The illustrious Cardinal Commendoni suffered sixty epileptic paroxysms in the space of 24 hours, under which nature being debilitated and oppress'd he at leangth sank, and died. His skull being immediately taken off, I found his brain affected with a disorder of the hydrocephalous kind. -Gavassetti, 1586
The state of Status Epilepticus (SE) is one which evokes an almost visceral response of urgency. The physical manifestations of a mind in crisis are if nothing else, strong motivators to action. We are trained to act with decisiveness and certainty, yet due to a paucity of high quality trials, an ever-changing definitional diagnosis, and the utilizations of surrogate endpoints in place of true evidence of benefit, our understanding of the management of status epilepticus is been severely constrained.
In a recent article published in JAMA, Chamberlain et al examined the efficacy of diazepam vs lorazepam in the treatment of status epilepticus in a pediatric population (1). The authors randomized 273 children, ranging from 3 months to 18 years old, experiencing an episode of status (defined as 5 minutes or longer of seizure activity or multiple seizures without a return to baseline) to receive either 0.2 mg/kg of diazepam or 0.1 mg/kg of lorazepam IV. Though the authors found no significant difference in their primary or secondary endpoints (seizure cessation within 10 minutes, rate of recurrence and time-to-seizure-cessation), certain limitations make it difficult to interpret the utility of this publication.
The authors enrolled patients with at least 5 minutes of seizure activity who had not received any anti-epileptic drugs (AEDs) en route to the hospital. This exclusionary criteria obviously affected their enrollment as over a 4-year period out of the 11,630 patients assessed for eligibility, only 273 patients were enrolled in the trial. 4,357 were excluded for no longer seizing upon arrival to the ED and 6,729 for other factors, presumably a large proportion receiving AED treatment before arriving to the hospital. Obviously this injures the trial’s external validity, as the child seizing upon presentation to the emergency department who has received AED treatments en route is a different and far more commonly encountered patient than one who has yet to receive any intervention. Thus the spectrum of disease encountered in this cohort is far less severe than in previous trials examining SE.
In fact this is only the last of many changes in enrollment criteria for patients involved in trials examining the various treatments for SE. The definition of status itself is continually in flux. In 1993 the American Epilepsy Society Working Group on Status Epilepticus defined status as “a seizure lasting 30 minutes or the occurrence of two or more seizures without recovery of consciousness in between” (2). Since this statement the temporal requirement to be considered SE has become progressively more lax. The Epilepsy Society Working Group subsequently lowered the time requirement to 20 minutes. In 1998 the Veterans Affairs Status Epilepticus Cooperation (VASEC) published a study comparing various treatment options for SE (3). Their enrollment criteria defined SE as 10 minutes of continuous seizure activity or multiple seizures without a return to baseline in between. That same year Lowenstein et al published an article in the NEJM reviewing the etiology of SE and recommended the definition of status be changed to continuous seizures lasting no more than 5 minutes (4). In 2001 the San Francisco Emergency Medical Services published the Pre-Hospital Treatment of Status Epilepticus (PHTSE) Trial, comparing pre-hospital efficacy of diazepam, lorazepam and placebo. The authors adopted Dr. Lowenstein’s suggestion, enrolling patients with seizure activity greater than 5 minutes (5). Since then, the majority of publications examining SE have used this 5 minute definition. Though the argument proposed by Dr. Lowenstein, that most seizures lasting more than 5 minutes require treatment is a valid one, the inclusion of these patients in the same category as those with continuous seizures for greater than 30 minutes seems misconstrued. In fact if you examine mortality in the Veterans study compared to that of the PHTSE cohort the 30-day mortality of patients fell from 37% to 9.2% (3,5). Clearly the acuity of the patients included in these respective cohorts is significantly different.
The second limitation seen both in the Chamberlain trial and throughout the recent SE literature is the belief that time-to-seizure-cessation is a clinically relevant endpoint. Though there is relatively robust data describing the association between seizure length and poor outcomes (3,4), the converse statement, that chemically shortening seizure length will in turn improve outcomes, is inherently flawed. In the PHTSE Trial, upon arrival to the hospital, 21% of patients' seizures terminated in the placebo group compared to 42.6% and 59.1% in the diazepam and lorazepam groups respectively(5). Despite the obvious clinical efficacy of both these medications in time-to-seizure-cessation, there were no statistical difference in mortality or functional neurological outcomes observed between the active or control groups. Likewise in the VASEC trial, the authors found lorazepam to be more efficacious than the other treatment strategies in stopping the seizures in a timely manner. Despite this superiority in time-to-seizure-cessation no mortality benefit was observed (3). They did find that those who were resistant to the first and second line agents were far more likely to have malignant cause of their SE. Clearly the underlying disease process that results in refractory status is the cause of the bad outcomes.
The only seemingly clinically relevant endpoint included in the Chamberlain publication was the rate of ventilatory support (defined as need for bag-valve-mask ventilation or endotracheal intubation) required in each group. This too was statistically equivalent. 16% and 17.6% of patients required some form of ventilatory assistance in either group (1). A similar number of patients required ventilatory assistance in the VASEC, PHTSE and RAMPART cohorts (3,5,6). In fact if you examine the respective groups in the PHTSE cohort the need for intubation did not differ whether the patients received lorazepam, diazepam or placebo (5), indicating that it is again the underlying pathology rather than the medical intervention that causes the subsequent airway compromise.
Our continued vacillations in the definition of SE have led to a much more benign disease process than the status of our forefathers. The acuity of the patients included in trials examining treatments for SE has been progressively decreasing over the past 15 years. In Chamberlain et al, 33% of the populations’ seizures were febrile in nature, which often require no further treatment. Compare that to the VASEC cohort where 33% had a life threatening cause of their SE. Given this dilution, identifying benefit for any treatment in a modern day SE cohort suffers from a significant Pollyanna effect. Additionally our persistent assumption that time-to-seizure-cessation is a clinically relevant endpoint further obscures our understanding of any true treatment effect our various interventions may provide.
Chamberlain et al demonstrated that with today’s broad spectrum of status the choice of your first line benzodiazepine matters very little. Whether this is because of the equal efficacy of the various medications or the fact that in most cases the seizures will resolve no matter what treatment is given. Without a true placebo group it is hard to say. What is clear is the underlying cause of the seizures is far more important than your choice of medication. Those who are resistant to your first and second line treatments are far more likely to track their lineage from the status of old, and have a malignant cause that should be pursued.
1.Chamberlain et al. Lorazepam vs Diazepam for Pediatric Status Epilepticus: A Randomized Clinical Trial. JAMA. 2014;311(16):1652-1660.
2. Brodie MJ Status epilepticus in adults. Lancet. 1990 Sep 1; 336(8714):551-2.
3. VA Status Epilepticus Cooperative Study Group: A comparison of four treatments for generalized convulsive status epilepticus. N Engl J Med 1998;339: 792–798
4. Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med. 1998; 338:970-976.
5. Alldredge BK, Gelb AM, Isaacs SM, et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N Engl J Med 2001;345:631-7
6. Silbergleit R, Durkalski V, Lowenstein D, Conwit R, Pancioli A, Palesch Y, Barsan W; NETT Investigators. Intramuscular versus Intravenous Therapy for Prehospital Status Epilepticus. N Engl J Med. 2012 Feb 16;366(7):591-600.