
      • Detyniecki K.
      Seizure cluster: definition, prevalence, consequences, and management.
      ].

      3. Treatment of seizure clusters: unmet needs and current landscape

      3.1 Undertreatment

      Given the unpredictable nature of seizures and seizure clusters, adequate treatment of seizure clusters involves 3 phases: developing and becoming familiar with an action plan to be implemented in the event of a seizure; ensuring necessary medications are obtained and are carried with the patient and/or are accessible at all locations frequented by the patient; and implementing the action plan on first signs of a seizure cluster (which may simply be first signs of a seizure in some patients). The ability to respond adequately to a cluster may be compromised if appropriate action is not taken during any of these phases. The success of seizure action plans rests on patients' and caregivers' learning about and accepting the need to treat seizures acutely. Samples of seizure action plans are included in Appendix A.
      The importance of patient awareness of seizure cluster risks and treatment benefits was highlighted in Penovich and colleagues' recent study involving adult patients with seizure clusters (n = 259), caregivers (n = 263), and clinicians (n = 339) [
      • 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.
      ]. Only a minority of patients (20%) reported that they would take a rescue medication in response to an emergent seizure cluster. Similarly, in a much earlier study by Tatum, survey responses from 76 adult patients with intractable epilepsy revealed that while two-thirds of respondents considered diazepam rectal gel a good treatment option and were not embarrassed by its use, 13% thought their ongoing breakthrough seizures were not sufficiently serious to warrant rescue treatment [
      • Tatum I.W.
      Adult patient perceptions of emergency rectal medications for refractory seizures.
      ]. The study by Penovich et al. also illustrated the need to bridge communication gaps between participating stakeholders; although 52% of clinicians reported a majority of their patients had a seizure action plan in place, only 30% of patients reported having one [
      • 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.
      ]. According to a survey of 100 families that included children with epilepsy, 87% had received a prescription for a rescue medication, but only 45% had a seizure action plan, and only 61% of those with a rescue medication prescription had received training on its use and administration [
      • Gainza-Lein M.
      • Benjamin R.
      • Stredny C.
      • McGurl M.
      • Kapur K.
      • Loddenkemper T.
      Rescue medications in epilepsy patients: a family perspective.
      ].
      Other studies have documented low prescribing rates and low usage rates for rescue medication for the treatment of seizure clusters. As reported in a retrospective study of adult patients with epilepsy (N = 4116), only 44% of those with a history of seizure clusters had received a prescription for a rescue medication [
      • Chen B.
      • Choi H.
      • Hirsch L.J.
      • Katz A.
      • Legge A.
      • Wong R.A.
      • et al.
      Prevalence and risk factors of seizure clusters in adult patients with epilepsy.
      ]. A prospective study of seizure clusters (N = 247) found that only 28% of 72 patients in the highest risk group had a rescue medication prescription [
      • Detyniecki K.
      • O'Bryan J.
      • Choezom T.
      • Rak G.
      • Ma C.
      • Zhang S.
      • et al.
      Prevalence and predictors of seizure clusters: a prospective observational study of adult patients with epilepsy.
      ]. Finally, a study of European pediatric patients with prolonged seizures (N = 286) found that, though most had a prescription for a rescue medication, about 25% of the study population had not received rescue treatment [
      • Vigevano F.
      • Kirkham F.J.
      • Wilken B.
      • Raspall-Chaure M.
      • Grebla R.
      • Lee D.
      • et al.
      Effect of rescue medication on seizure duration in non-institutionalized children with epilepsy.
      ].

      3.2 Undertreatment in educational settings

      Ensuring adequate rescue treatment of pediatric patients in educational settings is challenging, primarily because responsibilities for medication administration fall on school faculty. It is not surprising that low rates of adequate rescue treatment of pediatric patients with prolonged seizures/seizure clusters have been reported for the school environment [
      • Cross J.H.
      • Wait S.
      • Arzimanoglou A.
      • Beghi E.
      • Bennett C.
      • Lagae L.
      • et al.
      Are we failing to provide adequate rescue medication to children at risk of prolonged convulsive seizures in schools?.
      ]. Several investigators have summarized current and emerging rescue therapies and treatment guidelines in an effort to improve disease knowledge and the rates and effectiveness of treatment provided by school nurses and teachers [
      • Cross J.H.
      • Wait S.
      • Arzimanoglou A.
      • Beghi E.
      • Bennett C.
      • Lagae L.
      • et al.
      Are we failing to provide adequate rescue medication to children at risk of prolonged convulsive seizures in schools?.
      ,
      • Galemore C.A.
      Rescue medicine for epilepsy: new options for education settings.
      ,
      • Hartman A.L.
      • Devore C.D.
      • Doerrer S.C.
      Rescue medicine for epilepsy in education settings.
      ]. Training programs covering the use and administration of rescue medication may increase the confidence and reduce administration errors among school personnel responsible for intervention [
      • Dumeier H.K.
      • Neininger M.P.
      • Kaune A.
      • Schumacher P.M.
      • Merkenschlager A.
      • Kiess W.
      • et al.
      Seizure management by preschool teachers: a training concept focussing on practical skills.
      ]. More convenient (e.g., nasal rather than rectal) formulations should also improve the situation in schools, group homes, nursing homes, prisons, and other settings.

      3.3 Current treatment landscape

      The Epilepsy Foundation of America is actively working to develop consensus on best practices for rescue therapies, with input from all types of stakeholders—clinicians, patients, families, educators, pharmacists, school nurses, paramedics, and others—but at present, published guidelines do not exist. As a result, many patients at risk for seizure clusters lack a specific plan of action for emergent seizure clusters [
      • 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.
      ]. Results from a recent observational study showed that only 28% of patients with a recent history of seizure clusters had a rescue medication prescription, and the most frequently prescribed medication for rescue was oral lorazepam [
      • Detyniecki K.
      • O'Bryan J.
      • Choezom T.
      • Rak G.
      • Ma C.
      • Zhang S.
      • et al.
      Prevalence and predictors of seizure clusters: a prospective observational study of adult patients with epilepsy.
      ].
      Characteristics of an ideal rescue treatment for seizure clusters include rapid onset of efficacy across a range of seizure types, rapid bioavailability at therapeutic levels with consistent patient-to-patient pharmacokinetics, portability and ease of preparation/administration, sustained activity to prevent seizure recurrence, availability in adult and pediatric dosing formulations, extended shelf life at ambient temperatures, low abuse potential, and a favorable adverse event profile [
      • Cereghino J.J.
      Identification and treatment of acute repetitive seizures in children and adults.
      ,
      • Maglalang P.D.
      • Rautiola D.
      • Siegel R.A.
      • Fine J.M.
      • Hanson L.R.
      • Coles L.D.
      • et al.
      Rescue therapies for seizure emergencies: new modes of administration.
      ]. Pharmacologic treatment in the management of seizure clusters is currently based on benzodiazepines, which generally are well-tolerated in this setting [
      • Haut S.R.
      Seizure clusters: characteristics and treatment.
      ,
      • Jafarpour S.
      • Hirsch L.J.
      • Gainza-Lein M.
      • Kellinghaus C.
      • Detyniecki K.
      Seizure cluster: definition, prevalence, consequences, and management.
      ]. Commonly reported adverse events associated with benzodiazepines include lethargy, somnolence, and, rarely, respiratory depression, and intravenous (IV) and rectal administration of benzodiazepines has been associated with higher rates of respiratory adverse events in some but not all studies [
      • Haut S.R.
      • Seinfeld S.
      • Pellock J.
      Benzodiazepine use in seizure emergencies: a systematic review.
      ,
      • Alldredge B.K.
      • Gelb A.M.
      • Isaacs S.M.
      • Corry M.D.
      • Allen F.
      • Ulrich S.
      • et al.
      A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus.
      ].
      Until late 2019, diazepam rectal gel was the only US FDA-approved treatment for bouts of increased seizure activity in patients with epilepsy [
      • Haut S.R.
      • Seinfeld S.
      • Pellock J.
      Benzodiazepine use in seizure emergencies: a systematic review.
      ,
      ,
      ,
      ]. In clinical practice, however, oral alternatives (e.g., lorazepam) are often prescribed for acute rescue administration, especially in teenagers and adults, in whom rectal medications are highly unpopular [
      • Detyniecki K.
      • O'Bryan J.
      • Choezom T.
      • Rak G.
      • Ma C.
      • Zhang S.
      • et al.
      Prevalence and predictors of seizure clusters: a prospective observational study of adult patients with epilepsy.
      ]. Table 2 summarizes findings from prospective controlled studies of benzodiazepines used in various dosage forms for the acute treatment of seizures and seizure clusters. Only a few of these studies specifically assessed the treatment of seizure clusters; most involved treatment of emergent convulsive seizures of any etiology. Many also focused on the use of preparations obtained from hospital or compounding pharmacies, because the only commercially available approved therapies for seizure clusters at the time the studies were conducted were diazepam rectal gel and buccal midazolam, the latter used only in the European Union. Nevertheless, results from most of the studies of rectal, buccal, or intranasal benzodiazepine formulations showed reasonable efficacy, equal to or better than that of IV or rectal formulations, with seizures ceasing within 10 min in the majority of patients. Studies evaluating IV formulations (diazepam [
      • Lahat E.
      • Goldman M.
      • Barr J.
      • Bistritzer T.
      • Berkovitch M.
      Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study.
      ,
      • Mahmoudian T.
      • Zadeh M.M.
      Comparison of intranasal midazolam with intravenous diazepam for treating acute seizures in children.
      ,
      • Talukdar B.
      • Chakrabarty B.
      Efficacy of buccal midazolam compared to intravenous diazepam in controlling convulsions in children: a randomized controlled trial.
      ,
      • Thakker A.
      • Shanbag P.
      A randomized controlled trial of intranasal-midazolam versus intravenous-diazepam for acute childhood seizures.
      ] or lorazepam [
      • Arya R.
      • Gulati S.
      • Kabra M.
      • Sahu J.K.
      • Kalra V.
      Intranasal versus intravenous lorazepam for control of acute seizures in children: a randomized open-label study.
      ]) have consistently reported the shortest mean or median time from drug administration to seizure cessation (within 3 min; Table 2). Studies of nasal formulations of midazolam [
      • Lahat E.
      • Goldman M.
      • Barr J.
      • Bistritzer T.
      • Berkovitch M.
      Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study.
      ,
      • Mahmoudian T.
      • Zadeh M.M.
      Comparison of intranasal midazolam with intravenous diazepam for treating acute seizures in children.
      ,
      • Thakker A.
      • Shanbag P.
      A randomized controlled trial of intranasal-midazolam versus intravenous-diazepam for acute childhood seizures.
      ,
      • Bhattacharyya M.
      • Kalra V.
      • Gulati S.
      Intranasal midazolam vs rectal diazepam in acute childhood seizures.
      ,
      • Holsti M.
      • Dudley N.
      • Schunk J.
      • Adelgais K.
      • Greenberg R.
      • Olsen C.
      • et al.
      Intranasal midazolam vs rectal diazepam for the home treatment of acute seizures in pediatric patients with epilepsy.
      ,
      • Fisgin T.
      • Gurer Y.
      • Tezic T.
      • Senbil N.
      • Zorlu P.
      • Okuyaz C.
      • et al.
      Effects of intranasal midazolam and rectal diazepam on acute convulsions in children: prospective randomized study.
      ,
      • de Haan G.J.
      • van der Geest P.
      • Doelman G.
      • Bertram E.
      • Edelbroek P.
      A comparison of midazolam nasal spray and diazepam rectal solution for the residential treatment of seizure exacerbations.
      ] or lorazepam [
      • Arya R.
      • Gulati S.
      • Kabra M.
      • Sahu J.K.
      • Kalra V.
      Intranasal versus intravenous lorazepam for control of acute seizures in children: a randomized open-label study.
      ] have also reported relatively rapid treatment effects for aborting seizures (reported seizure cessation within about 1 to 5 min across studies). Reported times to seizure cessation across studies of buccal formulations of midazolam range from about 3 min to 8 min [
      • Talukdar B.
      • Chakrabarty B.
      Efficacy of buccal midazolam compared to intravenous diazepam in controlling convulsions in children: a randomized controlled trial.
      ,
      • McIntyre J.
      • Robertson S.
      • Norris E.
      • Appleton R.
      • Whitehouse W.P.
      • Phillips B.
      • et al.
      Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomised controlled trial.
      ,
      • Ashrafi M.R.
      • Khosroshahi N.
      • Karimi P.
      • Malamiri R.A.
      • Bavarian B.
      • Zarch A.V.
      • et al.
      Efficacy and usability of buccal midazolam in controlling acute prolonged convulsive seizures in children.
      ,
      • Nakken K.O.
      • Lossius M.I.
      Buccal midazolam or rectal diazepam for treatment of residential adult patients with serial seizures or status epilepticus.
      ,
      • Scott R.C.
      • Besag F.M.
      • Neville B.G.
      Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial.
      ,
      • Baysun S.
      • Aydin OF
      • Atmaca E.
      • Gurer Y.K.
      A comparison of buccal midazolam and rectal diazepam for the acute treatment of seizures.
      ], while times to cessation in rectally administered diazepam have been more variable across studies, ranging from 2 to 15 min [
      • Bhattacharyya M.
      • Kalra V.
      • Gulati S.
      Intranasal midazolam vs rectal diazepam in acute childhood seizures.
      ,
      • Holsti M.
      • Dudley N.
      • Schunk J.
      • Adelgais K.
      • Greenberg R.
      • Olsen C.
      • et al.
      Intranasal midazolam vs rectal diazepam for the home treatment of acute seizures in pediatric patients with epilepsy.
      ,
      • Fisgin T.
      • Gurer Y.
      • Tezic T.
      • Senbil N.
      • Zorlu P.
      • Okuyaz C.
      • et al.
      Effects of intranasal midazolam and rectal diazepam on acute convulsions in children: prospective randomized study.
      ,
      • de Haan G.J.
      • van der Geest P.
      • Doelman G.
      • Bertram E.
      • Edelbroek P.
      A comparison of midazolam nasal spray and diazepam rectal solution for the residential treatment of seizure exacerbations.
      ,
      • McIntyre J.
      • Robertson S.
      • Norris E.
      • Appleton R.
      • Whitehouse W.P.
      • Phillips B.
      • et al.
      Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomised controlled trial.
      ,
      • Ashrafi M.R.
      • Khosroshahi N.
      • Karimi P.
      • Malamiri R.A.
      • Bavarian B.
      • Zarch A.V.
      • et al.
      Efficacy and usability of buccal midazolam in controlling acute prolonged convulsive seizures in children.
      ,
      • Nakken K.O.
      • Lossius M.I.
      Buccal midazolam or rectal diazepam for treatment of residential adult patients with serial seizures or status epilepticus.
      ,
      • Scott R.C.
      • Besag F.M.
      • Neville B.G.
      Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial.
      ,
      • Baysun S.
      • Aydin OF
      • Atmaca E.
      • Gurer Y.K.
      A comparison of buccal midazolam and rectal diazepam for the acute treatment of seizures.
      ]. Outside the hospital or epilepsy specialty practice environment, it is essential that pharmacologic treatment modalities be designed to provide user-friendly intervention across multiple settings.
      Table 2Prospective controlled studies of benzodiazepines for acute treatment of seizures/seizure clusters.
      StudyAdministration routeComparatorSubjects/group sizePrimary assessmentPrimary outcome resultSecondary/other results
      Head-to-head studies of different benzodiazepine molecules
      Baysun et al., 2005 [
      • Baysun S.
      • Aydin OF
      • Atmaca E.
      • Gurer Y.K.
      A comparison of buccal midazolam and rectal diazepam for the acute treatment of seizures.
      ]
      DZP-RGMDZ-Bu43 pediatric patients (age, 2 mo–12 y) presenting with seizures



      Initial treatment MDZ-Bu in group 1 and DZP-RG in group 2; if no response within 10 min, alternate drug administered
      Prolonged convulsive seizuresSimilar initial response (seizure cessation)



      DZP-RG: 85%

      MDZ-Bu: 78%

      (P > 0.05)
      Agents had similar response times; seizure cessation within 5 min in >80% of patients (P > 0.05)
      Bhattacharyya et al., 2006 [
      • Bhattacharyya M.
      • Kalra V.
      • Gulati S.
      Intranasal midazolam vs rectal diazepam in acute childhood seizures.
      ]
      DZP-RGMDZ-IN46 pediatric patients (age, 3 mo–12 y)



      188 seizure episodes treated

      DZP-RG: n = 96

      MDZ-IN: n = 92
      Acute seizures of all typesSimilar rates of seizure cessation at 10 min



      DZP-RG: 89%

      MDZ-IN: 97%
      Respiratory rate and oxygen saturation significantly lower with DZP-RG vs MDZ-IN (P < 0.05)



      Time from drug administration to seizure cessation significantly shorter with MDZ-IN vs DZP-RG (117 vs 179 s; P= 0.005)
      Fisgin et al., 2002 [
      • Fisgin T.
      • Gurer Y.
      • Tezic T.
      • Senbil N.
      • Zorlu P.
      • Okuyaz C.
      • et al.
      Effects of intranasal midazolam and rectal diazepam on acute convulsions in children: prospective randomized study.
      ]
      DZP-RGMDZ-NS45 children (age, 1–13 y) presenting with acute seizures (all types)



      Initial treatment with DZP-RG on odd days (n = 22) and MDZ-NS on even days (n = 23); if no response within 10 min, alternate drug administered
      Acute convulsive seizuresPatients with seizure cessation within 10 min



      DZP-RG: 59%

      MDZ-NS: 87%

      (P < 0.05)
      Time to seizure termination



      DZP-RG: 32% (2–5 min)

      MDZ-NS: 39% (1–2 min)
      Holsti et al., 2007 [
      • Holsti M.
      • Sill B.L.
      • Firth S.D.
      • Filloux F.M.
      • Joyce S.M.
      • Furnival R.A.
      Prehospital intranasal midazolam for the treatment of pediatric seizures.
      ]
      DZP-RGMDZ-IN57 pediatric patients (age, <18 y)



      DZP-RG: n = 18

      MDZ-IN: n = 39



      Comparison of EMS-administered MDZ-IN vs historical DZP-RG controls
      Prolonged seizures in prehospital settingPatients treated with MDZ-IN vs DZP-RG were significantly less likely to experience seizures in ED, be admitted to hospital, and require intubation (multivariate analysis)Treatment with MDZ-IN vs DZP-RG significantly reduced risk for PICU admission and need for anticonvulsant treatment in ED
      Holsti et al., 2010 [
      • Holsti M.
      • Dudley N.
      • Schunk J.
      • Adelgais K.
      • Greenberg R.
      • Olsen C.
      • et al.
      Intranasal midazolam vs rectal diazepam for the home treatment of acute seizures in pediatric patients with epilepsy.
      ]
      DZP-RGMDZ-IN92 pediatric patients (age, <18 y)



      DZP-RG: n = 42

      MDZ-IN: n = 50



      Comparison of MDZ-IN vs DZP-RG for in-home rescue use
      Home-setting acute seizures requiring rescue treatmentTrend for reduced time to seizure cessation with MDZ-IN vs DZP-RG (median, 3.0 vs 4.3 min; P = 0.09)Similar total seizure time with MDZ-IN vs DZP-RG (median, 10.5 vs 12.5 min; P = 0.25)



      No other significant between-groups differences in secondary endpoints
      McIntyre et al., 2005 [
      • McIntyre J.
      • Robertson S.
      • Norris E.
      • Appleton R.
      • Whitehouse W.P.
      • Phillips B.
      • et al.
      Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomised controlled trial.
      ]
      DZP-RGMDZ-Bu177 pediatric patients (age, 7 mo–15 y) presenting with acute seizures



      DZP-RG: n = 85 (110 seizures)

      MDZ-Bu: n = 92 (109 seizures)
      Acute seizuresHigher rate of primary outcome “therapeutic success” (seizure cessation within 10 min, no respiratory depression, no recurrent seizure within 1 h) with MDZ-Bu vs DZP-RG (56% vs 27%; P < 0.001)Median time from treatment to seizure cessation shorter with MDZ-Bu vs DZP-RG (8 vs 15 min; P = 0.01)
      Mpimbaza et al., 2008 [
      • Mpimbaza A.
      • Ndeezi G.
      • Staedke S.
      • Rosenthal P.J.
      • Byarugaba J.
      Comparison of buccal midazolam with rectal diazepam in the treatment of prolonged seizures in Ugandan children: a randomized clinical trial.
      ]
      DZP-RGMDZ-Bu330 pediatric patients (3 mo–12 y) presenting with prolonged seizures in health clinic in Uganda



      DZP-RG: n = 165

      MDZ-Bu: n = 165



      Most patients had malaria, so many seizures were associated with fever
      Prolonged seizuresRate of treatment failure (no seizure cessation within 10 min or recurrent seizure within 1 h) higher with DZP-RG vs MDZ-Bu (43% vs 30%; P = 0.016)Treatment failure rates similar in patients with malaria

      DZP-RG: 36%

      MDZ-Bu: 32%

      (P = 0.534)



      Much higher with DZP-RG in patients without malaria

      DZP-RG: 56%

      MDZ-Bu: 27%

      (P = 0.002)
      Ashrafi et al., 2010 [
      • Ashrafi M.R.
      • Khosroshahi N.
      • Karimi P.
      • Malamiri R.A.
      • Bavarian B.
      • Zarch A.V.
      • et al.
      Efficacy and usability of buccal midazolam in controlling acute prolonged convulsive seizures in children.
      ]
      DZP-RSMDZ-Bu98 pediatric patients (age, 3 mo–12 y) with seizures lasting >5 min (or ongoing on ED arrival)



      DZP-RS: n = 49

      MDZ-Bu: n = 49
      Acute prolonged convulsive seizuresProportion with seizure cessation at 4 min

      DZP-RS: 49%

      MDZ-Bu: 88%



      5 min

      DZP-RS: 82%

      MDZ-Bu: 100%



      8 min

      DZP-RS: 100%
      Time to administration within 2 min

      DZP-RS patients: 22%

      MDZ-Bu patients: 82%



      3 min

      DZP-RS patients: 90%

      MDZ-Bu patients: 94%



      Parent satisfaction with treatment/route

      DZP-RS: 14%

      MDZ-Bu: 94%
      de Haan et al., 2010 [
      • de Haan G.J.
      • van der Geest P.
      • Doelman G.
      • Bertram E.
      • Edelbroek P.
      A comparison of midazolam nasal spray and diazepam rectal solution for the residential treatment of seizure exacerbations.
      ]
      DZP-RSMDZ-NS21 adults with intractable epilepsy and ≥10 exacerbations/year requiring rescue treatmentSeizure exacerbations requiring rescue treatmentSimilar rates of seizure cessation within 15 min



      DZP-RS: 56/63 (89%)

      MDZ-NS: 50/61 (82%)

      (P = NS)
      Similar mean time (min) to seizure cessation



      DZP-RS: 4.3

      MDZ-NS: 4.6



      Both agents well tolerated (similar AE rates)



      Caregivers/patients preferred convenience of MDZ-NS
      Malu et al., 2014 [
      • Malu C.K.
      • Kahamba D.M.
      • Walker T.D.
      • Mukampunga C.
      • Musalu E.M.
      • Kokolomani J.
      • et al.
      Efficacy of sublingual lorazepam versus intrarectal diazepam for prolonged convulsions in sub-Saharan Africa.
      ]
      DZP-RSLZP-SL

      (1 mg or 2.5 mg dissolving tablet)
      436 pediatric patients (age, 5 mo–10 y) presenting with seizures lasting >5 min, sub-Saharan Africa



      DZP-RS: n = 202

      LZP-SL: n = 234
      Prolonged convulsive seizuresSeizure cessation significantly faster with DZP-RS



      Proportion with cessation within 5 min

      DZP-RS: 38%

      LZP-SL: 28%



      10 min

      DZP-RS: 79%

      LZP-SL: 56%



      20 min

      DZP-RS: 91%

      LZP-SL: 83%

      (P = 0.012)
      Seizure recurrence within 24 h

      DZP-RS: 39%

      LZP-SL: 36%

      (P = 0.481)
      Nakken & Lossius, 2011 [
      • Nakken K.O.
      • Lossius M.I.
      Buccal midazolam or rectal diazepam for treatment of residential adult patients with serial seizures or status epilepticus.
      ]
      DZP-RSMDZ-BuAdult patients with convulsive or nonconvulsive serial seizures/status epilepticus at residential epilepsy center



      DZP-RS: n = 18 (37 seizures)

      MDZ-Bu: n = 16 (43 episodes)
      Serial seizures or status epilepticusSimilar rates of treatment success (seizure cessation within 10 min, no recurrence within 2 h)



      DZP-RS: 83.3%

      MDZ-Bu: 74.4%

      (P = NS)
      Mean time to seizure cessation similar with DZP-RS vs MDZ-Bu for all seizure types except convulsive status epilepticus (5.0 vs 2.8 min; P = 0.012)



      MDZ-Bu preferred by all unit nurses and 6/7 patients who received both treatments
      Scott et al., 1999 [
      • Scott R.C.
      • Besag F.M.
      • Neville B.G.
      Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial.
      ]
      DZP-RSMDZ-BuPediatric patients with prolonged (>5 min) seizures at residential epilepsy center



      DZP-RS: n = 14 (39 seizures)

      MDZ-Bu: n = 14 (40 seizures)
      Prolonged seizuresSimilar rates of response (seizure cessation within 10 min after treatment)



      DZP-RS: 59%

      MDZ-Bu: 75%

      (P = 0.16)
      Similar median time to seizure cessation with DZP-RS vs MDZ-Bu (8 vs 6 min; P = 0.31)



      Similar response rate and time to cessation for first treatment with each drug (9 pairs)
      Ivaturi et al., 2009 [
      • Ivaturi V.D.
      • Riss J.R.
      • Kriel R.L.
      • Cloyd J.C.
      Pharmacokinetics and tolerability of intranasal diazepam and midazolam in healthy adult volunteers.
      ]
      DZP-INMDZ-IN



      DZP-IV and MDZ-IV also evaluated
      3 healthy female volunteers (age, 20–24 y)



      4-way study
      PKMean tmax (min)

      DZP-IN: 28.8

      MDZ-IN: 21.6



      Mean Cmax (ng/mL)

      DZP-IN: 179.2

      MDZ-IN: 62.8
      Nasal pain (maximum, 3.2/10; mean, 1.2 at 15 min) with both DZP-IN and MDZ-IN; nasal drainage and watery eyes with both
      Lahat et al., 2000 [
      • Lahat E.
      • Goldman M.
      • Barr J.
      • Bistritzer T.
      • Berkovitch M.
      Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study.
      ]
      DZP-IVMDZ-IN44 children presenting with febrile seizures in ED



      DZP-IV: n = 23 (26 seizures)

      MDZ-IN: n = 21 (26 seizures)
      Prolonged febrile seizuresMean time from ED arrival to seizure cessation significantly shorter with MDZ-IN vs DZP-IV (6.1 vs 8.0 min; P < 0.001)Most of time difference from ED arrival to seizure cessation attributable to less time from arrival to treatment with MDZ-IN vs DZP-IV (3.5 vs 5.5 min); time from treatment to seizure cessation shorter with DZP-IV vs MDZ-IN (2.5 vs 3.1 min); P < 0.001 for both
      Mahmoudian & Zadeh, 2004 [
      • Mahmoudian T.
      • Zadeh M.M.
      Comparison of intranasal midazolam with intravenous diazepam for treating acute seizures in children.
      ]
      DZP-IVMDZ-IN70 pediatric patients (age, 2 mo–15 y) presenting with acute seizures



      DZP-IV: n = 35

      MDZ-IN: n = 35
      Acute seizuresIn both groups, all seizures controlled within 10 min; less mean time from administration to seizure cessation with DZP-IV vs MDZ-IN (2.94 vs 3.58 min; P = 0.007)Reduced time from seizure onset to treatment initiation with MDZ-IN vs DZP-IV
      Talukdar & Chakrabarty, 2009 [
      • Talukdar B.
      • Chakrabarty B.
      Efficacy of buccal midazolam compared to intravenous diazepam in controlling convulsions in children: a randomized controlled trial.
      ]
      DZP-IVMDZ-Bu120 pediatric patients presenting with convulsive seizures in ED



      DZP-IV: n = 60

      MDZ-Bu: n = 60
      Convulsive seizuresSimilar rates of response (cessation of all motor activity within 5 min)



      DZP-IV: 93%

      MDZ-Bu: 85%

      (P = 0.14)
      Total mean response time (seizure initiation to cessation) significantly shorter with DZP-IV vs MDZ-Bu (2.39 vs 2.98 min; P = 0.004)



      Time to treatment longer with DZP-IV



      Time from treatment to cessation longer with MDZ-Bu
      Thakker & Shanbag, 2013 [
      • Thakker A.
      • Shanbag P.
      A randomized controlled trial of intranasal-midazolam versus intravenous-diazepam for acute childhood seizures.
      ]
      DZP-IVMDZ-IN50 pediatric patients presenting with convulsive seizures lasting >10 min in ED



      DZP-IV: n = 23

      MDZ-IN: n = 27
      Acute seizuresSimilar rates of response (seizure cessation within 10 min)



      DZP-IV: 65%

      MDZ-IN: 67%

      (P > 0.05)
      Significantly longer mean time from hospital arrival to seizure cessation with DZP-IV vs MDZ-IN (17.2 vs 6.7 min) attributable to delayed initiation of treatment (time from treatment to response shorter with DZP-IV: 2.7 vs 3.0 min)
      Ahmad et al., 2006 [
      • Ahmad S.
      • Ellis J.C.
      • Kamwendo H.
      • Molyneux E.
      Efficacy and safety of intranasal lorazepam versus intramuscular paraldehyde for protracted convulsions in children: an open randomised trial.
      ]
      LZP-INPDH-IM160 pediatric patients (age, 2 mo–12 y) presenting with seizures lasting >5 min in Malawi



      LZP-IN: n = 80

      PDH-IM: n = 80
      Acute seizuresTrend toward more seizure cessation within 10 min with LZP-IN vs PDH-IM (75% vs 61%; P = 0.06)Proportion needing ≥2 rescue treatments

      LZP-IN: 10%

      PDH-IM: 26%

      (P = 0.007)



      Proportion with recurrent seizure within 24 h

      LZP-IN: 10%

      PDH-IM: 14%

      (P = 0.46)
      Diazepam (DZP) studies
      Cereghino et al., 2002 [
      • Cereghino J.J.
      • Cloyd J.C.
      • Kuzniecky R.I.
      Rectal diazepam gel for treatment of acute repetitive seizures in adults.
      ]
      DZP-RGPlacebo70 adults with ARS



      DZP-RG: n = 31

      Placebo: n = 39



      Pooled analysis of 2 studies
      ARSFewer seizures/h with DZP-RG vs placebo within 12-h postdose period (median, 0.00 vs 0.13; P = 0.002)Significantly more seizure-free patients with DZP-RG vs placebo (71% vs 28%; P = 0.001)



      Kaplan–Meier analysis of time to next seizure favored DZP-RG (P < 0.001)
      Dreifuss, 1998 [
      • Dreifuss F.E.
      • Rosman N.P.
      • Cloyd J.C.
      • Pellock J.M.
      • Kuzniecky R.I.
      • Lo W.D.
      • et al.
      A comparison of rectal diazepam gel and placebo for acute repetitive seizures.
      ]
      DZP-RGPlacebo125 patients (age, 2–60 y) with ≥4 ARS episodes within previous year and ≥1 within previous 3 moARSSignificantly lower median seizure frequency/h with DZP-RG (0) vs placebo (0.3)

      (P < 0.001)
      DZP-RG associated with significant improvement vs placebo in caregiver global assessment of treatment outcome (P < 0.001)
      Kriel et al., 1999 [
      • Kriel R.L.
      • Cloyd J.C.
      • Pellock J.M.
      • Mitchell W.G.
      • Cereghino J.J.
      • Rosman N.P.
      Rectal diazepam gel for treatment of acute repetitive seizures.
      ]
      DZP-RGPlacebo133 children (age, 2–17 y) with ARS



      DZP-RG: n = 68

      Placebo: n = 65



      Pooled analysis of 2 studies of similar design
      ARSSignificantly fewer seizures/h with DZP-RG vs placebo (median, 0.0 vs 0.25; P < 0.001)Significantly more seizure-free patients at 12 h with DZP-RG vs placebo (59% vs 31%; P = 0.001)



      Time to next seizure (Kaplan–Meier analysis) significantly longer with DZP-RG (P = 0.0002)
      Chiang et al., 2011 [
      • Chiang L.M.
      • Wang H.S.
      • Shen H.H.
      • Deng S.T.
      • Tseng C.H.
      • Chen Y.I.
      • et al.
      Rectal diazepam solution is as good as rectal administration of intravenous diazepam in the first-aid cessation of seizures in children with intractable epilepsy.
      ]
      DZP-RSDZP-IV administered rectally24 children (age, 2–18 y) with intractable epilepsy



      Seizures treated with DZP-IV for 3 mo, then DZP-RS for 3 mo
      Acute seizuresSeizure cessation within 10 min of first dose



      DZP-RS: 90/103 (87%)

      DZP-IV: 103/127 (81%)

      (P = NS)
      Seizure cessation within 10 min of second dose



      DZP-RS: 12/13 (92%)

      DZP-IV: 21/24 (88%)



      No significant differences between treatments on any measure
      Agarwal et al., 2013 [
      • Agarwal S.K.
      • Kriel R.L.
      • Brundage R.C.
      • Ivaturi V.D.
      • Cloyd J.C.
      A pilot study assessing the bioavailability and pharmacokinetics of diazepam after intranasal and intravenous administration in healthy volunteers.
      ]
      DZP-IN

      (2 formulations)
      DZP-IV24



      3-way crossover study; all subjects received each medication with washout between treatment periods
      PKAUC0-∞ (ng*h/mL)

      DZP-IN suspension: 5381

      DZP-IN solution: 7338

      DZP-IV: 4104



      tmax (h)

      DZP-IN suspension: 1.0

      DZP-IN solution: 1.5
      All agents well tolerated



      Subjects (n) with AEs

      DZP-IN suspension: 9

      DZP-IN solution: 8

      DZP-IV: 10



      All AEs mild to moderate
      Gizurarson et al.,1999 [
      • Gizurarson S.
      • Gudbrandsson F.K.
      • Jonsson H.
      • Bechgaard E.
      Intranasal administration of diazepam aiming at the treatment of acute seizures: clinical trials in healthy volunteers.
      ]
      DZP-INDZP-IV9 healthy volunteers



      Crossover PK study with low doses (2 mg each dosage form)
      PKMean (SD) DZP-IN tmax: 18 (11) minMean (SD) DZP-IN Cmax at 18 min (mean tmax) was 33% (22%) vs DZP-IV at 10 min postdose
      Henney et al., 2014 [
      • Henney III, H.R.
      • Sperling M.R.
      • Rabinowicz A.L.
      • Bream G.
      • Carrazana E.J.
      Assessment of pharmacokinetics and tolerability of intranasal diazepam relative to rectal gel in healthy adults.
      ]
      DZP-IN

      (5 mg, 20 mg)
      DZP-RG

      (20 mg)
      24 healthy volunteers



      Crossover PK study for all 3 treatments
      PKMean (SD) Cmax

      DZP-IN 5 mg: 96 (28) ng/mL

      DZP-IN 20 mg: 350 (103) ng/mL

      DZP-RG 20 mg: 352 (93) ng/mL



      Median tmax

      1.0 h, 1.0 h, 1.5 h, respectively
      Bioavailability similar across dosage forms



      DZP-IN exhibits linear PK
      Ivaturi et al., 2013 [
      • Ivaturi V.
      • Kriel R.
      • Brundage R.
      • Loewen G.
      • Mansbach H.
      • Cloyd J.
      Bioavailability of intranasal vs. rectal diazepam.
      ]
      DZP-IN



      3 different formulations

      Nas-A 10 mg

      Nas-B 10 mg

      Nas-B 13.4 mg
      DZP-RG12 healthy volunteers



      4-way crossover study
      PKMedian tmax 0.75 h for all 4 treatment types



      Mean Cmax (ng/mL)

      Nas-A 10 mg: 181.8

      Nas-B 10 mg: 151.3

      Nas-B 13.4 mg: 180.7

      DZP-RG: 160.9
      Mean maximal pain scores (scale, 0–10)



      Nas-A 10 mg: 2.6

      Nas-B 10 mg: 1.6

      Nas-B 13.4 mg: 1.4

      DZP-RG: 0.3
      Abou-Khalil et al., 2013 [
      • Kriel R.L.
      • Cloyd J.C.
      • Pellock J.M.
      • Mitchell W.G.
      • Cereghino J.J.
      • Rosman N.P.
      Rectal diazepam gel for treatment of acute repetitive seizures.
      ,
      • Abou-Khalil B.
      • Wheless J.
      • Rogin J.
      • Wolter K.D.
      • Pixton G.C.
      • Shukla R.B.
      • et al.
      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.
      ]
      DZP-IM

      (auto-injector)
      PlaceboDZP-IM: n = 82

      Placebo: n = 81
      ARSMean time to next seizure or rescue reduced with DZP-IM vs placebo



      HR for next event: 0.55 (95% CI, 0.34–0.88; P = 0.012)
      Reduced rates of rescue medication use and ED visits with DZP-IM
      Lorazepam (LZP) studies
      Arya et al., 2011 [
      • Arya R.
      • Gulati S.
      • Kabra M.
      • Sahu J.K.
      • Kalra V.
      Intranasal versus intravenous lorazepam for control of acute seizures in children: a randomized open-label study.
      ]
      LZP-INLZP-IV141 pediatric patients (age, 6–14 y) presenting with convulsive seizures



      LZP-IN: n = 71

      LZP-IV: n = 70
      Acute seizuresSimilar rates of seizure cessation within 10 min



      LZP-IN: 83%

      LZP-IV: 80%

      (P = 0.635)
      Similar rates of nonrecurrence within 1 h

      LZP-IN: 62%

      LZP-IV: 59%

      (P = 0.680)



      Median time to seizure cessation: 3 min in both groups (P = 0.900)



      Noninferiority study: LZP-IN judged not inferior to LZP-IV
      Alprazolam (ALZ) studies
      French et al., 2019 [
      • French J.A.
      • Wechsler R.
      • Gelfand M.A.
      • Pollard J.R.
      • Vazquez B.
      • Friedman D.
      • et al.
      Inhaled alprazolam rapidly suppresses epileptic activity in photosensitive participants.
      ]
      ALZ-IP

      (Staccato aerosolization pulmonary delivery system)
      Placebo5 adults with epilepsy and PPR (induction of epileptiform EEG with light flashes at varying standard frequencies)PPRSignificantly lower induced PPR activity at 2 min with ALZ-IP vs placebo at all tested doses (0.5, 1.0, 2.0 mg)Both ALZ-IP efficacy response (degree of PPR suppression) and side effect response (sedation) were dose related



      Approximately linear PK of Staccato ALZ-IP over tested dose range
      AE, adverse event; ALZ-IP, intrapulmonary alprazolam; ARS, acute repetitive seizures; AUC0-∞, area under the curve from time zero to infinity; Cmax, maximum serum concentration; DZP-IM, intramuscular diazepam; DZP-IN, intranasal diazepam; DZP-IV, intravenous diazepam; DZP-RG, diazepam rectal gel; DZP-RS, diazepam rectal solution; ED, emergency department; EEG, electroencephalogram; EMS, emergency medical services; HR, hazard ratio; LZP-IN, intranasal lorazepam; LZP-IV, intravenous lorazepam; LZP-SL, sublingual lorazepam; MDZ-Bu, buccal midazolam; MDZ-IN, intranasal midazolam; MDZ-IV, intravenous midazolam; MDZ-NS, midazolam nasal spray; NS, nonsignificant; PDH-IM, intramuscular paraldehyde; PICU, pediatric intensive care unit; PK, pharmacokinetics; PPR, photoparoxysmal response; SD, standard deviation; tmax, time to maximum plasma concentration.

      3.4 Emerging approaches to acute therapy for seizure clusters

      Given the reliance on benzodiazepines as rescue treatment for seizure clusters, it is unclear if traditional AEDs (e.g., phenytoin/fosphenytoin, valproate/valproic acid, levetiracetam, carbamazepine) can play a role as rescue therapies. Despite efforts to develop formulations suitable for rescue use, such agents have yet to demonstrate the bioavailability/absorption characteristics required for intramuscular or rectal administration [
      • Leppik I.E.
      • Patel S.I.
      Intramuscular and rectal therapies of acute seizures.
      ]. However, because benzodiazepines rapidly redistribute to fatty tissues after stopping seizures, traditional longer acting AEDs may be administered orally after successful rescue treatment, with seizure cessation and return to full alertness, to prevent recurrent seizures [
      • Cereghino J.J.
      Identification and treatment of acute repetitive seizures in children and adults.
      ].
      Most recent efforts around the development of rescue medications have focused on the route of administration, with key factors being portability, ease of use, rapidity of effect, and their ability to abort seizure clusters, usually by preventing the occurrence of further seizures within the cluster. The most heavily investigated routes include rectal, intramuscular, buccal, sublingual, oral, and intranasal; other potentially useful routes are subcutaneous and intrapulmonary [
      • Cereghino J.J.
      Identification and treatment of acute repetitive seizures in children and adults.
      ,
      • Maglalang P.D.
      • Rautiola D.
      • Siegel R.A.
      • Fine J.M.
      • Hanson L.R.
      • Coles L.D.
      • et al.
      Rescue therapies for seizure emergencies: new modes of administration.
      ,
      • Chin R.F.
      What are the best ways to deliver benzodiazepines in children/patients with prolonged convulsive seizures?.
      ,
      • Rogawski M.A.
      • Heller A.H.
      Diazepam buccal film for the treatment of acute seizures.
      ,
      • Tanimoto S.
      • Pesco Koplowitz L.
      • Lowenthal R.E.
      • Koplowitz B.
      • Rabinowicz A.L.
      • Carrazana E.
      Evaluation of pharmacokinetics and dose proportionality of diazepam after intranasal administration of NRL-1 to healthy volunteers.
      ,
      • Detyniecki K.
      • Van Ess P.J.
      • Sequeira D.J.
      • Wheless J.W.
      • Meng T.C.
      • Pullman W.E.
      Safety and efficacy of midazolam nasal spray in the outpatient treatment of patients with seizure clusters-a randomized, double-blind, placebo-controlled trial.
      ]. Intravenous administration is reserved for medical settings with qualified personnel [
      • Haut S.R.
      • Seinfeld S.
      • Pellock J.
      Benzodiazepine use in seizure emergencies: a systematic review.
      ].
      Factors reported to have the greatest impact on choice of administration route include the surface area available for drug absorption, the blood flow across the absorptive surface, and the lipophilicity of the treatment agent—the greater the better for all three [
      • Maglalang P.D.
      • Rautiola D.
      • Siegel R.A.
      • Fine J.M.
      • Hanson L.R.
      • Coles L.D.
      • et al.
      Rescue therapies for seizure emergencies: new modes of administration.
      ]. In general, greater drug lipophilicity is associated with more rapid absorption but poorer solubility in aqueous solutions. Each potential administration route is associated with one or more possible drawbacks and advantages (Table 3) [
      • Haut S.R.
      Seizure clusters: characteristics and treatment.
      ,
      • Cereghino J.J.
      Identification and treatment of acute repetitive seizures in children and adults.
      ,
      • Maglalang P.D.
      • Rautiola D.
      • Siegel R.A.
      • Fine J.M.
      • Hanson L.R.
      • Coles L.D.
      • et al.
      Rescue therapies for seizure emergencies: new modes of administration.
      ,
      • Rau J.L.
      The inhalation of drugs: advantages and problems.
      ].
      Table 3Potential drawbacks and advantages for rescue medication administration routes [
      • Haut S.R.
      Seizure clusters: characteristics and treatment.
      ,
      • Cereghino J.J.
      Identification and treatment of acute repetitive seizures in children and adults.
      ,
      • Maglalang P.D.
      • Rautiola D.
      • Siegel R.A.
      • Fine J.M.
      • Hanson L.R.
      • Coles L.D.
      • et al.
      Rescue therapies for seizure emergencies: new modes of administration.
      ,
      • Rau J.L.
      The inhalation of drugs: advantages and problems.
      ].
      Administration routePotential drawbacksPotential advantages
      Oral• Delayed absorption/bioavailability

      • Aspiration

      • Patient difficulty/refusal and need for cooperation
      • Patient/caregiver convenience and familiarity

      • Low cost
      Buccal/sublingual• Aspiration (for liquids)

      • Inaccessibility (if seizure involves oral area)
      • Can be rapidly administered and absorbed
      Intranasal• Variable absorption (based on secretions/mucus load)

      • Reactive secretions (possible aspiration risk)

      • Nasal irritation/pain
      • Can be rapidly administered and absorbed
      Inhaled/intrapulmonary• Possibly variable absorption

      • Possible need for patient cooperation
      • Minimal dose-preparation needed

      • May allow use of relatively small doses

      • More rapid drug absorption than other parenteral routes
      Intramuscular• Risk of abscess

      • Discomfort

      • Use of needle
      • Can be rapidly administered

      • Reliable absorption
      Rectal• Socially unacceptable in many settings

      • Potential problem for unrelated caregivers

      • Slow administration, especially in older and clothed patients

      • Possibly variable absorption
      • Widely used and well-studied

      • Rapidly absorbed
      Intravenous• Difficult to administer (requires substantial medical expertise)

      • Setup time
      • Very rapid effect

      • High bioavailability

      • Optimal route in hospital settings
      Intranasal formulations of midazolam and diazepam were recently approved [
      ,
      ,
      • Detyniecki K.
      • Van Ess P.J.
      • Sequeira D.J.
      • Wheless J.W.
      • Meng T.C.
      • Pullman W.E.
      Safety and efficacy of midazolam nasal spray in the outpatient treatment of patients with seizure clusters-a randomized, double-blind, placebo-controlled trial.
      ,
      • Sperling M.R.
      • Haas K.F.
      • Krauss G.
      • Seif Eddeine H.
      • Henney III, H.R.
      • Rabinowicz A.L.
      • et al.
      Dosing feasibility and tolerability of intranasal diazepam in adults with epilepsy.
      ,
      • Henney III, H.R.
      • Sperling M.R.
      • Rabinowicz A.L.
      • Bream G.
      • Carrazana E.J.
      Assessment of pharmacokinetics and tolerability of intranasal diazepam relative to rectal gel in healthy adults.
      ,
      • Sperling M.
      • Hogan R.
      • Biton V.
      • Tarquinio D.
      • Carrazana E.
      A 12-month, open-label, repeat-dose safety study of Valtoco™ (NRL-1, diazepam nasal spray) in patients with epilepsy: interim report (P1.5–028).
      ], and a buccal formulation of midazolam has been available in Europe since 2011 [
      ]. Other formulations being developed for rescue treatment of seizure clusters include [
      • Sperling M.R.
      • Haas K.F.
      • Krauss G.
      • Seif Eddeine H.
      • Henney III, H.R.
      • Rabinowicz A.L.
      • et al.
      Dosing feasibility and tolerability of intranasal diazepam in adults with epilepsy.
      ,
      • Henney III, H.R.
      • Sperling M.R.
      • Rabinowicz A.L.
      • Bream G.
      • Carrazana E.J.
      Assessment of pharmacokinetics and tolerability of intranasal diazepam relative to rectal gel in healthy adults.
      ,
      • Sperling M.
      • Hogan R.
      • Biton V.
      • Tarquinio D.
      • Carrazana E.
      A 12-month, open-label, repeat-dose safety study of Valtoco™ (NRL-1, diazepam nasal spray) in patients with epilepsy: interim report (P1.5–028).
      ] diazepam buccal film [
      • Rogawski M.A.
      • Heller A.H.
      Diazepam buccal film for the treatment of acute seizures.
      ,
      • Heller A.H.
      • Wargacki S.
      • Jung C.
      • Wyatt D.J.
      • Schobel M.
      Safety and pharmacokinetics of diazepam buccal soluble film [abstract].
      ,
      • Heller A.H.
      • Wargacki S.
      • Stalvey T.J.
      • Wyatt D.J.
      • Schobel M.
      Comparative pharmacokinetics of diazepam buccal soluble film and diazepam rectal gel [abstract].
      ] and alprazolam for inhalation [
      • Jafarpour S.
      • Hirsch L.J.
      • Gainza-Lein M.
      • Kellinghaus C.
      • Detyniecki K.
      Seizure cluster: definition, prevalence, consequences, and management.
      ,
      • French J.A.
      • Wechsler R.
      • Gelfand M.A.
      • Pollard J.R.
      • Vazquez B.
      • Friedman D.
      • et al.
      Inhaled alprazolam rapidly suppresses epileptic activity in photosensitive participants.
      ].

      4. Summary

      Establishment of an accepted consensus definition of seizure clusters is perhaps the most urgent need regarding seizure clusters and their management. As with many initially ill-defined clinical scenarios or conditions, further study of seizure clusters may identify multiple subtypes and etiologies that require distinct management strategies. It is possible that management of seizure clusters may require highly individualized treatment plans based on general guidelines for initial treatment selection, followed by empirical evaluation of available agents. Until seizure clusters are more comprehensively recognized as an important clinical phenomenon, the development of effective and safe management strategies and new treatment agents will be hindered.
      A surprisingly large proportion of patients with epilepsy do not have an action plan in place, and many have not received a prescription medication for seizure rescue. Two sample seizure action plans appear in Appendix A. One is a generalized plan, and the other was developed for school use. Ideally, a seizure action plan should be developed collaboratively by patients and their physicians, and shared with appropriate personnel at school, worksite, group home, or other settings.
      Initiating and continuing development of pharmacologic treatment options across a range of administration routes is essential. As it is highly unlikely that any single medication or delivery system will suit all patients, multiple therapeutic options are needed so that the most appropriate agent(s) can be selected for each individual patient.
      When the disease course of seizure clusters and the risk factors for their development are more fully understood, it may be possible to pursue prophylactic treatment approaches to reduce the risk for seizure clusters and, though outside the scope of this discussion, even the risk for seizures of any type. There has been inadequate study of the potential for progression from seizure clusters to status epilepticus or sudden unexpected death in epilepsy, but the risk is certainly not zero. There has been almost no investigation of the extent of long-lasting or permanent harm from seizure clusters to either brain function or seizure diathesis. The hope is that the latest effective and more convenient rescue therapies—those recently approved and those to come—will help expedite these investigations, decrease the occurrence of status epilepticus and ED visits, and improve quality of life for patients with seizure clusters.

      Funding

      Technical editorial and medical writing assistance were provided under the direction of the authors by Michael Morren, RPh, MBA, of Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, and funded by Aquestive Therapeutics, Inc.

      Declaration of competing interest

      Dr. Gidal has received research support from Eisai , Neurelis, Sunovion, and UCB Pharma and consultant fees for advising Aquestive, Eisai, and Greenwich, and has served as a speaker for Eisai and Greenwich.
      Dr. Klein has served as a consultant or advisory board member for Abbott, Alliance, Aquestive, Eisai, OB Pharmaceuticals, SK Life Science, and UCB Pharma; has served as a speaker for Aquestive, Eisai, Sunovion, and UCB Pharma; and has received research grant support from Eisai .
      Dr. Hirsch has received research support to Yale University for investigator-initiated studies from Eisai, Proximagen, Sunovion, and The Daniel Raymond Wong Neurology Research Fund at Yale; consultation fees for advising from Adamas, Aquestive, Ceribell, Eisai, Marinus, Medtronic, Monteris, Neuropace, and UCB; royalties for authoring chapters for UpToDate-Neurology, and from Wiley for coauthoring the book Atlas of EEG in Critical Care, by Hirsch and Brenner; and honoraria for speaking from Neuropace.

      Appendix A. Sample seizure action plans

      Epilepsy Foundation of America, Inc.
      ©2020 Epilepsy Foundation of America, Inc. Permission to reproduce Seizure Response Plan (SAP) is granted by the Epilepsy Foundation of America, Inc.
      Accessed May 20, 2020.
      American Academy of Pediatrics
      Four-page plan for school submission/use.
      ©American Academy of Pediatrics. Permission to reproduce Seizure Action Plan for School is granted by the American Academy of Pediatrics.
      Accessed December 12, 2019.

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