Journal Identification = EPD Article Identification = 0687 Date: October 28, 2014 Time: 3:21 pm Prolonged Epileptic Seizures: identification and treatment Epileptic Disord 2014; 16 (Suppl. 1): S44-S49 Overview of clinical efficacy and risk data of benzodiazepines for prolonged seizures Lieven Lagae Department of Development and Regeneration, Section Paediatric Neurology, University Hospitals KULeuven, Leuven, Belgium ABSTRACT – An historical overview is provided regarding the use of ben- zodiazepines for the treatment of acute prolonged convulsive seizures. It is clear that intravenous benzodiazepines remain a first step for the in- hospital treatment of prolonged seizures or status epilepticus. However, in the community, in a pre-hospital situation, intravenous administration is not possible. In recent years, it was shown that rectal, buccal, intranasal, and intramuscular administration of benzodiazepines is very effective as a first and safe treatment step. In many cases, rectal diazepam is not socially acceptable anymore, and therefore more emphasis is now put on buccal, intranasal, and intramuscular administration. At present, based on the avail- able data, midazolam is the product of choice for the acute treatment of prolonged convulsive seizures. Key words: epilepsy, acute prolonged seizures, benzodiazepine, midazo- lam, diazepam, status epilepticus The risks of acute and especially data from the FEBSTAT study indi- prolonged convulsive seizures are cate that a prolonged febrile seizure now well established. Apart from can entail MRI-visible changes in possible secondary injuries (e.g. about 10% of the children scanned head trauma, drowning, and burn- within 72 hours of their seizure (see ing), prolonged seizures can induce also Van Landingham et al. [1998]). significant medical emergencies Some of these children will go on to such as cardiac arrhythmias, lung develop mesial temporal sclerosis congestion, liver failure, and rhab- and concurrent refractory temporal Correspondence: domyolysis (Jovic et al., 2011; lobe epilepsy (Shinnar et al., 2012; doi:10.1684/epd.2014.0687 Lieven Lagae Department of Development Kravljanac et al., 2011; Varelas et al., Harden, 2013; Yoong et al., 2013). By and Regeneration, 2013). Increased seizure duration is definition, a prolonged convulsive Section Paediatric Neurology, associated with increased morbid- seizure is the start of an imminent University Hospitals KULeuven, ity.The effects of prolonged seizures status epilepticus and appropriate Herestraat 49, 3000 Leuven, Belgium on the epileptogenic process is still action to stop the seizure is there- <[email protected]> a matter of debate, but preliminary fore warranted. It is reassuring to see S44 Epileptic Disord, Vol. 16, Supplement 1, October 2014 Journal Identification = EPD Article Identification = 0687 Date: October 28, 2014 Time: 3:21 pm Clinical efficacy of BZP for prolonged seizures that many doctors now include an acute seizure treat- More than 50% of all patients were known to have ment protocol in their overall epilepsy treatment plan epilepsy and one of the most frequent causes (in (Lagae, 2011; Wait et al., 2013). Until recently, acute overall around 20%) of their status epilepticus was treatment was still reserved for a medical setting, a chronic antiepileptic drug level in the blood that such as an ambulance or the emergency department. was too low, probably illustrating the well known, Since a critical turning point for developing status but underestimated, low treatment compliance in epilepticus is at around 5-10 minutes of seizure activ- epilepsy.In the three groups, it took around 16 minutes ity, initial action in a medical setting might already to get to the emergency department. In the lorazepam be too late (Shinnar et al., 2001). Smith et al. (1996) and DZP groups, the status epilepticus was terminated showed that 80% of the seizures lasting for more than in 59.1 and 42.6%, respectively. In the placebo group, five minutes will continue for >30 minutes. There- spontaneous cessation was observed in only 21.1%. fore, attention has shifted towards “pre-hospital” and Although this difference between active treatment and “community-based” treatment options. This implies placebo is very clear, one should not ignore that a large that a first-treatment action could also be administered group continued to have a status epilepticus even after by non-medically trained people, such as parents, BZP treatment. One of the most likely explanations teachers, or a partner of the patient. It is very clear is the delayed administration of adequate rescue from the community-based study of Chin et al. (2008) drugs, again a strong argument to start treatment in that pre-hospital treatment significantly reduces the the community, before the arrival of medically trained duration of status epilepticus. personnel. Further analysis showed that lorazepam This first step in the treatment of a convulsing patient was significantly more effective than DZP. This find- should therefore be effective, simple, and safe. In this ing represented the start to promote intravenous review,we will therefore focus on the benzodiazepines lorazepam as the first step in the majority of treatment (BZP), as these are the most potent and direct-acting protocols of status epilepticus. The study also demon- drugs to stop an ongoing seizure. In particular, we strates the high morbidity of status epilepticus; 47.8% will discuss the non-intravenous use of BZP, as these (DZP group), 56.9% (LZP group), and 63% (placebo are the possible drug formulations for treatment in group) of patients had to be admitted to intensive pre-medical community settings. The mechanism of care for further diagnosis and treatment. Neurological BZP is well known; BZP activate the GABA-A receptor, deficits at hospital discharge were observed in around thereby inducing a hyperpolarisation with a decrease 16%. Perhaps even more illustrative were the mortality of excitability (for a detailed review on BZP mechanism data; in the LZP and DZP groups, this was 7.7 and and GABA receptors, see, for instance, Galanopoulou 4.5%, respectively, but as high as 15.7% in the placebo [2008] and Sankar [2012]). group. The gold standard: Influential non-intravenous BZP studies intravenous benzodiazepines Probably, the first study using rectal DZP for the treat- The study of Alldredge et al. (2001) is a pivotal study ment of acute seizures was published in 1979 by that illustrates the efficacy of intravenous BZP in Knudsen (1979). Rectal DZP (<3 years: 5-7.5 mg; >3 status epilepticus. In this study, 258 adults with a status years: 7.5-10 mg) was given to 44 children with 59 epilepticus were randomly assigned to three treatment seizure episodes. Children were between six months groups: lorazepam (2 mg), diazepam (DZP) (5 mg), and five years and all seizures were generalised convul- or placebo. This pre-hospital treatment was given by sive seizures. Of the 59 seizures, 35 were febrile trained ambulance personnel. In about 30% of the two seizures. With regards to febrile and non-febrile active study groups, a second similar dose of the study seizures, the results were the same, and 80% of the drug was given. This was similarly performed for 50% treated seizures (43/54) stopped within 5 minutes. of the placebo group. One of the primary outcome Another 7/54 of the seizures stopped after subsequent parameters was the cessation of the status epilepticus intravenous administration of DZP. A post hoc analysis upon arrival at the emergency department of the showed that earlier administration of rectal DZP was hospital. In both active treatment groups (lorazepam associated with a higher chance of success; if given and DZP), the mean duration of the prolonged seizure before 15 minutes of seizure duration, seizures were was around 30 minutes (lorazepam: 34±17.8 minutes; stopped in 96%. Later treatment (>15 minutes) was DZP: 31.3±14.5 minutes; placebo 46.7±38.8 minutes), successful in 57%, which is indeed comparable to the indicating that indeed the majority of patients data reported in the Alldredge study. In the Knudsen suffered from a status epilepticus, if one accepts the study, the rectal DZP administration did not cause any 30-minute-duration definition of status epilepticus. significant respiratory depression. Epileptic Disord, Vol. 16, Supplement 1, October 2014 S45 Journal Identification = EPD Article Identification = 0687 Date: October 28, 2014 Time: 3:21 pm L. Lagae Respiratory depression clearly is the most important The study of McIntyre et al. (2005) examined in more possible side effect to deal with, but, as was already detail, and in a larger patient group, the efficacy of shown in this DZP study, it should not be over- buccal MDZ versus rectal DZP; 109 prolonged seizure emphasized. In this respect, the study of Chin et al. episodes were treated with buccal MDZ and 110 with (2008) clearly showed that respiratory depression can rectal DZP. In this study, the time to stop the seizures be observed only after two or more dosages of BZP. was significantly shorter for buccal MDZ (median: 8 This was also confirmed in a recent study by Spatola et minutes; range: 5-20) than for rectal DZP (median: 15 al. (2013). Therefore, when necessary, it is advocated to minutes; range: 5-31 minutes; p=0.01). In the MDZ give a second dosage of BZP, but under medical super- group, 65% of the seizures stopped within 10 minutes, vision and best in a setting where respiratory support whereas this was the case in 41% of the DZP group. can be given. This difference in efficacy is also reflected in another The study of Dreifuss et al. (1998), albeit using a outcome parameter; whereas subsequent intravenous different study design and outcome parameters, basi- lorazepam was required in 33% of the MDZ group, it cally confirms the Knudsen study.In the Dreifuss study, was required in 57% of the DZP group. In addition, this feasibility of rectal DZP gel for prolonged seizures in a study also investigated how many seizures recurred home-based setting was studied.