Intranasal Midazolam is Rapidly Effective in Status Epilepticus

Lara Kay, MD

Recent pharmacologic-electroencephalogram (EEG) study data suggest that intranasal midazolam (Nayzilam; UCB) is both effective and well-tolerated in the acute treatment of status epilepticus.

During continuous EEG observation, the clinical and EEG effects of treatment with a 5-mg dose (range, 2.5—15; mean, 6.4) were observed within 5:05 minutes (median, 4:56; range, 0:29–14:53) and 4:07 minutes (median, 3:50; range, 2:20–5:40), respectively. As such, the investigators, led by Lara Kay, MD, department of neurology and LOEWE Center for Personalized Translational Epilepsy Research, Goethe University of Frankfurt, noted that the treatment is easily applicable and rapidly effective as an option in place of buccal and intramuscular administrations as first-line treatment if an intravenous (IV) route is not available.

“Our results are consistent with the Prehospital Treatment of Status Epilepticus (PHTSE) trial findings, which revealed efficacy rates of 59.1% for intravenous lorazepam and 42.6% for intravenous diazepam, as well as with the RAMPART study, which presented efficacy rates of 63.4% for intravenous lorazepam and 73.4% for intramuscular midazolam,” Kay and colleagues wrote.

The study included 42 adults (mean age, 52.7 ±22.7 years), with 55.8% (n = 24) experiencing nonconvulsive status epilepticus. Half of the patients (n = 21) had been diagnosed with a remote‐symptomatic, or structural, cause of their status epilepticus, while 16.7% of patients (n = 7) had an acute symptomatic cause. The remaining 33.3% (n = 14) of patients had unknown etiology due to nonstructural epilepsy or progressive disease. At admission, 42.9% of patients (n = 18) were not taking any antiepileptic drugs. The mean number of antiepileptic therapies was 1.3 (range, 0—3) with 9.5% (n = 4) on monotherapy and 47.6% (n = 20) on polytherapy. Levetiracetam (n = 15), lamotrigine (n = 8), valproate (n = 6), brivaracetam (n = 6) and lacosamide (n = 4) were the 5 mainly used. The 23.8% (n = 10) of patients on antiepileptic drugs reduced their intake during video‐EEG‐monitoring prior to status epilepticus onset.

Overall, 57.1% (n = 24) were responders, with status epilepticus episodes halting without the administration of any other therapies but intranasal midazolam.

In addition to the aforementioned 4:07-minute ß-band increase visible on EEG in 10 of 24 patients, this increase did not differ between responders (n = 6) and nonresponders (n = 4). The increase began approximately 4:30 minutes after application, plateaued for roughly 3 minutes to 7:30 minutes, then diminished back to baseline within 2 minutes.

“The strength of our analysis is the investigation of [intranasal midazolam] under continuous EEG monitoring, which allowed for not only the exact determination of time to [status epilepticus] control but also of the occurrence of ß‐band increase as an early surrogate marker for midazolam brain entry time,” Kay and colleagues wrote.

Adverse events were recorded in 14.3% (n = 6) of patients, with nasal irritations present in 11.9% (n = 5) and prolonged sedation occurring in 2.6% (n =1).

“Our study provides important findings for everyday clinical practice, as different studies have shown that non-intravenous benzodiazepines can be applied faster in comparison with intravenous solutions,” Kay and coinvestigators detailed. “The rapid application of anticonvulsants is crucial for the treatment of status epilepticus, as the drug effectiveness is inversely proportional to the seizure duration. Especially considering the time taken to prepare the intravenous solution or an intravenous line, the administration of intranasal midazolam may prevent treatment delay, which is an important risk factor in the context of a refractory status epilepticus.”

Intranasal midazolam was approved by the FDA for seizure clusters in May 2019. The benzodiazepine, which is is supplied as 2 single-use nasal spray units, each containing a 5-mg dose of midazolam in 0.1 mL solution, can be administered in the outpatient setting by a non-healthcare professional in patients actively seizing and where a seizure cluster occurs.

REFERENCE

Kay L, Merkel N, von Blomberg A, et al. Intranasal midazolam as first‐line in-hospital treatment for status epilepticus: a pharmaco‐EEG cohort study. Annals Clin Trans Neurol. Published online November 4, 2019. doi: 10.1002/acn3.50932.