In the January/February issue of Epilepsy Currents, the American Epilepsy Society put forth a guideline on the management of convulsive status epilepticus (CSE) in adult and pediatric patients (1).
While I do appreciate the efforts put forth by the authors who reviewed the available evidence related to CSE, some points from the guideline are worth addressing and further consideration. This is not an all-inclusive list by any means, but the points detailed below are those that I made note of as I perused through the guideline.
1. Consensus Definition for CSE
This definition is pretty much consistent across the board, especially in comparison to those guidelines put forth by the Status Epilepticus Guideline Writing Committee of the Neurocritical Care Society (2). Specifically, two major time points are key here for CSE: the five-minute mark of continuous seizure activity with recovery of consciousness that requires prompt treatment, and the 30-minute mark where seizure activity is continuous and can lead to detrimental long-term consequences if left untreated.
2. Thiamine Before Dextrose?
During the initial stabilization of the patient with recognized CSE, one aspect that is highlighted within the suggested treatment algorithm is administration of thiamine prior to dextrose, which, interestingly enough, is also recommended in the treatment algorithm of the guidelines put forth by the Neurocritical Care Society (1-2). This has been a perpetuated theoretical lesson taught to clinicians in the past few decades with very little evidence supporting this practice, as challenged by recent literature, and may put patients at risk of exacerbation of hypoglycemia (3-4). Sure, if thiamine supplementation is deemed necessary in high-risk patients, it should absolutely be administered; but delaying administration of dextrose in such a patient is not worthwhile.
3. Benzodiazepines as First-Line Therapy…Along with Phenobarbital
The authors of the guideline conducted a relatively thorough evaluation of the current literature surrounding benzodiazepines, and particularly alternative routes of administration when intravenous access is not readily available (1). Some may consider that the dosing limitations put forth are on the lower end (e.g. maximum one-time dose of lorazepam 4 mg IV that may be repeated [is there really a ceiling for benzodiazepine dosing?]), but that is certainly up for debate. In addition, it is interesting to note that phenobarbital is actually listed as an option during the initial phase of treatment in the setting where first-line treatment with IM midazolam, IV lorazepam, or IV diazepam is not possible (1).
4. Dosing of Second-Line Treatment Options
Here, we focus in on the dosing recommendations for valproic acid and levetiracetam. The guideline suggests that for those patients who continue to experience CSE, second-line therapy may include fosphenytoin at a dose of 20 mg/kg PE IV, valproic acid (VPA) at a dose of 40 mg/kg IV, or levetiracetam (LEV) at a dose of 60 mg/kg IV (1). The doses of VPA and LEV seem extraordinary, and the only literature to truly support these recommendations originate from formal evaluation of these doses in pediatric patients, not in adults. Most of the literature that exists that has formally evaluated these agents for status epilepticus in adults calls for doses of upwards of 20 mg/kg IV. For this guideline to provide a blanket and bold recommendation of these doses of VPA and LEV for both of these patient populations is somewhat disconcerting.
5. Falling Flat on Recommendations for Third-Line Therapy
The guidelines fail to venture forward with providing concrete recommendations for third-line therapy. The authors provide suggestions for possible agents to administer patients who may continue experiencing CSE, which include repetition of second-line therapy or “anesthetic doses of thiopental, midazolam, pentobarbital, or phenobarbital (all with continuous EEG monitoring)” (1). No guidance is provided as to what these “anesthetic” doses should be, as both initial dosing and methods for titration, which is of little to no benefit for those who referring to these recommendations.
6. What Happened To…?
If one were to hold down the “CTRL F” key on their keyboard and type in the word “ketamine” in the guideline, 0 of 0 matches will be found. I am not sure how you can have a reasonable discussion related to CSE without mentioning ketamine. It seems rather strange that through their review of the currently available literature related to ketamine for CSE. As the associated editorial of this guideline suggests (5), the guideline does not address refractory status epilepticus. However, practically speaking, this makes it rather difficult to apply the guideline at the bedside, especially since the guideline sparsely addresses third-line therapy. In addition, there is no mention of pyridoxine within the guideline, and there is sufficient literature supporting its use as a treatment option for status epilepticus (which we covered here), especially in pediatric patients who may have unrecognized pyridoxine deficiency or in those patients where the etiology of the seizure may be unknown (or worse, unrecognized as isoniazid toxicity).
7. Time
The time frame for initiation of first-line therapy is 5 to 20 minutes; second-line therapy is suggested for administration at the 20- to 40-minute period, and third-line therapy at 40 to 60 minutes (1). For some folks, the time frame suggested for treatment in this guideline may be too long and potentially detrimental to the patient. In addition, this time frame may suggest for clinicians to wait before moving onto the next treatment option in the algorithm. In contrast, it is worth noting that the guideline from the Neurocritical Care Society specifically states “…there is no well defined period of observation that has been determined to be safe, and no data to suggest that watchful waiting is safer than proceeding with more aggressive treatment. Hence, we recommend proceeding with additional treatment immediately…(2).” Furthermore, in a recent publication related to convulsive status epilepticus, the time frame is rather aggressive and more consistent with those recommendations from the Neurocritical Care Society (6).
8. Level U
All of the recommendations related to therapy beyond first-line are all considered to be Level U by the authors, which is defined as “data inadequate or insufficient; given current knowledge, treatment is unproven” (1). It seems that this classification of recommendation (or lack thereof) is unique to the American Academy of Neurology (7). This certainly begs the question of the rationale for putting forth an “evidence-based” guideline with extensive investment of time and resources if the majority of the recommendations in said guideline are “unproven” to work – at least in the eyes of the folks writing the guideline.
References:
- Glauser T, Shinnar S, Gloss D, et al. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr 2016; 16:48-61.
- Brophy GM, Bell R, Claassen J, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17:3-23.
- Hack JB, Hoffman RS. Thiamine before glucose to prevent Wernicke encephalopathy: examining the conventional wisdom. JAMA 1998; 279:583-4.
- Schabelman E, Kuo D. Glucose before thiamine for Wernicke encephalopathy: a literature review. J Emerg Med 2012; 42:488-94.
- Harden CL. Commentary on SE Guidelines. Epilepsy Curr 2016; 16:62-3.
- Grover EH, Nazzal Y, Hirsch LJ. Treatment of Convulsive Status Epilepticus. Curr Treat Options Neurol 2016; 18:11.
- Getchius TS, Moses LK, French J, et al. AAN guidelines: A benefit to the neurologist. Neurology 2010; 75:1126-7.
EM PharmD 