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Definition
Refractory status epilepticus (RSE) is defined as a status epilepticus that fails to respond to first- and second-line anticonvulsant drug therapy. Super-refractory status epilepticus (SRSE) is a RSE that continues or recurs 24 h or more after the onset of anesthetic therapy, including those cases that recur on the reduction or withdrawal of anesthesia.

Epidemiology
It is estimated that 5-15% of all the cases with SE admitted to hospital will become super-refractory . SRSE in seen in 12 to 26% of SE cases and 13 to 42% of RSE cases

Physiology
Treatment of the RSE is general anesthetic drugs which interact with inhibitory GABA receptors. Once the status continues or recurs 24 h or more after the onset of anesthetic therapy, the stage of the status is more severe (SRSE). Treatment of SRSE is complicated by progressive cortical hyperexcitability believed to result in part from synaptic GABA receptor internalization and desensitization (Broomall E et al. 2014, Vaitkevicius H et al. 2017). As a result, the efficacy of general anesthetic drugs is reduced due to lack of availability of their biological target. Besides, withdrawal of anesthetic drugs during treatment often triggers seizure recurrence (Broomall E et al. 2014).

Treatment
Per definition, SRSE is a RSE which that continues or recurs 24 h or more after the onset of anesthetic therapy, including those cases that recur on the reduction or withdrawal of anesthesia. (Kantanen et al. 2015, Shorvon et al. 2011). Anesthetic drugs could be changed in quality, add another anesthetic and/or change doses at this point. Other therapies has been reported: addition of more antiepileptic drugs, hypothermia, magnesium, pyridoxine, immunotherapy, ketogenic diet, emergency neurosurgery, electroconvulsive therapy, cerebrospinal fluid drainage, vagal nerve stimulation and deep brain stimulation (Ferlisi M et al. 2012, Marawar et al. 2018). A successful therapy is considered when SRSE is completely controlled by the therapy, without breakthrough or withdrawal seizures, or discontinuation due to side-effects, or death during the therapy.

Anesthetic treatments
General anesthesia remains the backbone of therapy in refractory and super-refractory status epilepticus (Ferlisi M et al. 2012). Control of RSE and SRSE (without distinction between both of them) was found in 74% (678/920) of the reported cases. The rate of initial control on barbiturate was 64%, midazolam 78% and propofol 68%. Side-effects (usually hypotension or cardio-respiratory depression) were reported to require a change in therapy in 3% of patients on barbiturates, and 6% on propofol. The figures for failure on midazolam include a large group from one study (78/ 306 patients; Hayashi et al., 2007) in whom the reason for failure was not reported (Ferlisi M et al. 2012). The reported mortality rates were 19% on thiopental/pentobarbital infusions, 8% on propofol infusions and 2% on midazolam infusions (Ferlisi M et al. 2012). Propofol and midazolam were more recently introduced than the barbiturate anesthetics. Nowadays, only the most severe cases are more likely to be treated with barbiturates; or cases that are unresponsive to midazolam or propofol (Ferlisi M et al. 2012).

Second line therapy
This is a therapy that can be applied in those cases in which first line therapy is not controlling the status epilepticus and should be considered at some point after the initiation of anesthesia and antiepileptic drug therapy. How long after will depend on individual circumstances and it is not clear in the literature (Ferlisi M et al. 2012).

Emergency neurosurgery
Surgery appears to be a reasonable alternative in carefully selected patients and can successfully control both entities (Cuello-Oderiz et al., 2015, Duane et al. 2004, Lhatoo et al. 2007, Ma et al. 2001). A good long-term outcome was reported in 27 out of 36 cases (75%). The type of surgery included focal resection, multiple subpial transection, corpus callosectomy and hemispherectory (sometimes in combination) (Ferlisi M et al. 2012). It is unclear the optimal timing of surgery (Cuello-Oderiz et al. 2015). Numerous studies indicate that the outcome of late surgical treatment (after more than 30 ICU days) has been disappointing mainly because of the accumulating morbidity due to prolonged hospitalization (Lhatoo S.D. et al. 2007, Costello D.J. et al. 2006). They have suggested evaluating surgery plausibility after two weeks of medical treatment failure (Lhatoo S.D. et al. 2007, Costello D.J. et al. 2006).

Steroids and Immunotherapy
SRSE may be due to antibodies directed against neural elements. The first antibodies identified were against the voltage-gated potassium channels. Then antibodies against the N-methyl-D-aspartate receptor were discovered, which were found to be a common finding in previously cryptogenic status epilepticus. The second development has been the increasing evidence that inflammation plays an important role in epileptogenesis, and especially the activation of specific inflammatory signalling pathways such as the interleukin-1 receptor/toll-like receptor (IL-1R/TLR) pathway, both experimentally and in human tissue (Vezzani et al., 2009; Maroso et al., 2010; Vezzani and Ruegg, 2011; Zurolo et al., 2011). Currently, weak evidence for the use of immunotherapy is available. Prospective multicenter studies are necessary to assess the true efficacy (Ferlisi M et al. 2012, Khawaja AM et al. 2015).

Ketogenic diet
It has been suggested that as well as having a well-established anti-epileptic effect, the effectiveness of the ketogenic diet in SRSE may be due to a possible anti-inflammatory action, although conclusive experimental evidence of any such action is absent. The cases reported convincingly show an effect, and the diet should probably be tried in all severe cases of SRSE (Shorvon S and Ferlisi M et al. 2011).

Ketamine
Ketamine is an emerging medication for SRSE. Owing to its pharmacological properties, ketamine represents a practical alternative to conventional anesthetics (Ferlisi M et al. 2012, Rosatti et al. 2018). Ketamine, a non-competitive antagonist of the NMDA receptor, inhibits the transmission of excitatory potentials by inactivating the NMDA receptor at the phencyclidine binding site and is thought to have both neuroprotective and anti-inflammatory effects within the context of seizures (D. Golub et al. 2018). Anesthetists have long valued the cardio-stimulatory properties of ketamine that markedly contrast with the cardiovascular profiles of most alternative anesthetic agents (D. Golub et al. 2018). Regardless of the status epilepticus type, ketamine was twice as effective if administered early, with an efficacy rate as high as 64% in SRSE lasting 3 days and dropping to 32% when the mean SRSE duration was 26.5 days. Ketamine doses were extremely heterogeneous and did not appear to be an independent prognostic factor (Rosatti et al. 2018). Results from two ongoing studies (ClinicalTrials.gov identification number: NCT02431663 and NCT03115489) and further clinical trials will hopefully confirm the better efficacy and safety profile of ketamine compared with conventional anesthetics as third-line therapy in refractory status epilepticus, both in pediatric and adult populations. Novel treatments:

Allopregnanolone
Allopregnanolone, a neurosteroid that positively modulates synaptic and extrasynaptic GABAa receptors, has been proposed as a novel treatment (Broomall E, et al. 2014, Vaitkevicius H et al. 2017).

Ganaxolone
It is an experimental drug for potential medical use as an anxiolytic and anticonvulsant. Ganaxolone has been shown to protect against seizures in animal models, and to act a positive allosteric modulator of the GABAA receptor. (CT ID: NCT03350035).

Prognosis
Short-term and long-term outcomes tend to be poor with significant morbidity and mortality with only one-third of patients reaching baseline neurological status (Marawar et al. 2018). The mortality of patients with SRSE 36% (Kantanen et al. 2015).