Treatment of Seizure Clusters in Epilepsy: A Narrative Review on Rescue Therapies

Abstract

Epilepsy is a common neurological disorder in the United States, affecting approximately 1.2% of the population. Some people with epilepsy may experience seizure clusters, which are acute repetitive seizures that differ from the person's usual seizure pattern. Seizure clusters are unpredictable, are emotionally burdensome to patients and caregivers (including care partners), and require prompt treatment to prevent progression to serious outcomes, including status epilepticus and associated morbidity (e.g., lacerations, fractures due to falls) and mortality. Rescue medications for community use can be administered to terminate a seizure cluster, and benzodiazepines are the cornerstone of rescue treatment. Despite the effectiveness of benzodiazepines and the importance of a rapid treatment approach, as many as 80% of adult patients do not use rescue medication to treat seizure clusters. This narrative review provides an update on rescue medications used for treatment of seizure clusters, with an emphasis on clinical development and study programs for diazepam rectal gel, midazolam nasal spray, and diazepam nasal spray. Results from long-term clinical trials have shown that treatments for seizure clusters are effective. Intranasal benzodiazepines provide ease of use and patient and caregiver satisfaction in pediatric and adult patients. Adverse events attributed to acute rescue treatments have been characterized as mild to moderate, and no reports of respiratory depression have been attributed to treatment in long-term safety studies. The implementation of an acute seizure action plan to facilitate optimal use of rescue medications provides an opportunity for improved management of seizure clusters, allowing those affected to resume normal daily activities more quickly.

Keywords: Acute repetitive seizures; Benzodiazepines; Diazepam; Intranasal; Midazolam; Nasal spray; Rectal gel.

Fig. 1

Pathophysiology of seizure. Localization of key receptors that influence neuronal excitation during normal (a) and prolonged seizure conditions (b). During seizures, γ-aminobutyric acid A (GABA_A) receptors are internalized, and N-methyl-d-aspartic acid (NMDA) receptors accumulate in the postsynaptic membrane, resulting in loss of inhibition and increased excitation. These changes favor self-sustaining seizures and resistance to benzodiazepines [26]