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Novel drugs and early polypharmacotherapy in status epilepticus

  • Marta Amengual-Gual
    Correspondence
    Corresponding author at: Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children’s Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA.
    Affiliations
    Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    Pediatric Neurology Unit, Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain
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  • Iván Sánchez Fernández
    Affiliations
    Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    Department of Child Neurology, Hospital Sant Joan de Déu, Universidad de Barcelona, Spain
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  • Mark S. Wainwright
    Affiliations
    Department of Neurology, Division of Pediatric Neurology. University of Washington School of Medicine, Seattle, WA, USA
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Open ArchivePublished:August 07, 2018DOI:https://doi.org/10.1016/j.seizure.2018.08.004

      Highlights

      • Status epilepticus is a time-sensitive, life-threatening medical emergency.
      • Current guidelines recommend an early use of benzodiazepines.
      • Rescue medications have a relatively high rate of failure.
      • Novel drugs target the underlying pathophysiology of status epilepticus.
      • Early polytherapy may potentially improve seizure control.

      Abstract

      Purpose

      Rescue medications for status epilepticus (SE) have a relatively high rate of failure. The purpose of this review is to summarize the evidence for the efficacy of novel drugs and early polypharmacotherapy for SE.

      Method

      Literature review.

      Results

      New drugs and treatment strategies aim to target the pathophysiology of SE in order to improve seizure control and outcomes. Changes at the synapse level during SE include a progressive decrease in synaptic GABAA receptors and increase in synaptic NMDA receptors. These changes tend to promote self-sustaining seizures. Current SE guidelines recommend a rapid stepwise treatment using benzodiazepines in monotherapy as the first-line treatment, targeting GABAA synaptic receptors. Novel treatment approaches target GABAA synaptic and extrasynaptic receptors with allopregnanolone, and NMDA receptors with ketamine. Novel rescue treatments used for SE include topiramate, brivaracetam, and perampanel, which are already marketed in epilepsy. Some available drugs not marketed for use in epilepsy have been used in the treatment of SE, and other agents are being studied for this purpose. Early polytherapy, most frequently combining a benzodiazepine with a second-line drug or an NMDA receptor antagonist, might potentially increase seizure control with relatively minor increase in side effects. Although many preclinical studies support novel drugs and early polytherapy in SE, human studies are scarce and inconclusive. Currently, evidence is lacking to recommend specific combinations of these new agents.

      Conclusions

      Novel drugs and strategies target the underlying pathophysiology of SE with the intent to improve seizure control and outcomes.

      Keywords

      1. Introduction

      Status epilepticus (SE) is a life-threatening medical emergency. Current guidelines recommend a rapid stepwise treatment first using benzodiazepines in monotherapy, followed by a sequential addition of second-line drugs if SE continues [
      • Brophy G.M.
      • et al.
      Guidelines for the evaluation and management of status epilepticus.
      ]. Approximately one-third of cases of SE remain refractory (RSE) or super-refractory (SRSE) to treatment with benzodiazepines and second-line drugs [
      • Novy J.
      • Logroscino G.
      • Rossetti A.O.
      Refractory status epilepticus: a prospective observational study.
      ,
      • Rossetti A.O.
      • Lowenstein D.H.
      Management of refractory status epilepticus in adults: still more questions than answers.
      ]. RSE refers to an ongoing SE despite two appropriately selected and dosed antiepileptic drugs, including one benzodiazepine [
      • Sánchez Fernández I.
      • et al.
      Gaps and opportunities in refractory status epilepticus research in children: a multi-center approach by the Pediatric Status Epilepticus Research Group (pSERG).
      ]. SRSE refers to SE that continues 24 h or more after the onset of anesthetic therapy, including recurrences during the reduction or withdrawal of anesthetic agents [
      • Shorvon S.
      • Ferlisi M.
      The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol.
      ]. Novel rescue treatments and treatment strategies, such as early polytherapy, target the underlying mechanisms of SE with the intention of preventing progression to RSE and the hope of improving neurologic outcomes. In this review article, we summarize the literature on novel drugs and treatment approaches.

      2. Pathophysiology of status epilepticus

      Advances in pharmacologic approaches to the management of SE may be possible by a greater understanding of the roles of GABA and NMDA receptors. The pathophysiology of SE involves changes in the location and subunit composition of these neurotransmitter receptors. These changes promote self-sustaining seizures and, as SE continues, result in decreasing efficacy of drugs used to treat early stages of SE.
      Synaptic GABAA receptors produce phasic inhibitory currents in response to vesicular release of GABA. These receptors are widespread in the brain, are the target of benzodiazepines, and are internalized during SE decreasing neuronal inhibition [
      • Goodkin H.P.
      • Yeh J.L.
      • Kapur J.
      Status epilepticus increases the intracellular accumulation of GABAA receptors.
      ,
      • Naylor D.E.
      • Liu H.
      • Wasterlain C.G.
      Trafficking of GABA(A) receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus.
      ]. In contrast, glutamate receptors (mainly NMDA) accumulate in the synaptic membrane during SE, increasing excitation [
      • Naylor D.E.
      • Liu H.
      • Wasterlain C.G.
      Trafficking of GABA(A) receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus.
      ,
      • Wasterlain C.G.
      • et al.
      Molecular basis of self-sustaining seizures and pharmacoresistance during status epilepticus: the receptor trafficking hypothesis revisited.
      ,
      • Naylor D.E.
      • et al.
      Rapid surface accumulation of NMDA receptors increases glutamatergic excitation during status epilepticus.
      ,
      • Wasterlain C.G.
      • Chen J.W.
      Mechanistic and pharmacologic aspects of status epilepticus and its treatment with new antiepileptic drugs.
      ,
      • Niquet J.
      • et al.
      Benzodiazepine-refractory status epilepticus: pathophysiology and principles of treatment.
      ]. Unlike the widespread expression of synaptic GABAA receptors, extrasynaptic GABAA receptors are present only in hippocampus, thalamus, amygdala, hypothalamus, and cerebellum. Activation of these receptors produces non-desensitizing tonic inhibitory currents in response to extracellular GABA. However, these receptors are not targeted by benzodiazepines and are thought to represent a promising novel therapeutic target.
      The subunit composition of both GABA and glutamate receptors regulates their localization at the synapse, and their binding properties [
      • Naylor D.E.
      Glutamate and GABA in the balance: convergent pathways sustain seizures during status epilepticus.
      ]. The composition of these receptors changes during brain development and in response to seizures [
      • Brooks-Kayal A.R.
      • Pritchett D.B.
      Developmental changes in human gamma-aminobutyric acidA receptor subunit composition.
      ,
      • Silverstein F.S.
      • Jensen F.E.
      Neonatal seizures.
      ,
      • Wong H.K.
      • et al.
      Temporal and regional expression of NMDA receptor subunit NR3A in the mammalian brain.
      ,
      • Burnashev N.
      • et al.
      Divalent ion permeability of AMPA receptor channels is dominated by the edited form of a single subunit.
      ,
      • Kumar S.S.
      • et al.
      A developmental switch of AMPA receptor subunits in neocortical pyramidal neurons.
      ,
      • Sanchez R.M.
      • Jensen F.E.
      Maturational aspects of epilepsy mechanisms and consequences for the immature brain.
      ,
      • Brooks-Kayal A.R.
      • et al.
      Selective changes in single cell GABA(A) receptor subunit expression and function in temporal lobe epilepsy.
      ,
      • Swann J.W.
      • Le J.T.
      • Lee C.L.
      Recurrent seizures and the molecular maturation of hippocampal and neocortical glutamatergic synapses.
      ,
      • Crino P.B.
      • et al.
      Differential expression of glutamate and GABA-A receptor subunit mRNA in cortical dysplasia.
      ,
      • Finardi A.
      • et al.
      NMDA receptor composition differs among anatomically diverse malformations of cortical development.
      ,
      • Loddenkemper T.
      • et al.
      Subunit composition of glutamate and gamma-aminobutyric acid receptors in status epilepticus.
      ,
      • Talos D.M.
      • et al.
      Cell-specific alterations of glutamate receptor expression in tuberous sclerosis complex cortical tubers.
      ,
      • Talos D.M.
      • et al.
      Altered inhibition in tuberous sclerosis and type IIb cortical dysplasia.
      ]. In the immature brain and the developing brain exposed to repeated seizures, the composition of GABAA, NMDA and AMPA receptors (increased ratio of non-α1/α1 in GABAA receptors, GluN2B/GluN2A in NMDA receptors, and GluA1/GluA2 in AMPA receptors) leads to further excitability and promotes self-sustaining seizures [
      • Brooks-Kayal A.R.
      • Pritchett D.B.
      Developmental changes in human gamma-aminobutyric acidA receptor subunit composition.
      ,
      • Silverstein F.S.
      • Jensen F.E.
      Neonatal seizures.
      ,
      • Wong H.K.
      • et al.
      Temporal and regional expression of NMDA receptor subunit NR3A in the mammalian brain.
      ,
      • Burnashev N.
      • et al.
      Divalent ion permeability of AMPA receptor channels is dominated by the edited form of a single subunit.
      ,
      • Kumar S.S.
      • et al.
      A developmental switch of AMPA receptor subunits in neocortical pyramidal neurons.
      ,
      • Sanchez R.M.
      • Jensen F.E.
      Maturational aspects of epilepsy mechanisms and consequences for the immature brain.
      ,
      • Brooks-Kayal A.R.
      • et al.
      Selective changes in single cell GABA(A) receptor subunit expression and function in temporal lobe epilepsy.
      ,
      • Swann J.W.
      • Le J.T.
      • Lee C.L.
      Recurrent seizures and the molecular maturation of hippocampal and neocortical glutamatergic synapses.
      ,
      • Crino P.B.
      • et al.
      Differential expression of glutamate and GABA-A receptor subunit mRNA in cortical dysplasia.
      ,
      • Finardi A.
      • et al.
      NMDA receptor composition differs among anatomically diverse malformations of cortical development.
      ,
      • Loddenkemper T.
      • et al.
      Subunit composition of glutamate and gamma-aminobutyric acid receptors in status epilepticus.
      ,
      • Talos D.M.
      • et al.
      Cell-specific alterations of glutamate receptor expression in tuberous sclerosis complex cortical tubers.
      ,
      • Talos D.M.
      • et al.
      Altered inhibition in tuberous sclerosis and type IIb cortical dysplasia.
      ]. In addition, GABAergic neurotransmission is excitatory in the immature brain, since the overexpression of the chlorine NKCC1 transporter promotes intracellular accumulation of chlorine [
      • Dzhala V.I.
      • et al.
      NKCC1 transporter facilitates seizures in the developing brain.
      ]. Collectively, this enhanced neuronal excitability makes the immature brain particularly susceptible to seizures and vulnerable to the development of abnormal neuronal networks during synaptogenesis and cortical formation [
      • Rakhade S.N.
      • Jensen F.E.
      Epileptogenesis in the immature brain: emerging mechanisms.
      ,
      • Rakhade S.N.
      • et al.
      Early alterations of AMPA receptors mediate synaptic potentiation induced by neonatal seizures.
      ].
      Disruption of the blood-brain barrier may also contribute to the mechanisms of epileptogenesis [
      • van Vliet E.A.
      • et al.
      Blood-brain barrier leakage may lead to progression of temporal lobe epilepsy.
      ]. Compromise of the blood-brain barrier, due to prolonged epileptic activity or acute neurologic insults, may allow the invasion of cells and molecules, such as leukocytes and albumin. Albumin can activate astrocytes through calcium signaling [
      • Nadal A.
      • Fuentes E.
      • McNaughton P.A.
      Glial cell responses to lipids bound to albumin in serum and plasma.
      ] and through increase of production of the pro-convulsant cytokine IL-1β [
      • Ralay Ranaivo H.
      • Wainwright M.S.
      Albumin activates astrocytes and microglia through mitogen-activated protein kinase pathways.
      ]. Increase in astrocyte excitability following albumin uptake has been proposed as novel mechanism of epileptogenesis linked to TGFβ-signaling [
      • Cacheaux L.P.
      • et al.
      Transcriptome profiling reveals TGF-beta signaling involvement in epileptogenesis.
      ]. The invading leukocytes, as well as others cells within the brain (such as activated microglia and astrocytes, neurons, endothelial cells of the blood-brain barrier, and blood-born macrophages) can synthetize and release substances with inflammatory properties leading to an inflammatory cascade -which may decrease the threshold for seizures- in response to multiple factors (such as infections, autoimmunity, and seizures as well) [
      • Vezzani A.
      • Friedman A.
      • Dingledine R.J.
      The role of inflammation in epileptogenesis.
      ]. These inflammatory substances can also actuate as neuromodulators and be involved in seizure generation, epileptogenesis and drug-resistance [
      • van Vliet E.A.
      • et al.
      Neuroinflammatory pathways as treatment targets and biomarker candidates in epilepsy: emerging evidence from preclinical and clinical studies.
      ,
      • Dey A.
      • et al.
      Anti-inflammatory small molecules to treat seizures and epilepsy: from bench to bedside.
      ]. An altered expression of some transport proteins or drug-metabolizing enzymes at blood-brain barrier may be an additional reason for antiepileptic drug resistance [
      • Han H.
      • et al.
      Breaking bad: the structure and function of the blood-brain barrier in epilepsy.
      ,
      • Bankstahl J.P.
      • Löscher W.
      Resistance to antiepileptic drugs and expression of P-glycoprotein in two rat models of status epilepticus.
      ]. A dysfunctional blood-brain barrier may also enhance or reduce the distribution of antiepileptic drugs into the brain [
      • Han H.
      • et al.
      Breaking bad: the structure and function of the blood-brain barrier in epilepsy.
      ].
      In conclusion, changes in the location and composition of some neurotransmitter receptors, the blood-brain barrier and neuroinflammation should be considered as potential targets for new antiepileptic drugs, as well as mechanisms of pharmacoresistance to current drugs.

      3. Antiepileptic drug options for the treatment of status epilepticus

      3.1 Classical drugs

      • -
        Benzodiazepines. Benzodiazepines are the first-line treatment in current guidelines –although studies did not show a better efficacy stopping seizures compared to ‘second-line treatments’- [
        • Sánchez Fernández I.
        • et al.
        Gaps and opportunities in refractory status epilepticus research in children: a multi-center approach by the Pediatric Status Epilepticus Research Group (pSERG).
        ,
        • Sánchez Fernández I.
        • Loddenkemper T.
        Therapeutic choices in convulsive status epilepticus.
        ]. Benzodiazepines are positive allosteric modulators of synaptic GABAA receptors [
        • Sánchez Fernández I.
        • et al.
        Gaps and opportunities in refractory status epilepticus research in children: a multi-center approach by the Pediatric Status Epilepticus Research Group (pSERG).
        ,
        • Sánchez Fernández I.
        • Loddenkemper T.
        Therapeutic choices in convulsive status epilepticus.
        ,
        • Trinka E.
        • Brigo F.
        • Shorvon S.
        Recent advances in status epilepticus.
        ,
        • Loddenkemper T.
        • Goodkin H.P.
        Treatment of pediatric status epilepticus.
        ].
      • -
        Phenytoin (fosphenytoin). Phenytoin stabilizes the inactive form of neuronal voltage-dependent sodium channels. The main adverse effects are its arrhythmogenicity and drug-drug interactions. Phenytoin has been classically considered the second-line treatment of SE, together with the medications detailed below –published studies show no major differences in effectiveness among second-line drugs- [
        • Sánchez Fernández I.
        • et al.
        Gaps and opportunities in refractory status epilepticus research in children: a multi-center approach by the Pediatric Status Epilepticus Research Group (pSERG).
        ,
        • Sánchez Fernández I.
        • Loddenkemper T.
        Therapeutic choices in convulsive status epilepticus.
        ,
        • Loddenkemper T.
        • Goodkin H.P.
        Treatment of pediatric status epilepticus.
        ].
      • -
        Phenobarbital. Phenobarbital is a long-acting barbiturate that enhances GABA-mediated inhibition. This drug may also antagonize AMPA receptors and inhibit neurotransmitter release. Its main adverse effects are potential central nervous system and respiratory depression, as well as drug-drug interactions [
        • Loddenkemper T.
        • Goodkin H.P.
        Treatment of pediatric status epilepticus.
        ].
      • -
        Valproate. Valproic acid acts through several mechanisms, including increasing GABA synthesis, inhibiting GABA transaminase, stabilizing voltage-gated sodium channels, and inhibiting T-type calcium channels. Valproate has potential side effects such as pancreatitis, hepatoxicity –mainly in patients with an underlying metabolic disorder-, hyperammonaemic encephalopathy, hematologic disorders, and drug-drug interactions. Carnitine supplementation is frequently given with valproate to reduce its potential toxicity. Valproate can exacerbate some metabolic diseases, and therefore, should be avoided in patients with some known or suspected metabolic disorders [
        • Loddenkemper T.
        • Goodkin H.P.
        Treatment of pediatric status epilepticus.
        ].
      • -
        Levetiracetam. Levetiracetam inhibits neurotransmitter release due to its binding to the synaptic vesicle protein 2A (SV2A). Recent studies suggest that this drug may also modulate glutamate receptors (mainly AMPA) [
        • Carunchio I.
        • et al.
        Modulation of AMPA receptors in cultured cortical neurons induced by the antiepileptic drug levetiracetam.
        ,
        • Lee C.Y.
        • Chen C.C.
        • Liou H.H.
        Levetiracetam inhibits glutamate transmission through presynaptic P/Q-type calcium channels on the granule cells of the dentate gyrus.
        ]. The most limiting adverse effect of levetiracetam is agitation or irritability, which is typically not severe, but very common. Levetiracetam is a relatively safe drug without major drug-drug interactions [
        • Loddenkemper T.
        • Goodkin H.P.
        Treatment of pediatric status epilepticus.
        ].
      • -
        Lacosamide. Lacosamide enhances the slow inactivation of voltage-dependent sodium channels. This drug is the newest drug among the second-line treatments. Lacosamide could cause cardiac conduction disorders. No drug-drug interactions are known [
        • Loddenkemper T.
        • Goodkin H.P.
        Treatment of pediatric status epilepticus.
        ].
      • -
        Continuous infusions of midazolam, thiopental, pentobarbital, or propofol. If SE is ongoing despite first and second-line treatments, an admission to an intensive care unit (ICU) and the administration of sedative drugs by intravenous perfusion is recommended in current guidelines [
        • Loddenkemper T.
        • Goodkin H.P.
        Treatment of pediatric status epilepticus.
        ].

      3.2 Novel drugs

      3.2.1 Gender-based differences, allopregnanolone and hormone-based therapy

      A neurosteroid is a steroid synthetized within the brain by the glia which has neurological effects [
      • Reddy D.S.
      Neurosteroids: endogenous role in the human brain and therapeutic potentials.
      ]. A neuroactive steroid is a steroid with neurological activity, but synthetized outside the central nervous system after conversion of adrenal, gonadal or placental steroids. Neuroactive steroids, derived from progesterone, deoxycorticosterone or testosterone, can cross the blood-brain barrier and modify brain function and structure [
      • Reddy D.S.
      Neurosteroids: endogenous role in the human brain and therapeutic potentials.
      ].
      Neurosteroids and neuroactive steroids are essential for the sex-dependent differences in brain development, function and structure. The metabolism and levels of neurosteroids or neuroactive steroids, as well as the neuronal receptors and networks affected by them vary with gender. These properties could explain why epilepsy shows gender-based differences regarding incidence, etiology, progression, and responsiveness to treatment [
      • Samba Reddy D.
      Sex differences in the anticonvulsant activity of neurosteroids.
      ,
      • Reddy D.S.
      • Estes W.A.
      Clinical potential of neurosteroids for CNS disorders.
      ,
      • Reddy D.S.
      Neurosteroids and their role in sex-specific epilepsies.
      ]. For example, men exhibit greater seizure susceptibility in general, while women have greater seizure susceptibility fluctuation due to hormonal variations; women also are more susceptible to some epileptic syndromes which are much more complex and often intractable [
      • Hauser W.A.
      • Annegers J.F.
      • Kurland L.T.
      Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935-1984.
      ,
      • McHugh J.C.
      • Delanty N.
      Epidemiology and classification of epilepsy: gender comparisons.
      ,
      • Frye C.A.
      Hormonal influences on seizures: basic neurobiology.
      ,
      • Herzog A.G.
      Catamenial epilepsy: update on prevalence, pathophysiology and treatment from the findings of the NIH Progesterone Treatment Trial.
      ].
      Neurosteroids –such as allopregnanolone, tetrahydrodeoxycorticosterone (THDOC), and androstanediol- interact with GABAA receptors. At high concentrations, neurosteroids directly activate these receptors; at low concentrations, they behave as potent positive allosteric agonists. There are two types of GABAA receptors based on their location: the synaptic and extrasynaptic GABAA receptors (explained in pathophysiology section). Neurosteroids act on both receptors, showing a greater affinity for the extrasynaptic ones [
      • Reddy D.S.
      • Estes W.A.
      Clinical potential of neurosteroids for CNS disorders.
      ,
      • Reddy D.S.
      Role of hormones and neurosteroids in epileptogenesis.
      ]. Neurosteroids could be a therapeutic option for SE since they target extrasynaptic GABAA receptors, which are not subject to inhibition during SE by other antiepileptic drugs as synaptic GABAA receptors are.
      Allopregnanolone has been studied as potential therapy for the treatment of SE. Many preclinical studies based on animal models of SE show favorable outcomes when using allopregnanolone or other neuroactive steroids [
      • Lévesque M.
      • et al.
      Allopregnanolone decreases interictal spiking and fast ripples in an animal model of mesial temporal lobe epilepsy.
      ,
      • Dhir A.
      • Chopra K.
      On the anticonvulsant effect of allopregnanolone (a neurosteroid) in neonatal rats.
      ,
      • Rogawski M.A.
      • et al.
      Neuroactive steroids for the treatment of status epilepticus.
      ,
      • Kokate T.G.
      • et al.
      Neuroactive steroids protect against pilocarpine- and kainic acid-induced limbic seizures and status epilepticus in mice.
      ,
      • Leśkiewicz M.
      • et al.
      Effects of neurosteroids on kainate-induced seizures, neurotoxicity and lethality in mice.
      ,
      • Frye C.A.
      • Scalise T.J.
      Anti-seizure effects of progesterone and 3alpha,5alpha-THP in kainic acid and perforant pathway models of epilepsy.
      ,
      • Frye C.A.
      The neurosteroid 3 alpha, 5 apha-THP has antiseizure and possible neuroprotective effects in an animal model of epilepsy.
      ,
      • Althaus A.L.
      • et al.
      The synthetic neuroactive steroid SGE-516 reduces status epilepticus and neuronal cell death in a rat model of soman intoxication.
      ,
      • Shiri Z.
      • et al.
      Neurosteroidal modulation of in vitro epileptiform activity is enhanced in pilocarpine-treated epileptic rats.
      ,
      • Lonsdale D.
      • Burnham W.M.
      The anticonvulsant effects of allopregnanolone against amygdala-kindled seizures in female rats.
      ]. A few human studies also show promising results. In 2014, Broomall et al. reported the first use of allopregnanolone in two children with SRSE [
      • Broomall E.
      • et al.
      Pediatric super-refractory status epilepticus treated with allopregnanolone.
      ]. Both patients were allopregnanolone responders after the unsuccessful use of other multiple antiepileptic drugs [
      • Broomall E.
      • et al.
      Pediatric super-refractory status epilepticus treated with allopregnanolone.
      ]. Similarly, Vaitkevicius et al. reported the effective use of allopregnanolone in two adults with SRSE in 2017 [
      • Vaitkevicius H.
      • et al.
      First-in-man allopregnanolone use in super-refractory status epilepticus.
      ]. Initial human studies on neuroactive steroids suggested good efficacy [
      • Reddy K.
      • Reife R.
      • Cole A.J.
      SGE-102: a novel therapy for refractory status epilepticus.
      ]. An open-label multicenter phase1 / phase 2 initially showed evidence to support the use of brexanolone – a proprietary formulation of allopregnanolone– as adjunctive therapy in SRSE [
      • Rosenthal E.S.
      • et al.
      Brexanolone as adjunctive therapy in super-refractory status epilepticus.
      ]. However, the follow-up phase 3 STATUS trial failed to show any difference in the primary outcome (weaning from third line agents) between standard of care and patients treated with brexanolone [
      SAGE Therapeutics reports top-line results from phase 3 STATUS trial of brexanolone in super-refractory status epilepticus.
      ]. Supporting the idea of allopregnanolone as a potential drug for SE, a recent study showed that the levels of this neurosteroid are decreased in cerebrospinal fluid of patients during SE [
      • Meletti S.
      • et al.
      Decreased allopregnanolone levels in cerebrospinal fluid obtained during status epilepticus.
      ]. Other similar neuroactive steroids, such as ganaxolone, are being studied for refractory focal seizures, refractory catamenial epilepsy, infantile spasms, or neonatal seizures [
      • Reddy D.S.
      Neurosteroids: endogenous role in the human brain and therapeutic potentials.
      ,
      • Nohria V.
      • Giller E.
      • Ganaxolone
      ,
      • Sperling M.R.
      • Klein P.
      • Tsai J.
      Randomized, double-blind, placebo-controlled phase 2 study of ganaxolone as add-on therapy in adults with uncontrolled partial-onset seizures.
      ,
      • Yawno T.
      • et al.
      Ganaxolone: a new treatment for neonatal seizures.
      ].
      The role of estrogens in SE remains unclear [
      • Velísková J.
      • et al.
      Females, their estrogens, and seizures.
      ]. In a kainic acid-induced SE mouse model, acute inhibition of estrogen synthesis suppresses SE [
      • Sato S.M.
      • Woolley C.S.
      Acute inhibition of neurosteroid estrogen synthesis suppresses status epilepticus in an animal model.
      ]. However, strogens may have a protecting effect in a pilocarpine-induced temporal lobe epilepsy mouse model [
      • Pereira M.
      • et al.
      Estrogen effects on pilocarpine-induced temporal lobe epilepsy in rats.
      ].

      3.2.2 Ketamine and drugs targeting the NMDA receptor

      Functional changes in the N-methyl-D-aspartate (NMDA) glutamate receptor are involved in the pathophysiology of SE (see pathophysiology section). Therefore, NMDA receptor antagonists are theoretically a good approach to the treatment of SE [
      • Dorandeu F.
      Ketamine for the treatment of (super) refractory status epilepticus? Not quite yet.
      ,
      • Dorandeu F.
      • et al.
      Treatment of status epilepticus with ketamine, are we there yet?.
      ,
      • Mazarati A.M.
      • Wasterlain C.G.
      N-methyl-D-asparate receptor antagonists abolish the maintenance phase of self-sustaining status epilepticus in rat.
      ]. Currently, ketamine is the only intravenous NMDA receptor antagonist available in most countries. Ketamine also interacts with other receptors (opioid, monoaminergic, muscarinic and nicotinic receptors), ion channels (L-calcium and sodium channels), and modulates some cytokines (IL-1, 6, 8, 10; TNF-α), which confers some anti-inflammatory properties to this drug [
      • Eldufani J.
      • Nekoui A.
      • Blaise G.
      Non-anesthetic effects of ketamine, a review article Authors.
      ,
      • Peltoniemi M.A.
      • et al.
      Ketamine: a review of clinical pharmacokinetics and pharmacodynamics in anesthesia and pain therapy.
      ].
      Most human studies assessing the efficacy of ketamine in RSE and SRSE are small retrospective series or isolated cases focused on a late use of this drug when the patient is already on polytherapy, which limits any conclusions about efficacy [
      • Zeiler F.A.
      • et al.
      NMDA antagonists for refractory seizures.
      ,
      • Fang Y.
      • Wang X.
      Ketamine for the treatment of refractory status epilepticus.
      ,
      • Höfler J.
      • et al.
      (S)-Ketamine in refractory and super-refractory status epilepticus: a retrospective study.
      ,
      • Ilvento L.
      • et al.
      Ketamine in refractory convulsive status epilepticus in children avoids endotracheal intubation.
      ,
      • Shrestha G.S.
      • et al.
      Intravenous ketamine for treatment of super-refractory convulsive status epilepticus with septic shock: a report of two cases.
      ,
      • Tarocco A.
      • Ballardini E.
      • Garani G.
      Use of ketamine in a newborn with refractory status epilepticus: a case report.
      ,
      • Synowiec A.S.
      • et al.
      Ketamine use in the treatment of refractory status epilepticus.
      ,
      • Gaspard N.
      • et al.
      Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multicenter study.
      ,
      • Esaian D.
      • et al.
      Ketamine continuous infusion for refractory status epilepticus in a patient with anticonvulsant hypersensitivity syndrome.
      ,
      • Rosati A.
      • et al.
      Efficacy and safety of ketamine in refractory status epilepticus in children.
      ,
      • Hsieh C.Y.
      • et al.
      Terminating prolonged refractory status epilepticus using ketamine.
      ,
      • Prüss H.
      • Holtkamp M.
      Ketamine successfully terminates malignant status epilepticus.
      ,
      • Zeiler F.A.
      Early use of the NMDA receptor antagonist ketamine in refractory and superrefractory status epilepticus.
      ,
      • Zeiler F.A.
      • et al.
      Ketamine for medically refractory status epilepticus after elective aneurysm clipping.
      ,
      • Sheth R.D.
      • Gidal B.E.
      Refractory status epilepticus: response to ketamine.
      ]. Nevertheless, the use of ketamine for RSE management is increasing given the apparently favorable results in these retrospective series [
      • Keros S.
      • et al.
      Increasing ketamine use for refractory status epilepticus in US pediatric hospitals.
      ]. Ketamine has fewer cardiovascular and respiratory side effects than other anesthetics used for the treatment of SRSE [
      • Ilvento L.
      • et al.
      Ketamine in refractory convulsive status epilepticus in children avoids endotracheal intubation.
      ]. Traditionally, ketamine has been avoided in patients with increased intracranial pressure due to its potential hypertensive effect, but this association has been called into question [
      • Cohen L.
      • et al.
      The effect of ketamine on intracranial and cerebral perfusion pressure and health outcomes: a systematic review.
      ,
      • Green S.M.
      • Andolfatto G.
      • Krauss B.S.
      Ketamine and intracranial pressure: no contraindication except hydrocephalus.
      ,
      • Wang X.
      • et al.
      Ketamine does not increase intracranial pressure compared with opioids: meta-analysis of randomized controlled trials.
      ]. Dissociative psychosis could be a potential side effect, but the combination of ketamine with a benzodiazepine mitigates this risk. The first multicenter, randomized, controlled, open-label study assessing the efficacy of ketamine in RSE in children is going on in Italy [
      • Rosati A.
      • et al.
      Efficacy of ketamine in refractory convulsive status epilepticus in children: a protocol for a sequential design, multicentre, randomised, controlled, open-label, non-profit trial (KETASER01).
      ]. An early use of ketamine for the treatment of SE, mainly in combination with other drugs, is being studied in animal models with promising results (see early polytherapy section).

      3.2.3 Other drugs

      3.2.3.1 Topiramate

      Topiramate was successfully used for the treatment of RSE and SRSE in small case series [
      • Shelton C.M.
      • et al.
      Enteral topiramate in a pediatric patient with refractory status epilepticus: a case report and review of the literature.
      ,
      • Asadi-Pooya A.A.
      • et al.
      Treatment of refractory generalized convulsive status epilepticus with enteral topiramate in resource limited settings.
      ,
      • Hottinger A.
      • et al.
      Topiramate as an adjunctive treatment in patients with refractory status epilepticus: an observational cohort study.
      ,
      • Brigo F.
      • et al.
      Topiramate in the treatment of generalized convulsive status epilepticus in adults: a systematic review with individual patient data analysis.
      ,
      • Madžar D.
      • et al.
      Assessing the value of topiramate in refractory status epilepticus.
      ]. Topiramate acts through multiple mechanisms: enhanced GABA-mediated inhibition, inhibition of sodium currents, enhanced potassium channel conduction, inhibition of L-type calcium channels, decrease of glutamatergic transmission, and inhibition of carbonic anhydrase [
      • Loddenkemper T.
      • Goodkin H.P.
      Treatment of pediatric status epilepticus.
      ]. The main adverse effect of topiramate is metabolic acidosis. The combination topiramate-valproate should be considered with caution due to the increasing risk of hyperammonaemic encephalopathy. Topiramate is only available enterally, which limits its use in acute situations.

      3.2.3.2 Brivaracetam

      Brivaracetam has the same mechanism of action as levetiracetam -inhibits neurotransmitter release due to its binding to the synaptic vesicle protein 2A (SV2A)-, but it seems to have higher affinity and, consequently, a faster brain permeability and action onset [
      • Nicolas J.M.
      • et al.
      Brivaracetam, a selective high-affinity synaptic vesicle protein 2A (SV2A) ligand with preclinical evidence of high brain permeability and fast onset of action.
      ]. Brivaracetam seems to be a safe drug without major drug-drug interactions, and less behavioral side effects compared to levetiracetam. Preclinical studies support the use of brivaracetam in SE, although its use in humans is limited to a small retrospective series of patients with RSE or SRSE with inconclusive results [
      • Strzelczyk A.
      • et al.
      Brivaracetam in the treatment of focal and idiopathic generalized epilepsies and of status epilepticus.
      ,
      • Strzelczyk A.
      • et al.
      Treatment of refractory and super-refractory status epilepticus with brivaracetam: a cohort study from two German university hospitals.
      ,
      • Niquet J.
      • et al.
      Acute and long-term effects of brivaracetam and brivaracetam-diazepam combinations in an experimental model of status epilepticus.
      ].

      3.2.3.3 Perampanel

      Perampanel targets non-NMDA glutamate receptors. It is a selective, non-competitive antagonist of AMPA receptors. As AMPA receptors are involved in the pathophysiology of SE, perampanel may potentially help in SE [
      • Strzelczyk A.
      • et al.
      Perampanel in the treatment of focal and idiopathic generalized epilepsies and of status epilepticus.
      ]. Although some preclinical studies support the effectiveness of perampanel [
      • Hanada T.
      • Ido K.
      • Kosasa T.
      Effect of perampanel, a novel AMPA antagonist, on benzodiazepine-resistant status epilepticus in a lithium-pilocarpine rat model.
      ], this drug has only been analyzed in a few retrospective case reports and series of RSE [
      • Rösche J.
      • Kampf C.
      • Benecke R.
      Possible effect of perampanel on focal status epilepticus after generalized tonic-clonic status epilepticus.
      ,
      • Rohracher A.
      • et al.
      Perampanel in patients with refractory and super-refractory status epilepticus in a neurological intensive care unit.
      ,
      • Redecker J.
      • et al.
      Efficacy of perampanel in refractory nonconvulsive status epilepticus and simple partial status epilepticus.
      ] with no conclusive results, possibly due to its late use in the course of treatment of RSE, the use of relatively low doses, and the administration via nasogastric tube.

      3.2.3.4 Drugs targeting the immune system

      Current immunotherapy in epilepsy is based on immunosuppressants (adrenocorticotropic hormone –ACTH-, corticosteroids, immunoglobulins, plasmapheresis, and monoclonal antibodies), and it is only used in certain conditions (some epileptic types such as infantile spasms, Lennox-Gastaut, severe encephalitis or autoimmune conditions). Novel approaches are focused on targeting key proinflammatory mediators potentially involved in neuroinflammation related to epilepsy [
      • Vezzani A.
      • Friedman A.
      • Dingledine R.J.
      The role of inflammation in epileptogenesis.
      ,
      • van Vliet E.A.
      • et al.
      Neuroinflammatory pathways as treatment targets and biomarker candidates in epilepsy: emerging evidence from preclinical and clinical studies.
      ,
      • Dey A.
      • et al.
      Anti-inflammatory small molecules to treat seizures and epilepsy: from bench to bedside.
      ,
      • Falip M.
      • Salas-Puig X.
      • Cara C.
      Causes of CNS inflammation and potential targets for anticonvulsants.
      ,
      • Ravizza T.
      • et al.
      High Mobility Group Box 1 is a novel pathogenic factor and a mechanistic biomarker for epilepsy.
      ]:
      • -
        Interleukin-1 and its receptor (IL-1, IL-1R)/ High mobility group box 1 (HMGB1) and Toll-like receptor signaling (TLR4). IL-1β, IL-6, TLR4, TNF-α and other cytokines can induce COX-2 through NF-κB.
      • -
        Transforming growth factor β signaling (TGF-β), which regulates albumin uptake into astrocytes.
      • -
        Cyclooxygenase-2 (COX-2), responsible for the synthesis of prostaglandins [
        • Santos A.C.
        • et al.
        EP2 receptor agonist ONO-AE1-259-01 attenuates pentylenetetrazole- and pilocarpine-induced seizures but causes hippocampal neurotoxicity.
        ].
      • -
        NOX2 (a NADPH oxidase), which generates reactive oxygen and nitrogen species (ROS/RNS) that can cause oxidative stress and contribute to SE-induced cytokine production [
        • McElroy P.B.
        • et al.
        Scavenging reactive oxygen species inhibits status epilepticus-induced neuroinflammation.
        ].
      • -
        Others: Tumor necrosis factor alpha (TNF-α), complement system, chemokines.
      Van Vliet et al. and Dey et al. have recently published detailed reviews summarizing the seizure mechanisms related to the previous neuroinflammation pathways, as well as a compilation of all the preclinical and clinical studies on anti-inflammatory treatments in epilepsy [
      • van Vliet E.A.
      • et al.
      Neuroinflammatory pathways as treatment targets and biomarker candidates in epilepsy: emerging evidence from preclinical and clinical studies.
      ,
      • Dey A.
      • et al.
      Anti-inflammatory small molecules to treat seizures and epilepsy: from bench to bedside.
      ]. Regarding SE, an IL-1 receptor antagonist –anakinra- is the first drug targeting the immune system reported as effective in a patient with SRSE secondary to FIRES (febrile infection-related epilepsy syndrome) [
      • Kenney-Jung D.L.
      • et al.
      Febrile infection-related epilepsy syndrome treated with anakinra.
      ]. A favorable response to IL-1 blockade has also been reported in a few patients with intractable epilepsy [
      • DeSena A.D.
      • Do T.
      • Schulert G.S.
      Systemic autoinflammation with intractable epilepsy managed with interleukin-1 blockade.
      ,
      • Jyonouchi H.
      • Geng L.
      Intractable epilepsy (IE) and responses to Anakinra, a human recombinant IL-1 receptor agonist (IL-1ra): case reports.
      ]. In a preclinical study (using kainic acid-induced SE, diazepam-refractory, in a mouse model), the combination of IL-1 receptor antagonist with diazepam terminated established prolonged SE [
      • Xu Z.H.
      • et al.
      Interleukin-1 receptor is a target for adjunctive control of diazepam-refractory status epilepticus in mice.
      ]. Furthermore, the administration of IL-1β reduced the efficacy of diazepam, suggesting that IL-1β accumulation may contribute to refractoriness of diazepam in prolonged SE [
      • Xu Z.H.
      • et al.
      Interleukin-1 receptor is a target for adjunctive control of diazepam-refractory status epilepticus in mice.
      ].
      It is remarkable that many studies about epileptogenesis emphasize the role of the immune system, and many preclinical neuroprotective strategies targeting the immune system show promising results [
      • Gross A.
      • et al.
      Toll-like receptor 3 deficiency decreases epileptogenesis in a pilocarpine model of SE-induced epilepsy in mice.
      ,
      • Benson M.J.
      • Manzanero S.
      • Borges K.
      The effects of C5aR1 on leukocyte infiltration following pilocarpine-induced status epilepticus.
      ,
      • Liang L.P.
      • et al.
      Neuroprotective effects of AEOL10150 in a rat organophosphate model.
      ,
      • Rojas A.
      • et al.
      Inhibition of the prostaglandin E2 receptor EP2 prevents status epilepticus-induced deficits in the novel object recognition task in rats.
      ].

      3.2.3.5 Cannabinoids

      Recently, there has been an increasing interest for cannabinoids in the field of epilepsy, although there is scarce and contradictory evidence supporting its use [
      • Friedman D.
      • Devinsky O.
      Cannabinoids in the treatment of epilepsy.
      ]. The endogenous cannabinoid system seems to play a role in modulating neuronal excitability, but the exact mechanism remains unclear. Cannabidiol may work through increasing the levels of clobazam and valproate [
      • Detyniecki K.
      • Hirsch L.J.
      Cannabidiol for epilepsy: trying to see through the haze.
      ,
      • Devinsky O.
      • Cross J.H.
      • Wright S.
      Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome.
      ]. Whether cannabidiol has a direct anticonvulsant effect or simply increases the levels of other antiepileptic drugs is unknown. Some pre-clinical studies suggest that cannabinoids may be useful for the treatment of SE [
      • Wallace M.J.
      • et al.
      The endogenous cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy.
      ,
      • Deshpande L.S.
      • et al.
      Cannabinoid CB1 receptor antagonists cause status epilepticus-like activity in the hippocampal neuronal culture model of acquired epilepsy.
      ,
      • Deshpande L.S.
      • et al.
      Endocannabinoids block status epilepticus in cultured hippocampal neurons.
      ,
      • Shubina L.
      • Aliev R.
      • Kitchigina V.
      Attenuation of kainic acid-induced status epilepticus by inhibition of endocannabinoid transport and degradation in guinea pigs.
      ], but there is no clinical evidence supporting its use beyond increasing the level of other antiepileptic medications. Furthermore, cannabinoids can be epileptogenic depending on the quantity of cannabidiol and Δ9-tetrahydrocannabinol in the drug, and the underlying conditions of the patient [
      • Friedman D.
      • Devinsky O.
      Cannabinoids in the treatment of epilepsy.
      ]. Some studies show SE induced by synthetic cannabinoids [
      • Babi M.A.
      • Robinson C.P.
      • Maciel C.B.
      A spicy status: synthetic cannabinoid (spice) use and new-onset refractory status epilepticus-A case report and review of the literature.
      ,
      • Patel N.A.
      • et al.
      New-onset refractory status epilepticus associated with the use of synthetic cannabinoids.
      ]. The therapeutic use of cannabinoids for SRSE is presented in a single case report without seizure control [
      • Rosemergy I.
      • Adler J.
      • Psirides A.
      Cannabidiol oil in the treatment of super refractory status epilepticus. A case report.
      ].

      3.2.3.6 Bumetanide

      Bumetanide is a diuretic that inhibits the Na-K-Cl cotransporter (NKCC1) –a transporter that facilitates the accumulation of chlorine in neurons. Bumetanide has an anticonvulsant effect in kainic acid-induced SE animal models, suggesting a role of chloride homeostasis in seizure progression and development of pharmacoresistant SE [
      • Sivakumaran S.
      • Maguire J.
      Bumetanide reduces seizure progression and the development of pharmacoresistant status epilepticus.
      ,
      • Barmashenko G.
      • et al.
      Positive shifts of the GABAA receptor reversal potential due to altered chloride homeostasis is widespread after status epilepticus.
      ]. NKCC1 cotransporter seems to enhance nonsynaptic epileptiform activity [
      • Nogueira G.S.
      • et al.
      Enhanced nonsynaptic epileptiform activity in the dentate gyrus after kainate-induced status epilepticus.
      ]. In some preclinical studies, bumetanide alone was ineffective to terminate SE, but this drug potentiated the anticonvulsant effect of low doses of phenobarbital [
      • Töllner K.
      • et al.
      Bumetanide is not capable of terminating status epilepticus but enhances phenobarbital efficacy in different rat models.
      ]. Hypoxia-ischemia seems to induce NKCC1 cotransporters in some studies [
      • Hu J.J.
      • et al.
      Bumetanide reduce the seizure susceptibility induced by pentylenetetrazol via inhibition of aberrant hippocampal neurogenesis in neonatal rats after hypoxia-ischemia.
      ]. Based on the preclinical data and the distribution of chloride in the neonatal brain due to the overexpression of NKCC1 transporter (see pathophysiology section), a clinical trial was carried out in Europe to determine the effectiveness of bumetanide as an add-on to phenobarbital for the treatment of seizures in newborns with hypoxic ischemic encephalopathy. This Phase I-II study was stopped early for failure to show efficacy and potential increase in risk of hearing loss in the newborns treated with bumetanide [
      • Pressler R.M.
      • et al.
      Bumetanide for the treatment of seizures in newborn babies with hypoxic ischaemic encephalopathy (NEMO): an open-label, dose finding, and feasibility phase 1/2 trial.
      ]. A similar clinical trial to study bumetanide in newborns with refractory seizures is going on in Boston, US (phase I) [

      ClinicalTrials.gov. NIH, US National Library of Medicine. Identifier NCT00830531. Pilot study of bumetanide for newborn seizures. Available from: https://clinicaltrials.gov/ct2/show/NCT00830531.

      ].

      3.2.3.7 Valnoctamide and sec-butylpropylacetamide

      Valnoctamide is an amide derivative of valproic acid. This molecule seems to be more potent and to have less adverse effects –no teratogenicity- than valproate in animal models [
      • Shekh-Ahmad T.
      • et al.
      Stereoselective anticonvulsant and pharmacokinetic analysis of valnoctamide, a CNS-active derivative of valproic acid with low teratogenic potential.
      ,
      • Shekh-Ahmad T.
      • et al.
      The potential of sec-butylpropylacetamide (SPD) and valnoctamide and their individual stereoisomers in status epilepticus.
      ,
      • Spampanato J.
      • Dudek F.E.
      Valnoctamide enhances phasic inhibition: a potential target mechanism for the treatment of benzodiazepine-refractory status epilepticus.
      ,
      • Shekh-Ahmad T.
      • et al.
      Valnoctamide and sec-butyl-propylacetamide (SPD) for acute seizures and status epilepticus.
      ]. Sec-butylpropylacetamide (SPD) is a homologue of valnoctamide even more potent than valnoctamide in some animal models [
      • White H.S.
      • et al.
      A new derivative of valproic acid amide possesses a broad-spectrum antiseizure profile and unique activity against status epilepticus and organophosphate neuronal damage.
      ,
      • Bar-Klein G.
      • et al.
      Sec-Butyl-propylacetamide (SPD) and two of its stereoisomers rapidly terminate paraoxon-induced status epilepticus in rats.
      ]. No human studies are available yet.

      3.2.3.8 Others

      Other marketed drugs such as lidocaine, felbamate, pregabalin, and gabapentin are used in SE, although the evidence is scarce [
      • Zeiler F.A.
      • et al.
      Lidocaine for status epilepticus in adults.
      ,
      • Zeiler F.A.
      • et al.
      Lidocaine for status epilepticus in pediatrics.
      ,
      • Novy J.
      • Rossetti A.O.
      Oral pregabalin as an add-on treatment for status epilepticus.
      ]. Many unmarketed drugs for epilepsy treatment are being developed or studied with the goal of improving seizure control (adenosine-releasing silk, AMP-X-0079, 2-deoxy-glucose, huperzine A, imepitoin, minoclycine, NAX 801-2, pitolisant, PRX0023, VLB-01, glibenclamide, P2X7 receptor antagonist) [
      • Bialer M.
      • et al.
      Progress report on new antiepileptic drugs: a summary of the Twelfth Eilat Conference (EILAT XII).
      ,
      • Huang C.
      • et al.
      Inhibition of P2X7 receptor ameliorates nuclear factor-kappa B mediated neuroinflammation induced by status epilepticus in rat Hippocampus.
      ,
      • Lin Z.
      • et al.
      Glibenclamide ameliorates cerebral edema and improves outcomes in a rat model of status epilepticus.
      ,
      • Forte N.
      • et al.
      2-Deoxy-d-glucose enhances tonic inhibition through the neurosteroid-mediated activation of extrasynaptic GABAA receptors.
      ,
      • Pithadia A.B.
      • et al.
      Reversal of experimentally induced seizure activity in mice by glibenclamide.
      ,
      • Beamer E.
      • Fischer W.
      • Engel T.
      The ATP-Gated P2X7 receptor As a target for the treatment of drug-resistant epilepsy.
      ,
      • Henshall D.C.
      • Engel T.
      P2X purinoceptors as a link between hyperexcitability and neuroinflammation in status epilepticus.
      ,
      • Engel T.
      • et al.
      Seizure suppression and neuroprotection by targeting the purinergic P2X7 receptor during status epilepticus in mice.
      ,
      • Bazzigaluppi P.
      • et al.
      Hungry neurons: metabolic insights on seizure dynamics.
      ,
      • Shao L.R.
      • Stafstrom C.E.
      Glycolytic inhibition by 2-deoxy-d-glucose abolishes both neuronal and network bursts in an in vitro seizure model.
      ].

      4. Early polytherapy

      4.1 Early polytherapy, basic science rationale

      SE represents a life-threatening medical emergency, and an early and effective treatment is one of the key determinants associated with a favorable outcome [
      • Gaínza-Lein M.
      • et al.
      Association of time to treatment with short-term outcomes for pediatric patients with refractory convulsive status epilepticus.
      ]. Our current stepwise guidelines recommend the use of benzodiazepines in monotherapy as the first-line treatment. Nevertheless, published studies show no major differences in efficacy when compared with other antiepileptic drugs [
      • Treiman D.M.
      • et al.
      A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group.
      ].
      The benzodiazepine resistance in SE is time dependent - greater delay in treatment is associated with increased risk for RSE. This mechanism appears related to changes in neurotransmitters receptors over time. In experimental models, during prolonged seizures -unlike brief seizures-, GABAA receptors are internalized [
      • Goodkin H.P.
      • Yeh J.L.
      • Kapur J.
      Status epilepticus increases the intracellular accumulation of GABAA receptors.
      ,
      • Naylor D.E.
      • Liu H.
      • Wasterlain C.G.
      Trafficking of GABA(A) receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus.
      ,
      • Kapur J.
      • Coulter D.A.
      Experimental status epilepticus alters gamma-aminobutyric acid type A receptor function in CA1 pyramidal neurons.
      ] while glutamate receptors (mainly NMDA receptors) increase their concentration at the synapse [
      • Naylor D.E.
      • et al.
      Rapid surface accumulation of NMDA receptors increases glutamatergic excitation during status epilepticus.
      ]. This decrease in inhibition and increase in excitation promotes that seizures become self-sustaining as their duration increases, which could explain the time-dependent increase in pharmacoresistance [
      • Wasterlain C.G.
      • et al.
      Molecular basis of self-sustaining seizures and pharmacoresistance during status epilepticus: the receptor trafficking hypothesis revisited.
      ,
      • Goodkin H.P.
      • Liu X.
      • Holmes G.L.
      Diazepam terminates brief but not prolonged seizures in young, naïve rats.
      ,
      • Jones D.M.
      • et al.
      Characterization of pharmacoresistance to benzodiazepines in the rat Li-pilocarpine model of status epilepticus.
      ,
      • Alldredge B.K.
      • Wall D.B.
      • Ferriero D.M.
      Effect of prehospital treatment on the outcome of status epilepticus in children.
      ,
      • Eriksson K.
      • et al.
      Treatment delay and the risk of prolonged status epilepticus.
      ]. The benzodiazepine resistance could also be accentuated by other potential mechanisms including changes in other ion channels such as sodium or potassium, cholinergic mechanisms involving acetylcholine, increased expression of drug-metabolizing enzymes at blood-brain barrier, neuroinflammation, neuronal damage, and even by etiology of SE [
      • Joshi S.
      • et al.
      Status epilepticus: role for etiology in determining response to benzodiazepines.
      ].
      The pathophysiology of SE suggests the most effective pharmacologic intervention is likely to be early polytherapy –the use of combinations of antiepileptic drugs promptly with the onset of seizures. Despite this, there is still limited evidence on the efficacy of early polytherapy due to the scarcity of clinical studies, although it is remarkable that many preclinical studies support its implementation [
      • Alvarez V.
      • Rossetti A.O.
      Monotherapy or Polytherapy for First-Line Treatment of SE?.
      ,
      • Löscher W.
      Single versus combinatorial therapies in status epilepticus: novel data from preclinical models.
      ].

      4.2 Early polytherapy, animal models of SE

      Reddy et al. published a detailed review on experimental models of SE [
      • Reddy D.S.
      • Kuruba R.
      Experimental models of status epilepticus and neuronal injury for evaluation of therapeutic interventions.
      ], which can be classified as follows:
      • -
        Electrical models: perforant pathway stimulation and self-sustaining stimulation [
        • Mazarati A.M.
        • et al.
        Self-sustaining status epilepticus after brief electrical stimulation of the perforant path.
        ].
      • -
        Chemical models: kainic acid, pilocarpine, lithium-pilocarpine, organophosphates, flurothyl, and cobalt-homocysteine thiolactone [
        • Walton N.Y.
        • Treiman D.M.
        Rational polytherapy in the treatment of status epilepticus.
        ].
      • -
        Thermal models: hyperthermia or febrile seizures.
      • -
        In vitro models: low magnesium in brain slices, high potassium in brain slices, 4-aminopyridine in brain slices, and organotypic slice cultures.
      • -
        Refractory models: lithium-pilocarpine [
        • Walton N.Y.
        • Treiman D.M.
        Rational polytherapy in the treatment of status epilepticus.
        ], kainic acid, and diisopropyl-flurophosphate (DFP).
      An isolated animal model cannot recapitulate the diverse etiologies of SE in the human, but the combination of these models could cover the spectrum of human SE and provide an appropriate experimental model.

      4.3 Potential appropriate combinations based on animal models

      It seems reasonable that early polytherapy is composed of a benzodiazepine and a second-line drug. The following combinations have been tested on animal models (Table 1):
      • -
        Diazepam–phenytoin. In 1996, Walton and Treiman showed that phenytoin-diazepam combination was more effective than each drug alone in a cobalt - homocysteine thiolactone rat model, without differences in side effects [
        • Walton N.Y.
        • Treiman D.M.
        Rational polytherapy in the treatment of status epilepticus.
        ]. Interestingly, they observed that the combination was more effective if phenytoin was administered before diazepam [
        • Walton N.Y.
        • Treiman D.M.
        Rational polytherapy in the treatment of status epilepticus.
        ].
      • -
        Diazepam - phenobarbital ± scopolamine. In 1996, Walton and Treiman showed that phenobarbital-diazepam combination was more effective than each drug alone in a cobalt - homocysteine thiolactone rat model, without differences in side effects [
        • Walton N.Y.
        • Treiman D.M.
        Rational polytherapy in the treatment of status epilepticus.
        ]. In 2008, Bankstahl and Löscher showed that a diazepam - phenobarbital combination effectively stopped SE in a lithium-pilocarpine rat model (in a study to test a Pgp inhibitor, a blood-brain barrier protein potentially involved in drug resistance) [
        • Bankstahl J.P.
        • Löscher W.
        Resistance to antiepileptic drugs and expression of P-glycoprotein in two rat models of status epilepticus.
        ]. In 2015, Löscher pointed out that this combination was not sufficient to prevent SE recurrence. However, when scopolamine (a muscarinic antagonist) was added to this combination, SE was rapidly terminated without recurrence, suggesting that cholinergic activity may be also involved in SE maintenance [
        • Löscher W.
        Single versus combinatorial therapies in status epilepticus: novel data from preclinical models.
        ,
        • Hillert M.H.
        • et al.
        Dynamics of hippocampal acetylcholine release during lithium-pilocarpine-induced status epilepticus in rats.
        ]. Furthermore, scopolamine was related to an antiepileptogenic effect [
        • Löscher W.
        Single versus combinatorial therapies in status epilepticus: novel data from preclinical models.
        ].
      • -
        Diazepam - ketamine / midazolam–ketamine. Niquet et al. showed that midazolam – ketamine combination was more effective than valproate-midazolam combination, valproate-ketamine combination, double-dose of midazolam, ketamine and valproate in monotherapy in a severe lithium-pilocarpine rat model. Furthermore, the midazolam-ketamine combination was related to an antiepileptogenic effect and reduction of acute neuronal injury induced by SE [
        • Niquet J.
        • et al.
        Midazolam-ketamine dual therapy stops cholinergic status epilepticus and reduces Morris water maze deficits.
        ]. Martin and Kapur also showed that a diazepam – ketamine combination was more effective than each drug alone in terminating SE in a lithium-pilocarpine rat model [
        • Martin B.S.
        • Kapur J.
        A combination of ketamine and diazepam synergistically controls refractory status epilepticus induced by cholinergic stimulation.
        ]. MK-801 (a noncompetitive NMDA receptor antagonist) followed by diazepam, and only in this order, was effective in a lithium - pilocarpine rat model [
        • Walton N.Y.
        • Treiman D.M.
        Rational polytherapy in the treatment of status epilepticus.
        ]. NPC-17742 (a competitive NMDA receptor antagonist) followed by diazepam was also effective in a cobalt - homocysteine thiolactone rat model [
        • Walton N.Y.
        • Treiman D.M.
        Rational polytherapy in the treatment of status epilepticus.
        ].
      • -
        Benzodiazepines - ketamine - valproate / benzodiazepines - ketamine–brivaracetam. A low dose combination of the previous triple therapy (diazepam or midazolam-ketamine-valproate or diazepam-ketamine-brivaracetam) was more effective than each drug in monotherapy and some dual therapies tested, showing synergistic properties [
        • Niquet J.
        • et al.
        Treatment of experimental status epilepticus with synergistic drug combinations.
        ,
        • Niquet J.
        • et al.
        Simultaneous triple therapy for the treatment of status epilepticus.
        ,
        • Wasterlain C.G.
        • et al.
        Rational polytherapy in the treatment of acute seizures and status epilepticus.
        ], on a severe cholinergic rat model. In addition, a lower dose of drug was effective in combination treatments, without additional side effects. Midazolam-ketamine-valproate was also more effective than midazolam-fosphenytoin-valproate, highlighting the importance of blocking the NMDA receptor in SE [
        • Niquet J.
        • et al.
        Simultaneous triple therapy for the treatment of status epilepticus.
        ].
      • -
        Diazepam - levetiracetam / diazepam–brivaracetam. The diazepam-levetiracetam combination was more effective than diazepam alone for the termination of SE, even when both drugs were given in lower dosage than usual [
        • Mazarati A.M.
        • et al.
        Anticonvulsant effects of levetiracetam and levetiracetam-diazepam combinations in experimental status epilepticus.
        ]. Levetiracetam seems to be a universal enhancer of many antiepileptic drugs –mainly with GABAergics or anti-glutamatergics-, without showing differences in side effects, and independently of the animal model used [
        • Kaminski R.M.
        • et al.
        Benefit of combination therapy in epilepsy: a review of the preclinical evidence with levetiracetam.
        ]. The diazepam-brivaracetam combination has also been tested showing better results in combination, and with lower doses as well [
        • Niquet J.
        • et al.
        Acute and long-term effects of brivaracetam and brivaracetam-diazepam combinations in an experimental model of status epilepticus.
        ]. Both studies were carried out in a rat model of perforant pathway stimulation of self-sustaining SE.
      • -
        Diazepam–perampanel. The diazepam – perampanel combination was more effective than diazepam alone, and as effective as perampanel but with less dose in dual therapy, in a lithium-pilocarpine SE rat model [
        • Hanada T.
        • Ido K.
        • Kosasa T.
        Effect of perampanel, a novel AMPA antagonist, on benzodiazepine-resistant status epilepticus in a lithium-pilocarpine rat model.
        ].
      • -
        Diazepam- IL-1 receptor antagonist. This combination was more effective than each drug alone in a kainic acid-induced SE rat model [
        • Xu Z.H.
        • et al.
        Interleukin-1 receptor is a target for adjunctive control of diazepam-refractory status epilepticus in mice.
        ].
      • -
        Atropine - ketamine. Although this review is focused on early polytherapy, it is remarkable that this combination proved effective in the delayed treatment of SE in a soman-poisoned male guinea pig model [
        • Dorandeu F.
        • et al.
        Efficacy of the ketamine-atropine combination in the delayed treatment of soman-induced status epilepticus.
        ].
      Table 1Compilation of animal and human studies about early polytherapy in status epilepticus.
      EP: early polytherapy. +: in favor of early polytherapy. -: inconclusive for early polytherapy. C-HT: cobalt-homocysteine thiolactone. L-P : lithium-pilocarpine. PPS: perforant pathway stimulation. KA: kainic acid. SD: Sprague-Dawley. WT: wild-type. DZP: diazepam. PB: phenobarbital. PHT: phenytoin. MDZ: midazolam. KET: ketamine. BRV: brivaracetam. LEV: levetiracetam. VPA: valproate. PER: perampanel. IL-1Ra: IL-1 receptor antagonist. LZP: lorazepam. BZD: benzodiazepine. CZP: clonazepam. MK-801: noncompetitive NMDA receptor antagonist. NPC-17742: competitive NMDA receptor antagonist. SE: status epilepticus. AEDs: antiepileptic drugs. GYKI52466: AMPA antagonist. GCSE: generalized convulsive status epilepticus. FPHT: fosphenytoin. h: hour. w: week. m: month. min: minutes. vs: versus. x2: double dose.

      4.4 Early polytherapy, human studies

      There are few human studies on early polytherapy. In 1998, the ‘Veterans Affairs Status Epilepticus Cooperative Study Group’ carried out a randomized, double blind, multicenter trial comparing four treatments for generalized convulsive SE in adults: lorazepam, phenobarbital, phenytoin, or a combination of diazepam and phenytoin [
      • Treiman D.M.
      • et al.
      A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group.
      ]. The trial showed no differences among the arms in an intention-to-treat analysis. As initial treatment for overt generalized convulsive SE, lorazepam was superior to phenytoin. In 2010, another randomized controlled trial in children compared lorazepam to diazepam-phenytoin combination, showing that lorazepam was as efficacious and safe as the combination diazepam-phenytoin, and therefore, the use of lorazepam as a single drug was recommended [
      • Sreenath T.G.
      • et al.
      Lorazepam versus diazepam-phenytoin combination in the treatment of convulsive status epilepticus in children: a randomized controlled trial.
      ]. In 2010, a cohort study focused on the evaluation of professional practice in front of generalized convulsive SE in adults showed that the combination of diazepam or clonazepam with fosphenytoin allowed a high rate of SE termination than benzodiazepines alone, emphasizing that it could be related to an early use of long-acting antiepileptic drugs other than benzodiazepines [
      • Aranda A.
      • et al.
      Generalized convulsive status epilepticus management in adults: a cohort study with evaluation of professional practice.
      ]. Recently, a randomized, double-blind, phase 3 trial comparing prehospital treatment with levetiracetam plus clonazepam to placebo plus clonazepam in SE found no statistical differences [
      • Navarro V.
      • et al.
      Prehospital treatment with levetiracetam plus clonazepam or placebo plus clonazepam in status epilepticus (SAMUKeppra): a randomised, double-blind, phase 3 trial.
      ]. Nevertheless, levetiracetam does not specifically target the underlying and evolving pathophysiology of SE, although a few recent studies suggest this drug may also modulate glutamate receptors [
      • Carunchio I.
      • et al.
      Modulation of AMPA receptors in cultured cortical neurons induced by the antiepileptic drug levetiracetam.
      ,
      • Lee C.Y.
      • Chen C.C.
      • Liou H.H.
      Levetiracetam inhibits glutamate transmission through presynaptic P/Q-type calcium channels on the granule cells of the dentate gyrus.
      ]. Although this review article is focused on early polytherapy, it is worthy of note that later combinations in RSE or SRSE, such as midazolam-pentobarbital or propofol-ketamine, have shown favorable outcomes [
      • Tasker R.C.
      • et al.
      Refractory status epilepticus in children: intention to treat with continuous infusions of midazolam and pentobarbital.
      ,
      • Sabharwal V.
      • et al.
      Propofol-ketamine combination therapy for effective control of super-refractory status epilepticus.
      ].

      4.5 Early polytherapy, potential risks

      The main potential risk of early polytherapy would be the increase of potential adverse effects. Early polytherapy implies an additional risk of side effects with no benefit for patients who would have responded to monotherapy with benzodiazepines. However, approximately one third of patients require a second-line antiepileptic drug. For this reason, non-life-threatening side effects may be less important than the potential to have a rapid and effective termination of seizures. Furthermore, many studies suggest that when using early polytherapy less dose of each drug is needed, decreasing potential side effects. The risk-benefit ratio of early polytherapy in SE seems rational, but the literature on this topic is still limited.

      5. Future directions

      Novel drugs targeting the underlying pathophysiology of SE are developed with the goal of improving seizure control and outcomes. SE can be caused by a wide variety of etiologies including infections, metabolic disorders, genetic conditions, and immunologic processes, as well as responses to drugs may be modified by genetic polymorphisms. Accordingly, even for drugs which target the underlying pathophysiology of SE, there are major challenges in translating their efficacy in pre-clinical studies into efficacy in clinical trials. These characteristics of children with SE are a major challenge to any attempt to establish a single common, well-defined and effective treatment algorithm for SE, RSE or SRSE, since treatment should ideally be adapted to each specific etiology and patient characteristics. Future directions should be addressed to identify and treat mechanisms which are common to multiple etiologies and which incorporate understanding of the pharmacogenetic factors that regulate drug target engagement and pharmacokinetics. Many fundamental questions regarding the treatment of SE and progression to SRSE remain unanswered, including: what is the best drug combination?; what is the optimal sequence of drug administration?; what is the most effective time-lag between each drug?; what is the best dosage when combining drugs?; are there any modifiable mechanisms of pharmacoresistance?; which patients will become refractory to benzodiazepines?; what is the exact role of the blood-brain barrier and the immune system in SE?; should new drugs target receptors involved in seizure termination?; what are the mechanisms underlying seizure termination? A better understanding of these questions could help to achieve a more successful treatment algorithm for SE, and therefore, to reduce the percentage of treatment failure and adverse drug effects.

      6. Conclusions

      A better understanding of the pathophysiology of SE allows for developing well-targeted novel drugs and improving the management approach of this condition. The early combination of antiepileptic drugs targeting different receptors involved in the dynamic synaptic changes during SE may potentially improve seizure control and outcomes.

      Ethics

      This study complied with biomedical research ethical standards.

      Funding

      This study was supported by the Epilepsy Research Fund .

      Declaration of interest

      Mark Wainwright is a member of the Clinical Advisory Board for Sage Therapeutics.
      The authors report no potential conflicts of interest.

      Contributors

      Marta Amengual-Gual participated in drafting and revising the manuscript for content, including medical writing for content, in study concept and design, and study supervision.
      Iván Sánchez Fernández participated in revising the manuscript for content, including medical writing for content, in study concept and design, and study supervision or coordination.
      Mark Wainwright participated in medical writing for content, in study concept and design, and study supervision or coordination.

      Acknowledgements

      Marta Amengual-Gual is funded by a grant for the study of status epilepticus from “ Fundación Alfonso Martín Escudero ”.
      Iván Sánchez Fernández is funded by the Epilepsy Research Fund and was funded by a grant for the study of epileptic encephalopathies from “Fundación Alfonso Martín Escudero” and by the HHV6 Foundation.

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