Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Neurological Sciences
Published in: Neurological Sciences 10/2021

01-10-2021 | Status Epilepticus | Review Article

Rescue therapies for seizure emergencies: current and future landscape

Author: Debopam Samanta

Published in: Neurological Sciences | Issue 10/2021

Login to get access

Abstract

Introduction

Seizure emergencies—status epilepticus and seizure clusters—require rapid evaluation and treatment. Several consensus-based guidelines support a prompt use of intravenous benzodiazepines as the first-line therapy in seizure emergencies. However, most seizure emergencies start outside the hospital settings. Until recently, approved prehospital rescue therapies were limited to rectal diazepam and buccal midazolam (Europe only).

Methods

The author provides a narrative review of rescue therapies for seizure emergencies based on a comprehensive literature review (PubMed and OvidSP vendors with appropriate keywords to incorporate recent evidence) to highlight the changing landscape of seizure recue therapies.

Results

A commercial version of intranasal midazolam was approved by the FDA in 2019 for 12 ≥ years old with seizure clusters. In 2020, the FDA also approved a proprietary vitamin E solution–based diazepam nose spray to abort seizure clusters in ≥ 6 years old subjects. Other than these two new options, the author discussed two previously approved therapies: rectal diazepam and buccal midazolam. The review also includes the use of intramuscular diazepam and midazolam, clonazepam wafer, sublingual and intranasal lorazepam in seizure emergencies. Besides the availability of new therapies from successful trials in controlled settings, the real-world challenges of using rescue medicines in community settings are slowly emerging.

Discussion

With multiple options, a more robust and updated cost-effective analysis of different rescue medicines needs to be performed using effectiveness data from the literature and cost data from publicly available market prices. Further research is also ongoing to develop alternative non-intravenous treatment options for outpatient settings. Lastly, several other non-benzodiazepine drugs, such as allopregnanolone, propofol, and brivaracetam, are also currently under development for seizure emergencies.
Literature
1.
Jafarpour S, Hirsch LJ, Gaínza-Lein M, Kellinghaus C, Detyniecki K (2018) Seizure cluster: definition, prevalence, consequences, and management. Seizure
2.
Trinka E, Cock H, Hesdorffer D et al (2015) A definition and classification of status epilepticus–report of the ILAE task force on classification of status epilepticus. Epilepsia 56(10):1515–1523PubMedCrossRef
3.
4.
Glauser T, Shinnar S, Gloss D et al (2016) Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the american epilepsy society. Epilepsy Curr 16(1):48–61PubMedPubMedCentralCrossRef
5.
Brophy GM, Bell R, Claassen J et al (2012) Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 17(1):3–23PubMedCrossRef
6.
Gaínza-Lein M, Fernández IS, Jackson M et al (2018) Association of time to treatment with short-term outcomes for pediatric patients with refractory convulsive status epilepticus. JAMA Neurol 75(4):410–418PubMedPubMedCentralCrossRef
7.
Lambrechtsen FA, Buchhalter JR (2008) Aborted and refractory status epilepticus in children: a comparative analysis. Epilepsia 49(4):615–625PubMedCrossRef
8.
Hayashi K, Osawa M, Aihara M et al (2007) Efficacy of intravenous midazolam for status epilepticus in childhood. Pediatr Neurol 36(6):366–372PubMedCrossRef
9.
Eriksson K, Metsaranta P, Huhtala H, Auvinen A, Kuusela AL, Koivikko M (2005) Treatment delay and the risk of prolonged status epilepticus. Neurology 65(8):1316–1318PubMedCrossRef
10.
Lewena S, Young S (2006) When benzodiazepines fail: how effective is second line therapy for status epilepticus in children? Emerg Med Australas 18(1):45–50PubMed
11.
Chin RF, Neville BG, Peckham C, Wade A, Bedford H, Scott RC (2008) Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol 7(8):696–703PubMedPubMedCentralCrossRef
12.
13.
14.
15.
Dreifuss FE, Rosman NP, Cloyd JC et al (1998) A comparison of rectal diazepam gel and placebo for acute repetitive seizures. N Engl J Med 338(26):1869–1875PubMedCrossRef
16.
17.
Mitchell WG, Conry J, Crumrine P et al (1999) An open-label study of repeated use of diazepam rectal gel (diastat) for episodes of acute breakthrough seizures and clusters: safety, efficacy, and tolerance. Epilepsia 40(11):1610–1617PubMedCrossRef
18.
Tomlin S (2011) Medicines tailored for childrenâ€" the introduction of buccal midazolam. Pharm J 287(7665):161
19.
Scott RC, Besag FM, Neville BG (1999) Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial. Lancet 353(9153):623–626PubMedCrossRef
20.
Ashrafi MR, Khosroshahi N, Karimi P et al (2010) Efficacy and usability of buccal midazolam in controlling acute prolonged convulsive seizures in children. Eur J Paediatr Neurol 14(5):434–438PubMedCrossRef
21.
Talukdar B, Chakrabarty B (2009) Efficacy of buccal midazolam compared to intravenous diazepam in controlling convulsions in children: a randomized controlled trial. Brain Dev 31(10):744–749PubMedCrossRef
22.
23.
McIntyre J, Robertson S, Norris E et al (2005) Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomised controlled trial. Lancet 366(9481):205–210PubMedCrossRef
24.
Schwagmeier R, Alincic S, Striebel H (1998) Midazolam pharmacokinetics following intravenous and buccal administration. Br J Clin Pharmacol 46(3):203–206PubMedPubMedCentralCrossRef
25.
McDonough JH, Van Shura KE, LaMont JC, McMonagle JD, Shih T (2009) Comparison of the intramuscular, intranasal or sublingual routes of midazolam administration for the control of soman-induced seizures. Basic Clin Pharmacol Toxicol 104(1):27–34PubMedCrossRef
26.
Garnett WR, Barr WH, Edinboro LE, Karnes HT, Mesa M, Wannarka GL (2011) Diazepam autoinjector intramuscular delivery system versus diazepam rectal gel: a pharmacokinetic comparison. Epilepsy Res 93(1):11–16PubMedCrossRef
27.
Lamson MJ, Sitki-Green D, Wannarka GL, Mesa M, Andrews P, Pellock J (2011) Pharmacokinetics of diazepam administered intramuscularly by autoinjector versus rectal gel in healthy subjects. Clin Drug Investig 31(8):585–597PubMedCrossRef
28.
Abou-Khalil B, Wheless J, Rogin J et al (2013) 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. Epilepsia 54(11):1968–1976PubMedCrossRef
29.
Rogin J, Wheless J, Abou-Khalil B et al (2014) Safety and effectiveness of long-term treatment with diazepam auto-injector administered by caregivers in an outpatient setting for the treatment of acute repetitive seizures. Epilepsia 55(9):1444–1451PubMedCrossRef
30.
Silbergleit R, Durkalski V, Lowenstein D et al (2012) Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med 366(7):591–600PubMedPubMedCentralCrossRef
31.
Silbergleit R, Lowenstein D, Durkalski V, Conwit R, NETT Investigators (2013) Lessons from the RAMPART study—and which is the best route of administration of benzodiazepines in status epilepticus. Epilepsia 54:74–77PubMedPubMedCentralCrossRef
32.
Welch RD, Nicholas K, Durkalski-Mauldin VL et al (2015) Intramuscular midazolam versus intravenous lorazepam for the prehospital treatment of status epilepticus in the pediatric population. Epilepsia 56(2):254–262PubMedPubMedCentralCrossRef
33.
Kapoor M, Cloyd JC, Siegel RA (2016) A review of intranasal formulations for the treatment of seizure emergencies. J Control Release 237:147–159PubMedCrossRef
34.
McMullan J, Sasson C, Pancioli A, Silbergleit R (2010) Midazolam versus diazepam for the treatment of status epilepticus in children and young adults: a meta-analysis. Acad Emerg Med 17(6):575–582PubMedPubMedCentralCrossRef
35.
Thakker A, Shanbag P (2013) A randomized controlled trial of intranasal-midazolam versus intravenous-diazepam for acute childhood seizures. J Neurol 260(2):470–474PubMedCrossRef
36.
37.
Holsti M, Dudley N, Schunk J et al (2010) Intranasal midazolam vs rectal diazepam for the home treatment of acute seizures in pediatric patients with epilepsy. Arch Pediatr Adolesc Med 164(8):747–753PubMedCrossRef
38.
Mahmoudian T, Zadeh MM (2004) Comparison of intranasal midazolam with intravenous diazepam for treating acute seizures in children. Epilepsy Behav 5(2):253–255PubMedCrossRef
39.
40.
Hardmeier M, Zimmermann R, Rüegg S et al (2012) Intranasal midazolam: pharmacokinetics and pharmacodynamics assessed by quantitative EEG in healthy volunteers. Clin Pharmacol Ther 91(5):856–862PubMedCrossRef
41.
Bancke LL, Dworak HA, Rodvold KA, Halvorsen MB, Gidal BE (2015) Pharmacokinetics, pharmacodynamics, and safety of USL 261, a midazolam formulation optimized for intranasal delivery, in a randomized study with healthy volunteers. Epilepsia 56(11):1723–1731PubMedCrossRef
42.
Altman H, Dworak H, Halvorsen M (2013) Safety and pharmacodynamics of USL261, a novel formulation of midazolam optimized for intranasal administration, in subjects with epilepsy. Epilepsy Curr 13(Suppl. 1):164
43.
Hayes R, Bancke L, Halvorsen M (2013) Pharmacokinetics of USL261, a novel formulation of intranasal midazolam optimized for intranasal administration, in subjects with epilepsy. Epilepsy Curr 13(Suppl. 1):167
44.
45.
Berg AK, Myrvik MJ, Van Ess PJ (2017) Pharmacokinetics, pharmacodynamics, and tolerability of USL261, midazolam nasal spray: randomized study in healthy geriatric and non-geriatric adults. Epilepsy Behav 71:51–59PubMedCrossRef
46.
Detyniecki K, Van Ess PJ, Sequeira DJ, Wheless JW, Meng T, Pullman WE (2019) Safety and efficacy of midazolam nasal spray in the outpatient treatment of patients with seizure clusters—a randomized, double-blind, placebo-controlled trial. Epilepsia 60(9):1797–1808PubMedCrossRef
47.
Prime B. UCB announces NAYZILAM®(midazolam) nasal spray now approved by FDA to treat intermittent, stereotypic episodes of frequent seizure activity in people living with epilepsy in the US.https://​www.​cureepilepsy.​org/​news/​.​Accessed 2/16/2021
48.
Boddu SH, Kumari S (2020) A short review on the intranasal delivery of diazepam for treating acute repetitive seizures. Pharmaceutics 12(12):1167PubMedCentralCrossRef
49.
Sperling MR, Haas KF, Krauss G et al (2014) Dosing feasibility and tolerability of intranasal diazepam in adults with epilepsy. Epilepsia 55(10):1544–1550PubMedCrossRef
50.
51.
Hogan RE, Tarquinio D, Sperling MR et al (2020) Pharmacokinetics and safety of VALTOCO (NRL-1; diazepam nasal spray) in patients with epilepsy during seizure (ictal/peri-ictal) and nonseizure (interictal) conditions: a phase 1, open-label study. Epilepsia 61(5):935–943PubMedPubMedCentralCrossRef
52.
53.
54.
Greenblatt DJ, Miller LG, Shader RI (1987) Clonazepam pharmacokinetics, brain uptake, and receptor interactions. J Clin Psychiatry 48(Suppl):4–11PubMed
55.
Troester MM, Hastriter EV, Ng Y (2010) Dissolving oral clonazepam wafers in the acute treatment of prolonged seizures. J Child Neurol 25(12):1468–1472PubMedCrossRef
56.
Wallace A, Wirrell E, Payne E (2019) Seizure rescue medication use among US pediatric epilepsy providers: a survey of the pediatric epilepsy research consortium. J Pediatr 212:111–116PubMedCrossRef
57.
Arya R, Gulati S, Kabra M, Sahu JK, Kalra V (2011) Intranasal versus intravenous lorazepam for control of acute seizures in children: a randomized open-label study. Epilepsia 52(4):788–793PubMedCrossRef
58.
Yager JY, Seshia SS (1988) Sublingual lorazepam in childhood serial seizures. Am J Dis Child 142(9):931–932PubMed
59.
Ahmad S, Ellis JC, Kamwendo H, Molyneux E (2006) Efficacy and safety of intranasal lorazepam versus intramuscular paraldehyde for protracted convulsions in children: an open randomised trial. Lancet 367(9522):1591–1597PubMedCrossRef
60.
Malu CKK, Kahamba DM, Walker TD et al (2014) Efficacy of sublingual lorazepam versus intrarectal diazepam for prolonged convulsions in sub-saharan africa. J Child Neurol 29(7):895–902PubMedCrossRef
61.
Vigevano F, Kirkham FJ, Wilken B et al (2018) Effect of rescue medication on seizure duration in non-institutionalized children with epilepsy. Eur J Paediatr Neurol 22(1):56–63PubMedCrossRef
62.
Gaínza-Lein M, Benjamin R, Stredny C, McGurl M, Kapur K, Loddenkemper T (2017) Rescue medications in epilepsy patients: a family perspective. Seizure 52:188–194PubMedCrossRef
63.
Schumacher PM, Kaune A, Merkenschlager A et al (2018) Optimizing parents’ performance in anticonvulsant rescue medication administration. Epilepsy Behav 84:37–43PubMedCrossRef
64.
Sánchez Fernández I, Gaínza-Lein M, Loddenkemper T (2017) Nonintravenous rescue medications for pediatric status epilepticus: a cost-effectiveness analysis. Epilepsia 58(8):1349–1359PubMedCrossRef
65.
Lee D, Gladwell D, Batty AJ, Brereton N, Tate E (2013) The cost effectiveness of licensed oromucosal midazolam (buccolam®) for the treatment of children experiencing acute epileptic seizures: an approach when trial evidence is limited. Pediatr Drugs 15(2):151–162CrossRef
66.
Maglalang PD, Rautiola D, Siegel RA et al (2018) Rescue therapies for seizure emergencies: new modes of administration. Epilepsia 59:207–215PubMedCrossRef
67.
French JA, Wechsler R, Gelfand MA et al (2019) Inhaled alprazolam rapidly suppresses epileptic activity in photosensitive participants. Epilepsia 60(8):1602–1609PubMedCrossRef
68.
Zolkowska, D., Wu, C. Y., & Rogawski, M. A. (2021). Intranasal Allopregnanolone Confers Rapid Seizure Protection: Evidence for Direct Nose-to-Brain Delivery. Neurotherapeutics, 18(1), 544–555.
Metadata
Title
Rescue therapies for seizure emergencies: current and future landscape
Author
Debopam Samanta
Publication date
01-10-2021
Publisher
Springer International Publishing
Published in
Neurological Sciences / Issue 10/2021
Print ISSN: 1590-1874
Electronic ISSN: 1590-3478
DOI
https://doi.org/10.1007/s10072-021-05468-9

Other articles of this Issue 10/2021

Neurological Sciences 10/2021 Go to the issue

COVID-19

Predictors of survival in older adults hospitalized with COVID-19

Letter to the Editor

A new phenotype of MT-ND6 gene mutation for Leber’s hereditary optic neuropathy

Letter to the Editor

Asynchronous bithalamic infarction in presence of artery of Percheron

Review Article

Efficacy of low-level laser therapy in nerve injury repair—a new era in therapeutic agents and regenerative treatments

Original Article

Novel biallelic mutations in POLG gene: large deletion and missense variant associated with PEO

Brief Communication

Acetylcholinesterase inhibitor responsive myasthenia in a Filipino male with X-linked recessive spinal and bulbar muscular atrophy