Dear Anthony,

thank you for your response. Although there is a debate going on about the term "refractory status epileptics", partially based on the facts you stated above, the term "status epileptics" is broadly accepted to be very important, as it only stands for the condition in which seizure activity lasts longer than it does in most cases (i.e., >5 minutes or several repetitive seizures without recovery to baseline in between) - a life threatening condition that calls for immediate treatment escalation in contrast to self and rapidly ending epileptic seizures. Why not treating all seizures aggressively right from the start? Well, recent data (also our own preliminary data) indicate, that the use of for example of continuous i.v. anesthetic agents (that are often administered for seizure control after antiepileptic drugs have failed) are independently associated with higher mortality in a cohort of patients with status epilepticus. It remains challenging to choose between fast and aggressive treatment for rapid seizure control with the risk of adverse events etc. and less aggressive treatment that has less treatment related risks but increases the chance of brain damage...

However, I absolutely agree that rapid and early treatment of ongoing seizure activity should not be delayed because of "complicated" guidelines and definitions, especially as there is evidence (although limited) that prolonged seizure activity can lead to brain injury.

Variou studies have used different definitions. The more widely accepted definition is seizure clinical or electrographic persisting despite 2 or more ACD.

I agree with Ajaya. However, as delay of ACD escalation or adaption may have adverse effects on treatment success, some epileptologists suggest a more narrow definition of refractory status epilepticus as mentioned above - a proposal that does not take the potential risks of early treatment escalation (including coma induction with anesthetic drugs) into account. What is your opinion?

Indeed, definition of refractory status epilepticus (RSE) remains questionable.

As a Medical critical care physician and in our team, we consider that RSE occurs if seizures recurred within the 20-30 minutes after the consensual treatment: IV midazolam (0.015mg/kg) and phenobarbital (loading dose 15 mg/k), or fosphenytoin (20mg/kg) and a new dose of midazolam. Thus we use thiopental with an initial bolus (20sec) of 2mg/kg, repeated every 5 min if seizures persist, and then 3 to 5mg/kg/hour for at least 24 hours. In absence of RSE control, we associate thiopental to midazolam (0.1 to 0.5mg/kg/h) and of course hemodynamic support if necessary. Very rarely, RSE persist clinically or on EEG, thus we use midazolam and Ketamin. After the occurrence of a fatal “propofol infusion syndrome” in an idiopathic RSE, propofol is no longer used in our ICU.

Furthermore, i would discuss the RSE mortality. At evidence, the outcome is secondary to the leading causes. Thus, I am not sure that RSE mortality, per se, is 10-40 %. If a patient suffers from severe spontaneous intracerebral hemorrhage, death may be due to withdrawal of life support for perceived futility or to brain death. In this case, I would not consider that the death is secondary to RSE. In my opinion, for the therapeutic evaluation and the neurologic outcome it would be of interest to take into account the two types of status epilepticus: the idiopathic ant those secondary to severe intracranial disease. Indeed, in our ICU, within the last three decades, all the idiopathic RSE survive, except the case of “propofol infusion syndrome”.

Thank you for your valuable contribution Dr. Brivet. I absolutely agree with your comment on the mortality range. Especially patients with a non-acute etiology, such as for example known epilepsy with low levels of antiepileptic drugs, good outcome can be observed frequently. However, studies that focus on outcome regarding the different groups of etiologies as categorized by the International League Against Epilepsy (ILAE) and that also takecare withdrawal into account are scarce. Alghough systematic data on care withdrawal are important in terms of a "selffullfilling prophecy", their are lacking in several studies.

Thank you all - especially Raoul - for the exciting questions and discussion. Hoping that my answer is not too late, I will add some lines. Refractory status epilepticus (RSE) and refractory epilepsy - in my opinion - are rather worthless terms. Epileptologists prefer to speak about best treatment of epilepsies and the treatment of all variants of status epiletipcus (SE), not only to mention epileptic seizures control.

The incidence of grand-mal-status ranges from 18 – 28/100 000 inhabitants/year. I agree with Francois: The US-statistic number of mortality (40 %) is probably a bit too high. In Europe “mortality” of SE ranges from 3 (!) -33 % (Holtkamp et al. 2003; Meierkord et al. 2010). However, we prefer the term "lethality" to discribe the fatality of SE regarding clinical statistics and no definite numbers concerning the prevalence of SE in a certain European population. I think this could help to avoid the term “refractory”:

Important for any treatment of SE is the time factor, not wasting the time (I agree with Raoul and Anthony), not beginning with thinking over some known and sometimes unexplained fatal results - regardless of any interesting pospective or restrospective discussion - but to describe the very beginning of SE (convulsive or non-convulsive) and Video-EEG-Monitoring of each single epileptic seizure (focal, partial or generalized). That ist not new, but always important, I suppose.

Doubtless there is a rare “malignant variant” of SE (Holtkamp et al. 2005). In such subtle SE i.v. anaesthesia is required. On the other hand many types of generalized and some types of nonconvulsive SE cause little permanent neurologic sequelae (Kaplan, 2000). Anaesthesia is not required in the most cases.

SE as result of intoxication, encephalitis, brain tumor, stroke - or the beginning with early focal postraumatic fits - is not very difficult to treat (with benzodiazepine and phenytoine), if there is not (yet) a big progress of brain edema. The lethality, due mainly to the causing illness and comorbidity is 20 % (higher in the elderly, especially in some cases of nonconvulsive SE). RSE is not the leading cause of death. In this point I agree with Francois, too.

According to literature and our experience SE in chonical epilepsies has an overall lethality of only 4 % !

In most cases of noncompliance, drug - or alcohol and sleep withdrawal and in all cases of status pseudo-epilepticus we have not to use the questionable term “refractory”. Why in the rest of it? What is the sense and purpose? Even when the end will be fatal in 3 - 33 % of severe SE, who will think of RSE, when seizures, epilepsies and status begin?

Kaplan PW. No, some types of nonconvulsive status epilepticus

cause little permanent neurologic sequelae (or:

‘‘the cure may be worse than the disease’’). Clin Neurophysiol

2000; 30: 377–382.

Holtkamp M, Masuhr F, Harms L, Einhaupl KM, Meierkord

H, Buchheim K. The management of refractory

generalised convulsive and complex partial status epilepticus

in three European countries: a survey among epileptologists

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Neurosurg Psychiatry 2003; 74: 1095–1099.

Holtkamp M, Othman J, Buchheim K, Masuhr F, Schielke

E, Meierkord H. A ‘‘malignant’’ variant of status

epilepticus. Arch Neurol 2005; 62: 1428–1431.

Meierkord H, Boon P, Engelsen, B, K. Gocke,

S. Shorvonf, S Tinuper P, Holtkamp M:

EFNS guideline on the management

of status epilepticus in adults. Eur J Neurol 17(2010) 348-355.

Dear Dr. Masuhr,

please apologize my late response to your interesting answer. I would like to add some additional thoughts. We all agree that time to treatment and treatment response is crucial for seizure control and favorable outcome. Several studies have tried to provide evidence that delay in treatment of ongoing seizure activity may cause or accelerate neuronal injury. However, prospective randomized studies comparing immediate start of treatment with delayed treatment initiation are ethically unacceptable – a restriction that explains the preponderance of retrospective study designs that may be hampered by the lack of accurate data ascertainment at the start of status epilepticus, especially as nonconvulsive forms often remain undetected. However, there is some evidence from an early review of status epilepticus, where first-line therapy administered in the first 30 minutes stopped seizures in 80% of patients (1). In addition, a positive correlation between poor outcome and delay to treatment initiation was shown in a study on patients with generalized tonic-clonic status epilepticus (2). In a controlled trial comparing lorazepam, diazepam and placebo for out-of-hospital treatment of SE, seizure control after treatment initiation is significantly lower in patients receiving placebo as first treatment and therefore delayed antiepileptic therapy (3).

In light of these data your suggestion that we probably should avoid the term "refractory status epilepticus" (RSE) and should focus more on the "lethality" seem more than reasonable. However, there are some aspects that might point into another direction. Previous studies identified nonconvulsive status epilepticus (4, 5) acute symptomatic etiologies (5, 6), altered level of consciousness (7), absent history of seizures (7), and levels of acute-phase proteins (8) to be associated with RSE and unfavorable outcome. The only available clinical scoring system for patients with status epilepticus was developed for early prediction of death (i.e., Status Epilepticus Severity Score [STESS](9, 10) ), usable disputably for treatment guidance. However, although STESS identifies patients at risk for death, it has not been tested for its ability to predict early treatment response. Further, knowledge of risk of death does not inform choices regarding the intensity of treatment. In other words, would we escalate or de-escalate treatment if we know that the likelihood of a patient to die is high? Rapid induction of drug-induced coma may put patients at additional risk of adverse effects (11-14). Conversely, inadequate or delayed treatment may allow ongoing seizure activity - an independent risk factor for increased mortality (15). Therefore, I believe that we should not only focus on "lethality" but also on how to predict early treatment response.

Refereces:

1. Lowenstein, DH, Alldredge, B.K. Status epilepticus at an urban public hospital in the 1980s. Neurology 1993; 43: 483-488.

2. Sagduyu, A, et al. Generalized tonic-clonic status epilepticus: causes, treatment, complications and predictors of case fatality. J Neurol 1998; 245: 640-646.

3. Alldredge, BK et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N Engl J Med 2001; 345: 631-637.

4. Mayer SA, et al. Refractory status epilepticus: frequency, risk factors, and impact on outcome. Arch Neurol 2002; 59: 205-210.

5. Agan K, et al. Predictors of refractoriness in a Turkish status epilepticus data bank. Epilepsy Behav 2009; 14: 651-654.

6. Holtkamp M, et al. Predictors and prognosis of refractory status epilepticus treated in a neurological intensive care unit. J Neurol Neurosurg Psychiatry 2005; 76: 534-539.

7. Novy J, Logroscino G, Rossetti AO. Refractory status epilepticus: a prospective observational study. Epilepsia 2010; 51: 251-256.

8. Sutter R, et al. Acute phase proteins and mortality in status epilepticus: a five-year observational cohort study. Crit Care Med 2013; 41: 1526–1533.

9. Rossetti AO, et al. Status Epilepticus Severity Score (STESS): a tool to orient early treatment strategy. J Neurol 2008; 255: 1561-1566.

10. Sutter R, et al. Independent external validation of the Status Epilepticus Severity Score. Crit Care Med 2013; in press.

11. Kowalski RG, et al. Third-line antiepileptic therapy and outcome in status epilepticus: The impact of vasopressor use and prolonged mechanical ventilation. Crit Care Med 2012; 40: 2677-2684.

12. Power KN, et al. Propofol treatment in adult refractory status epilepticus. Mortality risk and outcome. Epilepsy Res 2011; 94: 53-60.

13. Sutter R, Tschudin-Sutter S, Grize L, et al. Associations between infections and clinical outcome parameters in status epilepticus: A retrospective 5-year cohort study. Epilepsia 2012; 53: 1489-1497.

14. Hocker SE, Britton JW, Mandrekar JN, Wijdicks EF, Rabinstein AA. Predictors of outcome in refractory status epilepticus. Arch Neurol 2013; epub ahead of print.

15. Young GB, et al. An assessment of nonconvulsive seizures in the intensive care unit using continuous EEG monitoring: an investigation of variables associated with mortality. Neurology 1996; 47: 83-89.

Thank you Dr. Schapera for your important question.

Indeed, the Neurocritical Care Society has recently published new guidelines for treatment of SE (1). These are based on consensus and only few prior controlled trials have compared different treatment regimens for status epilepticus so far. Thus successful management approaches have mostly been developed empirically. However, according to a recent prospective study, the prognostic role of treatment adherence to such guidelines or recommendations seems questionable, providing evidence that status epilepticus drug treatment, after consideration of robust predictors such as etiology, age, status epilepticus severity, and comorbidities, seems to have no major effect on prognosis even if administered violating current guidelines (2).

It remains to be determined whether specific types of status epilepticus should be treated differently or not. In types of partial status epilepticus in which patients are awake (i.e., simple partial status), coma induction for ongoing seizure activity seems to be critical and the risks of anesthesia may outweigh its benefits. In addition, patients with prolonged simple or partial complex status often have good outcomes without anesthetic drugs (3). In such patients the use of non-sedating antiepileptic drugs should be considered whenever possible in order to avoid prolonged seizure activity with the in-debatable risk of aspiration as well as avoiding a decrease of the level of consciousness and additional risks for anesthesia related adverse events. In order to tailor treatment to different types of status epilepticus early prediction of the risk of treatment refractoriness is important.

1. Brophy, GM et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17: 3-23.

2. Rossetti, AO, et al. Treatment deviating from guidelines does not influence status epilepticus prognosis. J Neurol 2013; 260: 421-428 (2013).

3. Sutter R, et al. Epidemiology, diagnosis, and management of nonconvulsive status epilepticus: Opening Pandora’s box. Neurol Clin Pract 2012; 275-286.

Dr. Sutter

I will try to add to this timely debate about one of the most lethal medical emergencies.

As Henry Gastaut has stated, there are so many types of status epilepticus as the number of seizure types. And we now have consistent evidence to assert that antiepileptic drugs differ in their effectiveness in treating different seizures. Treiman's work was done at a time when one had limited number of antiepileptic drugs for intravenous use. For example, we still didn't have valuable drugs such as phosphenytoin, valproic acid or levetiracetam for this purpose.

So, I think it is time to revisit this research hypothesis, now comparing different types of management, including new antiepileptic drugs, because, if we can select patients who respond to at least two conventional antiepileptic drugs, we are saving a portion of patients of potential deleterious effects of anesthetics. Personally, the current concept of failure to respond to two antiepileptic drugs is one that attracts me.

It is clear that the responsiveness of status epilepticus is directly related to its etiology, but we're dealing with a situation highly lethal, with little time to act, and trying to balance benefits and risks of our clinical management in the central nervous system.

Thank you all.

Yes, I agree with a lot of new arguments. Thank you, Dr. Sutter, Dr. Shapera and Dr. Bragatti! However the term “refractory” or “therapy-refractory” status epilepticus in my opinion is not very useful regarding the emergency treatment of severe epilepsies and to get any prognosis with prediction accuracy. Students could be confused, it seems to be more than a real statistical result, sometimes pretending to be a prognosis – always hardly encouraging.

Dear sir

First of all I should say that in some references mentioned that patients who remain unresponsive to the third-level choice of pharmacologic intervention are by definition in refractory status epilepticus. (Rosen's Emergency Medicine (2014),Chapter 18 / Seizures; page 159)

But it's not rational that wait and watch ongoing seizing activity to administering second or third line treatment !!!

On the other hand in some situation of status epilepticus that short self abortive seizing activity last in episode of postictal stat and before catch the baseline level of consciousness another seizure occurs, may cost to wait for appearance of drugs effect.

In my opinion, physician judgment case by case