Rescue therapies for seizure clusters: Pharmacology and target of treatments

Abstract

The primary goal of treatment for seizure clusters is cessation of the cluster to avoid progression to more severe conditions, such as prolonged seizures and status epilepticus. Rescue therapies are key components of treatment plans for patients with seizure clusters. Three rescue therapies are approved in the United States for the treatment of seizure clusters: diazepam rectal gel, midazolam nasal spray, and diazepam nasal spray. This review characterizes the pharmacological function of rescue therapies for seizure clusters, as well as describing γ‐aminobutyric acid A (GABAA) receptor functions. GABAA receptors are heteropentamers, consisting primarily of α1‐6, β1‐3, γ2, and δ subunits in the central nervous system. These subunits can traffic to and from the membrane to regulate membrane potential. Benzodiazepines, such as diazepam and midazolam, are positive allosteric modulators of GABAA receptors, the activation of which leads to an increase in intracellular chloride, hyperpolarization of the cell membrane, and a reduction in excitation. GABAA receptor subunit mutations, dysregulation of trafficking, and degradation are associated with epilepsy. Although benzodiazepines are effective GABAA receptor modulators, individual formulations have unique profiles in practice. Diazepam rectal gel is an effective rescue therapy for seizure clusters; however, adults and adolescents may have social reservations regarding its administration. Intranasal delivery of midazolam or diazepam is a promising alternative to rectal administration because these formulations offer easy, socially acceptable administration and exhibit a rapid onset. Off‐label benzodiazepines, such as orally disintegrating lorazepam and intranasal use of an intravenous formulation of midazolam via nasal atomizer, are less well characterized regarding bioavailability and tolerability compared with approved agents.

Introduction to use of an acute seizure action plan for seizure clusters and guidance for implementation

“…More details about rescue therapies are discussed by Gidal and Detyniecki in Rescue Therapies for Seizure Clusters: Pharmacology and Target of Treatments in this supplement. 27 The ASAP can be customized to include patientspecific details such as type of seizure, type of home setting, emergency contact information, details for recognizing whether a seizure is atypical, information on how and when to administer first aid, step-by-step instructions for administration of prescribed treatment, and information on how to recognize the patient's seizure milestones (e.g., when to start medication and when to transition to requesting emergency assistance).…”

“…These details also should be easy for the physician to modify when there are changes in the prescribed therapy. More details about rescue therapies are discussed by Gidal and Detyniecki in Rescue Therapies for Seizure Clusters: Pharmacology and Target of Treatments in this supplement 27 …”

Consequences: Bench to home

“…76,77 (See Gidal and Detyniecki, Rescue Therapies for Seizure Clusters: Pharmacology and Target of Treatments in this supplement for more details regarding current and future therapies. 78 ) Alternative routes could alleviate concerns from staff members over administration of treatment for patients who require long-term care. In all, rescue medications for seizure clusters may reduce health care utilization and improve management in the community setting and long-term care facilities by giving patients and caregivers a greater sense of control.…”

“…Alternative routes of administration have been approved (i.e., two intranasal formulations) or are in development (e.g., buccal or intrapulmonary formulations) and represent an important area of ongoing research. 76,77 (See Gidal and Detyniecki, Rescue Therapies for Seizure Clusters: Pharmacology and Target of Treatments in this supplement for more details regarding current and future therapies. 78 ) Alternative routes could alleviate concerns from staff members over administration of treatment for patients who require long‐term care.…”

Future opportunities for research in rescue treatments

“…(See Gidal and Detyniecki, Rescue Therapies for Seizure Clusters: Pharmacology and Target of Treatments for information on rescue medications. 4 ) Other analyses of possible treatment subgroups include those by underlying condition (e.g., encephalopathies, catamenial seizure clusters, complex febrile seizures) and frequency (e.g., more/fewer than two events per month). Differences in outcomes according to self-administration versus caregiver administration would be important to characterize, especially in patients who experience prolonged auras or focal aware seizures.…”