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25 years of advances in the definition, classification and treatment of status epilepticus

  • Eugen Trinka
    Correspondence
    Corresponding author at: Department of Neurology, Christian Doppler Klinik, Paracelsus Medical University Salzburg, Centre for Cognitive Neuroscience Salzburg, Ignaz Harrerstrasse 79, A-5020 Salzburg, Austria. Fax: +43 572 5534899.
    Affiliations
    Department of Neurology, Paracelsus Medical University Salzburg, and Christian Doppler Medical Centre, Salzburg, Austria

    Centre for Cognitive Neurosciences Salzburg, Salzburg, Austria

    University for Medical Informatics and Health Technology, UMIT, Hall in Tirol, Austria
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  • Reetta Kälviäinen
    Affiliations
    Epilepsy Center, Neurocenter, Kuopio University Hospital, Kuopio, Finland

    Institute of Clinical Medicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
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Open ArchivePublished:November 14, 2016DOI:https://doi.org/10.1016/j.seizure.2016.11.001

      Highlights

      • Morbidity and mortality of SE correlate with duration of status, the rapid identification of the cause of SE, age and comorbidity.
      • Treatment should be started when a seizure is abnormally prolonged (time-point t1).
      • Time point t1 for generalized tonic clonic seizures is at 5 min, and for focal seizures at 10 min.
      • At time-point t2 neuronal damage may begin, and indicates that SE should be controlled latest by that time.
      • A staged protocol with early, established, refractory and super-refractory stages is the hallmark of current SE treatment.

      Abstract

      Purpose

      Status epilepticus (SE) requires not only urgent symptomatic treatment with antiepileptic drugs but also rapid identification and treatment of its cause. This narrative review summarizes the most important advances in classification and treatment of SE.

      Method

      Data sources included MEDLINE, EMBASE, ClinicalTrials.gov, and back tracking of references in pertinent studies, reviews, and books.

      Results

      SE is now defined as “a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures (after time point t1). It is a condition, which can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures.” A new diagnostic classification system of SE introduces four axes: semiology, aetiology, EEG correlates, and age.
      For the acute treatment intravenous benzodiazepines (lorazepam, diazepam, clonazepam) and intramuscular midazolam appear as most effective treatments for early SE. In children, buccal or intranasal midazolam are useful alternatives. In established SE intravenous antiepileptic drugs (phenytoin, valproate, levetiracetam, phenobarbital, and lacosamide) are in use. Treatment options in refractory SE are intravenous anaesthetics; ketamine, magnesium, steroids and other drugs have been used in super-refractory SE with variable outcomes.

      Conclusion

      Over the past 25 years major advances in definition, classification and understanding of its mechanisms have been achieved. Despite this up to 40% of patients in early status cannot be controlled with first line drugs. The treatment of super-refractory status is still an almost evidence free zone.

      Keywords

      1. Introduction

      Status epilepticus has an estimated incidence of up to 61 episodes per 100,000 per year and an overall mortality of 20% (range 1.9–40%) [
      • Betjemann J.P.
      • Lowenstein D.H.
      Status epilepticus in adults.
      ,
      • Kantanen A.M.
      • Reinikainen M.
      • Parviainen I.
      • Ruokonen E.
      • Ala-Peijari M.
      • Backlund T.
      • et al.
      Incidence and mortality of super-refractory status epilepticus in adults.
      ]. There has been considerable development in the past 25 years in the understanding of its pathophysiology, causes, clinical features, EEG changes, prognosis and treatment [
      • Trinka E.
      • Brigo F.
      • Shorvon S.
      Recent advances in status epilepticus.
      ,
      • Shorvon S.
      • Trinka E.
      The 5th London-Innsbruck colloquium on status epilepticus and acute seizures.
      ]. The purpose of this narrative review in the 25-year anniversary issue of “SeizureThe European Epilepsy Journal” is to give an update on definition, classification and therapeutic options for patients in SE.

      2. Recent advances in the definition and classification of status epilepticus

      Status epilepticus is often referred to the “maximum expression of epilepsy”, but status is also a severe expression of an acute brain insult or systemic disturbance, which leads to excessive hyperexcitation of nervous tissue. The modern definition and classification of status epilepticus has its roots back to the 10th Marseilles Colloquium (the 10th European Electroencephalographic Meeting) in 1962, which was completely devoted to status epilepticus. Gastaut and co-workers proposed a definition, which was consistent with the meaning of the original term status in Latin: “Status epilepticus is a term whenever a seizure that persists for a sufficient length of time or is repeated frequently enough to produce a fixed and enduring condition” [
      • Gastaut H.
      Clinical and electroencephalographical classification of epileptic seizures.
      ,
      • Gastaut H.
      A propos d'une classification symptomatologique des Çtats de mal Çpileptiques.
      ,
      • Gastaut H.
      Clinical and electroencephalographical classification of epileptic seizures.
      ]. Although there was no duration specified in the definition, Gastaut later proposed 60 min to define status epilepticus [
      • Gastaut H.
      Classification of status epilepticus.
      ]. In the revision of 1981, the definition was minimally changed into a “seizure” that “persists for a sufficient length of time or is repeated frequently enough that recovery between attacks does not occur.” [
      Proposal for revised clinical and electroencephalographic classification of epileptic seizures. From the Commission on Classification and Terminology of the International League Against Epilepsy.
      ]. Status was classified under the terms “prolonged or repetitive seizures (status epilepticus)”and was divided into partial (e.g., Jacksonian), or generalized (e.g., absence status or tonic-clonic status). “When very localized motor status occurs, it is referred to as epilepsia partialis continua”. These concepts, while highly valuable, were imprecise, as they did not define the duration of a seizure that was fixed and enduring “or” sufficient length. In the past, experts suggested that 30 min of ongoing seizure activity could be regarded as “fixed and enduring”. Over the past two decades the timelines in clinical trials and treatment recommendations were progressively moved to 20 min [
      Treatment of convulsive status epilepticus. Recommendations of the Epilepsy Foundation of America's Working Group on status epilepticus.
      ] and to 10 min [
      • Treiman D.M.
      • Meyers P.D.
      • Walton N.Y.
      • Collins J.F.
      • Colling C.
      • Rowan A.J.
      • et al.
      A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group.
      ]. Lowenstein et al. suggested in 1999 that a generalized tonic clonic seizure that is longer than the usual two to three minutes is prolonged, and should be treated as SE [
      • Lowenstein D.H.
      • Bleck T.
      • Macdonald R.L.
      It's time to revise the definition of status epilepticus.
      ]. The time limit for convulsive status was consequently set to 5 min, which opened the door to change our view on the classical definitions of SE. The Commission of Classification and Terminology of the International League Against Epilepsy and the Commission on Epidemiology charged a Task Force with clinical researchers and epidemiologists to revise the classification of status epilepticus in 2009. The Task force came out in 2015 with the following definition: Status epilepticus is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally prolonged seizures (after time point t1). It is a condition, which can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures [
      • Trinka E.
      • Cock H.
      • Hesdorffer D.
      • Rossetti A.O.
      • Scheffer I.E.
      • Shinnar S.
      • et al.
      A definition and classification of status epilepticus-report of the ILAE task force on classification of status epilepticus.
      ]. This new definition of SE gives a good guidance, when emergency treatment must be considered. In general, time point t1 is the time when treatment should be started, which is at 5 min for generalized tonic clonic seizures, and at 10 min for focal seizures with or without impairment of consciousness. Time-point t2 marks the time at which neuronal damage or self-perpetuating alteration of neuronal networks may begin, and indicates that SE should be controlled latest by that time; 30 min in case of generalized tonic clonic seizures (Fig. 1).
      Fig. 1
      Fig. 1Operational dimensions with t1 indicating the time that emergency treatment of SE should be started and t2 denoting the time at which long term consequences may be expected. Time (t1), when a seizure is likely to be prolonged leading to continuous seizure activity. Time (t2), when a seizure may cause long-term consequences (including neuronal injury, neuronal death, alteration of neuronal networks and functional deficits). For generalized tonic clonic status the stages have been added (stage I 5–10 min; stage II 10–30 min; stage III 30–30 min)
      [
      • Trinka E.
      • Cock H.
      • Hesdorffer D.
      • Rossetti A.O.
      • Scheffer I.E.
      • Shinnar S.
      • et al.
      A definition and classification of status epilepticus-report of the ILAE task force on classification of status epilepticus.
      ]
      .
      The task force also came out with a new classification, built on four axes [
      • Trinka E.
      • Cock H.
      • Hesdorffer D.
      • Rossetti A.O.
      • Scheffer I.E.
      • Shinnar S.
      • et al.
      A definition and classification of status epilepticus-report of the ILAE task force on classification of status epilepticus.
      ]: (i) semiology, (ii) etiology, (iii) EEG correlates, and (iv) age. The backbone of the classification is the semiology. The various clinical forms of status epilepticus are differentiated along two taxonomic criteria: motor activity and impairment of consciousness falling into two major groups: [
      • Betjemann J.P.
      • Lowenstein D.H.
      Status epilepticus in adults.
      ] status epilepticus with prominent motor symptoms, including all convulsive forms, and [
      • Kantanen A.M.
      • Reinikainen M.
      • Parviainen I.
      • Ruokonen E.
      • Ala-Peijari M.
      • Backlund T.
      • et al.
      Incidence and mortality of super-refractory status epilepticus in adults.
      ] those without prominent motor symptoms representing the non-convulsive forms of status epilepticus (NCSE) (see Table 1). Each group can be divided again according to the degree of impairment of consciousness, which is highly clinically relevant. Comatose NCSE represents a life threatening condition that requires urgent and consequent treatment, whereas NCSE proper without coma occurs most often in the form of absence status or focal status with impairment of consciousness (older terms for this conditions were “psychomotor status” or “complex partial status epilepticus”) [
      • Trinka E.
      • Cock H.
      • Hesdorffer D.
      • Rossetti A.O.
      • Scheffer I.E.
      • Shinnar S.
      • et al.
      A definition and classification of status epilepticus-report of the ILAE task force on classification of status epilepticus.
      ,
      • Bauer G.
      • Trinka E.
      Nonconvulsive status epilepticus and coma.
      ]. The etiology of status is divided into two groups: (i) known or symptomatic and (ii) unknown or cryptogenic. The symptomatic group can be subdivided into acute symptomatic, remote symptomatic and progressive symptomatic. The new classification also provides a list of known causes of status as an appendix to the classification, which can be updated periodically as new information emerges. Status epilepticus often occurs in the context of genetic epilepsy syndromes, but there is always a trigger for the status itself, such as fever, electrolyte disturbance or other intrinsic factors [
      • Trinka E.
      • Hofler J.
      • Zerbs A.
      Causes of status epilepticus.
      ].
      Table 1Axis 1 of the classification of status epilepticus (SE)
      • Trinka E.
      • Cock H.
      • Hesdorffer D.
      • Rossetti A.O.
      • Scheffer I.E.
      • Shinnar S.
      • et al.
      A definition and classification of status epilepticus-report of the ILAE task force on classification of status epilepticus.
      .
      The third axis of the classification comprises EEG correlates of status. In convulsive SE the clinical presentation is most often clear and artefacts obscure the EEG, thus the EEG is of little value. The opposite is true for the non-convulsive forms of status epilepticus, where a correct diagnosis is often not possible without EEG. In the most extreme forms the patient is in deep coma, and only an EEG can reveal the epileptiform or rhythmic discharges leading to the diagnosis [
      • Bauer G.
      • Trinka E.
      Nonconvulsive status epilepticus and coma.
      ,
      • Trinka E.
      • Leitinger M.
      Which EEG patterns in coma are nonconvulsive status epilepticus?.
      ]. The task force recommends describing the EEG correlate of status in a patient using the following descriptors: name of pattern, morphology, location, time-related features, modulation, and effect of intervention, and use the recently proposed terminology by the American Clinical Neurophysiology Society [
      • Hirsch L.J.
      • LaRoche S.M.
      • Gaspard N.
      • Gerard E.
      • Svoronos A.
      • Herman S.T.
      • et al.
      American clinical neurophysiology society's standardized critical care EEG terminology: 2012 version.
      ] and the diagnostic “Salzburg EEG criteria for NCSE” (Table 2) [
      • Trinka E.
      • Leitinger M.
      Which EEG patterns in coma are nonconvulsive status epilepticus?.
      ,
      • Beniczky S.
      • Hirsch L.J.
      • Kaplan P.W.
      • Pressler R.
      • Bauer G.
      • Aurlien H.
      • et al.
      Unified EEG terminology and criteria for nonconvulsive status epilepticus.
      ,
      • Kaplan P.W.
      EEG criteria for nonconvulsive status epilepticus.
      ,
      • Leitinger M.
      • Beniczky S.
      • Rohracher A.
      • Gardella E.
      • Kalss G.
      • Qerama E.
      • et al.
      Salzburg consensus criteria for non-convulsive status epilepticus—approach to clinical application.
      ] as a practical guide for diagnosis. In a recent retrospective diagnostic accuracy study using EEG recordings from patients admitted for neurological symptoms or signs of NCSE to three centers (Danish Epilepsy Centre, Dianalund, Denmark; Aarhus University Hospital, Aarhus, Denmark; and Paracelsus Medical University, Salzburg, Austria) in two countries (Austria and Denmark) confirmed the high clinical utility for the “Salzburg EEG criteria for NCSE” [
      • Leitinger M.
      • Trinka E.
      • Gardella E.
      • Rohracher A.
      • Kalss G.
      • Qerama E.
      • et al.
      Diagnostic accuracy of the Salzburg EEG criteria for non-convulsive status epilepticus: a retrospective study.
      ]. The sensitivity was 97.7% (95% CI 87.9–99.6) and specificity was 89.6% (95% CI 80.8–94.6); overall accuracy was 92.5% (95% CI 88.3–97.5). The positive predictive value was 84.0% (95% CI 74.1–91.5) and negative predictive value was 98.6% (95% CI 94.4–100).
      Table 2Salzburg EEG consensus criteria for nonconvulsive status epilepticus
      • Beniczky S.
      • Hirsch L.J.
      • Kaplan P.W.
      • Pressler R.
      • Bauer G.
      • Aurlien H.
      • et al.
      Unified EEG terminology and criteria for nonconvulsive status epilepticus.
      ,
      • Leitinger M.
      • Beniczky S.
      • Rohracher A.
      • Gardella E.
      • Kalss G.
      • Qerama E.
      • et al.
      Salzburg consensus criteria for non-convulsive status epilepticus—approach to clinical application.
      ,
      • Leitinger M.
      • Trinka E.
      • Gardella E.
      • Rohracher A.
      • Kalss G.
      • Qerama E.
      • et al.
      Diagnostic accuracy of the Salzburg EEG criteria for non-convulsive status epilepticus: a retrospective study.
      .
      The new classification underwent a feasibility study: 488 episodes of status epilepticus were retrospectively assessed and classified according to the clinical tradition and the new classification. 230 (47%) had a generalized convulsive, and 29 (6%) had a nonconvulsive SE in coma; both categories overlapped almost perfectly between the two classifications. However in focal SE, which was markedly heterogeneous, the new classification appears to better reflect the clinical reality, offering more relevant subdivisions, which also differ in mortality rates [
      • Rossetti A.O.
      • Trinka E.
      • Stahli C.
      • Novy J.
      New ILAE versus previous clinical status epilepticus semiologic classification: analysis of a hospital-based cohort.
      ].

      3. Recent advances in the treatment of status epilepticus

      The management of status epilepticus and its pharmacological treatment still represents an area with limited evidence derived from high-quality, adequately powered randomized controlled trials (RCTs) to inform clinical practise. However, there have been clear advances in the understanding of the pathomechanisms, which have led to more effective treatment strategies. The therapeutic principle “time is brain” applies not only for stroke but also for status epilepticus, as the prognosis of SE worsens with increasing duration of seizure activity [
      • Madzar D.
      • Geyer A.
      • Knappe R.U.
      • Gollwitzer S.
      • Kuramatsu J.B.
      • Gerner S.T.
      • et al.
      Association of seizure duration and outcome in refractory status epilepticus.
      ,
      • Towne A.R.
      • Pellock J.M.
      • Ko D.
      • DeLorenzo R.J.
      Determinants of mortality in status epilepticus.
      ]. Indeed, prompt recognition and earliest treatment of status epilepticus is associated with lower morbidity and mortality, fewer drugs required in hospitals, and reduction in seizure duration [
      • Alldredge B.K.
      • Wall D.B.
      • Ferriero D.M.
      Effect of prehospital treatment on the outcome of status epilepticus in children.
      ,
      • Silbergleit R.
      • Durkalski V.
      • Lowenstein D.
      • Conwit R.
      • Pancioli A.
      • Palesch Y.
      • et al.
      Intramuscular versus intravenous therapy for prehospital status epilepticus.
      ]. The cost of status in the refractory stages are high and a recent study in Germany has estimated €1,365/day [
      • Kortland L.M.
      • Alfter A.
      • Bahr O.
      • Carl B.
      • Dodel R.
      • Freiman T.M.
      • et al.
      Costs and cost-driving factors for acute treatment of adults with status epilepticus: a multicenter cohort study from Germany.
      ]. Nevertheless, there is only limited industry interest to develop new treatments to prevent refractory status.
      Until late 1980s there was large variation in patient stabilization procedures, laboratory measures, and sequence of medications in the management of SE [
      • Kalviainen R.
      Status epilepticus treatment guidelines.
      ]. In the year 1993, the Epilepsy Foundation of America convened a working group on SE. They published guidelines and a treatment protocol [
      Treatment of convulsive status epilepticus. Recommendations of the Epilepsy Foundation of America's Working Group on status epilepticus.
      ], which was based on a literature review and input from experts. Some key treatment principles of this guideline still remain valid. All treatment protocols recognize a staged approach to treatment with different drugs used in early (stage I), established (stage II), refractory (stage III) and super-refractory SE (stage IV) (Fig. 2) and emphasize prompt recognition and treatment of persisting seizure activity at each stage aiming to reduce morbidity, mortality, and long-term consequences of status epilepticus (beyond t2). Most recent reviews focus on the pharmacotherapy of status, but general measures of neurological emergencies and a thorough search for the causes are equally important [
      • Shorvon S.
      • Baulac M.
      • Cross H.
      • Trinka E.
      • Walker M.
      The drug treatment of status epilepticus in Europe: consensus document from a workshop at the first London Colloquium on status epilepticus.
      ,
      • Brophy G.M.
      • Bell R.
      • Claassen J.
      • Alldredge B.
      • Bleck T.P.
      • Glauser T.
      • et al.
      Guidelines for the evaluation and management of status epilepticus.
      ,
      • Jones S.
      • Pahl C.
      • Trinka E.
      • Nashef L.
      A protocol for the inhospital emergency drug management of convulsive status epilepticus in adults.
      ].
      Fig. 2
      Fig. 2Clinical course of convulsive status epilepticus.
      (Fig. 1 from Reference [
      • Trinka E.
      • Hofler J.
      • Leitinger M.
      • Brigo F.
      Pharmacotherapy for status epilepticus.
      ])
      Most clinical trials have been performed in the early stages of status epilepticus, which has been the subject of several RCTs and critical assessment in systematic reviews with meta-analyses [
      • Prasad K.
      • Krishnan P.R.
      • Al Roomi K.
      • Sequeira R.
      Anticonvulsant therapy for status epilepticus.
      ,

      Prasad M, Krishnan PR, Sequeira R, Al-Roomi K. Anticonvulsant therapy for status epilepticus. The Cochrane database of systematic reviews, 2014. 9 CD003723. PubMed PMID: 25207925.

      ,
      • Brigo F.
      • Nardone R.
      • Tezzon F.
      • Trinka E.
      A common reference-based indirect comparison meta-analysis of buccal versus intranasal midazolam for early status epilepticus.
      ,
      • Brigo F.
      • Nardone R.
      • Tezzon F.
      • Trinka E.
      Nonintravenous midazolam versus intravenous or rectal diazepam for the treatment of early status epilepticus: a systematic review with meta-analysis.
      ,
      • McMullan J.
      • Sasson C.
      • Pancioli A.
      • Silbergleit R.
      Midazolam versus diazepam for the treatment of status epilepticus in children and young adults: a meta-analysis.
      ,
      • Sofou K.
      • Kristjansdottir R.
      • Papachatzakis N.E.
      • Ahmadzadeh A.
      • Uvebrant P.
      Management of prolonged seizures and status epilepticus in childhood: a systematic review.
      ,
      • Brigo F.
      • Storti M.
      • Del Felice A.
      • Fiaschi A.
      • Bongiovanni L.G.
      IV valproate in generalized convulsive status epilepticus: a systematic review.
      ,
      • Brigo F.
      • Bragazzi N.
      • Nardone R.
      • Trinka E.
      Direct and indirect comparison meta-analysis of levetiracetam versus phenytoin or valproate for convulsive status epilepticus.
      ,
      • Brigo F.
      • Bragazzi N.L.
      • Bacigaluppi S.
      • Nardone R.
      • Trinka E.
      Is intravenous lorazepam really more effective and safe than intravenous diazepam as first-line treatment for convulsive status epilepticus? A systematic review with meta-analysis of randomized controlled trials.
      ,
      • Brigo F.
      • Igwe S.C.
      • Nardone R.
      • Tezzon F.
      • Bongiovanni L.G.
      • Trinka E.
      A common reference-based indirect comparison meta-analysis of intravenous valproate versus intravenous phenobarbitone for convulsive status epilepticus.
      ,
      • Trinka E.
      • Hofler J.
      • Leitinger M.
      • Brigo F.
      Pharmacotherapy for status epilepticus.
      ,
      • Trinka E.
      • Hofler J.
      • Leitinger M.
      • Rohracher A.
      • Kalss G.
      • Brigo F.
      Pharmacologic treatment of status epilepticus.
      ,
      • Trinka E.
      • Hofler J.
      • Zerbs A.
      • Brigo F.
      Efficacy and safety of intravenous valproate for status epilepticus: a systematic review.
      ] and included in treatment protocols or practical guidelines [
      • Shorvon S.
      • Baulac M.
      • Cross H.
      • Trinka E.
      • Walker M.
      The drug treatment of status epilepticus in Europe: consensus document from a workshop at the first London Colloquium on status epilepticus.
      ,
      • Brophy G.M.
      • Bell R.
      • Claassen J.
      • Alldredge B.
      • Bleck T.P.
      • Glauser T.
      • et al.
      Guidelines for the evaluation and management of status epilepticus.
      ,
      • Jones S.
      • Pahl C.
      • Trinka E.
      • Nashef L.
      A protocol for the inhospital emergency drug management of convulsive status epilepticus in adults.
      ,
      • Meierkord H.
      • Boon P.
      • Engelsen B.
      • Gocke K.
      • Shorvon S.
      • Tinuper P.
      • et al.
      EFNS guideline on the management of status epilepticus in adults.
      ,
      • Capovilla G.
      • Beccaria F.
      • Beghi E.
      • Minicucci F.
      • Sartori S.
      • Vecchi M.
      Treatment of convulsive status epilepticus in childhood: recommendations of the Italian league against epilepsy.
      ].
      The most effective treatment of early status epilepticus is intravenous benzodiazepines, which are able to control status promptly in about two thirds of all patients [
      • Trinka E.
      • Brigo F.
      • Shorvon S.
      Recent advances in status epilepticus.
      ,
      • Trinka E.
      • Hofler J.
      • Leitinger M.
      • Brigo F.
      Pharmacotherapy for status epilepticus.
      ]. Benzodiazepines exert their antiepileptic properties by enhancing the inhibitory neurotransmission through increasing channel opening frequency of the GABA-A receptors, with subsequent increased chloride conductance and neuronal hyperpolarization [
      • Trinka E.B.F.
      Benzodiazepines used in the treatment of epilepsy.
      ]. The benzodiazepines commonly used as first-treatment in SE are lorazepam, diazepam, midazolam and clonazepam (Fig. 3). Intravenous lorazepam is less lipid-soluble (octanol/water partition coefficient for lorazepam is 73 [
      • Schütz H.
      Benzodiazepines II. A handbook. Basic data, analytical methods, pharmacokonetics, and comprehensive literature.
      ]) and hence does not undergo a rapid redistribution into peripheral tissues as diazepam, which should also result in a clinical longer duration of action [
      • Trinka E.B.F.
      Benzodiazepines used in the treatment of epilepsy.
      ,
      • Greenblatt D.J.
      • Divoll M.
      Diazepam versus lorazepam: relationship of drug distribution to duration of clinical action.
      ]. Previous meta-analyses [

      Prasad M, Krishnan PR, Sequeira R, Al-Roomi K. Anticonvulsant therapy for status epilepticus. The Cochrane database of systematic reviews, 2014. 9 CD003723. PubMed PMID: 25207925.

      ] of all randomized controlled studies [
      • Leppik I.E.
      • Derivan A.T.
      • Homan R.W.
      • Walker J.
      • Ramsay R.E.
      • Patrick B.
      Double-blind study of lorazepam and diazepam in status epilepticus.
      ,
      • Appleton R.
      • Sweeney A.
      • Choonara I.
      • Robson J.
      • Molyneux E.
      Lorazepam versus diazepam in the acute treatment of epileptic seizures and status epilepticus.
      ,
      • Alldredge B.K.
      • Gelb A.M.
      • Isaacs S.M.
      • Corry M.D.
      • Allen F.
      • Ulrich S.
      • et al.
      A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus.
      ] found lorazepam to be superior. Since the Cochrane Review another large trial was performed in children with status epilepticus (273 patients; 140 randomized to diazepam and 133 to lorazepam), which failed to show a superiority of lorazepam in terms of seizure control [
      • Chamberlain J.M.
      • Okada P.
      • Holsti M.
      • Mahajan P.
      • Brown K.M.
      • Vance C.
      • et al.
      Lorazepam vs diazepam for pediatric status epilepticus: a randomized clinical trial.
      ]. Moreover in this study children who received lorazepam were more often sedated. In a recent systematic review with meta-analysis of randomized controlled trials five RCTs were included, with a total of 656 patients, 320 randomly allocated to IV LZP and 336 to IV DZP. No statistically significant differences were found between IV LZP and IV DZP for clinical seizure cessation (RR 1.09; 95% CI 1.00–1.20), continuation of SE requiring a different drug (RR 0.76; 95% CI 0.57–1.02), seizure cessation after a single dose of medication (RR 0.96; 95% CI 0.85–1.08), need for ventilator support RR 0.93; 95% CI 0.61–1.43, and clinically relevant hypotension [
      • Brigo F.
      • Bragazzi N.L.
      • Bacigaluppi S.
      • Nardone R.
      • Trinka E.
      Is intravenous lorazepam really more effective and safe than intravenous diazepam as first-line treatment for convulsive status epilepticus? A systematic review with meta-analysis of randomized controlled trials.
      ]. The authors concluded consequently “Despite its favorable pharmacokinetic profile, a systematic appraisal of the literature does not provide evidence to strongly support the preferential use of IV LZP as first-line treatment of convulsive SE over IV DZP”. An overview on the staged treatment approach is given in Fig. 3.
      Fig. 3
      Fig. 3Staged treatment protocol for early (stage I), established (stage II) and refractory (stage III) convulsive status epilepticus. Timelines for stage I–III given are general approximations and may vary depending on clinical circumstances, cause, and age of the patient.
      (Fig. 1 from Reference [
      • Trinka E.
      • Hofler J.
      • Leitinger M.
      • Rohracher A.
      • Kalss G.
      • Brigo F.
      Pharmacologic treatment of status epilepticus.
      ])
      In the past decades alternative routes of administrations have been explored. A landmark study intramuscular midazolam was compared to intravenous lorazepam as first-line treatment for convulsive status epilepticus in a double blind, randomized, non-inferiority design. This study included 893 children and adults treated by paramedics before admission to hospital [
      • Silbergleit R.
      • Durkalski V.
      • Lowenstein D.
      • Conwit R.
      • Pancioli A.
      • Palesch Y.
      • et al.
      Intramuscular versus intravenous therapy for prehospital status epilepticus.
      ]. Seizures were controlled in 73.4% with intramuscular midazolam, and in 63.4% with intravenous lorazepam (absolute difference 10%; 95% CI: 4.0 to 16.1%; p < 0.001 for both non inferiority and superiority). Among patients whose seizures ceased before arrival to the emergency department, the median time to drug administration was significantly shorter in the midazolam group (1.2 min vs 4.8 min), although clinical seizure cessation occurred earlier after lorazepam administration (1.6 min vs. 3.3 min) [
      • Silbergleit R.
      • Durkalski V.
      • Lowenstein D.
      • Conwit R.
      • Pancioli A.
      • Palesch Y.
      • et al.
      Intramuscular versus intravenous therapy for prehospital status epilepticus.
      ].
      Intranasal and buccal administration of benzodiazepines have been studied extensively over the past years. The water-soluble midazolam offers pharmacological advantages over the lipophilic lorazepam and diazepam. In a comprehensive meta-analysis the efficacy and safety of non-intravenous midazolam in adults and children were compared to rectal or intravenous diazepam. Nineteen studies with 1933 seizures in 1602 patients were included. For seizure cessation, non-IV midazolam was as effective as diazepam (any route) (1933 seizures; RR: 1.03; 95% CIs: 0.98–1.08). No difference in adverse effects was found between non-IM midazolam and diazepam by any route (1933 seizures; RR: 0.87; 95% CIs: 0.50–1.50) [
      • Brigo F.
      • Nardone R.
      • Tezzon F.
      • Trinka E.
      Nonintravenous midazolam versus intravenous or rectal diazepam for the treatment of early status epilepticus: a systematic review with meta-analysis.
      ]. A common reference based meta-analysis compared intranasal to buccal administration midazolam [
      • Brigo F.
      • Nardone R.
      • Tezzon F.
      • Trinka E.
      A common reference-based indirect comparison meta-analysis of buccal versus intranasal midazolam for early status epilepticus.
      ]. Intravenous or rectal diazepam or intravenous lorazepam served as the reference for indirect comparisons. The authors did not find a difference in efficacy between intranasal and buccal midazolam, but found a large width and asymmetrical distribution of confidence intervals around the obtained OR of 2.81 (95% CI 0.39–20.12) comparing intranasal midazolam with rectal diazepam for serious adverse effects [
      • Brigo F.
      • Nardone R.
      • Tezzon F.
      • Trinka E.
      A common reference-based indirect comparison meta-analysis of buccal versus intranasal midazolam for early status epilepticus.
      ]. However, overall, these data indicate that midazolam administered by non-intravenous routes represents a practical, rapid, reasonably safe and effective alternative to either intravenous lorazepam or intravenous/rectal diazepam as first-line treatment of early status epilepticus in out of hospital settings (Fig. 4).
      Fig. 4
      Fig. 4Treatment options for early (stage I) status epilepticus, when intravenous routes are not available.
      (Fig. 2 from Reference [
      • Trinka E.
      • Hofler J.
      • Leitinger M.
      • Rohracher A.
      • Kalss G.
      • Brigo F.
      Pharmacologic treatment of status epilepticus.
      ])
      Approximately 40% of patients with generalized convulsive SE (GCSE) are refractory to benzodiazepine treatment [
      • Treiman D.M.
      • Meyers P.D.
      • Walton N.Y.
      • Collins J.F.
      • Colling C.
      • Rowan A.J.
      • et al.
      A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group.
      ,
      • Silbergleit R.
      • Durkalski V.
      • Lowenstein D.
      • Conwit R.
      • Pancioli A.
      • Palesch Y.
      • et al.
      Intramuscular versus intravenous therapy for prehospital status epilepticus.
      ,
      • Alldredge B.K.
      • Gelb A.M.
      • Isaacs S.M.
      • Corry M.D.
      • Allen F.
      • Ulrich S.
      • et al.
      A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus.
      ]. This ongoing seizure activity is referred to as established SE (or stage II). In established SE, intravenous antiepileptic drugs (phenytoin/fosphenytoin, valproate, levetiracetam, phenobarbital, and lacosamide) are most commonly used, but there is no class I evidence for choosing one over the other. This unsatisfactory situation has several consequences: firstly most patients are treated off label. Recent data from a registry in Germany, Austria, and Switzerland [
      • Kellinghaus C.
      • Lang N.
      • Rossetti A.O.
      • Ruegg S.
      • Tilz C.
      • Trinka E.
      • et al.
      Making SENSE–Sustained Effort Network for treatment of status epilepticus as a multicenter prospective registry.
      ] and a global audit [
      • Ferlisi M.
      • Hocker S.
      • Grade M.
      • Trinka E.
      • Shorvon S.
      International steering committee of the StEp A. Preliminary results of the global audit of treatment of refractory status epilepticus.
      ] suggests that 34% of patients in the early stages and 91% in the later stages receive off label treatment. Secondly, status epilepticus, with its high mortality and severe morbidity is a shaky ground for the pharma industry to embark in high-class trials with unknown return of investments. And thirdly, there are no well-defined regulatory pathways for drugs to treat later stages of status epilepticus. This leaves the clinicians uninformed about the best choice in the established stage of status epilepticus and they have to take decisions under uncertainty, with all the medico-legal consequences. Guidelines, which are based on currently available evidence are only a weak remedy, because the evidence they are based on is weak. There are several comprehensive narrative reviews on the pharmacologic treatment of status [
      • Trinka E.
      • Brigo F.
      • Shorvon S.
      Recent advances in status epilepticus.
      ,
      • Trinka E.
      • Hofler J.
      • Leitinger M.
      • Brigo F.
      Pharmacotherapy for status epilepticus.
      ,
      • Trinka E.
      • Hofler J.
      • Leitinger M.
      • Rohracher A.
      • Kalss G.
      • Brigo F.
      Pharmacologic treatment of status epilepticus.
      ], summarizing the current evidence. The succus is, that there are no double-blind, but six randomized open studies with valproate and two with levetiracetam. A meta-analysis found higher rates of seizure cessation with valproate 75.7% (95% CI 63.7–84.8) and phenobarbital 73.6%, (95% CI 58.3–84.8) than with levetiracetam (68.5%, 95% CI 56.2–78.7) or phenytoin (50.2%, 95% CI 34.2–66.1). Based on the favorable tolerability profile of levetiracetam and valproate, the authors prefer these drugs in established SE over phenytoin/fosphenytoin (Fig. 3). Currently a large NIH funded trial (Established Status Epilepticus Trial, ESET) is on the way, which is designed as a multicenter, randomized, blinded, comparative effectiveness study of fosphenytoin, valproic acid, or levetiracetam in the emergency department treatment of patients with benzodiazepine-refractory status epilepticus [ClinicalTrials.gov Identifier: NCT01960075] [
      • Cock H.R.
      • Group E.
      Established status epilepticus treatment trial (ESETT).
      ,
      • Bleck T.
      • Cock H.
      • Chamberlain J.
      • Cloyd J.
      • Connor J.
      • Elm J.
      • et al.
      The established status epilepticus trial 2013.
      ]. The trial is currently recruiting and first results can be expected in 2017. Until the results of this trial are available, newer drugs such as lacosamide will be used extensively in established and refractory status epilepticus [
      • Lang N.
      • Lange M.
      • Schmitt F.C.
      • Bos M.
      • Weber Y.
      • Evers S.
      • et al.
      Intravenous lacosamide in clinical practice-results from an independent registry.
      ,
      • Hofler J.
      • Trinka E.
      Lacosamide as a new treatment option in status epilepticus.
      ].
      In a review of 136 patients with refractory SE (50% non-convulsive SE, 31% focal SE, and 19% convulsive SE) treated with lacosamide an overall success rate of 56% was reported with adverse events observed in 25% (mostly mild sedation) [
      • Hofler J.
      • Trinka E.
      Lacosamide as a new treatment option in status epilepticus.
      ]. These findings have been confirmed by a subsequent cohort study [
      • Sutter R.
      • Marsch S.
      • Ruegg S.
      Safety and efficacy of intravenous lacosamide for adjunctive treatment of refractory status epilepticus: a comparative cohort study.
      ] and by a case series conducted in 55 patients with SE and 43 patients with acute repetitive seizures [
      • Garces M.
      • Villanueva V.
      • Mauri J.A.
      • Suller A.
      • Garcia C.
      • Lopez Gonzalez F.J.
      • et al.
      Factors influencing response to intravenous lacosamide in emergency situations: LACO-IV study.
      ]. The most commonly used bolus dose was 400 mg, followed by a daily dose of 200–400 mg lacosamide leading to abrogation of seizures in 56% (76/136) [
      • Hofler J.
      • Trinka E.
      Lacosamide as a new treatment option in status epilepticus.
      ]. Intravenous brivaracetam is already on the market and experts feel that there is a certain potential for this drug in status epilepticus, but so far no reports in humans have been published.
      In 31–43% of patients in established status epilepticus are not controlled with antiepileptic drugs [
      • Mayer S.A.
      • Claassen J.
      • Lokin J.
      • Mendelsohn F.
      • Dennis L.J.
      • Fitzsimmons B.F.
      Refractory status epilepticus: frequency, risk factors, and impact on outcome.
      ,
      • Holtkamp M.
      • Othman J.
      • Buchheim K.
      • Meierkord H.
      Predictors and prognosis of refractory status epilepticus treated in a neurological intensive care unit.
      ]. In this stage, also called refractory status epilepticus, intravenous anesthetic drugs (thiopental/pentobarbital, midazolam, or propofol) have been, and still are, commonly used in the past 30 years (Fig. 3). In a global audit of 488 episodes of RSE, continuous midazolam infusion was the most widely used anesthetic in (59%) followed by propofol (32%) and barbiturates (8%) [
      • Ferlisi M.
      • Hocker S.
      • Grade M.
      • Trinka E.
      • Shorvon S.
      International steering committee of the StEp A. Preliminary results of the global audit of treatment of refractory status epilepticus.
      ]. In two systemic reviews none of the treatments currently available was superior to another [
      • Claassen J.
      • Hirsch L.J.
      • Emerson R.G.
      • Mayer S.A.
      Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review.
      ,
      • Ferlisi M.
      • Shorvon S.
      The outcome of therapies in refractory and super-refractory convulsive status epilepticus and recommendations for therapy.
      ]. Propofol may be associated with metabolic acidosis, rhabdomyolysis, renal failure and heart failure [
      • Niermeijer J.M.
      • Uiterwaal C.S.
      • Van Donselaar C.A.
      Propofol in status epilepticus: little evidence, many dangers?.
      ]. This propofol infusion syndrome occurs less likely, when treatment duration is less than 48 h and doses does not exceed 5 mg/kg/h. Midazolam seems to be the safest drug at this stage with the lowest rate of cardiovascular and metabolic complication, while barbiturates seem to be most often associated with cardiovascular complications, severe immunosuppression, and infections in the [
      • Claassen J.
      • Hirsch L.J.
      • Emerson R.G.
      • Mayer S.A.
      Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review.
      ,
      • Ferlisi M.
      • Shorvon S.
      The outcome of therapies in refractory and super-refractory convulsive status epilepticus and recommendations for therapy.
      ]. The use of anesthetics in refractory and super-refractory SE was associated with more infections during status epilepticus (43% vs 11%; p < 0.0001) and a 2.9-fold relative risk for death (2.88; 95% confidence interval 1.45–5.73) in a 6-year prospective cohort study including 171 patients (63 of them received intravenous anesthetics) [
      • Sutter R.
      • Marsch S.
      • Fuhr P.
      • Kaplan P.W.
      • Ruegg S.
      Anesthetic drugs in status epilepticus: risk or rescue? A 6-year cohort study.
      ].
      These findings fueled the search for more efficacious and better tolerated treatments in refractory and super-refractory status. Ketamine has gained much interest, due to its pharmacological properties. Its strong antagonistic effect on the N-methyl-d-aspartate (NMDA) — glutamate receptors [
      • Fujikawa D.G.
      Neuroprotective effect of ketamine administered after status epilepticus onset.
      ], which play a key role in the advanced forms of status epilepticus [
      • Borris D.J.
      • Bertram E.H.
      • Kapur J.
      Ketamine controls prolonged status epilepticus.
      ,
      • Kapur J.
      • Coulter D.A.
      Experimental status epilepticus alters gamma-aminobutyric acid type A receptor function in CA1 pyramidal neurons.
      ,
      • Mazarati A.M.
      • Wasterlain C.G.
      N-methyl-D-asparate receptor antagonists abolish the maintenance phase of self-sustaining status epilepticus in rat.
      ]. There are three retrospective case series to date [
      • Gaspard N.
      • Foreman B.
      • Judd L.M.
      • Brenton J.N.
      • Nathan B.R.
      • McCoy B.M.
      • et al.
      Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multicenter study.
      ,
      • Synowiec A.S.
      • Singh D.S.
      • Yenugadhati V.
      • Valeriano J.P.
      • Schramke C.J.
      • Kelly K.M.
      Ketamine use in the treatment of refractory status epilepticus.
      ,
      • Basha M.M.
      • Alqallaf A.
      • Shah A.K.
      Drug-induced EEG pattern predicts effectiveness of ketamine in treating refractory status epilepticus.
      ] and 10 case reports [
      • Walker M.C.
      • Howard R.S.
      • Smith S.J.
      • Miller D.H.
      • Shorvon S.D.
      • Hirsch N.P.
      Diagnosis and treatment of status epilepticus on a neurological intensive care unit.
      ,
      • Kofke W.A.
      • Bloom M.J.
      • Van Cott A.
      • Brenner R.P.
      Electrographic tachyphylaxis to etomidate and ketamine used for refractory status epilepticus controlled with isoflurane.
      ,
      • Ubogu E.E.
      • Sagar S.M.
      • Lerner A.J.
      • Maddux B.N.
      • Suarez J.I.
      • Werz M.A.
      Ketamine for refractory status epilepticus: a case of possible ketamine-induced neurotoxicity.
      ,
      • Robakis T.K.
      • Hirsch L.J.
      Literature review, case report, and expert discussion of prolonged refractory status epilepticus.
      ,
      • Pruss H.
      • Holtkamp M.
      Ketamine successfully terminates malignant status epilepticus.
      ,
      • Yeh P.S.
      • Shen H.N.
      • Chen T.Y.
      Oral ketamine controlled refractory nonconvulsive status epilepticus in an elderly patient.
      ,
      • Kramer A.H.
      Early ketamine to treat refractory status epilepticus.
      ,
      • Zeiler F.A.
      • Kaufmann A.M.
      • Gillman L.M.
      • West M.
      • Silvaggio J.
      Ketamine for medically refractory status epilepticus after elective aneurysm clipping.
      ,
      • Shrestha G.S.
      • Joshi P.
      • Chhetri S.
      • Karn R.
      • Acharya S.P.
      Intravenous ketamine for treatment of super-refractory convulsive status epilepticus with septic shock: a report of two cases.
      ,
      • Hsieh C.Y.
      • Sung P.S.
      • Tsai J.J.
      • Huang C.W.
      Terminating prolonged refractory status epilepticus using ketamine.
      ] reporting 94 episodes of refractory status epilepticus in adults treated with ketamine leading to successful termination of status epilepticus in 63% [
      • Trinka E.
      • Hofler J.
      • Leitinger M.
      • Rohracher A.
      • Kalss G.
      • Brigo F.
      Pharmacologic treatment of status epilepticus.
      ]. Ketamine is a racemic mixture containing equal amounts of two enantiomers, (S)- and (R)-ketamine. Ketamine is extensively metabolized by N-demethylation producing norketamine, a non-competitive NMDA receptor antagonist that may also exhibit enantioselective pharmacological activity. (S)-Ketamine has different pharmacodynamic activities and is a two to threefold more potent analgesic agent than (R)-ketamine. (S)-Ketamine administered alone has a higher clearance than in the racemic mixture resulting in quicker elimination, shorter duration of action and a faster recovery from anesthesia [
      • White P.F.
      • Schuttler J.
      • Shafer A.
      • Stanski D.R.
      • Horai Y.
      • Trevor A.J.
      Comparative pharmacology of the ketamine isomers. Studies in volunteers.
      ]. The S-enantiomer was also associated with a more rapid recovery of psychomotor skills than the racemic mixture [
      • Engelhardt W.
      • Stahl K.
      • Marouche A.
      • Hartung E.
      Recovery time after (S)-ketamine or ketamine racemate. Recovery time after short anesthesia in volunteers.
      ]. Thus the use of (s)-ketamine in refractory and super-refractory status should have clinically relevant advantages. One large single center study from Austria reported on 42 patients who were treated with (s)-ketamine. The median duration of status epilepticus was 10 days; the median latency from SE onset to the first administration of (s)-ketamine was 3 days. In 64% of patients (s)-ketamine was the last drug before cessation of status. However, in five patients, it was given with propofol at the same time, so a definite causal inference could not be drawn. Median duration of administration was 4 days. Overall (s)-ketamine treatment was well tolerated, adverse effects were not observed, and overall mortality was 45.2% [
      • Hofler 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.
      ].
      The new antiepileptic drug perampanel also exerts its mechanism on the antiglutamatergic pathways. Unlike ketamine it does not act, even at high doses on the NMDA receptors, but is a non-competitive antagonist at the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor [
      • Hanada T.
      • Hashizume Y.
      • Tokuhara N.
      • Takenaka O.
      • Kohmura N.
      • Ogasawara A.
      • et al.
      Perampanel: a novel, orally active, noncompetitive AMPA-receptor antagonist that reduces seizure activity in rodent models of epilepsy.
      ,
      • Rogawski M.A.
      • Hanada T.
      Preclinical pharmacology of perampanel, a selective non-competitive AMPA receptor antagonist.
      ]. Perampanel was administered via nasogastric tube in 22 cases. The initial median dose was 4 mg, which was uptitrated to median 12 mg [
      • Rohracher A.
      • Hofler J.
      • Kalss G.
      • Leitinger M.
      • Kuchukhidze G.
      • Deak I.
      • et al.
      Perampanel in patients with refractory and super-refractory status epilepticus in a neurological intensive care unit.
      ,
      • Redecker J.
      • Wittstock M.
      • Benecke R.
      • Rosche J.
      Efficacy of perampanel in refractory nonconvulsive status epilepticus and simple partial status epilepticus.
      ,
      • Rosche J.
      • Kampf C.
      • Benecke R.
      Possible effect of perampanel on focal status epilepticus after generalized tonic-clonic status epilepticus.
      ]. The patient numbers in these case series are low (largest single center experience with 12 cases) and patients too heterogeneous to draw valid conclusions on efficacy.
      Another new strategy in the treatment of super-refractory status epilepticus involved neurosteroid. As status evolves over time, synaptic GABA-A receptors are internalized from the synaptic membrane to the cytosol leading to a lack of efficacy of benzodiazepines in later stages of SE, while extrasynaptic GABA-A receptors do not undergo internalization [
      • Naylor D.E.
      • Liu H.
      • Wasterlain C.G.
      Trafficking of GABA(A) receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus.
      ,
      • Naylor D.E.
      • Wasterlain C.G.
      GABA synapses and the rapid loss of inhibition to dentate gyrus granule cells after brief perforant-path stimulation.
      ]. The neuroactive steroid allopregnanolon acts as a positive allosteric modulator of synaptic and extrasynaptic GABA-A receptors [
      • Rogawski M.A.
      • Loya C.M.
      • Reddy K.
      • Zolkowska D.
      • Lossin C.
      Neuroactive steroids for the treatment of status epilepticus.
      ]. In animal models the efficacy of allopregnanolon in cessation of established SE was observed. The evidence in humans is limited to only three patients (one adult, two children) with super-refractory SE reported to date. In all reported cases, allopregnanolon led to control of SE allowing the general anesthetics to be weaned [
      • Broomall E.
      • Natale J.E.
      • Grimason M.
      • Goldstein J.
      • Smith C.M.
      • Chang C.
      • et al.
      Pediatric super-refractory status epilepticus treated with allopregnanolone.
      ]. Following successful completion of a phase I/II study (ClinicalTrials.gov Identifier: NCT02052739; results not in the public domain) in superrefractory status epilepticus, an US based company is currently conducting a large multicenter phase III trial with the neuroactive steroid (ClinicalTrials.gov Identifier: NCT02477618). The aims of the trial are very ambitious and irrespective, whether the trial meets the endpoint, important data on the causes, clinical presentations and EEG in superrefractory status will be gathered.
      Other treatments than the intravenous anesthetics (thiopental, pentobarbital, midazolam, propofol, ketamine,) including non-pharmacologic therapies were used in this stage of status epilepticus (inhalational anesthetics, topiramate, lacosamide, pregabaline, levetiracetam, magnesium, pyridoxine, immunotherapy) and non-pharmacological treatments (hypothermia, ketogenic diet, emergency neurosurgery, electroconvulsive therapy, cerebrospinal fluid drainage, vagal nerve stimulation and deep brain stimulation) [
      • Ferlisi M.
      • Shorvon S.
      The outcome of therapies in refractory and super-refractory convulsive status epilepticus and recommendations for therapy.
      ]. Ferlisi and Shorvon have reviewed these treatments and their outcomes [
      • Ferlisi M.
      • Shorvon S.
      The outcome of therapies in refractory and super-refractory convulsive status epilepticus and recommendations for therapy.
      ,
      • Shorvon S.
      • Ferlisi M.
      The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol.
      ].
      There is growing evidence of inflammation as an important factor in epileptogenesis, as well as the increasing discovery of antibodies against neural targets as underlying cause of some forms of encephalopathies presenting with seizures and refractory status epilepticus [
      • Vezzani A.
      • Ruegg S.
      The pivotal role of immunity and inflammatory processes in epilepsy is increasingly recognized: introduction.
      ]. Therefore, anti-inflammatory agents like steroids and immunoglobulines as well as plasma exchange in super-refractory SE becomes more frequent despite any evidence supporting its use without a proven or suspected underlying immunological disorder [
      • Shorvon S.
      • Ferlisi M.
      The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol.
      ]. There are potential side effects associated with immunosuppression, such as severe infections and metabolic disturbances, which are to be taken into account when a trial with anti-inflammatory drugs in super-refractory SE is considered. The recently published clinical algorithm is helpful in making the decision for a potentially harmful treatment [
      • Graus F.
      • Titulaer M.J.
      • Balu R.
      • Benseler S.
      • Bien C.G.
      • Cellucci T.
      • et al.
      A clinical approach to diagnosis of autoimmune encephalitis.
      ].

      4. Conclusion

      There have been major advances in the clinical field with a new definition and classification, which gives clinicians a better guidance as to when to treat, how aggressive to treat, and how to avoid over- or under-treatment of this condition. In the treatment arena new small companies embark in the development of niche products, such as neurosteroids in super refractory status epilepticus or new alternative methods of application. The increased interest in status epilepticus has alerted clinicians to treat early and more appropriate and search consequently for the causes of status in each patient. Despite these achievements there are many unmet needs, beginning with identification of cause directed treatments not only to prevent status recurrence but also to protect the brain from the consequences of status and the development of epilepsy to the better delineation of the subtypes of status. This can only be achieved through better understanding of the mechanisms of status in different causes and major efforts to bridge the gap between preclinical knowledge to human applications.

      Conflict of interest statement

      There was no funding related to the preparation of this article.
      Eugen Trinka has acted as a paid consultant to Eisai, Ever Neuropharma, Biogen Idec, Medtronics, Bial, and UCB and has received speakers’ honoraria from Bial, Eisai, GL Pharma, GlaxoSmithKline, Boehringer, Viropharma, Actavis, and UCB Pharma in the past 3 years.
      Eugen Trinka has received research funding from UCB Pharma , Biogen-Idec , Red Bull , Merck , the European Union , FWF Österreichischer Fond zur Wissenschaftsförderung , and Bundesministerium für Wissenschaft und Forschung , Jubiläumsfond der Östrerreichischen Nationalbank . Eugen Trinka is also part of the investigators planning the ESET-Trial and member of the Task Force on Classification of status epilepticus of the ILAE.
      Reetta Kälviäinen has acted as paid consultant to Eisai, Fennomedical, GW Pharmaceuticals, Orion, Pfizer, Sage Therapeutics, and UCB and received speaker’s honoraria from Eisai, UCB, and Orion in the past 3 years; and research support for her institute from the Academy of Finland, Vaajasalo Foundation, Saastamoinen Foundation, UCB, and Eisai.

      References

        • Betjemann J.P.
        • Lowenstein D.H.
        Status epilepticus in adults.
        Lancet Neurol. 2015; 14 (PubMed PMID: 25908090): 615-624
        • Kantanen A.M.
        • Reinikainen M.
        • Parviainen I.
        • Ruokonen E.
        • Ala-Peijari M.
        • Backlund T.
        • et al.
        Incidence and mortality of super-refractory status epilepticus in adults.
        Epilepsy Behav: E&B. 2015; 49 (PubMed PMID: 26141934): 131-134
        • Trinka E.
        • Brigo F.
        • Shorvon S.
        Recent advances in status epilepticus.
        Curr Opin Neurol. 2016; 29 (PubMed PMID: 26886360): 189-198
        • Shorvon S.
        • Trinka E.
        The 5th London-Innsbruck colloquium on status epilepticus and acute seizures.
        Epilepsy Behav: E&B. 2015; 49 (PubMed PMID: 26052077): 1-3
        • Gastaut H.
        Clinical and electroencephalographical classification of epileptic seizures.
        Epilepsia. 1970; 11: 102-113
        • Gastaut H.
        A propos d'une classification symptomatologique des Çtats de mal Çpileptiques.
        in: Gastaut H. Roger J. Lob H. Les Çtats de mal Çpileptiques. Masson, Paris1967: 1-8
        • Gastaut H.
        Clinical and electroencephalographical classification of epileptic seizures.
        Epilepsia. 1969; 10: S2-S13
        • Gastaut H.
        Classification of status epilepticus.
        in: Status epilepticus mechanisms of brain damage and treatment advances in neurology. vol 34. Raven Press, New York1983: 15-35
      1. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. From the Commission on Classification and Terminology of the International League Against Epilepsy.
        Epilepsia. 1981; 22: 489-501
      2. Treatment of convulsive status epilepticus. Recommendations of the Epilepsy Foundation of America's Working Group on status epilepticus.
        JAMA. 1993; 270: 854-859
        • Treiman D.M.
        • Meyers P.D.
        • Walton N.Y.
        • Collins J.F.
        • Colling C.
        • Rowan A.J.
        • et al.
        A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group.
        N Engl J Med. 1998; 339: 792-798
        • Lowenstein D.H.
        • Bleck T.
        • Macdonald R.L.
        It's time to revise the definition of status epilepticus.
        Epilepsia. 1999; 40: 120-122
        • Trinka E.
        • Cock H.
        • Hesdorffer D.
        • Rossetti A.O.
        • Scheffer I.E.
        • Shinnar S.
        • et al.
        A definition and classification of status epilepticus-report of the ILAE task force on classification of status epilepticus.
        Epilepsia. 2015; 56 (PubMed PMID: 26336950): 1515-1523
        • Bauer G.
        • Trinka E.
        Nonconvulsive status epilepticus and coma.
        Epilepsia. 2010; 51 (PubMed PMID: 19744116): 177-190
        • Trinka E.
        • Hofler J.
        • Zerbs A.
        Causes of status epilepticus.
        Epilepsia. 2012; 53 (PubMed PMID: 22946730): 127-138
        • Trinka E.
        • Leitinger M.
        Which EEG patterns in coma are nonconvulsive status epilepticus?.
        Epilepsy Behav: E&B. 2015; 49 (PubMed PMID: 26148985): 203-222
        • Hirsch L.J.
        • LaRoche S.M.
        • Gaspard N.
        • Gerard E.
        • Svoronos A.
        • Herman S.T.
        • et al.
        American clinical neurophysiology society's standardized critical care EEG terminology: 2012 version.
        J Clin Neurophys. 2013; 30 (PubMed PMID: 23377439): 1-27
        • Beniczky S.
        • Hirsch L.J.
        • Kaplan P.W.
        • Pressler R.
        • Bauer G.
        • Aurlien H.
        • et al.
        Unified EEG terminology and criteria for nonconvulsive status epilepticus.
        Epilepsia. 2013; 54 (PubMed PMID: 24001066): 28-29
        • Kaplan P.W.
        EEG criteria for nonconvulsive status epilepticus.
        Epilepsia. 2007; 48 (PubMed PMID: 18329995): 39-41
        • Leitinger M.
        • Beniczky S.
        • Rohracher A.
        • Gardella E.
        • Kalss G.
        • Qerama E.
        • et al.
        Salzburg consensus criteria for non-convulsive status epilepticus—approach to clinical application.
        Epilepsy Behav: E&B. 2015; 49 (PubMed PMID: 26092326): 158-163
        • Leitinger M.
        • Trinka E.
        • Gardella E.
        • Rohracher A.
        • Kalss G.
        • Qerama E.
        • et al.
        Diagnostic accuracy of the Salzburg EEG criteria for non-convulsive status epilepticus: a retrospective study.
        Lancet Neurol. 2016; 15 (PubMed PMID: 27571157): 1054-1062
        • Rossetti A.O.
        • Trinka E.
        • Stahli C.
        • Novy J.
        New ILAE versus previous clinical status epilepticus semiologic classification: analysis of a hospital-based cohort.
        Epilepsia. 2016; (PubMed PMID 27249322)
        • Madzar D.
        • Geyer A.
        • Knappe R.U.
        • Gollwitzer S.
        • Kuramatsu J.B.
        • Gerner S.T.
        • et al.
        Association of seizure duration and outcome in refractory status epilepticus.
        J Neurol. 2016; 263 (PubMed PMID: 26725091): 485-491
        • Towne A.R.
        • Pellock J.M.
        • Ko D.
        • DeLorenzo R.J.
        Determinants of mortality in status epilepticus.
        Epilepsia. 1994; 35: 27-34
        • Alldredge B.K.
        • Wall D.B.
        • Ferriero D.M.
        Effect of prehospital treatment on the outcome of status epilepticus in children.
        Pediatr Neurol. 1995; 12 (PubMed PMID: 7619187): 213-216
        • Silbergleit R.
        • Durkalski V.
        • Lowenstein D.
        • Conwit R.
        • Pancioli A.
        • Palesch Y.
        • et al.
        Intramuscular versus intravenous therapy for prehospital status epilepticus.
        N Engl J Med. 2012; 366 (PubMed PMID: 22335736 Pubmed Central PMCID: 3307101): 591-600
        • Kortland L.M.
        • Alfter A.
        • Bahr O.
        • Carl B.
        • Dodel R.
        • Freiman T.M.
        • et al.
        Costs and cost-driving factors for acute treatment of adults with status epilepticus: a multicenter cohort study from Germany.
        Epilepsia. 2016; (PubMed PMID 27753082)
        • Kalviainen R.
        Status epilepticus treatment guidelines.
        Epilepsia. 2007; 48 (PubMed PMID: 18330014): 99-102
        • Shorvon S.
        • Baulac M.
        • Cross H.
        • Trinka E.
        • Walker M.
        The drug treatment of status epilepticus in Europe: consensus document from a workshop at the first London Colloquium on status epilepticus.
        Epilepsia. 2008; 49: 1277-1285
        • Brophy G.M.
        • Bell R.
        • Claassen J.
        • Alldredge B.
        • Bleck T.P.
        • Glauser T.
        • et al.
        Guidelines for the evaluation and management of status epilepticus.
        Neurocrit Care. 2012; 17 (PubMed PMID: 22528274): 3-23
        • Jones S.
        • Pahl C.
        • Trinka E.
        • Nashef L.
        A protocol for the inhospital emergency drug management of convulsive status epilepticus in adults.
        Practical Neurol. 2014; 14 (PubMed PMID: 24810377): 194-197
        • Prasad K.
        • Krishnan P.R.
        • Al Roomi K.
        • Sequeira R.
        Anticonvulsant therapy for status epilepticus.
        Br J Clin Pharmacol. 2007; 63: 640-647
      3. Prasad M, Krishnan PR, Sequeira R, Al-Roomi K. Anticonvulsant therapy for status epilepticus. The Cochrane database of systematic reviews, 2014. 9 CD003723. PubMed PMID: 25207925.

        • Brigo F.
        • Nardone R.
        • Tezzon F.
        • Trinka E.
        A common reference-based indirect comparison meta-analysis of buccal versus intranasal midazolam for early status epilepticus.
        CNS Drugs. 2015; (PubMed PMID 26293745)
        • Brigo F.
        • Nardone R.
        • Tezzon F.
        • Trinka E.
        Nonintravenous midazolam versus intravenous or rectal diazepam for the treatment of early status epilepticus: a systematic review with meta-analysis.
        Epilepsy Behav: E&B. 2015; 49 (PubMed PMID: 25817929): 325-336
        • McMullan J.
        • Sasson C.
        • Pancioli A.
        • Silbergleit R.
        Midazolam versus diazepam for the treatment of status epilepticus in children and young adults: a meta-analysis.
        Acad Emerg Med. 2010; 17 (PubMed PMID: 20624136): 575-582
        • Sofou K.
        • Kristjansdottir R.
        • Papachatzakis N.E.
        • Ahmadzadeh A.
        • Uvebrant P.
        Management of prolonged seizures and status epilepticus in childhood: a systematic review.
        J Child Neurol. 2009; 24 (PubMed PMID: 19332572): 918-926
        • Brigo F.
        • Storti M.
        • Del Felice A.
        • Fiaschi A.
        • Bongiovanni L.G.
        IV valproate in generalized convulsive status epilepticus: a systematic review.
        Eur J Neurol. 2012; 19 (PubMed PMID: 22182304): 1180-1191
        • Brigo F.
        • Bragazzi N.
        • Nardone R.
        • Trinka E.
        Direct and indirect comparison meta-analysis of levetiracetam versus phenytoin or valproate for convulsive status epilepticus.
        Epilepsy Behav: E&B. 2016; 64 (PubMed PMID: 27736657): 110-115
        • Brigo F.
        • Bragazzi N.L.
        • Bacigaluppi S.
        • Nardone R.
        • Trinka E.
        Is intravenous lorazepam really more effective and safe than intravenous diazepam as first-line treatment for convulsive status epilepticus? A systematic review with meta-analysis of randomized controlled trials.
        Epilepsy Behav: E&B. 2016; 64 (PubMed PMID: 27732915): 29-36
        • Brigo F.
        • Igwe S.C.
        • Nardone R.
        • Tezzon F.
        • Bongiovanni L.G.
        • Trinka E.
        A common reference-based indirect comparison meta-analysis of intravenous valproate versus intravenous phenobarbitone for convulsive status epilepticus.
        Epileptic Disord. 2013; 15 (PubMed PMID: 23981687): 314-323
        • Trinka E.
        • Hofler J.
        • Leitinger M.
        • Brigo F.
        Pharmacotherapy for status epilepticus.
        Drugs. 2015; (PubMed PMID 26310189)
        • Trinka E.
        • Hofler J.
        • Leitinger M.
        • Rohracher A.
        • Kalss G.
        • Brigo F.
        Pharmacologic treatment of status epilepticus.
        Expert Opin Pharmacother. 2016; 17 (PubMed PMID: 26629986): 513-534
        • Trinka E.
        • Hofler J.
        • Zerbs A.
        • Brigo F.
        Efficacy and safety of intravenous valproate for status epilepticus: a systematic review.
        CNS Drugs. 2014; (PubMed PMID: 24806973)
        • Meierkord H.
        • Boon P.
        • Engelsen B.
        • Gocke K.
        • Shorvon S.
        • Tinuper P.
        • et al.
        EFNS guideline on the management of status epilepticus in adults.
        Eur J Neurol. 2010; 17 (PubMed PMID: 20050893): 348-355
        • Capovilla G.
        • Beccaria F.
        • Beghi E.
        • Minicucci F.
        • Sartori S.
        • Vecchi M.
        Treatment of convulsive status epilepticus in childhood: recommendations of the Italian league against epilepsy.
        Epilepsia. 2013; 54 (PubMed PMID: 24099053): 23-34
        • Trinka E.B.F.
        Benzodiazepines used in the treatment of epilepsy.
        in: Shorvon S.P.E. Engel J. The treatment of epilepsy. 4th ed. Wyley, Chichester, UK2015: 398-417
        • Schütz H.
        Benzodiazepines II. A handbook. Basic data, analytical methods, pharmacokonetics, and comprehensive literature.
        Springer, Heidelberg, New York1989
        • Greenblatt D.J.
        • Divoll M.
        Diazepam versus lorazepam: relationship of drug distribution to duration of clinical action.
        in: Status epileptics mechanisms of brain damage and treatment advances in neruology. vol. 34. Raven Press, New York1983: 487-491
        • Leppik I.E.
        • Derivan A.T.
        • Homan R.W.
        • Walker J.
        • Ramsay R.E.
        • Patrick B.
        Double-blind study of lorazepam and diazepam in status epilepticus.
        J Am Med Assoc. 1983; 249: 1452-1454
        • Appleton R.
        • Sweeney A.
        • Choonara I.
        • Robson J.
        • Molyneux E.
        Lorazepam versus diazepam in the acute treatment of epileptic seizures and status epilepticus.
        Dev Med Child Neurol. 1995; 37: 682-688
        • Alldredge B.K.
        • Gelb A.M.
        • Isaacs S.M.
        • Corry M.D.
        • Allen F.
        • Ulrich S.
        • 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
        • Chamberlain J.M.
        • Okada P.
        • Holsti M.
        • Mahajan P.
        • Brown K.M.
        • Vance C.
        • et al.
        Lorazepam vs diazepam for pediatric status epilepticus: a randomized clinical trial.
        JAMA. 2014; 311 (PubMed PMID: 24756515): 1652-1660
        • Kellinghaus C.
        • Lang N.
        • Rossetti A.O.
        • Ruegg S.
        • Tilz C.
        • Trinka E.
        • et al.
        Making SENSE–Sustained Effort Network for treatment of status epilepticus as a multicenter prospective registry.
        BMC Neurol. 2015; 15 (PubMed PMID: 26554812. Pubmed Central PMCID. 4641362)
        • Ferlisi M.
        • Hocker S.
        • Grade M.
        • Trinka E.
        • Shorvon S.
        International steering committee of the StEp A. Preliminary results of the global audit of treatment of refractory status epilepticus.
        Epilepsy Behav: E&B. 2015; 49 (PubMed PMID: 25952268): 318-324
        • Cock H.R.
        • Group E.
        Established status epilepticus treatment trial (ESETT).
        Epilepsia. 2011; 52 (PubMed PMID: 21967363): 50-52
        • Bleck T.
        • Cock H.
        • Chamberlain J.
        • Cloyd J.
        • Connor J.
        • Elm J.
        • et al.
        The established status epilepticus trial 2013.
        Epilepsia. 2013; 54 (PubMed PMID: 24001084): 89-92
        • Lang N.
        • Lange M.
        • Schmitt F.C.
        • Bos M.
        • Weber Y.
        • Evers S.
        • et al.
        Intravenous lacosamide in clinical practice-results from an independent registry.
        Seizure. 2016; 39 (PubMed PMID: 27161669): 5-9
        • Hofler J.
        • Trinka E.
        Lacosamide as a new treatment option in status epilepticus.
        Epilepsia. 2013; 54 (PubMed PMID: 23293881): 393-404
        • Sutter R.
        • Marsch S.
        • Ruegg S.
        Safety and efficacy of intravenous lacosamide for adjunctive treatment of refractory status epilepticus: a comparative cohort study.
        CNS Drugs. 2013; 27 (PubMed PMID: 23533010): 321-329
        • Garces M.
        • Villanueva V.
        • Mauri J.A.
        • Suller A.
        • Garcia C.
        • Lopez Gonzalez F.J.
        • et al.
        Factors influencing response to intravenous lacosamide in emergency situations: LACO-IV study.
        Epilepsy Behav: E&B. 2014; 36 (PubMed PMID: 24922617): 144-152
        • Mayer S.A.
        • Claassen J.
        • Lokin J.
        • Mendelsohn F.
        • Dennis L.J.
        • Fitzsimmons B.F.
        Refractory status epilepticus: frequency, risk factors, and impact on outcome.
        Arch Neurol. 2002; 59: 205-210
        • Holtkamp M.
        • Othman J.
        • Buchheim K.
        • Meierkord H.
        Predictors and prognosis of refractory status epilepticus treated in a neurological intensive care unit.
        J Neurol Neurosurg Psychiatry. 2005; 76: 534-539
        • Claassen J.
        • Hirsch L.J.
        • Emerson R.G.
        • Mayer S.A.
        Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review.
        Epilepsia. 2002; 43: 146-153
        • Ferlisi M.
        • Shorvon S.
        The outcome of therapies in refractory and super-refractory convulsive status epilepticus and recommendations for therapy.
        Brain. 2012; 135 (PubMed PMID: 22577217): 2314-2328
        • Niermeijer J.M.
        • Uiterwaal C.S.
        • Van Donselaar C.A.
        Propofol in status epilepticus: little evidence, many dangers?.
        J Neurol. 2003; 250: 1237-1240
        • Sutter R.
        • Marsch S.
        • Fuhr P.
        • Kaplan P.W.
        • Ruegg S.
        Anesthetic drugs in status epilepticus: risk or rescue? A 6-year cohort study.
        Neurology. 2014; 82 (PubMed PMID: 24319039. Pubmed Central PMCID: 3945664): 656-664
        • Fujikawa D.G.
        Neuroprotective effect of ketamine administered after status epilepticus onset.
        Epilepsia. 1995; 36: 186-195
        • Borris D.J.
        • Bertram E.H.
        • Kapur J.
        Ketamine controls prolonged status epilepticus.
        Epilepsy Res. 2000; 42: 117-122
        • Kapur J.
        • Coulter D.A.
        Experimental status epilepticus alters gamma-aminobutyric acid type A receptor function in CA1 pyramidal neurons.
        Ann Neurol. 1995; 38: 893-900
        • Mazarati A.M.
        • Wasterlain C.G.
        N-methyl-D-asparate receptor antagonists abolish the maintenance phase of self-sustaining status epilepticus in rat.
        Neurosci Lett. 1999; 265: 187-190
        • Gaspard N.
        • Foreman B.
        • Judd L.M.
        • Brenton J.N.
        • Nathan B.R.
        • McCoy B.M.
        • et al.
        Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multicenter study.
        Epilepsia. 2013; 54 (PubMed PMID: 23758557. Pubmed Central PMCID: 3731413): 1498-1503
        • Synowiec A.S.
        • Singh D.S.
        • Yenugadhati V.
        • Valeriano J.P.
        • Schramke C.J.
        • Kelly K.M.
        Ketamine use in the treatment of refractory status epilepticus.
        Epilepsy Res. 2013; 105 (PubMed PMID: 23369676): 183-188
        • Basha M.M.
        • Alqallaf A.
        • Shah A.K.
        Drug-induced EEG pattern predicts effectiveness of ketamine in treating refractory status epilepticus.
        Epilepsia. 2015; 56 (PubMed PMID: 25759241): e44-e48
        • Walker M.C.
        • Howard R.S.
        • Smith S.J.
        • Miller D.H.
        • Shorvon S.D.
        • Hirsch N.P.
        Diagnosis and treatment of status epilepticus on a neurological intensive care unit.
        QJM. 1996; 89: 913-920
        • Kofke W.A.
        • Bloom M.J.
        • Van Cott A.
        • Brenner R.P.
        Electrographic tachyphylaxis to etomidate and ketamine used for refractory status epilepticus controlled with isoflurane.
        J Neurosurg Anesthesiol. 1997; 9 (PubMed PMID: 9239591): 269-272
        • Ubogu E.E.
        • Sagar S.M.
        • Lerner A.J.
        • Maddux B.N.
        • Suarez J.I.
        • Werz M.A.
        Ketamine for refractory status epilepticus: a case of possible ketamine-induced neurotoxicity.
        Epilepsy Behav. 2003; 4: 70-75
        • Robakis T.K.
        • Hirsch L.J.
        Literature review, case report, and expert discussion of prolonged refractory status epilepticus.
        Neurocrit Care. 2006; 4: 35-46
        • Pruss H.
        • Holtkamp M.
        Ketamine successfully terminates malignant status epilepticus.
        Epilepsy Res. 2008; 82 (PubMed PMID: 18804344): 219-222
        • Yeh P.S.
        • Shen H.N.
        • Chen T.Y.
        Oral ketamine controlled refractory nonconvulsive status epilepticus in an elderly patient.
        Seizure. 2011; 20 (PubMed PMID: 21724423): 723-736
        • Kramer A.H.
        Early ketamine to treat refractory status epilepticus.
        Neurocrit care. 2012; 16 (PubMed PMID: 22237581): 299-305
        • Zeiler F.A.
        • Kaufmann A.M.
        • Gillman L.M.
        • West M.
        • Silvaggio J.
        Ketamine for medically refractory status epilepticus after elective aneurysm clipping.
        Neurocrit Care. 2013; 19 (PubMed PMID: 23702695): 119-124
        • Shrestha G.S.
        • Joshi P.
        • Chhetri S.
        • Karn R.
        • Acharya S.P.
        Intravenous ketamine for treatment of super-refractory convulsive status epilepticus with septic shock: a report of two cases.
        Indian J Crit Care Med. 2015; 19 (PubMed PMID: 25983437. Pubmed Central PMCID: 4430749): 283-285
        • Hsieh C.Y.
        • Sung P.S.
        • Tsai J.J.
        • Huang C.W.
        Terminating prolonged refractory status epilepticus using ketamine.
        Clin Neuropharmacol. 2010; 33 (PubMed PMID: 20098301): 165-167
        • White P.F.
        • Schuttler J.
        • Shafer A.
        • Stanski D.R.
        • Horai Y.
        • Trevor A.J.
        Comparative pharmacology of the ketamine isomers. Studies in volunteers.
        Br J Anaesth. 1985; 57 (PubMed PMID: 3970799): 197-203
        • Engelhardt W.
        • Stahl K.
        • Marouche A.
        • Hartung E.
        Recovery time after (S)-ketamine or ketamine racemate. Recovery time after short anesthesia in volunteers.
        Anaesthesist. 1998; 47 (PubMed PMID: 9567151 Aufwachzeit nach (S)-Ketamin- oder Ketamin-Razemat. Aufwachzeit nach Kurznarkosen bei Probanden): 184-192
        • Hofler 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; 30 (PubMed PMID: 27465262. Pubmed Central PMCID: 4996879): 869-876
        • Hanada T.
        • Hashizume Y.
        • Tokuhara N.
        • Takenaka O.
        • Kohmura N.
        • Ogasawara A.
        • et al.
        Perampanel: a novel, orally active, noncompetitive AMPA-receptor antagonist that reduces seizure activity in rodent models of epilepsy.
        Epilepsia. 2011; 52 (PubMed PMID: 21635236): 1331-1340
        • Rogawski M.A.
        • Hanada T.
        Preclinical pharmacology of perampanel, a selective non-competitive AMPA receptor antagonist.
        Acta Beurol Scand Suppl. 2013; 197 (PubMed PMID: 23480152. Pubmed Central PMCID: 4506647): 19-24
        • Rohracher A.
        • Hofler J.
        • Kalss G.
        • Leitinger M.
        • Kuchukhidze G.
        • Deak I.
        • et al.
        Perampanel in patients with refractory and super-refractory status epilepticus in a neurological intensive care unit.
        Epilepsy Behav: E&B. 2015; 49 (PubMed PMID: 25962657): 354-358
        • Redecker J.
        • Wittstock M.
        • Benecke R.
        • Rosche J.
        Efficacy of perampanel in refractory nonconvulsive status epilepticus and simple partial status epilepticus.
        Epilepsy Behav: E&B. 2015; 45 (PubMed PMID: 25819947): 176-179
        • Rosche J.
        • Kampf C.
        • Benecke R.
        Possible effect of perampanel on focal status epilepticus after generalized tonic-clonic status epilepticus.
        Acta Neurol Belgica. 2014; 114 (PubMed PMID: 23801431): 243-244
        • Naylor D.E.
        • Liu H.
        • Wasterlain C.G.
        Trafficking of GABA(A) receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus.
        J Neurosci. 2005; 25: 7724-7733
        • Naylor D.E.
        • Wasterlain C.G.
        GABA synapses and the rapid loss of inhibition to dentate gyrus granule cells after brief perforant-path stimulation.
        Epilepsia. 2005; 46: 142-147
        • Rogawski M.A.
        • Loya C.M.
        • Reddy K.
        • Zolkowska D.
        • Lossin C.
        Neuroactive steroids for the treatment of status epilepticus.
        Epilepsia. 2013; 54 (PubMed PMID: 24001085. Pubmed Central PMCID: 3772544): 93-98
        • Broomall E.
        • Natale J.E.
        • Grimason M.
        • Goldstein J.
        • Smith C.M.
        • Chang C.
        • et al.
        Pediatric super-refractory status epilepticus treated with allopregnanolone.
        Ann Neurol. 2014; 76 (PubMed PMID: 25363147. Pubmed Central PMCID: 4534165): 911-915
        • Shorvon S.
        • Ferlisi M.
        The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol.
        Brain. 2011; 134 (PubMed PMID: 21914716): 2802-2818
        • Vezzani A.
        • Ruegg S.
        The pivotal role of immunity and inflammatory processes in epilepsy is increasingly recognized: introduction.
        Epilepsia. 2011; 52 (PubMed PMID: 21542838): 1-4
        • Graus F.
        • Titulaer M.J.
        • Balu R.
        • Benseler S.
        • Bien C.G.
        • Cellucci T.
        • et al.
        A clinical approach to diagnosis of autoimmune encephalitis.
        Lancet Neurol. 2016; 15 (PubMed PMID: 26906964 Pubmed Central PMCID: 5066574): 391-404