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Is there a need for further trials on treatment of acute seizures?

Children with seizures experience a spectrum of events extending from isolated, brief seizures to status epilepticus (SE), incorporating a full range of recurrent unprovoked seizures and prolonged or acute repetitive seizures. Similarly, semiology varies from partial to generalized, non-convulsive to violent and continuing convulsions. This symposium has clearly discussed the early recognition and treatment of repetitive and prolonged seizures because of the deleterious effect with various degrees of morbidity and mortality. Prompt recognition and management leads to the best chance of successful outcome. Further treatment paradigms appropriate for use in out of hospital settings and in hospital are emphasized and recommended. These protocols must be well designed, and if they are appropriate, can be followed by the inexperienced and experienced, either caregivers or medical professionals. Even with emphasis of prompt treatment over the past twenty years there exists a variety of poorly executed protocols. This presentation therefore asks the question whether additional clinical trials are necessary, not only to answer for what purpose but also clearly the impact additional studies may have.

The current definition of SE has shortened from a thirty minute duration of continual recurrent seizures without recovery (ILAE 1981) to the "operational definition of five minutes or more of continuous seizures or two discrete seizures between which there is incomplete recovery of consciousness" (Lowenstein et al. 1999). The latter definition and aggressive early treatment certainly justified by experimental and clinical data have demonstrated a tenfold lower rate of mortality for seizures lasting less than thirty minutes. Furthermore, ample data suggests much improved response to first line therapies if treated earlier. The definition of SE in neonates, however, is even more controversial, as not only timing is argued but categories of electro clinical, electrographic and clinical only have been recognized (Morton and Pellock 2012).

Multiple authors have noted outcome of status epilepticus and prolonged or recurrent seizures are dependent upon age, etiology and duration of events. Infants younger than one year of age represent a subgroup of children with the highest incidence of SE, whether events, total incidents or recurrences are counted (DeLorenzo et al. 1996; Logroscino et al. 1997, Glauser et al. in press). Similarly, causes associated with SE in children are age dependent Shinnar et al. (1997) reported that more than 80% of children younger than two years of age have SE from a febrile or acute symptomatic cause. Cryptogenic or remote symptomatic causes are more common in older children. In adults sub therapeutic levels of antiepileptic drugs, remote causes and cerebrovascular disease were the three most common causes of SE (DeLorenzo et al. 1995). Thus the situation of a child developing SE will differ from neonates to adolescents. Any trial of treatment needs to consider appropriate dosing, route of administration, along with time to treatment and definition of repetitive or clusters of seizures and SE. Although difficult to evaluate treatment effects by etiology, large studies may demonstrate differences.


SE and acute repetitive seizures (clusters) represent neurologic medical emergencies. The goals of treatment are as noted in Table 1.

Most prolonged seizures occur out of hospital. Following initial emergent and supportive care and treatment of potential hypoglycemia, benzodiazepine administration represents the most favored and evidence based acute treatment for seizures. Various routes of administration exist, but intravenous is recommended when readily available. Following one or two doses of benzodiazepine, various protocols have been designed and reviewed with some organizations proposing guidelines, such as the Neurocritical Care Society and American Epilepsy Society. Following benzodiazepine administration, fosphenytoin/phenytoin and valproate are frequently recommended with some centers continuing the use of phenobarbital. Because of the complexity of studies and clinician bias, there is still argument regarding the best first and second line therapy. However most would agree that the utilization of benzodiazepine is only a first line intervention. Thus, the primary query may concern which benzodiazepine to use for first line treatment. However most would agree that the utilization of benzodiazepine is the preferred first line intervention (Rossetti and Lowenstein 2011). Thus the primary inquiry may concern which benzodiazepine to use for the first line treatment.

Before discussing whether trials could possibly determine which benzodiazepine treatment is superior, a brief review of second line therapy and trials will be discussed. During the past two decades protocols were developed in both Europe and the United States which delineated early, established and refractory stages of SE and treatment algorithms. The Veterans Administration study (Treiman et al. 1998) compared combined diazepam and phenytoin, phenytoin alone, phenobarbital and lorazepam for the treatment of SE and established the more rapid efficacy of benzodiazepine. Subsequently, protocols for refractory SE have been developed and are generally accepted, modified and adopted by different groups (Rosetti and Lowenstein 2011, Riviello et al. 2013). Second line preference for phenytoin/fosphenytoin continues but others, especially for children, have suggested valproate or phenobarbital as nearly equivalent. Third line treatment includes midozalam, propofol and levetiracetam. Pentobarbital, propofol and anesthetic agents are typically reserved for refractory or supra refractory cases (Shorvon and Ferlisi 2011, Rossetti and Lowenstein 2011). Multi-center, randomized, double blind trials were designed to determine the most effect and/or least effective treatments of established status epilepticus in a patient older than the age of two years as opposed to comparing fosphenytoin, levetiracetam and valproate. The primary outcome measure is cessation of clinical seizure activity and improving mental status without serious adverse effects or further intervention at sixty minutes after administration of study drug (Bleck et al. 2013).


Currently in the United States only the FDA approved drug recommended for treatment of break through seizures is rectal diazepam gel. The National Institute of Clinical Excellence (NICE) recommends rectal diazepam with buccal diazepam for out of hospital initial therapy for prolonged seizures in children (NICE 2012). In other countries, additional preparations are licensed. Furthermore, a number of unlicensed methods of administrating benzodiazepines have been popularized and are currently in use worldwide. Diazepam, alprazolam, clobazam, clonazepam, lorazepam and midazolam have been used through intravenous, oral, intramuscular, buccal, nasal and rectal routes. Thus there is a need for further studies evaluating initial treatment of seizure emergencies. Although there is also a need for pediatric studies of other anti-epileptic drugs, this discussion will focus on first line treatment of pediatric seizures.

This discussion highlights the issue of first line treatment for pediatric seizures.


Pre-hospital treatment with multiple benzodiazepine preparations has been demonstrated to reduce seizure activity significantly compared with seizures that remain untreated until the patient reaches the emergency department. The optimal agent for treatment of pediatric seizure emergencies remains unclear, although a recent article concluded that IV lorazepam is the expert consensus for first line treatment of prolonged seizures in children (Riviello et al. 2013). Another suggests intramuscular midazolam is superior (Silbergleit et al. 2013). Studies that specifically evaluate the pediatric population are limited, and the age range of children recruited varies. A study can recruit patients as young as 1 month of age (Fisgin et al. 2002) or use a less than 18 years old criteria (Holsti et al. 2010). The recruitment age of patients in pediatric studies has a larger role than in adult studies because of medication dosing. Children are dosed with benzodiazepines based on weight and age (DiastatR) and if the study does not account for both of these factors the results are affected.

Location of recruitment will also affect the patient population. Studies that are performed in locations such as Sub Saharan Africa will have different etiologies of prolonged seizures because of the high incidence of cerebral malaria (Malu et al. 2013). The etiology of the seizures may affect the outcome and response of patients recruited, and makes it difficult to compare studies from different regions. The availability of medications will also be based on the region the study was performed. For example, IV lorazepam is not available in France, and a first line benzodiazepine used is clonazepam (Hubert et al. 2009), but not available in the United States.

Inclusion criteria and outcome vary between studies. Seizure emergencies include acute seizures management of repetitive seizures, prolonged seizure and SE. The inclusion criteria definition can vary within each of these situations and the possibilities are too numerous to enumerate. There are primary outcome and secondary outcome measures that include time to treatment, superiority of route of administration or drug, seizure cessation and seizure recurrence. The different outcomes make comparison and analysis of multiple studies challenging.


There are numerous studies that compare the different benzodiazepines as abortive treatment in children, but the formulation of the medications used differs even when similar routes are used. Midazolam is an example of a medication that has been studied as an intranasal medication option, but some studies drip the available intravenous formulation into the nose (Bhattacharyya et al. 2006, Javadzadeh et al. 2012, Lahatet et al. 2000, Mahmoudian and Zadeh 2004, Thakker and Shanbag 2012), while others sprayed it into the nares (Fisgin et al. 2002, Holsti et al. 2010). Buccal midazolam formulations include maelade and the classic intravenous preparation. This can affect the efficacy and adversity of the treatment because different delivery preparations and systems are difficult to compare. Nevertheless, efficacy is reported.


It is difficult to compare studies when there are different routes of medications, especially when two different medications are compared. It is well accepted that the time required to administer an IV preparation in a convulsing patient can delay treatment and prolong seizure duration. For example, studies have concluded that seizure cessation was faster with diazepam, but the time to administer IV diazepam was greater than intranasal midazolam (Javadzadeh et al. 2012, Lahat et al. 2000, Mahmoudian and Zadeh 2004). Time and ability to establish IV access has led some to interosseous administration. The overall treatment effect (time to administer treatment and achieve seizure cessation) was significantly improved with intranasal midazolam when compared with IV diazepam (Bhattacharyya et al. 2006, Javadzadeh et al. 2012, Mahmoudian and Zadeh 2004, Thakker and Shanbag 2013). Comparing rectal, intranasal and IV formulations can cause confusion because of the factors that affect time to administration.

The RAMPART trial (Rapid Anticonvulsant Medication Prior to Arrival Trial), reported a double-blind randomized clinical trial to determine if the efficacy of IM midazolam is non-inferior by a margin of 10% to that of IV lorazepam in patients treated by paramedics for SE (Silbergleit et al. 2013). SE was defined as the patient actively convulsing upon EMS arrival. The study concluded patients treated with IM midazolam were more likely to have stopped seizing on arrival to the emergency department and were less likely to require any hospitalization or admission to an intensive care unit. This was a large study, included adults and pediatric patients, and concluded that IM midazolam is not less effective, but not superior. Further review of the results of the study team support "intramuscular midazolam is the best option for the prehospital treatment of status epilepticus" (Silbergleit et al. 2013).

A meta-analysis was published in 2010 to evaluate midazolam versus diazepam in children and young adults (McMullan et al. 2010). The study concluded that for seizure cessation midazolam by any route was superior to diazepam, non-IV midazolam was as effective as IV diazepam and buccal midazolam is superior to rectal diazepam for achieving seizure control. The limitation of this meta-analysis is that all studies included were relatively small and were not standardized in dose, outcomes and inclusion criteria. The results support that more studies, that are larger and standardized, are needed to determine superiority of a benzodiazepine.


Cross and colleagues recently published an intriguing paper entitled "Are we failing to provide adequate rescue medication to children at risk of prolonged convulsive seizures in schools?" They highlight current guidelines recommending immediate treatment of children to prevent progression to status epilepticus and emphasize that a more systematic response is needed to ensure that children receive rescue medication regardless of where their seizure occurs. In the United States, local regulations may allow or disallow administration of benzodiazepine. Certain cultures will find it socially difficult to administer the rectal formulation in all but the youngest of children. Furthermore, international agreement and availability of medication differs. In 2009, Hubert reported that intravenous lorazepam was not available in France. Furthermore, buccal midazolam is not licensed in the United States. Their suggestion of using intravenous clonazepam may be appropriate in some countries but this preparation is not available in the United States.

With this degree of practical concern and controversy, the academic scientist clinician must certainly request additional studies to answer which agent is the most effective and safe therapy for the management of acute seizures in children. In the UK, Chin reported that only one in every six children with SE admitted to the Pediatric Intensive Care Unit was appropriately treated using existing current guidelines. In the United States the Febrile Status Epilepticus Study (FEBSTAT) demonstrated significant diversity, not only in home therapy for those with recurrent events but by emergency services for initial treatment of SE. Furthermore, inadequate dosing was administered in a third of patients (Seinfeld et al. in press). Similar disparities are noted across the UK and Europe for the administration of rescue medications in children with prolonged acute convulsive seizures in the community (Wait et al. 2013).


A large study to determine pediatric guidelines or algorithm for the treatment of seizure clusters (ARS) and prolonged should be performed. Although it is accepted that treatment with benzodiazepine is first line and treatment should not be delayed there is none to determine optimal benzodiazepine route, dose or preparation.

There are fewer studies performed in acute pediatric seizures compared to adults. Larger pediatric studies are needed in pediatric seizure emergencies to determine first line treatment and subsequent treatment. There is mounting evidence that supports multiple safe and effective alternative routes of benzodiazepine administration for rapid treatment of seizure emergencies in children. These studies must carefully define definition for treatments, appropriate dosing, age and etiology of subjects, clearer outcome criteria (clinical, electrographic, or both), tolerability, and safety. Our belief is that there may be no single agent or method of administration optimal for all patients. Different age groups and personal preference of patient or caregiver will determine the "best" preparation for that individual. Nevertheless, studies would tell us if various compounds were comparable in their efficacy and/or time to effectiveness. Certainly other factors will be important.

So, do we need further studies? YES! Will this be easy to accomplish? No!

Our advice is to proceed with caution using large consortia with well-defined study criteria and end points. We all strive to provide the best and most efficient treatment of potential seizure emergencies in children. Perhaps the greatest need for studies is to establish the acceptance of these therapies among those treating children. These investigations require the interaction of social scientists with medical professionals and lay organizations to establish best practices.

Overall, the acute treatment of epilepsy emergencies in children has markedly improved with availability of out of hospital therapies. Additional studies to determine the most efficacious maximally safe, and best tolerated treatments are needed. W must also learn from those receiving and administering these treatments to optimize treatment for children of various ages an differing requirements. Still, we have unmet needs.

Reprinted with Permission: Pellock JM, Seinfeld S. Is there a nee< for further trials for the treatment of acute seizures? Epileptic Disord. 2014; Vol. 16, Supplement 1 (


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John M. Pellock, MD is Professor and Chairman, Division of Child Neurology at the Children's Hospital of Richmond, Virginia Commonwealth University/ Medical College of Virginia Hospitals, Richmond, Virginia.

Syndi Seinfeld, DO is Assistant Professor, Child Neurology at the Children's Hospital of Richmond, Virginia Commonwealth University/Medical College of Virginia Hospitals, Richmond, Virginia.


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Author:Pellock, John M.; Seinfeld, Syndi
Publication:The Exceptional Parent
Article Type:Essay
Geographic Code:1USA
Date:Aug 1, 2014
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