Study Selection and Characteristics Of Included Studies

The screening of 185 articles identified via two databases (Embase and Medline) yielded 12 studies (including one study [17] identified during a detailed review process) with a total of 929 patients (without rigorous stratification by age group) treated with in-MDZ that addressed aspects of efficacy and tolerability of in-MDZ application for antiseizure treatment in adults (Fig. 1).

Fig. 1

Study flow diagram. *These seven articles have been added, of which three had to be excluded because they only included healthy study participants

Most of the included studies (66.7%) were published after 2018 [17,18,19,20,21,22,23,24]. The only two randomized trials [18, 19] were multicentric (with their main site in the United States) and accounted for 22.1% of the overall patient cohort with a total of 205 patients who received in-MDZ (Table 1). The remaining ten cohort studies, except for the study by Wheless et al. [20], were all monocentric and mostly retrospective. Among all retrospective studies, the majority were conducted in Germany, followed by other European countries (Netherlands and Switzerland), North America, and Australia (Fig. 2).

Table 1 Characteristics of the included studies with patients with status epilepticus, epileptic seizure, or known epilepsyFig. 2

Included studies according to country of origin and over time. The geographical distribution refers to the country of the main site (as indicated by the host institution of the corresponding author). The point size corresponds to the number of studies. The Khartis software (Sciences Po Cartography Laboratory, 2017) was used to create the visualizations

Successful treatment was mainly defined clinically as suppressed seizure activity within 10 to 15 min [18, 20, 22, 25]. The exception was two studies [17, 26] that did not explicitly define what was considered a successful treatment response (in some studies, successful treatment implied a subsequent absence of seizures for 2 to 6 h [18, 20, 25]). For seizure recurrence, the majority of studies applied a time frame of 6 h [17,18,19,20] and/or 24 h [17, 24, 27], with one study confining recurrence to a very early recurrence (within 1 h after first application) [28]. Data on seizure termination and recurrence after the first administration of in-MDZ were available for 8 of 12 studies (66.7%) (Table 1).

The in-MDZ doses administered mostly ranged from 2.5 to 10 mg per single dose [17,18,19,20,21,22, 24,25,26,27,28], with weight-adapted dosing reported in only one study [23] and an allowed maximum dose of 20 mg. Repetitive doses were permitted explicitly in five studies [17, 18, 20, 22, 23, 26]; in the remaining studies, repetitive administration was not permitted or specified.

Of a total of 12 included studies, two studies compared the efficacy of in-MDZ administration for seizure termination with placebo [18, 19], two studies compared the efficacy of in-MDZ administration versus no in-MDZ application within the same individuals [24, 27], and four studies compared the efficacy of in-MDZ administration with other administration routes and/or other benzodiazepines (rectal diazepam [25], intranasal diazepam [22], different regimens [intravenous midazolam, intramuscular midazolam, rectal, intravenous, or intramuscular diazepam] [23], and intravenous lorazepam [17]). One study had a comparator that was not further specified (mentioned as “previously used alternative emergency medication” [28]), and the remaining three studies [20, 21, 26] had no comparator.

Efficacy of in-MDZ Administration for Antiseizure Treatment In Adults

A mean of 72.7% seizures stopped after the first administration of in-MDZ, with a standard deviation (SD) of 18% (Fig. 3). This compares to various other treatments: 70% success with placebo in one randomized study [18], 89–100% with rectal diazepam in two studies [23, 25], 63% with intranasal diazepam [22], and 57% with intravenous midazolam [23]. The highest success rate with in-MDZ was observed in studies in which a dose of 10 mg was administered or at least recommended [25, 26]. After the first in-MDZ treatment, seizures recurred in 36.5% of cases (SD 15.9%). For other treatments, recurrence rates were 61–63% with placebo [18], 60–75% without midazolam [24, 27], 0–9.5% with rectal diazepam [23, 25], and 43% with intravenous midazolam [23].

Fig. 3

Successful seizure termination and reported side effects related to intranasal midazolam administration. *Mean value. **Percentages based only on one available study for each comparator. #Total number of patients treated with available data on successful seizure termination (no stratification by age group possible due to lack of information). IN-DZP intranasal diazepam, IN-MDZ intranasal midazolam, IV-MDZ intravenous midazolam

Tolerability of Intranasal Midazolam Administration for Antiseizure Treatment in Adults

Nine of 12 (75%) studies reported side effects in detail. The most commonly reported adverse events after in-MDZ administration were dizziness (three studies [20, 22, 25]; mean 23.5% [SD 38.6%]), confusion (one study [17]; 17.4%), local irritation (eight studies [18,19,20,21,22, 24, 25, 27]; mean 16.6% [SD 9.6%]), sedation (eight studies [17,18,19,20,21,22, 24, 25]; mean 12.7% [SD 9.7%]), and respiratory difficulties (three studies [17, 24, 27]; mean 5.7% [SD 9.8%]; Fig. 3). Less common adverse events included nausea (three studies [19, 20, 24]; mean 4.9% [SD 4.1%]), abnormal product taste (three studies [18,19,20]; mean 4% [SD 2.2%]), suicidal ideation (one study [19]; 3.6%), headache (six studies [18,19,20, 22, 24, 25]; mean 2.6% [SD 2.7%]), convulsions (one study [20]; 3%), and restlessness (one study [25]; 2%). In the two studies with (administered or at least recommended) a higher in-MDZ dose (10 mg), there was no excess of respiratory depression reported [25, 26]. However, in one of the two studies, which reported adverse effects in detail, a relatively high proportion of patients reported drowsiness (two of three study participants) [25]. In addition, one study [17] reporte