Seizure Clusters: Current Concepts in Definition and Treatment

Seizure clusters (SCs) are an acute and transient increase in seizure frequency relative to an individual patient's baseline and are associated with an increased risk of injury, morbidity, and potentially mortality if not promptly and adequately treated. Despite their clinical importance, the management of SCs remains highly heterogeneous, primarily due to the absence of a universally accepted definition, which is determined also by the wide variability in seizure semiology and baseline individual burden;, as well as by differences in care settings. Outpatient treatment relies largely on caregivers' ability to recognize SCs and administer rescue medication, whereas inpatient management may also involve invasive routes of administration. We conducted a literature review identifying 32 original articles addressing the treatment of SCs. The analysis focused on definitions, efficacy outcomes, and adverse events across three clinical scenarios: outpatient, Emergency Department (EDs) and Epilepsy Monitoring Units. The results show that in the outpatient setting, the available evidence suggests that diazepam nasal spray (DZP-NS), midazolam nasal spray (MDZ-NS), and oral lorazepam (LZP) solution may demonstrate comparable efficacy and safety. However, comparisons are limited by heterogeneity in studies' designs, patient populations and outcome definitions, as well as by the absence of head-to-head trials. Moreover, geographic differences in drug availability (e.g., USA vs. Europe) limit the development of universally applicable treatment protocols. Consequently, the off-label use of oral benzodiazepines, including clobazam, clonazepam, and lorazepam, remains common when oral therapy is feasible, despite limited evidence. The implementation of a patient-specific Acute Seizure Action Plan (ASAP) incorporating an individualized SC definition is recommended. In contrast, inpatient management shows greater consensus, largely reflecting first-line treatment paradigms for status epilepticus. These include prompt intravenous benzodiazepine administration, followed by the intravenous loading of antiseizure medications such as brivaracetam or lacosamide in cases of seizure recurrence. In ED settings, "empirical" definitions of SCs (i.e., more than three seizures within 24 h) may facilitate timely intervention.