You do not have to be an Emergency Physician for very long before you encounter your first case of status epilepticus. You are taught early in your career of the well known pathway of how to treat status. Thankfully most cases of status do not progress further down this pathway than your initial intervention. For the further you go, the darker it becomes, and thus more uncertainty is present. Maybe the pathway is taught in such a standardized manner to waylay our fears as our attempts to treat our patient fail and despite our best efforts the patient continues to convulse in front of us.
I will forego discussing the various definitions of status epilepticus as they are multiple and ever changing. That being said, it is commonly accepted that is the longer a seizure lasts the more detrimental effects it has on the patient (2). This has led to the assumption that if longer seizures are worse, ending the seizure early must be of some benefit to the patient. From this assumption it is easy to take the logical leap that any medical interventions which have the capability of terminating a seizure will also reduce the damage the seizure would have caused to the patient.
What this extrapolation has created in the medical literature is the “door to balloon time” of seizure medication. All the studies have focused on how quickly a seizure medication will end an episode and yet very few actually examine if the patient gains any clinically relevant benefits, such as decreased mortality or improved neurological outcomes. What is unknown, or never really explored, is if the length of an episode of status is the causative factor of the damage or rather just a symptom of a serious underlying pathology.
Excuse my graphic analogy but if a treatment protocol was proposed in which the first intervention was to shoot every seizure patient in the head with 3 rounds from a 9mm handgun I am sure this would produce the fastest intervention to seizure cessation outcomes. Everyone would agree the side effect, specifically death, from such an intervention would greatly outweigh the benefits. In the following review we will discuss the various options for treating status epilepticus and their relative efficacy. We will try to determine if the length of a seizure and its resistance to our medical interventions is a marker of poor prognosis or a variable we can truly intervene on.
There is a long and colorful history when it comes to the drugs which have been used to treat status. It was even proposed by a group of neurologists out of the Sunland Training Center in Florida that intravenous urea (Urevert) at a dose of 1.5 g/kg would terminate a bout of status. In 1956 phenytoin was first proposed in published case reports as a useful treatment alternative and a few years later in 1961 benzodiazepines were introduced. Chlordiazepoxide (Librium) was the first to be licensed in 1960 and this was followed by diazepam (Valium) in 1963. (10)
Most of the early literature on the efficacy of these various interventions suffers from the same flaws. They are dominated by case reports and randomized control trials too underpowered to deem any useful information from. It wasn’t until 1998, when a large RCT comparing 4 different treatment protocols was published, that we had some concrete information.
In September of 1998 the New England Journal of Medicine published an article by Treiman et al titled “A COMPARISON OF FOUR TREATMENTS FOR GENERALIZED CONVULSIVE STATUS EPILEPTICUS.”
This article compared the treatment efficacy between phenobarbital, phenytoin, diazepam plus phenytoin, and lorazepam. The study was a double blind randomized trial and examined the efficacy of these treatments in both overt status as well as subtle status. Treatment was considered successful if all clinical and electrical evidence of seizure activity stopped within 20 minutes after the start of the infusion, and did not recur during the period from 20 to 60 minutes after the start of treatment.
570 patients were enrolled (395 with overt status epilepticus and 175 with subtle status epilepticus) in this study. Overall lorazepam was the most effective in time to cessation of the 4 treatment protocols(though that difference only became statistically significant when comparing it to the phenytoin treatment arm) followed by phenobarbital, diazepam plus phenytoin and finally phenytoin alone. Interestingly all 4 treatments were far more effective in overt status then in subtle status.
Although there were clinically significant differences in time to cessation of seizure there were no significant differences in mortality or neurological outcome between the 4 treatment groups. This brings up the obvious question, “Is time to cessation of seizure really a clinically relevant question?”
Mortality rates were 27% for patients with overt status and 64.7% for patients with subtle status irrespective of what treatment group they were part of. Pt’s who were controlled by the initial treatment fared much better than those that required a rescue medication, but it is unclear whether this was due to stopping the seizure or the severity of the patients underlying illness.
In 2001 the first large RCT comparing lorazepam, diazepam, or placebo was published(4). In this study patients with status (seizure lasting greater than 5 minutes), were randomized to either lorazepam, diazepam or placebo injections during transport to the hospital. Upon arrival to the ED all patients received treatment, at the discretion of each individual physician. It is not a true comparison between treatment and no treatment, but it does address the theory as to whether early cessation of a seizure is a clinically relevant measure. Unfortunately only 206 people total were enrolled in this study, which divided into 3 study groups, leaves the study severely underpowered to truly examine the clinically relevant question we desire. We are able to extract some interesting inferences from the results.
As you would expect both the lorazepam group and the diazepam grouped fared far better than the placebo group when comparing the primary outcome (percent of patients whose seizure stopped before arrival to the hospital). 21% of status stopped with placebo injection, while lorazepam and diazepam stopped 59.1% and 42.6% of cases respectively.
The study reveals no statistically significant difference in mortality between the 3 groups, but it does seem there is a clinical difference. The mortality in the lorazepam, diazepam, and placebo groups were 5 (7.7%), 3 (4.5%), 11 (15.7%) respectively. Obviously there is a difference between the placebo and the two active groups. Though the group that fared the best was the diazepam group, which by time to seizure cessation standard did not perform the best. As for neurological deficits, there were no trends towards benefit. 16.9%, 17.9%, 14.3% of each group suffered some permanent neurological deficits respectively.
Even though lorazepam stopped the seizure by the time of arrival to hospital 16.5% more frequently than diazepam, this did not translate into any mortality or neurological benefits. We continue to investigate the relationship between time to cessation and clinically relevant outcomes.
The third large high quality trial on AEDs in status epilepticus was published in February of 2012. In this study intramuscular midazolam is compared to IV lorazepam in pre-hospital treatment of status. Unfortunately in this study, the researchers have wholeheartedly embraced the “needle-to-cessation of seizure time” as a marker of a medication’s success and fail to provide us with any patient oriented outcomes (death, neurological deficits). As such we are unable to draw any conclusions other than IM midazolam can be used just as effectively as IV benzodiazepines when using needle-to-cessation time as your benchmark.
To sum up what we have learned so far, benzodiazepines in general (and lorazepam specifically) perform the best when using the time-to-cessation benchmark. No first line seizure medication has proven to have superior efficacy when looking at mortality or neurological deficits. Finally the meta-analysis done by Kameshwar et al in 2007 published in the British Journal of Clinical Pharmacology was unable to find a mortality benefit between any of the treatment options when combining all the trials looking at this topic.
This brings us to the next question. What do we do if our first line treatment fails? This is where the literature is far more stark and has far fewer straws to grasp. The common pathway that is traditionally followed was benzo, phenytoin, phenobarbital, and if all of these fail to work a propofol or midazolam infusion.
In the VA trial, the arm that received both diazepam and phenytoin fared no better at initial seizure control than the lorazepam alone. Some studies have quoted an added benefit of low as 5% (7) after the primary medication has failed, while others boast rates as high as 84% (8). These mixed results question the true efficacy of phenytoin as a treatment for stopping acute seizures altogether. Some “experts” advocate for phenytoin to be thought of as a long term maintenance drug and should be loaded at presentation along with your primary medication. Not in the hopes that it will add much in efficacy to primary cessation but rather create a therapeutic drug level in the serum for maintenance after the patient is stabilized (7).
Alternatives that have been suggested are valproate or a diazepam infusion. In a small study comparing these two medications in patients resistant to the primary medication (benzodiazepines). They found that valproate and diazepam infusions were equally efficacious (around 50%) in seizure cessation. Mortality or neurological outcomes cannot even truly be assessed as the studies involved are so small that the differences in efficacy would have to be quite large (which they are not) to be seen in these populations.
Finally what is our the tertiary agent of choice? Here we find ourselves diving further into expert opinion and conjecture with even sparser evidence to guide us. Various protocols have been recommended over the years. The most common being phenobarbital, propofol, or a midazolam infusion. There are no high quality RCTs comparing these medications. A large systematic review (6) that examined the extent if the literature found no real quantifiable differences in the three medications when it came to reducing mortality or neurological deficits. Only one RCT compares propofol to thiopental in the treatment on refractory status. (12) The trial was meant to recruit 150 patients but was stopped after 3 years because of lack of recruitment after only enrolling 24 patients. Obviously there was no statistical difference in mortality or neurological outcomes.
Upon review of the current literature it is clear that there is a lack of evidence regarding the best treatment for status epilepticus. Though the various medications demonstrate variable efficacy when looking at time to cessation of seizure, no drug has proven itself superior when looking at mortality or residual neurological deficits. It is clear that seizures that are resistant to first line treatment, have much poorer outcomes than those which respond to our primary outcome. In the VA study the patients with subtle status epilepticus fared much worse than patients with overt status. The causes of the subtle events overall were much more severe than when compared to the overt events ( 56.7% vs. 32.0% of them had a life threatening event and 38.1% vs. 6.3% had cardiopulmonary arrest). This is obviously reflected both in the patient’s resistance to any of the 4 treatments ( the first treatment was only successful in 14.9% of patients with subtle seizures compared to 55.5% of patients with overt seizures) as well as the overall mortality rate ( 64.7% compared to 27%). Even in the overt status group, the subgroup which did not respond to the initial treatment doubled its mortality when compared to those that did respond (4).
Though this literature seems more frustrating than enlightening, I think there is some insight that can be drawn from it when taken as a whole. It seems that your initial treatment may have a small effect on morbidity and mortality, though it is unclear if the specific choice of that first drug makes a difference. For the population who will respond to your primary dose of benzodiazepines, there is a benefit (albeit small) to giving these medications early. After which, the medication you give seems to have less of an effect on morbidity and mortality than the underlying cause of the seizure. That is not to say it is not important to stop the seizure with whatever secondary or tertiary medications you chose, but to be aware that the cause of the seizure is probably of a more insidious origin. So be an emergency physician, control the airway, resuscitate the patient, and try to identify a cause that you can actively intervene on (ie meningitis, drug overdose, sepsis, TBI, etc)
- DeLorenzo RJ, Hauser WA, Towne AR, Boggs JG, Pellock JM, Penberthy L, Barnett L, Fortner CA, Ko D. A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia. Neurology 1996;46:1029–1035.
- Jane G. Boggs, M.D. Mortality Associated with Status Epilepticus. Epilepsy Curr. 2004 January; 4(1): 25–27.
- Treiman DM, Meyers PD, Walton NY, Collins JF, Colling C, Rowan AJ, Handforth A, Faught E, Calabrese VP, Uthman BM, Ramsay RE, Mamdani MB.. DVA Status Epilepticus Cooperative Study Group: A comparison of four treatments for generalized convulsive status epilepticus. N Engl J Med 1998;339: 792–798
- 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
- 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.
- Claassen J, Hirsch LJ, Emerson RG, et al. Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review. Epilepsia 2002;43:146–53.
- Dan Millikan, MD,BrianRice, MD,Rober tSilbergleit, MD. Emergency Treatment of Status Epilepticus: Current Thinking. Emerg Med Clin N Am 27 (2009) 101–113
- Agarwal P, Kumar N, Chandra R, Gupta G, Antony AR, Garg N. Randomized study of intravenous valproate and phenytoin in status epilepticus. Seizure. 2007 Sep;16(6):527-32. Epub 2007 Jul 9
- Chen WB, Gao R, Su YY, Zhao JW, Zhang YZ, Wang L, Ren Y, Fan CQ. Valproate versus diazepam for generalized convulsive status epilepticus: a pilot study. Eur J Neurol. 2011 Dec;18(12):1391-6. doi: 10.1111/j.1468-1331.2011.03420.x. Epub 2011 May 9.
- Neligan A, Shorvon SD. The history of status epilepticus and its treatment. Epilepsia. 2009 Mar;50 Suppl 3:56-68. doi: 10.1111/j.1528-1167.2009.02040.x.
- Kameshwar Prasad, Pudukode R Krishnan, Khaldoon Al-Roomi, and Reginald Sequeira. Anticonvulsant therapy for status epilepticus. Br J Clin Pharmacol 63:6 640–647 640
- Rossetti AO, Milligan TA, Vulliemoz S, Michaelides C, Bertschi M, Lee JW. A randomized trial for the treatment of refractory status epilepticus. Neurocrit Care 2011; 14: 4–10.
Thanks for all your help!
- Peer reviewed by Brent Thoma
- Special thanks to Rebecca Talmud
University of Maryland
Resuscitation Fellowship Graduate