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Towards acute pediatric status epilepticus intervention teams: Do we need “Seizure Codes”?

Open ArchivePublished:April 13, 2018DOI:https://doi.org/10.1016/j.seizure.2018.04.011

      Highlights

      • Time to treatment of pediatric status epilepticus remains delayed.
      • Multiple barriers to timely management exist in the pre- and in-hospital settings.
      • Proposed interventions to improve time to treatment are reviewed.
      • Status epilepticus should be recognized as a time-sensitive emergency.
      • Acute intervention teams can be developed to improve status epilepticus management.

      Abstract

      Purpose

      To identify areas of treatment delay and barriers to care in pediatric status epilepticus, review ongoing quality improvement initiatives, and provide suggestions for further innovations to improve and standardize these patient care processes.

      Methods

      Narrative review of current status epilepticus management algorithms, anti-seizure medication administration and outcomes associated with delays, and initiatives to improve time to treatment. Articles reviewing or reporting quality improvement initiatives were identified through a PubMed search with keywords “status epilepticus,” “quality improvement,” “guideline adherence,” and/or “protocol;” references of included articles were also reviewed.

      Results

      Rapid initiation and escalation of status epilepticus treatment has been associated with shortened seizure duration and more favorable outcomes. Current evidence-based guidelines for management of status epilepticus propose medication algorithms with suggested times for each management step. However, time to antiseizure medication administration for pediatric status epilepticus remains delayed in both the pre- and in-hospital settings. Barriers to timely treatment include suboptimal preventive care, inaccurate seizure detection, infrequent or restricted use of home rescue medications by caregivers and pre-hospital emergency personnel, delayed summoning and arrival of emergency personnel, and use of inappropriately dosed medications. Ongoing quality improvement initiatives in the pre- and in-hospital settings targeting these barriers are reviewed.

      Conclusion

      Improved preventive care, seizure detection, and rescue medication education may advance pre-hospital management, and we propose the use of acute status epilepticus intervention teams to initiate and incorporate in-hospital interventions as time-sensitive “Seizure Code” emergencies.

      Abbreviations:

      ASM (antiseizure medication), ED (emergency department), EMS (emergency medical services), GABA (gamma-aminobutyric acid), IV (intravenous), OR (odds ratio), RR (relative risk), SE (status epilepticus)

      Keywords

      1. Introduction

      Status epilepticus (SE) is one of the most common pediatric neurologic emergencies, affecting between 17 and 23/100,000 children per year and 10–20% of pediatric epilepsy patients [
      • Chin R.F.
      • Neville B.G.
      • Peckham C.
      • Bedford H.
      • Wade A.
      • Scott R.C.
      Incidence, cause, and short-term outcome of convulsive status epilepticus in childhood: prospective population-based study.
      ,
      • Berg A.T.
      • Shinnar S.
      • Testa F.M.
      • Levy S.R.
      • Frobish D.
      • Smith S.N.
      • et al.
      Status epilepticus after the initial diagnosis of epilepsy in children.
      ,
      • Raspall-Chaure M.
      • Chin R.F.
      • Neville B.G.
      • Bedford H.
      • Scott R.C.
      The epidemiology of convulsive status epilepticus in children: a critical review.
      ]. While etiology and age are the main predictors of outcome after SE, seizure duration may additionally affect outcome. Importantly, seizure duration is the only modifiable risk factor [
      • Raspall-Chaure M.
      • Chin R.F.
      • Neville B.G.
      • Scott R.C.
      Outcome of paediatric convulsive status epilepticus: a systematic review.
      ]. Studies have yielded mixed results regarding the impact of seizure duration and adherence to management guidelines. Some studies have identified no impact on outcome related to adherence to treatment guidelines [
      • Rossetti A.O.
      • Alvarez V.
      • Januel J.M.
      • Burnand B.
      Treatment deviating from guidelines does not influence status epilepticus prognosis.
      ] or seizure duration [
      • Pujar S.S.
      • Neville B.G.
      • Scott R.C.
      • Chin R.F.
      Death within 8 years after childhood convulsive status epilepticus: a population-based study.
      ,
      • Pujar S.S.
      • Martinos M.M.
      • Cortina-Borja M.
      • Kling Chong W.K.
      • De Haan M.
      • Gillberg C.
      • et al.
      Long-term prognosis after childhood convulsive status epilepticus: a prospective cohort study.
      ]. Conversely, other studies have shown that rapid administration of antiseizure medications (ASMs) is associated with shorter seizure duration and more favorable outcomes including mortality [
      • Sanchez Fernandez I.
      • Abend N.S.
      • Agadi S.
      • An S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Time from convulsive status epilepticus onset to anticonvulsant administration in children.
      ,
      • Gainza-Lein M.
      • Sanchez Fernandez I.
      • Jackson M.
      • Abend N.S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Association of time to treatment with short-term outcomes for pediatric patients with refractory convulsive status epilepticus.
      ]. The Neurocritical Care and American Epilepsy Societies have published evidence-based and consensus guidelines with SE management algorithms and suggested treatment timelines [
      • Brophy G.M.
      • Bell R.
      • Claassen J.
      • Alldredge B.
      • Bleck T.P.
      • Glauser T.
      • et al.
      Guidelines for the evaluation and management of status epilepticus.
      ,
      • Glauser T.
      • Shinnar S.
      • Gloss D.
      • Alldredge B.
      • Arya R.
      • Bainbridge J.
      • et al.
      Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the American Epilepsy Society.
      ]. However, time to ASM administration is often substantially delayed in cases of both pre- and in-hospital seizure onset [
      • Sanchez Fernandez I.
      • Abend N.S.
      • Agadi S.
      • An S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Time from convulsive status epilepticus onset to anticonvulsant administration in children.
      ,
      • Pellock J.M.
      • Marmarou A.
      • DeLorenzo R.
      Time to treatment in prolonged seizure episodes.
      ].
      Barriers to timely management may occur at any step of the care process, from preventive care and education to acute, in-hospital management. Even prior to SE occurrence, lack of regular epilepsy clinic appointments are associated with a higher risk of emergency department (ED) visits or hospital admissions [
      • Patel A.D.
      • Wood E.G.
      • Cohen D.M.
      Reduced emergency department utilization by patients with epilepsy using QI methodology.
      ]. Seizure detection by patients, caregivers, and healthcare professionals may be inaccurate or missed [
      • Nijsen T.M.
      • Arends J.B.
      • Griep P.A.
      • Cluitmans P.J.
      The potential value of three-dimensional accelerometry for detection of motor seizures in severe epilepsy.
      ,
      • Hoppe C.
      • Poepel A.
      • Elger C.E.
      Epilepsy: accuracy of patient seizure counts.
      ]. Additionally, many caregivers report that they have not been trained to administer seizure rescue medication [
      • Gainza-Lein M.
      • Benjamin R.
      • Stredny C.
      • McGurl M.
      • Kapur K.
      • Loddenkemper T.
      Rescue medications in epilepsy patients: a family perspective.
      ] and demonstrate clinically relevant administration errors when observed [
      • Kaune A.
      • Schumacher P.M.
      • Hoppe S.C.
      • Syrbe S.
      • Bernhard M.K.
      • Frontini R.
      • et al.
      Administration of anticonvulsive rescue medication in children-discrepancies between parents’ self-reports and limited practical performance.
      ]. Some schools may be unable to administer rescue medications due to legal restrictions [
      • Terry D.
      • Paolicchi J.
      • Karn M.
      Acceptance of the use of diazepam rectal gel in school and day care settings.
      ], and school nurses may feel uncomfortable with acute seizure management [
      • Olympia R.P.
      • Wan E.
      • Avner J.R.
      The preparedness of schools to respond to emergencies in children: a national survey of school nurses.
      ]. Further delays exist in ambulance arrival time [
      • Hill C.E.
      • Parikh A.O.
      • Ellis C.
      • Myers J.S.
      • Litt B.
      Timing is everything: where status epilepticus treatment fails.
      ] and seizure recognition by emergency medical services (EMS) [
      • Seinfeld S.
      • Shinnar S.
      • Sun S.
      • Hesdorffer D.C.
      • Deng X.
      • Shinnar R.C.
      • et al.
      Emergency management of febrile status epilepticus: results of the FEBSTAT study.
      ], with pre-hospital ASMs administered in only a minority of patients [
      • Sanchez Fernandez I.
      • Abend N.S.
      • Agadi S.
      • An S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Time from convulsive status epilepticus onset to anticonvulsant administration in children.
      ,
      • Hill C.E.
      • Parikh A.O.
      • Ellis C.
      • Myers J.S.
      • Litt B.
      Timing is everything: where status epilepticus treatment fails.
      ,
      • Seinfeld S.
      • Shinnar S.
      • Sun S.
      • Hesdorffer D.C.
      • Deng X.
      • Shinnar R.C.
      • et al.
      Emergency management of febrile status epilepticus: results of the FEBSTAT study.
      ]. Even when ASM administration is initiated by EMS, it involves almost exclusively benzodiazepines without progression to second-line ASMs [
      • Sanchez Fernandez I.
      • Abend N.S.
      • Agadi S.
      • An S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Time from convulsive status epilepticus onset to anticonvulsant administration in children.
      ,
      • Seinfeld S.
      • Shinnar S.
      • Sun S.
      • Hesdorffer D.C.
      • Deng X.
      • Shinnar R.C.
      • et al.
      Emergency management of febrile status epilepticus: results of the FEBSTAT study.
      ]. In-hospital management is also often delayed [
      • Sanchez Fernandez I.
      • Abend N.S.
      • Agadi S.
      • An S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Time from convulsive status epilepticus onset to anticonvulsant administration in children.
      ], with inaccurate weight-based benzodiazepine dosing as well as delays in subsequent treatment steps [
      • Siefkes H.M.
      • Holsti M.
      • Morita D.
      • Cook L.J.
      • Bratton S.
      Seizure treatment in children transported to tertiary care: recommendation adherence and outcomes.
      ,
      • Tobias J.D.
      • Berkenbosch J.W.
      Management of status epilepticus in infants and children prior to pediatric ICU admission: deviations from the current guidelines.
      ].
      With the identification of these barriers to timely SE management, multiple centers have taken on initiatives to improve management and time to ASM administration [
      • Patel A.D.
      • Wood E.G.
      • Cohen D.M.
      Reduced emergency department utilization by patients with epilepsy using QI methodology.
      ,
      • 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.
      ,
      • Grefe A.B.
      • Aguilar K.A.
      • Duncan P.
      Benefit of an epilepsy nurse navigator in a pediatric neurology clinic.
      ,
      • Tourigny-Ruel G.
      • Diksic D.
      • Mok E.
      • McGillivray D.
      Quality assurance evaluation of a simple linear protocol for the treatment of impending status epilepticus in a pediatric emergency department 2 years postimplementation.
      ,
      • Williams R.P.
      • Banwell B.
      • Berg R.A.
      • Dlugos D.J.
      • Donnelly M.
      • Ichord R.
      • et al.
      Impact of an ICU EEG monitoring pathway on timeliness of therapeutic intervention and electrographic seizure termination.
      ,
      • Xie Y.
      • Morgan R.
      • Schiff L.
      • Hannah D.
      • Whelessm J.
      A computerized standard protocol order entry for pediatric inpatient acute seizure emergencies reduces time to treatment.
      ,
      • Harris M.L.
      • Malloy K.M.
      • Lawson S.N.
      • Rose R.S.
      • Buss W.F.
      • Mietzsch U.
      Standardized treatment of neonatal status epilepticus improves outcome.
      ]. The cost-effectiveness of each intervention has not yet been studied, but the cost for adult SE care in the United States [
      • Penberthy L.T.
      • Towne A.
      • Garnett L.K.
      • Perlin J.B.
      • DeLorenzo R.J.
      Estimating the economic burden of status epilepticus to the health care system.
      ] and Europe [
      • Kortland L.M.
      • Alfter A.
      • Bahr O.
      • Carl B.
      • Dodel R.
      • Freiman T.M.
      • et al.
      Costs and cost-driving factors for acute treatment of adults with status epilepticus: a multicenter cohort study from Germany.
      ] invites means for improvement. Gaps remain and provide opportunities for ongoing innovation and improvement. This review summarizes current guidelines on pediatric SE management, outcomes associated with delayed treatment and prolonged seizures, and barriers to rapid management, highlighting approaches which might lead to optimized care.

      2. Evidence guiding ASM choice and administration

      Prompt administration of benzodiazepines is recommended as first-line treatment. In a double-blind trial, 273 children with convulsive SE were randomized to receive either intravenous (IV) lorazepam or diazepam. Seizure cessation occurred in 72% of subjects in each group without differences in need for assisted ventilation. The authors concluded that IV lorazepam has similar safety and efficacy when compared to diazepam [
      • Chamberlain J.M.
      • Okada P.
      • Holsti M.
      • Mahajan P.
      • Brown K.M.
      • Vance C.
      • et al.
      Lorazepam vs diazepam for pediatric status epilepticus: a randomized clinical trial.
      ]. A meta-analysis found IV lorazepam to have fewer adverse effects than diazepam [
      • Appleton R.
      • Macleod S.
      • Martland T.
      Drug management for acute tonic-clonic convulsions including convulsive status epilepticus in children.
      ], though another mixed pediatric and adult meta-analysis found this trend not to be statistically significant [
      • Prasad M.
      • Krishnan P.R.
      • Sequeira R.
      • Al-Roomi K.
      Anticonvulsant therapy for status epilepticus.
      ]. Considering other benzodiazepine formulations when IV access is not available, a meta-analysis indicated that the most effective non-IV rescue medication for stopping seizures within 10 min of drug administration is intranasal midazolam, with rectal diazepam being less efficacious than both intranasal and buccal midazolam [
      • Arya R.
      • Kothari H.
      • Zhang Z.
      • Han B.
      • Horn P.S.
      • Glauser T.A.
      Efficacy of nonvenous medications for acute convulsive seizures: a network meta-analysis.
      ]. Additionally, in a cost-effectiveness analysis comparing non-IV first-line rescue medications, intranasal and buccal midazolam were the most cost-effective options while rectal diazepam was not cost-effective at any willingness to pay in the United States [
      • Sanchez Fernandez I.
      • Gainza-Lein M.
      • Loddenkemper T.
      Nonintravenous rescue medications for pediatric status epilepticus: a cost-effectiveness analysis.
      ]. European studies also found that buccal midazolam was more cost-effective than rectal diazepam [
      • Lee D.
      • Gladwell D.
      • Batty A.J.
      • Brereton N.
      • Tate E.
      The cost effectiveness of licensed oromucosal midazolam (Buccolam((R))) for the treatment of children experiencing acute epileptic seizures: an approach when trial evidence is limited.
      ,
      • Raspall-Chaure M.
      • Martinez-Bermejo A.
      • Sanchez-Carpintero R.
      • Ruiz-Falco Rojas M.L.
      • Verdu-Perez A.
      • Smeyers-Dura P.
      • et al.
      Cost-effectiveness of buccal midazolam in the treatment of prolonged convulsive seizures in the outpatient setting in Spain.
      ]. Given these data, evidence-based guidelines have stated that IV lorazepam and IV diazepam are effective for seizure termination [
      • Brophy G.M.
      • Bell R.
      • Claassen J.
      • Alldredge B.
      • Bleck T.P.
      • Glauser T.
      • et al.
      Guidelines for the evaluation and management of status epilepticus.
      ,
      • Glauser T.
      • Shinnar S.
      • Gloss D.
      • Alldredge B.
      • Arya R.
      • Bainbridge J.
      • et al.
      Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the American Epilepsy Society.
      ], and when IV access is not available then midazolam (intranasal, buccal or intramuscular) is potentially more effective than diazepam (IV or rectal) [
      • Glauser T.
      • Shinnar S.
      • Gloss D.
      • Alldredge B.
      • Arya R.
      • Bainbridge J.
      • et al.
      Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the American Epilepsy Society.
      ].
      Few studies have compared the effectiveness of second-line therapies. The ongoing Established Status Epilepticus Treatment Trial (ESETT) is evaluating levetiracetam, valproic acid, and fosphenytoin [
      • Cock H.R.
      Established status epilepticus treatment trial (ESETT).
      ]. Other international pediatric trials comparing levetiracetam and phenytoin in benzodiazepine-resistant SE are additionally underway and may offer further evidence [
      • Dalziel S.R.
      • Furyk J.
      • Bonisch M.
      • Oakley E.
      • Borland M.
      • Neutze J.
      • et al.
      A multicentre randomised controlled trial of levetiracetam versus phenytoin for convulsive status epilepticus in children (protocol): Convulsive status epilepticus paediatric trial (consept) - a predict study.
      ,
      • Lyttle M.D.
      • Gamble C.
      • Messahel S.
      • Hickey H.
      • Iyer A.
      • Woolfall K.
      • et al.
      A multicentre randomised controlled trial of levetiracetam versus phenytoin for convulsive status epilepticus in children (protocol): convulsive Status Epilepticus Paediatric Trial (ConSEPT) – a PREDICT study.
      ]. In surveys of neurologists [
      • Claassen J.
      • Hirsch L.J.
      • Mayer S.A.
      Emergency treatment with levetiracetam or phenytoin in status epilepticus in children-the EcLiPSE study: study protocol for a randomised controlled trial.
      ] and pediatric emergency medicine physicians in Australia and New Zealand [
      • Babl F.E.
      • Sheriff N.
      • Borland M.
      • Acworth J.
      • Neutze J.
      • Krieser D.
      • et al.
      Emergency management of paediatric status epilepticus in Australia and New Zealand: practice patterns in the context of clinical practice guidelines.
      ], fosphenytoin is chosen as the second-line ASM for the majority of children. A combined adult and pediatric meta-analysis comparing second-line ASM therapy reported that seizure cessation rates were 76%, 74%, 69%, and 50% with valproic acid, phenobarbital, levetiracetam, and phenytoin, respectively. This analysis concluded that there is insufficient evidence to support phenytoin as the preferred ASM in benzodiazepine-resistant SE [
      • Yasiry Z.
      • Shorvon S.D.
      The relative effectiveness of five antiepileptic drugs in treatment of benzodiazepine-resistant convulsive status epilepticus: a meta-analysis of published studies.
      ]. A recent comparison of IV levetiracetam to IV valproic acid in children found them to be equally effective, though valproic acid was associated with more adverse effects including liver dysfunction in 13% of cases [
      • Isguder R.
      • Guzel O.
      • Ceylan G.
      • Yilmaz U.
      • Agin H.
      A comparison of intravenous levetiracetam and valproate for the treatment of refractory status epilepticus in children.
      ]. Given these data, SE guidelines state that phenytoin, valproic acid, levetiracetam, and phenobarbital are appropriate second-line or urgent control therapy options, though there is currently insufficient evidence to suggest one ASM is preferred [
      • Brophy G.M.
      • Bell R.
      • Claassen J.
      • Alldredge B.
      • Bleck T.P.
      • Glauser T.
      • et al.
      Guidelines for the evaluation and management of status epilepticus.
      ,
      • Glauser T.
      • Shinnar S.
      • Gloss D.
      • Alldredge B.
      • Arya R.
      • Bainbridge J.
      • et al.
      Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the American Epilepsy Society.
      ]. Continuous infusions, including midazolam, pentobarbital, propofol, and ketamine, are considered appropriate management options for refractory SE treatments [
      • Brophy G.M.
      • Bell R.
      • Claassen J.
      • Alldredge B.
      • Bleck T.P.
      • Glauser T.
      • et al.
      Guidelines for the evaluation and management of status epilepticus.
      ,
      • Abend N.S.
      • Loddenkemper T.
      Management of pediatric status epilepticus.
      ,
      • Smith D.M.
      • McGinnis E.L.
      • Walleigh D.J.
      • Abend N.S.
      Management of status epilepticus in children.
      ]. However, there are even fewer data available to guide selections between these options.

      3. Time to treatment recommendations & outcomes associated with delays

      The recommendation for rapid administration of first-line benzodiazepines in SE stems from in vitro and animal models demonstrating the pathophysiology of neuronal excitation, increasing medication pharmacoresistance with longer seizures, and brain injury with prolonged seizures. In in vitro models, ongoing seizure activity promotes internalization of synaptic gamma-aminobutyric acid (GABA)-receptors and thus decreases neuronal inhibition [
      • Goodkin H.P.
      • Yeh J.L.
      • Kapur J.
      Status epilepticus increases the intracellular accumulation of GABAA receptors.
      ,
      • Naylor D.E.
      • Liu H.
      • Wasterlain C.G.
      Trafficking of GABA(A) receptors: loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus.
      ], with subsequent studies showing these receptor changes were associated with increasing pharmacoresistance to benzodiazepines [
      • Kapur J.
      • Macdonald R.L.
      Rapid seizure-induced reduction of benzodiazepine and Zn2+ sensitivity of hippocampal dentate granule cell GABAA receptors.
      ,
      • Walton N.Y.
      • Treiman D.M.
      Response of status epilepticus induced by lithium and pilocarpine to treatment with diazepam.
      ,
      • Mazarati A.M.
      • Baldwin R.A.
      • Sankar R.
      • Wasterlain C.G.
      Time-dependent decrease in the effectiveness of antiepileptic drugs during the course of self-sustaining status epilepticus.
      ,
      • Goodkin H.P.
      • Liu X.
      • Holmes G.L.
      Diazepam terminates brief but not prolonged seizures in young: naive rats.
      ]. In a prospective study in children experiencing prolonged seizures, seizures lasting longer than 5–7 min were less likely to terminate spontaneously than shorter seizures [
      • Shinnar S.
      • Berg A.T.
      • Moshe S.L.
      • Shinnar R.
      How long do new-onset seizures in children last?.
      ], likely owing to the aforementioned mechanisms. Further studies revealed neuronal cell death with seizures lasting longer than 30–80 min [
      • Horton R.W.
      • Meldrum B.S.
      Seizures induced by allylglycine, 3-mercaptopropionic acid and 4-deoxypyridoxine in mice and photosensitive baboons, and different modes of inhibition of cerebral glutamic acid decarboxylase.
      ,
      • Sloviter R.S.
      Epileptic brain damage in rats induced by sustained electrical stimulation of the perforant path: I. Acute electrophysiological and light microscopic studies.
      ,
      • Corsellis J.A.N.
      • Bruton C.J.
      ]. Hence, while the definition of SE was initially considered to be an ongoing seizure for 30 min or longer [
      Treatment of convulsive status epilepticus. Recommendations of the epilepsy foundation of America’s working group on status epilepticus.
      ], most recent management pathways suggest treatment after 5 min of seizure activity [
      • Trinka E.
      • Cock H.
      • Hesdorffer D.
      • Rossetti A.O.
      • Scheffer I.E.
      • Shinnar S.
      • et al.
      A definition and classification of status epilepticus–report of the ILAE task force on classification of status epilepticus.
      ].
      Though results are mixed and seizure duration is not a predictor of outcome in all studies [
      • Rossetti A.O.
      • Alvarez V.
      • Januel J.M.
      • Burnand B.
      Treatment deviating from guidelines does not influence status epilepticus prognosis.
      ,
      • Pujar S.S.
      • Neville B.G.
      • Scott R.C.
      • Chin R.F.
      Death within 8 years after childhood convulsive status epilepticus: a population-based study.
      ,
      • Pujar S.S.
      • Martinos M.M.
      • Cortina-Borja M.
      • Kling Chong W.K.
      • De Haan M.
      • Gillberg C.
      • et al.
      Long-term prognosis after childhood convulsive status epilepticus: a prospective cohort study.
      ], in some studies rapid SE treatment has been associated with shorter seizure duration and lower morbidity and mortality [
      • Sanchez Fernandez I.
      • Abend N.S.
      • Agadi S.
      • An S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Time from convulsive status epilepticus onset to anticonvulsant administration in children.
      ,
      • Gainza-Lein M.
      • Sanchez Fernandez I.
      • Jackson M.
      • Abend N.S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Association of time to treatment with short-term outcomes for pediatric patients with refractory convulsive status epilepticus.
      ,
      Treatment of convulsive status epilepticus. Recommendations of the epilepsy foundation of America’s working group on status epilepticus.
      ]. One prospective, population-based United Kingdom study demonstrated that for each minute delay from onset of SE to arrival at the ED, there was a 5% cumulative increase in the risk of the episode lasting more than 60 min [
      • Chin R.F.
      • Neville B.G.
      • Peckham C.
      • Wade A.
      • Bedford H.
      • Scott R.C.
      Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study.
      ]. In another retrospective analysis, 73% of children with aggressive ASM treatment within 60 min after initial treatment returned to neurological baseline during long-term follow-up (mean duration of 3.9 years), while all children not aggressively treated experienced new neurologic deficits and continued to deteriorate at follow-up [
      • Lambrechtsen F.A.
      • Buchhalter J.R.
      Aborted and refractory status epilepticus in children: a comparative analysis.
      ]. In a study of pediatric refractory SE, patients receiving an initial benzodiazepine after 10 min had higher odds of death (adjusted odds ratio (OR) 11.0), longer seizure duration (adjusted OR 2.6), higher rates of hypotension (adjusted OR 2.3), and higher likelihood of requiring continuous infusions (adjusted OR 1.8) than patients who received timely treatment [
      • Gainza-Lein M.
      • Sanchez Fernandez I.
      • Jackson M.
      • Abend N.S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Association of time to treatment with short-term outcomes for pediatric patients with refractory convulsive status epilepticus.
      ].
      In keeping with the management goal of rapid initiation and escalation of treatment, the 2012 Neurocritical Care Society consensus guideline recommends emergent initial ASM therapy (i.e. first-line treatment) within 5 min of seizure onset, urgent control ASM therapy (i.e. second-line treatment) within 5–10 min, and refractory SE therapy (i.e. third and fourth-line treatment) within 20–60 min [
      • Brophy G.M.
      • Bell R.
      • Claassen J.
      • Alldredge B.
      • Bleck T.P.
      • Glauser T.
      • et al.
      Guidelines for the evaluation and management of status epilepticus.
      ]. The 2016 American Epilepsy Society evidence-based guideline suggests initiation of treatment with a benzodiazepine at 5 min of ongoing seizure, second-line therapy at 20–40 min, and either repeating second-line therapy or moving directly to a continuous infusion by 40 min [
      • Glauser T.
      • Shinnar S.
      • Gloss D.
      • Alldredge B.
      • Arya R.
      • Bainbridge J.
      • et al.
      Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the American Epilepsy Society.
      ]. Fig. 1 summarizes a pediatric SE medication algorithm with a suggested timeline.
      Fig 1
      Fig 1Medication Algorithm and Suggested Time to Treatment A pediatric SE medication algorithm with a suggested timeline for medication administration is outlined. To follow this timeline, providers may order the next medication as the prior medication is administered. Optimal medication selections and doses may depend on efficacy data, patient and seizure characteristics, but also on institutional factors impacting which can be administered most rapidly. This is adapted from our institutional management plan in addition to those from the Neurocritical Care Society [
      • Brophy G.M.
      • Bell R.
      • Claassen J.
      • Alldredge B.
      • Bleck T.P.
      • Glauser T.
      • et al.
      Guidelines for the evaluation and management of status epilepticus.
      ] and American Epilepsy Society [
      • Glauser T.
      • Shinnar S.
      • Gloss D.
      • Alldredge B.
      • Arya R.
      • Bainbridge J.
      • et al.
      Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the American Epilepsy Society.
      ].
      Despite these adverse outcomes and proposed management guidelines, time to treatment is often delayed in pediatric SE. In a pediatric and adult cohort presenting with SE from 1989 to 1994, only 42% of patients received an ASM within 30 min of seizure onset.[
      • Pellock J.M.
      • Marmarou A.
      • DeLorenzo R.
      Time to treatment in prolonged seizure episodes.
      ] Comparatively, two decades later, in a multicenter observational prospective pediatric refractory SE cohort from 2011 to 2013, only 38% of patients received an ASM before hospital arrival. Further, first, second, and third ASMs were administered at a median (interquartile range) time of 28 (6–67) minutes, 40 (20–85) minutes, and 59 (30–120) minutes after SE onset [
      • Sanchez Fernandez I.
      • Abend N.S.
      • Agadi S.
      • An S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Time from convulsive status epilepticus onset to anticonvulsant administration in children.
      ].

      4. Barriers to timely management and methods of improving time to treatment

      Barriers to timely SE management may occur at any step of the care process spanning suboptimal preventive care, pre-hospital seizure detection and management initiation, and in-hospital advanced treatment. Table 1 summarizes these areas of delay and proposed interventions.
      Table 1Areas of Delay in Anti-Seizure Medication Administration and Proposed Interventions.
      Area of DelayProposed Interventions
      Lack of Preventive Care
      • Epilepsy urgent care clinics focusing on patient education and understanding [
        • Patel A.D.
        • Wood E.G.
        • Cohen D.M.
        Reduced emergency department utilization by patients with epilepsy using QI methodology.
        ]
      • Use of epilepsy nurse navigators [
        • Grefe A.B.
        • Aguilar K.A.
        • Duncan P.
        Benefit of an epilepsy nurse navigator in a pediatric neurology clinic.
        ]
      • Identification of patients without clinic access and high rates of ED utilization for targeted interventions [
        • Patel A.D.
        • Wood E.G.
        • Cohen D.M.
        Reduced emergency department utilization by patients with epilepsy using QI methodology.
        ]
      Seizure Detection by Caregivers/Patients
      • Accurate, individualized, and affordable multimodal seizure detection devices [
        • Onorati F.
        • Regalia G.
        • Caborni C.
        • Migliorini M.
        • Bender D.
        • Poh M.Z.
        • et al.
        Multicenter clinical assessment of improved wearable multimodal convulsive seizure detectors.
        ]
      Rescue Medication Use by Caregivers and Schools
      • Use of seizure action plans [
        • Gainza-Lein M.
        • Benjamin R.
        • Stredny C.
        • McGurl M.
        • Kapur K.
        • Loddenkemper T.
        Rescue medications in epilepsy patients: a family perspective.
        ]
      • Prescription and instruction regarding recue medications
      • Improved training and education on caregiver/school use of rescue medications [
        • 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.
        ]
      Summoning and Arrival of Emergency Personnel
      • Recognition of SE as a time-sensitive emergency and rapid summoning of EMS
      • Improved training of EMS providers on management of pediatric emergencies [
        • Shah M.I.
        • Carey J.M.
        • Rapp S.E.
        • Masciale M.
        • Alcanter W.B.
        • Mondragon J.A.
        • et al.
        Impact of high-fidelity pediatric simulation on paramedic seizure management.
        ]
      Medication Use by Pre-Hospital Emergency Personnel
      • Pre-hospital algorithms that are standardized with appropriate weight-based dosing [
        • Silverman E.C.
        • Sporer K.A.
        • Lemieux J.M.
        • Brown J.F.
        • Koenig K.L.
        • Gausche-Hill M.
        • et al.
        Prehospital care for the adult and pediatric seizure patient: current evidence-based recommendations.
        ]
      • Checking blood glucose levels should not significantly delay seizure treatment [
        • Silverman E.C.
        • Sporer K.A.
        • Lemieux J.M.
        • Brown J.F.
        • Koenig K.L.
        • Gausche-Hill M.
        • et al.
        Prehospital care for the adult and pediatric seizure patient: current evidence-based recommendations.
        ]
      • Pre-hospital algorithms with access to and use of second-line ASMs
      Use of Inappropriately Dosed Medications Pre- and In-Hospital
      • Assurance of appropriate weight-based dosing, particularly of benzodiazepines, through the use of action plans, pathways, [
        • Tourigny-Ruel G.
        • Diksic D.
        • Mok E.
        • McGillivray D.
        Quality assurance evaluation of a simple linear protocol for the treatment of impending status epilepticus in a pediatric emergency department 2 years postimplementation.
        ] or order sets [
        • Xie Y.
        • Morgan R.
        • Schiff L.
        • Hannah D.
        • Whelessm J.
        A computerized standard protocol order entry for pediatric inpatient acute seizure emergencies reduces time to treatment.
        ]
      In-Hospital ASM Use
      • Adherence to a hospital-approved SE medication pathway with outlined timing and weight-based dosing [
        • Tourigny-Ruel G.
        • Diksic D.
        • Mok E.
        • McGillivray D.
        Quality assurance evaluation of a simple linear protocol for the treatment of impending status epilepticus in a pediatric emergency department 2 years postimplementation.
        ]
      • Use of order sets in the electronic medical record for ordering medications according to pathway recommendations [
        • Xie Y.
        • Morgan R.
        • Schiff L.
        • Hannah D.
        • Whelessm J.
        A computerized standard protocol order entry for pediatric inpatient acute seizure emergencies reduces time to treatment.
        ]
      • SE acute intervention teams to rapidly respond at seizure onset [
        • Villamar M.C.A.
        • Ward-Mitchell R.
        • Bensalem-Owen M.
        Improvement in time to administration of second-line antiepileptic medications after implementation of an inpatient status epilepticus alert protocol.
        ]
      • Consideration of combination therapy and tentative ‘catch up’ dosing in case of initial delays
      Overall Coordination
      • SE acute intervention teams to guide comprehensive and integrated approaches to seizure management within a healthcare system
      Areas of treatment delay are highlighted with a summary of proposed interventions and future directions for improved time to treatment.

      4.1 Missed clinic visits and lack of preventive care and education

      Problems accessing care may lead to higher ED use and subsequent hospitalization due to seizures in patients with epilepsy. A case-control single center study found that patients with a higher number of missed epilepsy clinic visits were more likely to have an unplanned ED visit or admission (OR = 5.7) [
      • Patel A.D.
      Variables associated with emergency department and/or unplanned hospital utilization for children with epilepsy.
      ]. A pediatric hospital employed multiple quality improvement initiatives aiming to reduce ED and hospital utilization. Patients with multiple missed clinic visits and high ED utilization were identified for an intervention that included an urgent care epilepsy clinic that was easily accessible to patients, social work involvement, and longer than standard appointments to ensure the caregiver(s) received epilepsy education and services. Initiating an urgent care epilepsy clinic had the largest impact on ED and hospital utilization, resulting in a 28% and 43% reduction in ED visits and hospitalizations, respectively. These modifications were estimated to have saved over $2 million in healthcare costs [
      • Patel A.D.
      • Wood E.G.
      • Cohen D.M.
      Reduced emergency department utilization by patients with epilepsy using QI methodology.
      ]. Another institution employed an epilepsy nurse navigator, a nurse dedicated to meeting with families for support and education. Those who met with the navigator experienced lower ED utilization (more than one ED visit in 4% with the navigator versus 52% without the navigator), hospital admissions, 30-day readmissions, and episodes of SE (0% with the navigator versus 9% without the navigator) [
      • Grefe A.B.
      • Aguilar K.A.
      • Duncan P.
      Benefit of an epilepsy nurse navigator in a pediatric neurology clinic.
      ]. These findings highlight that interventions aimed at improving access and adherence to clinic care and patient/caregiver education, targeting patients with multiple missed clinic visits and higher ED utilization/admission rates, may result in meaningful healthcare utilization and clinical improvements.

      4.2 Seizure detection by caregivers/patients

      In the pre-hospital setting, seizure detection may be delayed or missed entirely by patients and caregivers. Studies have shown that even healthcare professionals may not identify many clinical seizures [
      • Nijsen T.M.
      • Arends J.B.
      • Griep P.A.
      • Cluitmans P.J.
      The potential value of three-dimensional accelerometry for detection of motor seizures in severe epilepsy.
      ] and self-reported seizure counts in adults are inaccurate [
      • Hoppe C.
      • Poepel A.
      • Elger C.E.
      Epilepsy: accuracy of patient seizure counts.
      ]. Seizure detection devices may offer a way to quantify seizures, and algorithms may detect impending seizures prior to onset through the monitoring of movement and physiologic parameters [
      • Ulate-Campos A.
      • Coughlin F.
      • Gainza-Lein M.
      • Fernandez I.S.
      • Pearl P.L.
      • Loddenkemper T.
      Automated seizure detection systems and their effectiveness for each type of seizure.
      ]. The increasing sensitivity and specificity of seizure detection devices may improve care for patients with epilepsy in the near future, though currently their use remains limited in routine care [
      • Onorati F.
      • Regalia G.
      • Caborni C.
      • Migliorini M.
      • Bender D.
      • Poh M.Z.
      • et al.
      Multicenter clinical assessment of improved wearable multimodal convulsive seizure detectors.
      ]. In general, multimodal devices are felt to be most promising with a focus on pairing a device able to identify an individual patient’s specific seizure type(s) [
      • Ulate-Campos A.
      • Coughlin F.
      • Gainza-Lein M.
      • Fernandez I.S.
      • Pearl P.L.
      • Loddenkemper T.
      Automated seizure detection systems and their effectiveness for each type of seizure.
      ,
      • Van de Vel A.
      • Cuppens K.
      • Bonroy B.
      • Milosevic M.
      • Jansen K.
      • Van Huffel S.
      • et al.
      Non-EEG seizure-detection systems and potential SUDEP prevention: state of the art.
      ]. Newer devices include a portable EEG headset that can be set up within minutes and translates the electrical signal into sound for seizure detection and quantification [
      • Munaretto J.W.R.
      • Grant A.
      • Chao J.
      • Parvizi J.
      Technical analysis of the ceribell EEG device.
      ]. Many caregivers report interest in this type of technology, though the accuracy and affordability and insurance coverage of the device were perceived as important [
      • Tovar Quiroga D.F.
      • Britton J.W.
      • Wirrell E.C.
      Patient and caregiver view on seizure detection devices: a survey study.
      ]. Further review of seizure detection devices is discussed in another article in this edition.

      4.3 Rescue medication use by caregivers and schools

      Non-IV rescue medications available at home and school probably improve SE outcomes. In the United States, rectal diazepam is currently available in a ready-to-use, dialed dosage delivery system for out-of-hospital treatment of SE by nonmedical caregivers. Rectal diazepam has shown better efficacy [
      • 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.
      ], better safety [
      • 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.
      ], superior patient/caregiver quality of life [
      • Kriel R.L.
      • Cloyd J.C.
      • Hadsall R.S.
      • Carlson A.M.
      • Floren K.L.
      • Jones-Saete C.M.
      Home use of rectal diazepam for cluster and prolonged seizures: efficacy, adverse reactions, quality of life, and cost analysis.
      ,
      • O’Dell C.
      • Shinnar S.
      • Ballaban-Gil K.R.
      • Hornick M.
      • Sigalova M.
      • Kang H.
      • et al.
      Rectal diazepam gel in the home management of seizures in children.
      ], and decreased ED visits when compared to placebo or no rescue medication [
      • Kriel R.L.
      • Cloyd J.C.
      • Hadsall R.S.
      • Carlson A.M.
      • Floren K.L.
      • Jones-Saete C.M.
      Home use of rectal diazepam for cluster and prolonged seizures: efficacy, adverse reactions, quality of life, and cost analysis.
      ,
      • O’Dell C.
      • Shinnar S.
      • Ballaban-Gil K.R.
      • Hornick M.
      • Sigalova M.
      • Kang H.
      • et al.
      Rectal diazepam gel in the home management of seizures in children.
      ]. In a retrospective review of pediatric patients, pre-hospital treatment with IV and rectal diazepam was associated with shorter seizure duration (32 versus 60 min in diazepam treatment versus no treatment groups, respectively) and fewer recurrent seizures after arrival to the ED (58% versus 85%) [
      • Alldredge B.K.
      • Wall D.B.
      • Ferriero D.M.
      Effect of prehospital treatment on the outcome of status epilepticus in children.
      ]. Additionally, in Europe, buccal midazolam is available in pre-filled syringes using age-based dosing and has established efficacy [
      • Arya R.
      • Kothari H.
      • Zhang Z.
      • Han B.
      • Horn P.S.
      • Glauser T.A.
      Efficacy of nonvenous medications for acute convulsive seizures: a network meta-analysis.
      ], in addition to cost-effectiveness in both the United Kingdom [
      • Lee D.
      • Gladwell D.
      • Batty A.J.
      • Brereton N.
      • Tate E.
      The cost effectiveness of licensed oromucosal midazolam (Buccolam((R))) for the treatment of children experiencing acute epileptic seizures: an approach when trial evidence is limited.
      ] and Spain [
      • Raspall-Chaure M.
      • Martinez-Bermejo A.
      • Sanchez-Carpintero R.
      • Ruiz-Falco Rojas M.L.
      • Verdu-Perez A.
      • Smeyers-Dura P.
      • et al.
      Cost-effectiveness of buccal midazolam in the treatment of prolonged convulsive seizures in the outpatient setting in Spain.
      ]. Despite these readily available forms, a multicenter prospective observational study found that only 33% of patients with prior SE were administered a rescue medication by caregivers for a subsequent prolonged seizure [
      • Sanchez Fernandez I.
      • Abend N.S.
      • Agadi S.
      • An S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Time from convulsive status epilepticus onset to anticonvulsant administration in children.
      ].
      A survey of caregivers of patients with epilepsy in the United States provided insight into the low usage of pre-hospital rescue medications. In this study, 29% of families reported not receiving training on how to use a recue medication [
      • Gainza-Lein M.
      • Benjamin R.
      • Stredny C.
      • McGurl M.
      • Kapur K.
      • Loddenkemper T.
      Rescue medications in epilepsy patients: a family perspective.
      ]. Having a seizure action plan was a predictor of knowing the name of the rescue medication, knowing when to give the rescue medication, knowing what to do if a seizure continues despite the rescue medication, and having the medication available at school [
      • Gainza-Lein M.
      • Benjamin R.
      • Stredny C.
      • McGurl M.
      • Kapur K.
      • Loddenkemper T.
      Rescue medications in epilepsy patients: a family perspective.
      ]. A study found that caregivers reported a high level of confidence administering buccal and rectal rescue medications, but clinically relevant drug-handling errors were identified in the majority of caregivers when observed giving medication to a mannequin, including 97% of caregivers administering rectal medication and 58% of caregivers administering buccal medication [
      • Kaune A.
      • Schumacher P.M.
      • Hoppe S.C.
      • Syrbe S.
      • Bernhard M.K.
      • Frontini R.
      • et al.
      Administration of anticonvulsive rescue medication in children-discrepancies between parents’ self-reports and limited practical performance.
      ]. Therefore, simply prescribing the rescue medication may be insufficient. Rather, improved rescue medication education/training and use of a seizure action plan may improve caregiver comfort and appropriate use of rescue medications in the out-of-hospital setting. Of note, a pediatric cohort study found no decrease in healthcare utilization (ED visits, hospitalizations, or phone calls) before and after use of a seizure action plan [
      • Roundy L.M.
      • Filloux F.M.
      • Kerr L.
      • Rimer A.
      • Bonkowsky J.L.
      Seizure action plans do not reduce health care utilization in pediatric epilepsy patients.
      ], though the outcome measures of this study may not have been optimal to determine if the plan made a difference in other patient outcomes.
      For school-aged children, the use of a seizure action plan and communication with the school is of particular importance since different school districts may have variable resources and legal requirements [
      • Hartman A.L.
      • Devore C.D.
      • Doerrer S.C.
      Rescue medicine for epilepsy in education settings.
      ,
      • Terry D.
      • Patel A.D.
      • Cohen D.M.
      • Scherzer D.
      • Kline J.
      Barriers to seizure management in schools: perceptions of school nurses.
      ]. In one United States survey, 19% of families reported their school could not administer rectal diazepam, often due to legal concerns [
      • Terry D.
      • Paolicchi J.
      • Karn M.
      Acceptance of the use of diazepam rectal gel in school and day care settings.
      ]. This barrier exists in Europe as well, with the use of seizure rescue medications often limited to a teacher willing to administer the medication [
      • Wait S.
      • Lagae L.
      • Arzimanoglou A.
      • Beghi E.
      • Bennett C.
      • Cross J.H.
      • et al.
      The administration of rescue medication to children with prolonged acute convulsive seizures in the community: what happens in practice?.
      ]. Another United States survey revealed school nurses feel less confident managing seizures than other pediatric emergencies, such as respiratory distress or anaphylaxis [
      • Olympia R.P.
      • Wan E.
      • Avner J.R.
      The preparedness of schools to respond to emergencies in children: a national survey of school nurses.
      ]. To intervene, a German study undertook a training program for preschool teachers and found that the training improved both level of confidence and competence with administering rectal and buccal seizure medications, improving rectal administration without error from 0.5% to 60% and buccal administration from 8% to 55% before and after training [
      • 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.
      ].

      4.4 Summoning and arrival of emergency personnel

      Time from seizure onset to arrival of emergency personnel and hospital transport is often delayed and without pre-hospital ASM administration. There are multiple potential time points for delay including caregivers calling/summoning EMS, activation and arrival of EMS, and seizure recognition by EMS providers. A review of pediatric and adult SE found that the median time to paramedic arrival was 13–30 min, time to ED arrival was 30–105 min, and that pre-hospital ASMs were administered to 34–51% of patients [
      • Hill C.E.
      • Parikh A.O.
      • Ellis C.
      • Myers J.S.
      • Litt B.
      Timing is everything: where status epilepticus treatment fails.
      ]. In addition, another study found that seizures were not recognized by EMS in 12% of cases [
      • Seinfeld S.
      • Shinnar S.
      • Sun S.
      • Hesdorffer D.C.
      • Deng X.
      • Shinnar R.C.
      • et al.
      Emergency management of febrile status epilepticus: results of the FEBSTAT study.
      ].
      A study in adults analyzed components of delay in the pre-hospital setting and identified the most substantial sources of delay as delays calling paramedics, difficulty with administering a rectal medication, and inability of paramedics to administer a second-line ASM [
      • Kamppi L.
      • Mustonen H.
      • Soinila S.
      Analysis of the delay components in the treatment of status epilepticus.
      ]. Studies have suggested that emergency personnel may have less experience treating children and therefore lack expertise [
      • Lammers R.L.
      • Byrwa M.J.
      • Fales W.D.
      • Hale R.A.
      Simulation-based assessment of paramedic pediatric resuscitation skills.
      ], have more difficulty obtaining IV access in pediatric patients [
      • Lillis K.A.
      • Jaffe D.M.
      Prehospital intravenous access in children.
      ], and feel an increased level of stress when caring for children [
      • Shah M.I.
      • Macias C.G.
      • Dayan P.S.
      • Weik T.S.
      • Brown K.M.
      • Fuchs S.M.
      • et al.
      An evidence-based guideline for pediatric prehospital seizure management using GRADE methodology.
      ,
      • Lammers R.
      • Byrwa M.
      • Fales W.
      Root causes of errors in a simulated prehospital pediatric emergency.
      ]. A recent study analyzing outcomes in pediatric SE patients treated by paramedics with or without completion of a pediatric simulation-based training course found pediatric trained paramedics were slightly more likely to administer a correct midazolam dose, though other outcomes did not differ between the two groups [
      • Shah M.I.
      • Carey J.M.
      • Rapp S.E.
      • Masciale M.
      • Alcanter W.B.
      • Mondragon J.A.
      • et al.
      Impact of high-fidelity pediatric simulation on paramedic seizure management.
      ]. Thus, another management optimization approach is to improve knowledge and comfort with the management of pediatric emergencies by emergency personnel.

      4.5 Medication use by pre-hospital emergency personnel

      Thirty-six percent of children in a refractory SE cohort [
      • Sanchez Fernandez I.
      • Abend N.S.
      • Agadi S.
      • An S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Time from convulsive status epilepticus onset to anticonvulsant administration in children.
      ] and 41% of children in the Consequences of Prolonged Febrile Seizures in Childhood (FEBSTAT) study received an ASM pre-hospital by EMS [
      • Seinfeld S.
      • Shinnar S.
      • Sun S.
      • Hesdorffer D.C.
      • Deng X.
      • Shinnar R.C.
      • et al.
      Emergency management of febrile status epilepticus: results of the FEBSTAT study.
      ]. The FEBSTAT study showed time from EMS arrival to first ASM administration was a median of 10 min, suggesting that even after EMS arrival there is further delay in medication administration [
      • Seinfeld S.
      • Shinnar S.
      • Sun S.
      • Hesdorffer D.C.
      • Deng X.
      • Shinnar R.C.
      • et al.
      Emergency management of febrile status epilepticus: results of the FEBSTAT study.
      ]. In the minority of patients who receive pre-hospital medication, management is most often limited to benzodiazepines and not second-line ASMs if benzodiazepines are ineffective. This was seen in the FEBSTAT study where only diazepam, lorazepam and midazolam were administered by EMS [
      • Seinfeld S.
      • Shinnar S.
      • Sun S.
      • Hesdorffer D.C.
      • Deng X.
      • Shinnar R.C.
      • et al.
      Emergency management of febrile status epilepticus: results of the FEBSTAT study.
      ]. A second-line medication (fosphenytoin) was administered to only 3% of patients in a refractory SE pediatric cohort [
      • Sanchez Fernandez I.
      • Abend N.S.
      • Agadi S.
      • An S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Time from convulsive status epilepticus onset to anticonvulsant administration in children.
      ].
      Pre-hospital medication algorithms for pediatric and adult SE from a single state in the United States provide highly varied recommendations regarding timeline, dosing, route and medications, often proposing low weight-based benzodiazepine dosing without mention of therapy beyond benzodiazepines [
      • Silverman E.C.
      • Sporer K.A.
      • Lemieux J.M.
      • Brown J.F.
      • Koenig K.L.
      • Gausche-Hill M.
      • et al.
      Prehospital care for the adult and pediatric seizure patient: current evidence-based recommendations.
      ]. Nine percent of these algorithms necessitate evaluation for hypoglycemia prior to benzodiazepine administration [
      • Silverman E.C.
      • Sporer K.A.
      • Lemieux J.M.
      • Brown J.F.
      • Koenig K.L.
      • Gausche-Hill M.
      • et al.
      Prehospital care for the adult and pediatric seizure patient: current evidence-based recommendations.
      ] which has been associated with further delay in benzodiazepine administration of 2–6 min [
      • Beskind D.L.
      • Rhodes S.M.
      • Stolz U.
      • Birrer B.
      • Mayfield T.R.
      • Bourn S.
      • et al.
      When should you test for and treat hypoglycemia in prehospital seizure patients?.
      ], although hypoglycemia is a relatively rare inciting factor [
      • Remick K.
      • Redgate C.
      • Ostermayer D.
      • Kaji A.H.
      • Gausche-Hill M.
      Prehospital glucose testing for children with seizures: a proposed change in management.
      ].
      There are currently no completed pediatric trials evaluating pre-hospital use of second-line therapy. In the adult literature, a randomized, double-blind, placebo-controlled superiority trial of pre-hospital use of clonazepam plus levetiracetam versus clonazepam plus placebo was conducted. The study ended early after finding no significant differences between groups (seizure cessation at 15 min in 84% versus 74% in the levetiracetam versus placebo groups) [
      • Navarro V.
      • Dagron C.
      • Elie C.
      • Lamhaut L.
      • Demeret S.
      • Urien S.
      • et al.
      Prehospital treatment with levetiracetam plus clonazepam or placebo plus clonazepam in status epilepticus (SAMUKeppra): a randomised, double-blind, phase 3 trial.
      ,
      • Schomer A.C.
      • Kapur J.
      The SAMUKeppra study in prehospital status epilepticus: lessons for future study.
      ]. The effect of second-line therapy may have been limited by small sample size [
      • Schomer A.C.
      • Kapur J.
      The SAMUKeppra study in prehospital status epilepticus: lessons for future study.
      ] or use of levetiracetam as opposed to alternative potential second-line ASMs, and this remains a future target for further study and intervention.
      While evidence for the most effective second-line ASM therapy is lacking, options for such therapies could be outlined in EMS algorithms and emergency personnel appropriately equipped with the ability to provide these medications in the pre-hospital setting. Additionally, standardization of algorithms to use appropriate weight-based dosing is of importance as existing algorithms are often under-dosing medications (see below) [
      • Silverman E.C.
      • Sporer K.A.
      • Lemieux J.M.
      • Brown J.F.
      • Koenig K.L.
      • Gausche-Hill M.
      • et al.
      Prehospital care for the adult and pediatric seizure patient: current evidence-based recommendations.
      ]. Issues with medication degradation in extreme heat settings experienced in ambulances should be considered when creating algorithms, and studies suggest midazolam may be most stable in these conditions [
      • Silverman E.C.
      • Sporer K.A.
      • Lemieux J.M.
      • Brown J.F.
      • Koenig K.L.
      • Gausche-Hill M.
      • et al.
      Prehospital care for the adult and pediatric seizure patient: current evidence-based recommendations.
      ,
      • McMullan J.T.
      • Jones E.
      • Barnhart B.
      • Denninghoff K.
      • Spaite D.
      • Zaleski E.
      • et al.
      Degradation of benzodiazepines after 120 days of EMS deployment.
      ]. Checking a blood glucose may certainly be helpful when indicated, but testing may be completed in conjunction with standard seizure management so as to not substantially delay seizure treatment. Adherence to a standardized algorithm approach may also potentially improve emergency personnel comfort in treating critically ill pediatric patients with or without IV access [
      • Shah M.I.
      • Macias C.G.
      • Dayan P.S.
      • Weik T.S.
      • Brown K.M.
      • Fuchs S.M.
      • et al.
      An evidence-based guideline for pediatric prehospital seizure management using GRADE methodology.
      ,
      • Lammers R.
      • Byrwa M.
      • Fales W.
      Root causes of errors in a simulated prehospital pediatric emergency.
      ].

      4.6 Use of inappropriately dosed medications pre- and in-hospital

      ASM dosing, particularly of benzodiazepines, is found to be inaccurate in a large proportion of pediatric SE cases. In one retrospective pediatric cohort, only 32% of patients received the recommended weight-based dose of a benzodiazepine, and most patients were under-dosed [
      • Siefkes H.M.
      • Holsti M.
      • Morita D.
      • Cook L.J.
      • Bratton S.
      Seizure treatment in children transported to tertiary care: recommendation adherence and outcomes.
      ]. In another prospective observational study of 100 consecutively treated cases of SE requiring intensive care unit admission, 23% were administered a benzodiazepine dose outside of the suggested range [
      • Tobias J.D.
      • Berkenbosch J.W.
      Management of status epilepticus in infants and children prior to pediatric ICU admission: deviations from the current guidelines.
      ]. High or repeat benzodiazepine dosing may lead to respiratory depression. Receiving more than two doses of benzodiazepines has been associated with an increased risk of intubation (relative risk (RR) 2.4) and intensive care unit admission (RR 1.7) [
      • Siefkes H.M.
      • Holsti M.
      • Morita D.
      • Cook L.J.
      • Bratton S.
      Seizure treatment in children transported to tertiary care: recommendation adherence and outcomes.
      ]. A similar association with receiving more than two doses of benzodiazepines and subsequent respiratory insufficiency was observed in another cross-sectional retrospective study [
      • Chin R.F.
      • Verhulst L.
      • Neville B.G.
      • Peters M.J.
      • Scott R.C.
      Inappropriate emergency management of status epilepticus in children contributes to need for intensive care.
      ]. Patients with an incorrect dose or absence of a seizure rescue medication were more likely to have an unplanned admission or ED evaluation (OR = 11.3) in a retrospective case-control study, and 80% of patients who utilized emergency care had an incorrect seizure rescue medication dose compared to 19% in patients who utilized care less frequently [
      • Patel A.D.
      Variables associated with emergency department and/or unplanned hospital utilization for children with epilepsy.
      ].
      Establishing appropriate, weight-based dosing of benzodiazepines is another target for intervention. The use of seizure action plans, standardized EMS and in-hospital medication algorithms, or weight-based order sets may improve correct dosing.

      4.7 In-hospital ASM use

      Management of SE in-hospital is also often delayed. In a multicenter refractory SE cohort, among patients with SE onset in the hospital, first and second ASMs were administered at a median (interquartile range) of 8 (5–15) minutes and 16 (10–40) minutes [
      • Sanchez Fernandez I.
      • Abend N.S.
      • Agadi S.
      • An S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Time from convulsive status epilepticus onset to anticonvulsant administration in children.
      ]. Adherence to an inpatient medication algorithm may improve time to treatment, and consensus guidelines have supported the use of these pathways [
      • Shorvon S.
      • Baulac M.
      • Cross H.
      • Trinka E.
      • Walker M.
      The drug treatment of status epilepticus in Europe: consensus document from a workshop at the first London Colloquium on Status Epilepticus.
      ,
      • Unterberger I.
      Status epilepticus do treatment guidelines make sense?.
      ]. In a quality improvement initiative to evaluate the safety and efficiency of a midazolam medication protocol for treatment of pediatric SE in an ED setting, 93% had adherence to midazolam as first-line therapy, with a median seizure duration of 6 min for those treated [
      • Tourigny-Ruel G.
      • Diksic D.
      • Mok E.
      • McGillivray D.
      Quality assurance evaluation of a simple linear protocol for the treatment of impending status epilepticus in a pediatric emergency department 2 years postimplementation.
      ]. Another intervention analyzed time to treatment of inpatient pediatric seizure management before and after employment of an activated order set for ASMs; after use of this intervention, time to first-line ASM administration significantly decreased from 7.7 to 3.7 min and time to second-line ASM administration decreased from 50 to 25 min [
      • Xie Y.
      • Morgan R.
      • Schiff L.
      • Hannah D.
      • Whelessm J.
      A computerized standard protocol order entry for pediatric inpatient acute seizure emergencies reduces time to treatment.
      ]. The use of a management pathway has also been shown to improve time to treatment in non-convulsive electrographic seizures during continuous EEG monitoring in critically ill children. In a study evaluating treatment before and after pathway initiation, the time from seizure onset to ASM administration decreased from a median (interquartile range) of 129 (71–189) minutes to 64 (50–101) minutes, and this was associated with a higher likelihood of seizure abortion with the initial ASM (67% versus 27%) [
      • Williams R.P.
      • Banwell B.
      • Berg R.A.
      • Dlugos D.J.
      • Donnelly M.
      • Ichord R.
      • et al.
      Impact of an ICU EEG monitoring pathway on timeliness of therapeutic intervention and electrographic seizure termination.
      ]. Mastery of following such hospital-proposed guidelines was demonstrated and achieved via high-fidelity simulation with pediatrics interns in one institution [
      • Malakooti M.R.
      • McBride M.E.
      • Mobley B.
      • Goldstein J.L.
      • Adler M.D.
      • McGaghie W.C.
      Mastery of status epilepticus management via simulation-based learning for pediatrics residents.
      ].
      While an adult study did not reveal improved outcomes with treatment protocol adherence to recommended medication doses and sequences [
      • Rossetti A.O.
      • Alvarez V.
      • Januel J.M.
      • Burnand B.
      Treatment deviating from guidelines does not influence status epilepticus prognosis.
      ], initiation of a SE alert team has been shown to decrease time to treatment in adults. In a single center study, a “status epilepticus alert” was created when a patient in SE was identified to summon a neurology resident, neuro-intensivist, house officer, rapid response team, and pharmacist for urgent evaluation. The time to treatment with the second ASM improved from 71 to 82 min before to 19 min after the intervention [
      • Villamar M.C.A.
      • Ward-Mitchell R.
      • Bensalem-Owen M.
      Improvement in time to administration of second-line antiepileptic medications after implementation of an inpatient status epilepticus alert protocol.
      ].
      Several pediatric studies have identified benefits associated with use of management algorithms. A study analyzed the effect of a SE treatment algorithm in neonates and reported that with 80% adherence to the protocol there was a reduction in the number of seizures that progressed to SE after implementation and also a decreased length of hospital stay (19 versus 26 days) [
      • Harris M.L.
      • Malloy K.M.
      • Lawson S.N.
      • Rose R.S.
      • Buss W.F.
      • Mietzsch U.
      Standardized treatment of neonatal status epilepticus improves outcome.
      ]. In another study evaluating care processes of patients admitted to a tertiary care hospital after presenting with SE, patients admitted to the intensive care unit were more likely to have deviated from a proposed medication algorithm than those admitted to the floor (66% versus 26%) and patients admitted to the intensive care unit were more likely to have received greater than two doses of a benzodiazepine than those admitted to the floor (65% versus 33%) [
      • Tirupathi S.
      • McMenamin J.B.
      • Webb D.W.
      Analysis of factors influencing admission to intensive care following convulsive status epilepticus in children.
      ]. In a retrospective study of children treated at community hospitals, 61% did not receive medications per protocol, most often receiving more than two doses of a benzodiazepine which yielded an increased risk of intubation (RR 2.4) and intensive care unit admission (RR 1.7) [
      • Siefkes H.M.
      • Holsti M.
      • Morita D.
      • Cook L.J.
      • Bratton S.
      Seizure treatment in children transported to tertiary care: recommendation adherence and outcomes.
      ].
      Given these data, consensus guidelines have supported the use of medication algorithms that include staged treatment with clearly outlined timelines [
      • Shorvon S.
      • Baulac M.
      • Cross H.
      • Trinka E.
      • Walker M.
      The drug treatment of status epilepticus in Europe: consensus document from a workshop at the first London Colloquium on Status Epilepticus.
      ,
      • Unterberger I.
      Status epilepticus do treatment guidelines make sense?.
      ], and studies have shown their effectiveness in improving both time to treatment [
      • Tourigny-Ruel G.
      • Diksic D.
      • Mok E.
      • McGillivray D.
      Quality assurance evaluation of a simple linear protocol for the treatment of impending status epilepticus in a pediatric emergency department 2 years postimplementation.
      ,
      • Williams R.P.
      • Banwell B.
      • Berg R.A.
      • Dlugos D.J.
      • Donnelly M.
      • Ichord R.
      • et al.
      Impact of an ICU EEG monitoring pathway on timeliness of therapeutic intervention and electrographic seizure termination.
      ,
      • Xie Y.
      • Morgan R.
      • Schiff L.
      • Hannah D.
      • Whelessm J.
      A computerized standard protocol order entry for pediatric inpatient acute seizure emergencies reduces time to treatment.
      ], and outcomes in pediatric SE [
      • Siefkes H.M.
      • Holsti M.
      • Morita D.
      • Cook L.J.
      • Bratton S.
      Seizure treatment in children transported to tertiary care: recommendation adherence and outcomes.
      ,
      • Harris M.L.
      • Malloy K.M.
      • Lawson S.N.
      • Rose R.S.
      • Buss W.F.
      • Mietzsch U.
      Standardized treatment of neonatal status epilepticus improves outcome.
      ,
      • Tirupathi S.
      • McMenamin J.B.
      • Webb D.W.
      Analysis of factors influencing admission to intensive care following convulsive status epilepticus in children.
      ]. Ultimately, an SE intervention team may further improve time to treatment and outcomes [
      • Villamar M.C.A.
      • Ward-Mitchell R.
      • Bensalem-Owen M.
      Improvement in time to administration of second-line antiepileptic medications after implementation of an inpatient status epilepticus alert protocol.
      ].

      5. Conclusion

      Etiology is consistently found to be a predictor of outcome in SE [
      • Raspall-Chaure M.
      • Chin R.F.
      • Neville B.G.
      • Scott R.C.
      Outcome of paediatric convulsive status epilepticus: a systematic review.
      ]. Though results are mixed [
      • Rossetti A.O.
      • Alvarez V.
      • Januel J.M.
      • Burnand B.
      Treatment deviating from guidelines does not influence status epilepticus prognosis.
      ,
      • Pujar S.S.
      • Neville B.G.
      • Scott R.C.
      • Chin R.F.
      Death within 8 years after childhood convulsive status epilepticus: a population-based study.
      ,
      • Pujar S.S.
      • Martinos M.M.
      • Cortina-Borja M.
      • Kling Chong W.K.
      • De Haan M.
      • Gillberg C.
      • et al.
      Long-term prognosis after childhood convulsive status epilepticus: a prospective cohort study.
      ], shorter seizure duration has also been associated with improved outcomes in pediatric SE and represents a potentially modifiable risk factor [
      • Gainza-Lein M.
      • Sanchez Fernandez I.
      • Jackson M.
      • Abend N.S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Association of time to treatment with short-term outcomes for pediatric patients with refractory convulsive status epilepticus.
      ]. Despite the demonstration of improved outcomes with rapid administration of appropriately dosed ASMs in both the out-of-hospital and in-hospital settings [
      • Gainza-Lein M.
      • Sanchez Fernandez I.
      • Jackson M.
      • Abend N.S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Association of time to treatment with short-term outcomes for pediatric patients with refractory convulsive status epilepticus.
      ], time to treatment is often delayed in both areas [
      • Sanchez Fernandez I.
      • Abend N.S.
      • Agadi S.
      • An S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Time from convulsive status epilepticus onset to anticonvulsant administration in children.
      ,
      • Pellock J.M.
      • Marmarou A.
      • DeLorenzo R.
      Time to treatment in prolonged seizure episodes.
      ]. As reviewed, there are encouraging ongoing quality improvement initiatives and targets for future interventions. Identifying patients with high ED utilization and missed preventive clinic visits for the use of urgent epilepsy clinics or nurse navigators has shown to have a large impact on healthcare utilization and costs [
      • Patel A.D.
      • Wood E.G.
      • Cohen D.M.
      Reduced emergency department utilization by patients with epilepsy using QI methodology.
      ,
      • Grefe A.B.
      • Aguilar K.A.
      • Duncan P.
      Benefit of an epilepsy nurse navigator in a pediatric neurology clinic.
      ]. In the pre-hospital setting, advances in affordable, insurance-covered seizure detection devices may improve seizure recognition and subsequently more rapid initiation and escalation of treatment [
      • Onorati F.
      • Regalia G.
      • Caborni C.
      • Migliorini M.
      • Bender D.
      • Poh M.Z.
      • et al.
      Multicenter clinical assessment of improved wearable multimodal convulsive seizure detectors.
      ]. Seizure action plans that incorporate use of rescue medications are associated with improved caregiver knowledge of rescue medications [
      • Gainza-Lein M.
      • Benjamin R.
      • Stredny C.
      • McGurl M.
      • Kapur K.
      • Loddenkemper T.
      Rescue medications in epilepsy patients: a family perspective.
      ]. Training programs for school nurses/teachers and caregivers may be employed to increase confidence and competency with seizure rescue medication use [
      • Gainza-Lein M.
      • Benjamin R.
      • Stredny C.
      • McGurl M.
      • Kapur K.
      • Loddenkemper T.
      Rescue medications in epilepsy patients: a family perspective.
      ,
      • 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.
      ]. Given the delays in EMS arrival and low EMS administration of ASMs [
      • Hill C.E.
      • Parikh A.O.
      • Ellis C.
      • Myers J.S.
      • Litt B.
      Timing is everything: where status epilepticus treatment fails.
      ], the understanding of SE as a time-sensitive emergency with rapid summoning, dispatch, and medication administration by emergency personnel is critical; further training of such personnel with pediatric patients and optimization of out-of-hospital management pathways may be beneficial [
      • Shah M.I.
      • Carey J.M.
      • Rapp S.E.
      • Masciale M.
      • Alcanter W.B.
      • Mondragon J.A.
      • et al.
      Impact of high-fidelity pediatric simulation on paramedic seizure management.
      ]. Standardization and use of pre-hospital medication algorithms that extend beyond weight-based benzodiazepine dosing for more extensive pre-hospital treatment are future aims for improvement [
      • Silverman E.C.
      • Sporer K.A.
      • Lemieux J.M.
      • Brown J.F.
      • Koenig K.L.
      • Gausche-Hill M.
      • et al.
      Prehospital care for the adult and pediatric seizure patient: current evidence-based recommendations.
      ]. In both the pre- and in-hospital settings, use of appropriately dosed ASMs is needed as inappropriate benzodiazepine doses are associated with higher rates of intensive care unit admissions [
      • Siefkes H.M.
      • Holsti M.
      • Morita D.
      • Cook L.J.
      • Bratton S.
      Seizure treatment in children transported to tertiary care: recommendation adherence and outcomes.
      ,
      • Chin R.F.
      • Verhulst L.
      • Neville B.G.
      • Peters M.J.
      • Scott R.C.
      Inappropriate emergency management of status epilepticus in children contributes to need for intensive care.
      ], and this may be accomplished through the use of seizure action plans, algorithms [
      • Tourigny-Ruel G.
      • Diksic D.
      • Mok E.
      • McGillivray D.
      Quality assurance evaluation of a simple linear protocol for the treatment of impending status epilepticus in a pediatric emergency department 2 years postimplementation.
      ], and order sets. Use of in-hospital medication algorithms, management pathways, and seizure action teams can yield faster time to treatment [
      • Tourigny-Ruel G.
      • Diksic D.
      • Mok E.
      • McGillivray D.
      Quality assurance evaluation of a simple linear protocol for the treatment of impending status epilepticus in a pediatric emergency department 2 years postimplementation.
      ,
      • Williams R.P.
      • Banwell B.
      • Berg R.A.
      • Dlugos D.J.
      • Donnelly M.
      • Ichord R.
      • et al.
      Impact of an ICU EEG monitoring pathway on timeliness of therapeutic intervention and electrographic seizure termination.
      ,
      • Xie Y.
      • Morgan R.
      • Schiff L.
      • Hannah D.
      • Whelessm J.
      A computerized standard protocol order entry for pediatric inpatient acute seizure emergencies reduces time to treatment.
      ] and improve outcomes [
      • Siefkes H.M.
      • Holsti M.
      • Morita D.
      • Cook L.J.
      • Bratton S.
      Seizure treatment in children transported to tertiary care: recommendation adherence and outcomes.
      ,
      • Harris M.L.
      • Malloy K.M.
      • Lawson S.N.
      • Rose R.S.
      • Buss W.F.
      • Mietzsch U.
      Standardized treatment of neonatal status epilepticus improves outcome.
      ,
      • Tirupathi S.
      • McMenamin J.B.
      • Webb D.W.
      Analysis of factors influencing admission to intensive care following convulsive status epilepticus in children.
      ].
      Overall, data suggest that improving time to treatment is crucial in improving management and outcomes in pediatric SE. Increased awareness and knowledge regarding the time-critical nature of SE is key. Improvements in preventive care, seizure detection, and rescue medication education may serve as initial targets for further innovation in the pre-hospital setting. Implementation of “Seizure Code Teams” may be one strategy to address these in-hospital issues. Ideally these teams would be interdisciplinary with representatives from EMS, ED, critical care, neurology, nursing, pharmacy, information technology, and quality improvement groups. Some members of the team might guide acute care of a seizing child, and the overall group would help develop broader pathways and management systems to optimize care throughout a healthcare system or region. Thus, this type of team may serve as a means of initiating and integrating improvement interventions.

      Conflicts of interest/disclosures

      Coral Stredny has no conflicts of interest or disclosures to report.
      Nicholas Abend receives primary investigator funding from NIH (NINDS) K02NS096058 and site investigator funding from EFA , PCORI , and UCB Pharma .
      Tobias Loddenkemper serves on the Council (and as Vice President and President Elect) of the American Clinical Neurophysiology Society, on the American Board of Clinical Neurophysiology, as committee chair at the American Epilepsy Society (Special Interest Group and Investigator Workshop Committees), as founder and consortium PI of the pediatric status epilepticus research group, as an Associate Editor for Seizure, and as an Associate Editor for Wyllie’s Treatment of Epilepsy 6th edition and 7th editions. He is part of pending patent applications to detect and predict seizures and to diagnose epilepsy. He receives research support from the NIH, PCORI, Epilepsy Research Fund , the American Epilepsy Society , the Epilepsy Foundation of America , the Epilepsy Therapy Project , the Pediatric Epilepsy Research Foundation , CURE , and received research grants from Lundbeck , Eisai , Upsher-Smith , Mallinckrodt , Sage , and Pfizer . He serves as a consultant for Zogenix, Engage, Amzell, Upsher Smith, Eisai, and Sunovion. He performs video electroencephalogram long-term and ICU monitoring, electroencephalograms, and other electrophysiological studies at Boston Children's Hospital and affiliated hospitals and bills for these procedures and he evaluates pediatric neurology patients and bills for clinical care. He has received speaker honorariums from national societies including the AAN, AES and ACNS, and for grand rounds at various academic centers. His wife, Dr. Karen Stannard, is a pediatric neurologist and she performs video electroencephalogram long-term and ICU monitoring, electroencephalograms, and other electrophysiological studies and bills for these procedures and she evaluates pediatric neurology patients and bills for clinical care.

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