Rationale:
Seizure clusters may last up to 24 hours and typically occur in the community setting, with 24% of patients lacking available rescue treatment reported to require paramedic or emergency-room care. In one study, rescue therapy was estimated to reduce need for emergency-room treatment by more than half. Approved outpatient treatments have differing profiles that may affect multiple aspects of healthcare utilization. The proportions of treated seizure clusters that require a second dose and the impact of the need for second doses on healthcare burden and utilization are summarized.
Method:
Large, long-term, open-label studies of approved seizure-cluster treatments designed for use by nonmedical caregivers were reviewed. Percentage of clusters controlled by the initial dose was compared with those requiring a second dose before 6 or 12 hours. Available data on hospitalizations after a second dose also were collected.
Results:
The identified studies were for use of diazepam rectal gel, intranasal midazolam, and diazepam nasal spray (Table). In the study of rectal diazepam, which reported seizure control for up to 12 hours after treatment but did not provide for second doses in the study design, 77% of administrations (1215/1578) prevented further seizures. In the study of intranasal midazolam, which measured seizure control for 10 minutes to 6 hours after treatment, 55.5% (1108/1998 seizure cluster episodes) of seizures were successfully treated in that timeframe, and a second dose was not administered in 61.5% of seizure episodes (1226/1998). The study of diazepam nasal spray found that no second dose was administered in 93.8% (3160/3370) of seizure episodes within 6 hours of the first dose and 91.2% (3074/3370) within 12 hours, as of the October 2019 data cut; if needed, second doses were to be given 4 to 12 hours after the initial dose per instructions in the protocol.
In the diazepam rectal gel study, 16 of the 363 seizure clusters were subsequently treated in the emergency department. In the intranasal midazolam study, 4 patients each had 1 serious adverse event (SAE) categorized as possibly (unlikely) treatment-related (convulsion, status epilepticus, dysesthesia, and upper gastrointestinal hemorrhage); possible association with a second dose was not reported. In the diazepam nasal spray study, no SAEs were considered treatment related; 3 SAEs occurred the day of/day after a second dose (increased seizures, 2; status epilepticus, 1). None required a dose change, and all resolved.
Conclusion:
Beyond the initial dose of treatment of seizure clusters, healthcare utilization may include a second dose and even hospitalization. Across these noncomparative open-label studies, need for a second dose ranged from < 10% to < 40% at 6 and 12 hours. Differences among approved therapies and routes of administration appear to have the potential to impact healthcare burden and should be considered when selecting rescue therapy for treatment of seizure clusters.
Funding:
:Neurelis, Inc.
FIGURES
Figure 1