Frequently asked questions
Can we accept incidental periodic discharges?
It is okay to tolerate some periodic/rhythmic discharges and even some brief seizures as long as they stay below the 10% hourly prevalence. This will soon be included in a new version of the NCSE criteria.
What to do if the family does not provide deferred consent?
It is very important to have a follow-up from all patients in both treatment arms to avoid biases. If a family refuses to provide deferred consent for the complete follow-up, please try to get permission for collection of only the primary outcome measure, i.e., death or the extended Glasgow Outcome Scale score at six months.
How to proceed with EEG registration if a patient is in the control group?
We aim to study the evolution of rhythmic and periodic EEG activity in both control and intervention group. Therefore, we prefer to continue EEG monitoring once a patient has been included in the trial, both in the intervention and in the control group. However, in the control group, the EEG should not be used to guide the treatment and there should be no prescription of antiseizure medication. Optimally, the monitor is switched off in the control group.
What is the rationale for the recommended high doses of anti-seizure medications and sedative agents for treatment of status epilepticus?
Regarding conventional anti-seizure medications (levetiracetam, valproic acid and lacosamide), we strongly advocate for the use of high loading doses. For levetiracetam and valproic acid, this is based on available guidelines, which are themselves based on several clinical trials, including a large randomized multicenter comparative trial that has demonstrated similar efficacy and safety of these drugs at these doses in generalized convulsive status epilepticus (Kapur et al.). For lacosamide, this is based on a randomized multicenter comparative trial that has demonstrated similar efficacy and safety of lacosamide 400-600 mg compared to fosphenytoin for nonconvulsive seizures and status epilepticus (Husain et al.).
There is also evidence from retrospective analysis of the TELSTAR cohort, combined with two prospective registries of post-anoxic status epilepticus, that higher doses of conventional anti-seizure medications are associated with better outcomes (De Stefano et al.).
Regarding sedative agents, we provide ranges of infusion rates. This is based on guidelines and experts’ opinion that recommend starting the infusion at a low rate and then titrate up under continuous EEG guidance until either seizure control, or tolerability or the maximal recommended rate is reached (Brophy et al.; Glauser et al.; Meierkord et al.; Minicucci et al.; Outin et al.; Rosenow et al.). In other words, there is no need to increase the rate further once status epilepticus is controlled. The provided ranges are derived from available guidelines or experts’ recommendations when they are not mentioned in guidelines.
In the American Epilepsy Society (AES) guidelines (Glauser et al.), the recommendation is as follows: “Thus, if second therapy fails to stop the seizures, treatment considerations should include repeating second-line therapy or anesthetic doses of either thiopental, midazolam, pentobarbital, or propofol (all with continuous EEG monitoring).” In the recent French national guidelines (Outin et al.), the recommendation is as follows: “Il est alors proposé de recourir à un coma thérapeutique au moyen d’un agent anesthésique intraveineux de type midazolam ou propofol ” (which can be translated (DeepL) as: “It is then proposed to use a therapeutic coma using an intravenous anesthetic such as midazolam or propofol”). In the recent German national guidelines (Rosenow et al.), the recommendation is as follows: “Der refraktäre konvulsive Status epilepticus soll mit Propofol oder Midazolam oder einer Kombination der beiden oder mit Thiopental in anästhetischen Dosen behandelt werden.” (which can be translated (DeepL) as: “Refractory convulsive status epilepticus should be treated with propofol or midazolam or a combination of the two or with thiopental in anesthetic doses.”). The Dutch guidelines recommend to: “Behandel een refractaire status epilepticus bij voorkeur door midazolam te starten of te verhogen, of te starten met een anestheticum (propofol of thiopental).” (which can be translated (DeepL) “Preferably treat a refractory status epilepticus by starting or increasing midazolam, or starting with an anesthetic (propofol or thiopental)”).
Midazolam
Regarding the recommended dose of midazolam, available guidelines provide the following ranges:
In the largest case series (Fernandes et al.), maximal infusion rates were reported up to 3.3 mg/(kg.h).
Propofol
Regarding the recommended dose of propofol, available guidelines provide the following ranges:
Ketamine
While mentioned in the European, US, German and French guidelines as a therapeutic option for super-refractory SE, recommended doses of ketamine are only provided in the French and Italian guidelines:
In the largest case series (Gaspard et al.; Höfler et al.), maximal infusion rates were reported up to 10.5 mg/(kg.h).
Brophy GM, Bell R, Claassen J, Alldredge B, Bleck TP, Glauser T, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care. 2012;17(1):3–23.
De Stefano P, Hofmeijer J, Quintard H, Damien C, Misirocchi F, Caroyer S, et al. Features, Outcome, and Treatment of Postanoxic Status Epilepticus. Neurology. 2025;105(4):e213913.
Kapur J, Elm J, Chamberlain JM, et al. Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus. N Engl J Med. 2019;381(22):2103-2113.
Fernandez A, Lantigua H, Lesch C, Shao B, Foreman B, Schmidt JM, et al. High-dose midazolam infusion for refractory status epilepticus. Neurology. 2014;82(4):359–65.
Gaspard N, Foreman B, Judd LM, Brenton JN, Nathan BR, McCoy BM, et al. Intravenous ketamine for the treatment of refractory status epilepticus: A retrospective multicenter study. Consortium F the CCEMR, editor. Epilepsia. 2013;54(8):1498–503.
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(1):48-61.
Höfler J, Rohracher A, Kalss G, Zimmermann G, Dobesberger J, Pilz G, et al. (S)-Ketamine in Refractory and Super-Refractory Status Epilepticus: A Retrospective Study. CNS Drugs. 2016 Jul 27;30(9):869–76.
Husain AM, Lee JW, Kolls BJ, et al. Randomized trial of lacosamide versus fosphenytoin for nonconvulsive seizures. Ann Neurol. 2018;83(6):1174-1185.
Meierkord H, Boon P, Engelsen B, Göcke K, Shorvon S, Tinuper P, et al. EFNS guideline on the management of status epilepticus in adults. Eur J Neurol. 2010;17(3):348–55.
Minicucci F, Ferlisi M, Brigo F, Mecarelli O, Meletti S, Aguglia U, et al. Management of status epilepticus in adults. Position paper of the Italian League against Epilepsy. Epilepsy Behav. 2020;102:106675.
Outin H, Lefort H, Peigne V, Guidelines FG for SE. Guidelines for the management of status epilepticus. Eur J Emerg Medicine. 2021;28(6):420–2.
Rosenow F, Weber J, (DGN) DG für N, (ÖGN) ÖG für N. S2k-Leitlinie: Status Epilepticus im Erwachsenenalter. Nervenarzt. 2021;92(10):1002–30.
Rossetti AO, Milligan TA, Vulliémoz S, Michaelides C, Bertschi M, Lee JW. A Randomized Trial for the Treatment of Refractory Status Epilepticus. Neurocritical Care. 2011;14(1):4–10.
There is also evidence from retrospective analysis of the TELSTAR cohort, combined with two prospective registries of post-anoxic status epilepticus, that higher doses of conventional anti-seizure medications are associated with better outcomes (De Stefano et al.).
Regarding sedative agents, we provide ranges of infusion rates. This is based on guidelines and experts’ opinion that recommend starting the infusion at a low rate and then titrate up under continuous EEG guidance until either seizure control, or tolerability or the maximal recommended rate is reached (Brophy et al.; Glauser et al.; Meierkord et al.; Minicucci et al.; Outin et al.; Rosenow et al.). In other words, there is no need to increase the rate further once status epilepticus is controlled. The provided ranges are derived from available guidelines or experts’ recommendations when they are not mentioned in guidelines.
In the American Epilepsy Society (AES) guidelines (Glauser et al.), the recommendation is as follows: “Thus, if second therapy fails to stop the seizures, treatment considerations should include repeating second-line therapy or anesthetic doses of either thiopental, midazolam, pentobarbital, or propofol (all with continuous EEG monitoring).” In the recent French national guidelines (Outin et al.), the recommendation is as follows: “Il est alors proposé de recourir à un coma thérapeutique au moyen d’un agent anesthésique intraveineux de type midazolam ou propofol ” (which can be translated (DeepL) as: “It is then proposed to use a therapeutic coma using an intravenous anesthetic such as midazolam or propofol”). In the recent German national guidelines (Rosenow et al.), the recommendation is as follows: “Der refraktäre konvulsive Status epilepticus soll mit Propofol oder Midazolam oder einer Kombination der beiden oder mit Thiopental in anästhetischen Dosen behandelt werden.” (which can be translated (DeepL) as: “Refractory convulsive status epilepticus should be treated with propofol or midazolam or a combination of the two or with thiopental in anesthetic doses.”). The Dutch guidelines recommend to: “Behandel een refractaire status epilepticus bij voorkeur door midazolam te starten of te verhogen, of te starten met een anestheticum (propofol of thiopental).” (which can be translated (DeepL) “Preferably treat a refractory status epilepticus by starting or increasing midazolam, or starting with an anesthetic (propofol or thiopental)”).
Midazolam
Regarding the recommended dose of midazolam, available guidelines provide the following ranges:
| Guidelines | Dose | Notes |
|---|---|---|
| 2010 European (Federation of Neurological Societies) guidelines | 0.05-0.4 mg/(kg.h) | |
| 2016 Italian (League Against Epilepsy) guidelines | 0.2-0.6 mg/(kg.h) | Acknowledge that high doses have the same safety profile as lower doses with reduced seizure recurrence and lower mortality rates |
| 2021 French (joint SRLF and SFMU) guidelines | 0.2-0.5 mg/(kg.h) | Acknowledge that higher doses up to 2.9 mg/(kg.h) are safe |
| 2021 German (Society of Neurology) guidelines | Up to 2.9 mg/(kg.h) | |
| 2012 US Neurocritical Care Society guidelines | 0.05-2 mg/(kg.h) | Suggest titrating up by 0.1–0.2 mg/kg boluses, increase infusion rate by 0.05–0.1 mg/(kg.h) every 3–4 h in case of breakthrough SE |
Propofol
Regarding the recommended dose of propofol, available guidelines provide the following ranges:
| Guidelines | Dose | Notes |
|---|---|---|
| 2010 European (Federation of Neurological Societies) guidelines | 4-10 mg/(kg.h) | |
| 2016 Italian (League Against Epilepsy) guidelines | 2-12 mg/(kg.h) | |
| 2021 French (joint SRLF and SFMU) guidelines | 3-4 mg/(kg.h) | Acknowledges that doses up to 5 mg/(kg.h) are safe |
| 2021 German (Society of Neurology) guidelines | 4–10 mg/(kg.h) | |
| 2012 US Neurocritical Care Society guidelines | 1.8-12 mg/(kg.h) | Warns against prolonged (> 48h) infusion of doses > 4.8 mg/(kg.h) |
While mentioned in the European, US, German and French guidelines as a therapeutic option for super-refractory SE, recommended doses of ketamine are only provided in the French and Italian guidelines:
| Guidelines | Dose | Notes |
|---|---|---|
| 2016 Italian (League Against Epilepsy) guidelines | 0.3-5 mg/(kg.h) | |
| 2021 French (joint SRLF and SFMU) guidelines | 0.5-5 mg/(kg.h) |
Brophy GM, Bell R, Claassen J, Alldredge B, Bleck TP, Glauser T, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care. 2012;17(1):3–23.
De Stefano P, Hofmeijer J, Quintard H, Damien C, Misirocchi F, Caroyer S, et al. Features, Outcome, and Treatment of Postanoxic Status Epilepticus. Neurology. 2025;105(4):e213913.
Kapur J, Elm J, Chamberlain JM, et al. Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus. N Engl J Med. 2019;381(22):2103-2113.
Fernandez A, Lantigua H, Lesch C, Shao B, Foreman B, Schmidt JM, et al. High-dose midazolam infusion for refractory status epilepticus. Neurology. 2014;82(4):359–65.
Gaspard N, Foreman B, Judd LM, Brenton JN, Nathan BR, McCoy BM, et al. Intravenous ketamine for the treatment of refractory status epilepticus: A retrospective multicenter study. Consortium F the CCEMR, editor. Epilepsia. 2013;54(8):1498–503.
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(1):48-61.
Höfler J, Rohracher A, Kalss G, Zimmermann G, Dobesberger J, Pilz G, et al. (S)-Ketamine in Refractory and Super-Refractory Status Epilepticus: A Retrospective Study. CNS Drugs. 2016 Jul 27;30(9):869–76.
Husain AM, Lee JW, Kolls BJ, et al. Randomized trial of lacosamide versus fosphenytoin for nonconvulsive seizures. Ann Neurol. 2018;83(6):1174-1185.
Meierkord H, Boon P, Engelsen B, Göcke K, Shorvon S, Tinuper P, et al. EFNS guideline on the management of status epilepticus in adults. Eur J Neurol. 2010;17(3):348–55.
Minicucci F, Ferlisi M, Brigo F, Mecarelli O, Meletti S, Aguglia U, et al. Management of status epilepticus in adults. Position paper of the Italian League against Epilepsy. Epilepsy Behav. 2020;102:106675.
Outin H, Lefort H, Peigne V, Guidelines FG for SE. Guidelines for the management of status epilepticus. Eur J Emerg Medicine. 2021;28(6):420–2.
Rosenow F, Weber J, (DGN) DG für N, (ÖGN) ÖG für N. S2k-Leitlinie: Status Epilepticus im Erwachsenenalter. Nervenarzt. 2021;92(10):1002–30.
Rossetti AO, Milligan TA, Vulliémoz S, Michaelides C, Bertschi M, Lee JW. A Randomized Trial for the Treatment of Refractory Status Epilepticus. Neurocritical Care. 2011;14(1):4–10.
How long should we pursue antiseizure treatment in the intervention group?
As long as needed to suppress (possible) ESE at the discretion of the treating team. The trial protocol does not include a minimum or maximum treatment duration.
When should we add a new antiseizure medication?
The treatment guideline can be found
here.
Subsequent treatment steps should be taken as soon as possible if a previous step insufficiently suppresses (possible) ESE. However, we prefer maximizing daily (tolerated) doses of levetiracetam, valproate, and lacosamide before adding an additional antiseizure medication.
How do we deal with prognostication?
According to current guidelines and local protocols, similar as in patients that are not included in the trial. All outcome predictors recommended by the ESICM/ERC or national guidelines (SSEP, NSE, EEG, CT, MRI) can be used. In case of a poor predicted outcome, life sustaining treatment can be interrupted, at the discretion of the treating team.
How often do you recommend a ‘wake-up call’ (stopping or lowering sedative medication) to check whether ESE has extinguished?
This will differ per patient. Generally, persisting incidental periodic/rhythmic discharges indicate a risk of recurrence upon weaning. This is mostly a motivation to pursue sedation at that point.
New periodic discharges appear during weaning. Does this always indicate refractory status epilepticus?
No. In some patients, periodic discharges that differ from those seen prior to anaesthesia can appear during weaning. This is sometimes referred to as GRAWs (generalized periodic discharges (GPDs) related to anaesthetic withdrawal). These should not be regarded as evidence of SE recurrence. GRAWs can usually be tolerated.