Abstract

Prolonged, self-sustaining seizures that can cause neuronal injury and respiratory compromise are called status epilepticus (SE). SE is a dynamic condition where drug responsiveness, electroencephalography, active neuronal circuits, and synapses change over time, which has prompted division into early, established, and refractory stages. As SE evolves, the neuronal circuits generating seizures also change dynamically, engaging more structures. We review the role of excitatory transmission in generating and sustaining SE. Organophosphates precipitate SE by enhancing glutamate release from the presynaptic terminals. GABAergic inhibition fails in the early stages of SE, especially in the hippocampus, and then the glutamatergic transmission is potentiated during established SE. AMPA receptor-mediated excitation increases due to the insertion of the GluA1 subunit into synaptic receptors. NMDA receptor-mediated excitation is enhanced, and blocking this receptor can prevent reduced GABAergic inhibition and enhanced glutamatergic transmission. These studies form the basis for clinical trials to treat SE with NMDA receptor antagonist ketamine and AMPA receptor antagonist perampanel.

Introduction

Status epilepticus (SE) is a prolonged, self-sustaining seizure that can cause brain injury or death, which requires prompt treatment. The incidence of SE ranges from 4.5 to 41 per 100,000 in the United States, and treatment can cost thousands of U.S. dollars per patient (Brophy et al. 2012; Guterman et al. 2021; Leitinger et al. 2019; Penberthy et al. 2005). Babies in the first year of life and adults older than 60 are at a higher risk of SE (DeLorenzo et al. 1996; Hesdorffer et al. 1998). The overall mortality due to SE is around 20% (Betjemann and Lowenstein 2015; Giovannini et al. 2015; Neligan et al. 2019). Some of the long-term outcomes of SE include hippocampal injury, recurrence of SE, cognitive effects, and other neurological deficits (Joshi and Goodkin 2020). A large body of clinical and experimental studies demonstrates that SE is a dynamic condition where ongoing seizure activity causes pathological changes in the brain that facilitate further seizures (Brophy et al. 2012; Chen and Wasterlain 2006; Joshi and Kapur 2012; Lothman 1990). The ILAE definition of SE recognizes two stages of SE: T1, where there is a breakdown of mechanisms terminating seizures and, when seizures last longer, T2, they cause neuronal injury or death (Joshi and Kapur 2012).

We propose that enhanced excitatory transmission plays a critical role in sustaining prolonged seizures, spread from the hippocampus to the bilateral neocortex, and neuronal injury and death following SE. In a previous edition of this textbook, we proposed that the breakdown of GABAergic inhibition in the hippocampus accounts for T1, the early stage of SE (Joshi and Kapur 2012). Subsequent clinical trials and laboratory studies further reinforce this notion. Two large Phase III clinical trials showed that benzodiazepines, which potentiate GABA-A receptor-mediated inhibitory neurotransmission, are the first-line therapy for SE (Alldredge et al. 2001; Chamberlain et al. 2014; Silbergleit et al. 2012; Treiman et al. 1998). Laboratory studies have further elaborated the mechanism of reduced GABAergic inhibition during SE. There is an accumulation of chloride within neurons due to modification of chloride transporter protein that reduces GABAergic inhibition and contributes to benzodiazepine resistance (Burman et al. 2019; Moore et al. 2018; Silayeva et al. 2015). We propose that once GABAergic inhibition has failed, controlling runaway excitation is a powerful way to terminate SE.

Cholinergic Agents and Glutamate Analogs Induce Status Epilepticus

There is growing evidence that cholinergic agents and organophosphates cause SE by enhancing excitatory transmission. Organophosphates (OPs), such as parathion, malathion insecticides, and soman, sarin, tabun, and VX, are agents of chemical warfare. Nerve agents have been used in the Gulf War, and by terrorist organizations in Japan and Syria, with devastating results (Morita et al. 1995; Okumura et al. 1996; Romano 2007). OPs are also used in pesticides and insecticides, which could also pose health risks. A well-characterized neurological effect of acute OP poisoning is the induction of prolonged seizures of SE (Deshpande et al. 2014; Garcia et al. 2003; Hoffmann and Papendorf 2006; McDonough and Shih 1997; Shih 1990; Shih and McDonough 1997; Shih et al. 1999, 2003; Todorovic et al. 2012). OPs irreversibly block the enzyme acetylcholinesterase and cause accumulation of acetylcholine at central and peripheral synapses (McDonough and Shih 1997; Shih 1982; Shih and McDonough 1997). Muscarinic agonist pilocarpine alone or in combination with lithium is commonly used to produce status epilepticus in experimental animals (Jope et al. 1986; Kapur et al. 1994; Lemos and Cavalheiro 1995). Studies have explored the cellular and molecular mechanisms underlying SE induced by cholinergic agents.

The hippocampus and connected limbic structures are active during cholinergic SE; therefore, we perform mechanistic studies in that structure (Clifford et al. 1987; Handforth and Treiman 1995). The three-layered rodent hippocampus consists of the dentate gyrus, Cornu Ammonis (CA) area 3, and area 1. Granule cells constitute excitatory neurons of the dentate gyrus, and pyramidal neurons are primary excitatory neurons in CA1 and CA3. Within two blades of the dentate gyrus is the hilus. The dentate gyrus receives excitatory projections from the entorhinal cortex and projects via mossy fibers to the CA3 region, which connects to the CA1 region via Schaffer collaterals.

Figure 70–1.

Organophosphates enhance presynaptic glutamate release. A. Organophosphates inhibit the enzyme acetylcholinesterase, which metabolizes acetylcholine. This results in the excessive accumulation of acetylcholine. B. The accumulated acetylcholine binds (more...)

We studied Paraoxon, an organophosphate cholinesterase inhibitor using patch-clamp electrophysiology to understand the mechanism of organophosphate-induced seizures. Paraoxon enhanced glutamatergic transmission on hippocampal granule cell synapses by increasing spontaneous excitatory postsynaptic currents (sEPSCs) in a concentration-dependent fashion (Kozhemyakin et al. 2010). The amplitude of action potential-independent (miniature) EPSCs was not increased, suggesting enhanced action potential–dependent release. Paraoxon reduced minimal stimulation-evoked EPSC failures and increased amplitude of evoked responses, and it also altered the paired-pulse ratio of evoked EPSCs. Muscarinic antagonist atropine blocked, and carbachol partially mimicked these paraoxon effects. The nicotinic receptor antagonist α-bungarotoxin did not block the effects of paraoxon; however, nicotine enhanced glutamatergic transmission. Cholinergic overstimulation enhances glutamatergic transmission by enhancing neurotransmitter release from presynaptic terminals.

We further explored the mechanism of muscarinic receptors modulation of glutamate release. The M1 receptor agonist, NcN-A-343, increased the frequency of mEPSCs but did not alter their amplitude. The M-channel blockers linopirdine and XE991 also increased the mEPSC frequency. Opening the M-channels with flupirtine had the opposite effect. Blocking P/Q- and N-type calcium channels abolished the effect of XE991 on mEPSCs. These data suggested that the inhibition of M-channels increases presynaptic calcium-dependent glutamate release in CA1 pyramidal neurons. Muscarinic activation inhibits M-channels, causing presynaptic terminal depolarization, which activates voltage-gated calcium channels, elevating the intracellular calcium concentration to increase glutamate release (Sun and Kapur 2012).

These studies suggested that we can terminate SE by reducing glutamate release. The neuropeptide somatostatin (SST) diminishes presynaptic glutamate release by activating SST type-2 receptors (SST2R). We investigated the mechanism of action of SST on excitatory synaptic transmission and its ability to treat SE. SST reduced sEPSCs at Schaffer collateral-CA1 synapses at concentrations up to 1 μM; higher concentrations did not affect the sEPSC frequency. SST also prevented paired-pulse facilitation of evoked EPSCs and did not alter action-potential-independent miniature EPSCs (mEPSCs). SST2R antagonist cyanamid-154806 blocked the SST effect, which the SST2R agonists, octreotide, and lanreotide mimicked. Both SST and octreotide reduced the firing rate of CA1 pyramidal neurons. SST either prevented or attenuated pilocarpine-induced SE within a range of doses.

Similarly, octreotide or lanreotide prevented or attenuated SE in more than 65% of animals. Compared to the pilocarpine model, octreotide was highly potent in preventing or attenuating electrically induced SE. Our results demonstrate that SST, through the activation of SST2Rs, diminishes presynaptic glutamate release and attenuates SE.

Glutamate Receptors

Glutamate is the principal excitatory neurotransmitter in the mammalian central nervous system. Three groups of ionotropic glutamate receptors are present in the brain: AMPA, NMDA, and kainite receptors. The activation of glutamate receptors leads to the influx of sodium and calcium ions into the neurons, which causes membrane depolarization and neuronal activation.

The AMPA receptors are ligand-gated sodium and calcium channels that mediate fast excitatory neurotransmission. The AMPA receptors are composed of four subunits, GluA1 to GluA4, which could assemble to form homo or heterodimers (Fig. 70–2A). The subunit composition varies across brain regions, and as discussed below, the seizure activity also alters the subunit composition (Derkach et al. 2007). The channel conductance, open probability, and permeability to calcium ions are dependent on the subunit composition; the receptors lacking the GluA2 subunits have enhanced conductance and longer open probability, and these receptors are permeable to calcium ions (Burnashev et al. 1992; Burnashev 2005; Swanson et al. 1997; Oh and Derkach 2005). Thus, the presence or absence of GluA2 subunits in the functional AMPA receptors could drastically affect calcium toxicity-induced neuronal injury and death following SE.

Figure 70–2.

A schematic showing hippocampal AMPAR and NMDAR and their SE-associated plasticity. A. The hippocampal AMPARs could be homo or hetero-tetramers assembled from GluA1, GluA2, and GluA3 subunits. The incorporation of GluA2 subunits renders calcium-impermeability (more...)

The second class of ionotropic glutamate receptors comprises NMDA receptors, voltage- and ligand-gated sodium and calcium channels (Fig. 70–2C). The activity of these channels depends on glutamate binding and accompanying depolarization, which relieves the magnesium block. Most of these receptors comprise two GluN1 subunits with either two GluN2 subunits or a combination of GluN2 and GluN3 subunits (Hansen et al. 2018; Karakas and Furukawa 2014; Lee et al. 2014; Traynelis et al. 2010). The GluN2 subunit has four isoforms, GluN2A to GluN2D, whereas the GluN3 subunit has two isoforms, GluN3A and GluN3B (Hansen et al. 2018). The identity of the GluN2 subunit isoform has a strong influence on the NMDA receptor function, and it regulates glutamate binding potency and the time course of the receptor deactivation (Chen et al. 2008; Monyer et al. 1992; Wyllie et al. 2013). In addition to glutamate, binding to glycine or D-serine, which act as co-agonists, is also necessary to activate these receptors (Mothet et al. 2015; Wolosker 2007). In contrast to the fast-activating AMPA receptors, the activation and decay of NMDA receptors are slower. Thus, the opening of these channels allows a prolonged entry of calcium ions into the neurons.

Kainate receptors comprise the third class of ionotropic glutamate receptors. These receptors are composed of GluK1 to GluK5 subunits, which co-assemble to form the receptor (Falcón-Moya1 et al. 2018; Jane et al. 2009). The GluK3 to GluK5 subunits can form homomeric receptors and heteromeric receptors assembled with GluK1 and GluK2 subunits. In addition to taking part in the postsynaptic glutamatergic transmission, these receptors are also involved in regulating glutamate release in the hippocampus (Chittajallu et al. 1996).

The activity and surface membrane expression of glutamate receptors are regulated by posttranslational modifications, including phosphorylation and palmitoylation (Chen and Roche 2007; Hayashi 2021; Lee et al. 2000; Lu and Roche 2012; Song and Huganir 2002; Salter et al. 2009). Additionally, RNA editing of some glutamate receptor subunits also influences the receptor function (Wright and Vissel 2012). In particular, the AMPA receptors incorporating the edited form of the GluA2 subunit are calcium impermeable, whereas those containing the unedited form are highly calcium permeable. The GluK1 and GluK2 subunits of KA receptors are also subject to RNA editing, which regulates the channel properties, including recovery from desensitization, calcium permeability, and conductance (Wright and Vissel 2012).

Glutamate Receptor Expression in the Brain

The glutamate receptors are expressed widely in the brain. In situ hybridization has revealed a high expression of kainate/AMPA receptors in the hippocampal dentate granule neurons, the pyramidal neurons of the hippocampus and cortex, and the cerebellar Purkinje cells (Harrison et al. 1990; Sato et al. 1993). In contrast, the thalamus and neocortex have a moderate expression of these receptors. The GluA1 subunit is the most widely expressed AMPA receptor subunit. Its expression is high in the hippocampus, olfactory bulbs, septum, and cerebellum (Keinanen et al. 1990) and moderate in the cortex and striatum; all cortical neuronal layers express the GluA1 subunit (Keinanen et al. 1990). In contrast, other subcortical regions have a weaker GluA1 subunit expression. The GluA2 subunit is also highly expressed in the olfactory bulbs, hippocampi, and cerebellum of adult animals, whereas its expression is moderate in the cortex. The GluA3 subunit is also highly expressed in the olfactory bulbs, cortex, and hippocampus. The expression of the GluA4 subunit seems to be primarily restricted to the olfactory bulbs and cerebellum, and moderate to weak expression is seen in the hippocampus. The GluA2 expression is low during early postnatal development, and the receptors expressed in neonatal animals are calcium permeable (Pellegrini-Giampietro et al. 1992). The expression of GluA2 increases with development, and calcium-permeable AMPA receptors are replaced with calcium-impermeable receptors.

The GluN1 subunit is the most widely and highly expressed NMDA receptor subunit in adulthood (Sanz-Clemente et al. 2013). Its expression is high in the hippocampus, cortex, olfactory bulbs, and cerebellum and moderate in other regions. The expression of GluN2A and GluN2C is negligible at birth and increases during postnatal development. In adulthood, the GluN2A expression pattern is similar to that of GluN1, whereas the expression of GluN2C is restricted to the cerebellum. In contrast to the developmental increase in GluN2A and GluN2C subunit expression, GluN2B and GluN2D are high at birth and decrease subsequently. In adulthood, GluN2B expression is restricted to the hippocampus.

The kainate receptors are also widely expressed in the adult brain, with a high expression in the hippocampus and cerebral cortex (Bahn et al. 1994). GluK5 is the most common kainate receptor subunit in the adult brain (Wisden and Seeburg 1993). Thus, all the three subtypes of glutamate receptors are expressed abundantly in the cortical and limbic regions, critical for ictogenesis and seizure spread during SE.

Glutamate Receptor Plasticity during SE

Experimental animal models in which SE is induced by chemoconvulsants, including kainic acid, pilocarpine, or organophosphates, or by electrical stimulation of the hippocampus or performant path have been used to obtain insights into molecular mechanisms of SE. Most of these studies have focused on changes occurring in the hippocampus. This highly ictogenic limbic region is also involved in seizure spread due to its extensive connections to other limbic structures and cortical and thalamic areas.

SE is associated with potentiation of AMPA receptor-mediated neurotransmission of CA1 pyramidal neurons (Joshi et al. 2017; Rajasekaran et al. 2012) (Fig. 70–2B, 2D). The receptors expressed in the animals in SE also have a higher calcium permeability (Rajasekaran et al. 2012). These changes in the properties of the receptors are associated with increased cell surface expression of the GluA1 subunit and reduced surface expression of the GluA2 subunits in the hippocampi of animals in SE (Joshi et al. 2017; Rajasekaran et al. 2012). Interestingly, both the CA1 pyramidal neurons and DGCs express calcium-permeable AMPA receptors during early SE (10 min from seizure onset); but only the changes in CA1 neurons persist (Rajasekaran et al. 2012). The seizure-like activity triggered by exposure of brain slices to 4-aminopyridine also induces similar plasticity of AMPA receptors in the entorhinal cortical neurons (Amakhin et al. 2018). Furthermore, the calcium permeability of AMPA receptors of cortical and hippocampal neurons also increased following SE (Malkin et al. 2016).

Recently we have found that even a single seizure also increases the expression of calcium-permeable AMPA receptors in the activated CA1 neurons (Naik et al. 2020). Thus, during SE, the uncontrolled seizure activity would increase the number of neurons having potentiated glutamatergic transmission through these receptors (Joshi and Kapur 2018a). The SE-induced potentiation of AMPA receptor-mediated neurotransmission is blocked in the mice lacking the GluA1 subunit. The seizure-associated behavior is also milder in the knockout mice, and mortality is reduced compared to wild-type animals (Adotevi et al. 2019). Additionally, the incidence of SE is also reduced in the mice lacking GluA1 subunits. Thus, AMPA receptors appear to play a critical role in the initiation of seizures.

Like the AMPA receptor plasticity, the NMDA receptor-mediated glutamatergic transmission is also potentiated during SE (Naylor et al. 2013; Wasterlain et al. 2013). The cell surface immunoreactivity of the GluN1 subunit and its colocalization with synapsin is higher in the DGCs of animals in SE (Naylor et al. 2013; Wasterlain et al. 2013). This externalization of NMDA receptors is accompanied by the enhancement of the NMDA receptor-mediated synaptic currents (Naylor et al. 2013; Wasterlain et al. 2013). Blockade of NMDA receptors with ketamine or MK-801 rapidly terminates SE induced by performant path stimulation (Mazarati et al. 1998). Indirect evidence also suggests potentiated NMDA receptor-mediated transmission during SE. Phosphorylation of NMDA receptors, which promotes their membrane insertion, is increased during SE (Huo et al. 2006; Scott et al. 2003). The phosphorylation of S890 and S897 residues of GluN1 subunit and that of T1387 and T1472 of GluN2A and GluN2B, respectively, is increased in the hippocampi of animals in SE (Niimura et al. 2005).

KA is a potent chemoconvulsant commonly used to trigger SE in experimental animals. The expression of GluK1 subunits is enhanced in experimental animals and humans with epilepsy (Li et al. 2010; Ullal et al. 2005). However, whether the KA receptor function is also potentiated during SE remains unexplored. Indirect evidence suggests that KA receptors are functional during SE and could be targeted for therapeutic purposes (Figueiredo et al. 2011).

Glutamate Receptor Antagonists in the Treatment of SE: Studies in Experimental Animals

NMDA and AMPA receptor antagonists are efficacious in terminating these prolonged seizures even when administered after the onset of refractoriness to benzodiazepines. Several NMDA receptor antagonists, including ketamine, dizocilpine (MK-801), 3-((R,S)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), and ifenprodil, which act through distinct mechanisms, have been used to terminate SE in experimental animals. Ketamine is a noncompetitive NMDA receptor antagonist. Ketamine and MK-801 are open-channel blockers, which occlude the flow of ions through these channels (Anis et al. 1983; Zorumski et al. 2016). In contrast, CPP and ifenprodil are competitive NMDA receptor antagonists. Ifenprodil action also depends on pH; it does not affect the receptor activity at physiological pH but blocks them at an acidic pH, which could arise during seizures (Mott et al. 1998). CPP and ifenprodil also show selectivity for the receptors composed of specific subunits, whereas ketamine and MK-801 are pan-NMDA receptor blockers.

NMDA receptor antagonists block the self-reinforcing effect of repeated seizures (Kapur and Lothman 1990). Seizures repeated every 5 minutes become more prolonged, and ketamine and MK 801 prevent this effect. In electrical stimulation models of SE, ketamine or MK-801 administered after the onset of seizures rapidly terminates SE (Mazarati and Wasterlain 1999; Prasad et al. 2002; Yen et al. 2004). Both these compounds are open-channel blockers, and the activation of NMDA receptors during SE would also make them available to these agents. In contrast to ketamine and MK-801, CPP and ifenprodil are less efficacious in terminating benzodiazepine-refractory SE (Yen et al. 2004). These findings suggested that nonspecific channel block is more effective than targeting specific receptors. In addition to being efficacious agents in treating seizures of SE, MK-801 or ketamine exert a synergistic action with diazepam to rapidly terminate benzodiazepine-refractory SE (Joshi et al. 2017; Martin and Kapur 2008).

Emerging evidence also shows that AMPA receptor antagonists are potent in terminating SE (Fritsch et al. 2010; Hanada et al. 2014; Pitkänen et al. 2007; Rajasekaran et al. 2012; Wu et al. 2017). GYKI 52466 and perampanel, selective, noncompetitive AMPA receptor antagonists, rapidly terminate SE when administered before or after the onset of benzodiazepine resistance (Fritsch et al. 2010; Hanada et al. 2014; Rajasekaran et al. 2012; Wu et al. 2017). Similarly, IEM-1460, an inhibitor of calcium-permeable, GluA2 subunit-lacking AMPA receptors, is also efficacious in terminating established SE (Adotevi et al. 2019). IME-1460 also attenuates the intensity of seizures and suppresses generalized seizures, which are known to increase the risk of death (Adotevi et al. 2019). AMPA receptor antagonism also seems to be effective in terminating SE in young animals (Dhir and Chavda 2016), indicating that these receptors could be a target to treat benzodiazepine-refractory seizures in adult and pediatric populations. Similar to a synergistic action observed between NMDA receptor antagonists and benzodiazepines, a combination treatment of perampanel, an AMPA receptor antagonist, and diazepam also terminates benzodiazepine-refractory SE (Hanada et al. 2014).

The role of KA receptor antagonists in the treatment of SE is not as well defined as that of the NMDA and AMPA receptors. LY293558 is a GluK1 subunit-specific antagonist, and it is shown to terminate soman-induced SE in rats (Figueiredo et al. 2011). However, LY293558 also antagonizes AMPA receptors, and the contribution of these actions in the observed anticonvulsant efficacy against soman-induced SE is unclear. The anticonvulsant actions of Topiramate are also thought to be partly due to the blockade of KA receptors (Gryder and Rogawski 2003), and a handful of studies suggest that this agent may be effective in treating refractory SE in patients (Bensalem and Fakhoury 2003; Fechner et al. 2019; Towne et al. 2003).

Glutamate Excitotoxicity and Cell Death

SE often causes neuronal injury (Joshi and Goodkin 2020; Niquet 2012). Magnetic resonance imaging (MRI) studies performed 72 hours after febrile SE in pediatric patients have found increased hippocampal T2 signal in 12% of the patients (Shinnar et al. 2012). Furthermore, in the patients with an acute increase in the hippocampal T2 signal, hippocampal volume reduction was evident a year later, indicating that injured neurons may perish (Lewis et al. 2014). MRI abnormalities have also been attributed to SE in adult patients (Chan et al. 1996; DeGiorgio et al. 1992; Milligan et al. 2009; Wieshmann et al. 1997). However, confounding effects of etiology of SE and other comorbidities make it challenging to conclude SE as a causative factor for neuronal injury in patients. Studies in experimental animals have provided unequivocal evidence of neurodegeneration following SE. Neurons of the limbic structures, including the hippocampus, entorhinal cortex, amygdala, and thalamus, and neocortical regions, are susceptible to injury (Brandt et al. 2004; Buckmaster and Jongen-Rêlo 1999; Castro et al. 2011; Covolan and Mello 2000; Drexel et al. 2012; Du et al. 1995; Fujikawa 1996, 2005; Meldrum 1986; Sankar et al. 1998; Singh et al. 2020; Sloviter 1999; Sun et al. 2014; Todorovic et al. 2012; Weiss et al. 1996). Degeneration of CA1 and CA3 pyramidal neurons and hilar interneurons is also observed in young animals, which are generally believed to better tolerate these prolonged seizures (Deshpande et al. 2007; Fujikawa 1995).

Glutamate toxicity is the principal cause of SE-induced neurodegeneration (Kritis et al. 2015; López et al. 1999; Niquet 2012; Sattler and Tymianski 2001; Weiss et al. 1996). In vitro seizure-like activity induced by exposure of cultured hippocampal neurons to a low-Mg²⁺ solution, which activates NMDA receptors, triggers cell death (Deshpande et al. 2007). Glutamate exposure of cultured neurons also leads to cell death (Ankarcrona et al. 1995; Simões et al. 2018; Stout et al. 1998). Multiple molecular mechanisms, including excessive production of reactive oxygen species, mitochondrial dysfunction, damage to the cytoskeleton, and DNA fragmentation, are associated with glutamate-induced cell death.

NMDA receptors play a significant role in SE-induced neurodegeneration. Administration of NMDA receptor antagonists before or following the onset of seizures prevents cell death without blocking the electrographic seizure activity (Brandt et al. 2003; Fujikawa et al. 1994, 2000; Fujikawa 1995). Neuronal depolarization following NMDA receptor activation could activate voltage-gated calcium channels. Intracellular calcium concentrations are elevated in the hippocampal neurons immediately following SE, and inhibition of NMDA receptors blocks this overload (Raza et al. 2004). In vitro SE-like activity also causes a sustained elevation of intracellular calcium in cultured hippocampal neurons (Pal et al. 1999). NMDA receptor activation was considered the main trigger for calcium entry into the neurons during SE. However, studies have now revealed the expression calcium-permeable AMPA receptors in the hippocampi of animals in SE (Joshi et al. 2017; Rajasekaran et al. 2012). Thus, AMPA receptor activation is also likely to cause neuronal calcium entry and activation of voltage-gated calcium channels. Increased intracellular calcium affects mitochondrial function and causes ER stress (Zündorf and Reiser 2011). It could also lead to reactive oxygen species generation since antioxidant mechanisms are also calcium-regulated (Zündorf and Reiser 2011). Thus, calcium entry through glutamate receptors could induce further cellular alterations.

NMDA Receptors Regulate the Plasticity of GABA-A and AMPA Receptors during SE

As discussed above, posttranslational modifications, including phosphorylation and dephosphorylation of neurotransmitter receptors, regulate their cell surface stability. The activity of protein kinases, which phosphorylate the receptors, and protein phosphatases, which dephosphorylate the neurotransmitter receptors, is regulated by intracellular calcium. Increased intracellular calcium through NMDA receptors during SE is likely to activate these proteins. We have found that the increased GluA1 subunit surface expression during SE is accompanied by dephosphorylation of S831 and S845 residues (Joshi et al. 2017). Furthermore, the blockade of NMDA receptors with MK-801 prevented the increased surface expression of GluA1 subunit-containing AMPA receptors and blocked the dephosphorylation of S845 during SE (Joshi et al. 2017). We and others have shown that dephosphorylation of the γ2 or β2/3 subunits of GABA-A receptors is associated with increased internalization of synaptic receptors during SE (Goodkin et al. 2008; Joshi et al. 2015; Terunuma et al. 2008). Activation of protein phosphatases, including calcineurin during SE, appears to cause dephosphorylation of GABA-A receptors since their blockade prevents the reduction in surface expression of γ2 subunit-containing receptors (Eckel et al. 2015; Joshi et al. 2015). Although the effect of NMDA receptor blockade during SE on the surface expression of GABA-A receptors has not been directly evaluated, NMDA receptor blockade during SE preserves the efficacy of benzodiazepines (Joshi et al. 2017; Rice and DeLorenzo 1999; Walton and Treiman 1991), which provides an indirect evidence that NMDA receptor blockade during SE maintains the surface expression of γ2 subunit-containing GABA-A receptors.

NMDA Receptors Regulate Epileptogenesis

Epileptogenesis transforms a healthy neuronal network into a hyperexcitable state that generates seizures. SE is a common epileptogenic trigger in experimental animals (Chen et al. 2021; Joshi et al. 2017; Lothman et al. 1990; Prasad et al. 2002; Rice and DeLorenzo 1998). The signaling triggered by activation of NMDA receptors during SE plays a critical role in epileptogenesis. Administration of NMDA receptor antagonists MK-801 or ketamine suppresses the onset of recurrent spontaneous seizures following SE (Joshi et al. 2017; Prasad et al. 2002; Rice and DeLorenzo 1998). Affected GABAergic inhibition is thought to contribute to the evolution of a hyperexcitable network, and the reduction in δ subunit-containing receptors is one of the factors. The decrease in the δ subunit-containing GABA-A receptors also affects the endogenous neurosteroid control of seizures (Joshi and Kapur 2018b; Peng et al. 2004; Rajasekaran et al. 2010). NMDA receptor activity regulates the δ subunit expression (Joshi and Kapur 2013), and their blockade during SE prevents the reduction in δ subunit expression and maintains the neurosteroid modulation of tonic current (Joshi et al. 2017). Whether glutamate receptor activation also regulates the plasticity of other GABA-A receptor subunits is unclear. The expression of α4 subunits increases transiently following recurrent spontaneous seizures (Grabenstatter et al. 2014), and this change could be regulated by the calcium influx occurring following glutamate receptor activation.

Glutamate Receptor Antagonists in the Treatment of SE

As described above, we treat SE initially with benzodiazepines based on three double-blind, randomized, controlled clinical trials. However, as time passes, seizures continue and become self-sustaining despite adequate doses of benzodiazepines, a state termed established SE. The Established Status Epilepticus Treatment Trial evaluated three second-line intravenous antiseizure medications under exception from informed consent (EFIC) rules for emergency research but was eventually stopped for meeting predetermined futility criteria (<1% chance of showing one of the treatments to be more or less effective). Among the initial analysis of 384 randomized children and adults, the posterior probability of achieving absence of clinically evident seizures and improved responsiveness at 60 minutes was less than 50% in patients receiving levetiracetam (47%), fosphenytoin (45%), or valproate (46%), even when pediatric enrollment was extended (Chamberlain et al. 2020; Kapur et al. 2019).

Mechanistic data and the low response rate to current therapies emphasize the need for testing these novel approaches that rapidly target mechanisms responsible for sustaining seizures and thereby increase the rate of achieving rapid, safe, and sustained termination of established SE. We hypothesize that blocking NMDA receptors breaks the vicious cycle of SE by blocking pathological synaptic plasticity and therefore plan ketamine for established status epilepticus treatment trial (KESETT).

Emerging evidence from clinical studies indicates that we can target glutamate receptors to treat refractory and super-refractory SE (Alkhachroum et al. 2020; Gaspard et al. 2013; Rosati et al. 2012; Sabharwal et al. 2015; Sheth and Gidal 1998; Synowiec et al. 2013). Ketamine is an FDA-approved NMDA receptor antagonist. Case series have revealed that ketamine administered after a delay of 5 to 8 days could suppress seizures in 57% to 91% of the patients (Alkhachroum et al. 2020; Gaspard et al. 2013; Rosati et al. 2012; Sabharwal et al. 2015; Synowiec et al. 2013). Furthermore, in most patients, the seizures remained suppressed even after discontinuation of the treatment (Alkhachroum et al. 2020). Anesthetics used for the treatment of refractory and super-refractory SE often cause respiratory depression. However, ketamine appeared to be safe and free of respiratory depression, suggesting that it could be superior due to lesser side effects (Alkhachroum et al. 2020). Ketamine also seems to be efficacious in treating refractory SE in pediatric patients (Mewasingh et al. 2003; Rosati et al. 2012; Sheth and Gidal 1998). In a prospective study of nine pediatric patients with refractory SE, ketamine was administered after a delay ranging from 5 hours to 26 days and after treatment of at least two agents, including benzodiazepines (Rosati et al. 2012); seizure suppression occurred in six out of the nine patients. Ketamine treatment was also efficacious in treating recurrent nonconvulsive SE episodes in a small group of pediatric patients (Mewasingh et al. 2003).

Clinical trials to determine the efficacy of ketamine for the treatment of refractory SE are ongoing. One clinical trial (Clinicaltrials.gov identifier NCT02431663) in pediatric patients concluded recently. This trial aimed to evaluate the efficacy of intravenous administration of ketamine in the treatment of refractory convulsive status epilepticus in children compared to administration of midazolam at high doses, thiopental, and/or Propofol. The findings of this trial to compare the efficacy of ketamine are awaited. Another ongoing clinical trial (Clinicaltrials.gov identifier NCT03115489) will evaluate the efficacy of ketamine infusion to treat refractory SE in adult patients. In this study, latency to burst suppression and seizure termination will be assessed as primary outcomes and mortality, duration of ventilator use, duration of ICU stays, and structural alterations 7–10 days after burst suppression will be evaluated as secondary outcomes.

Perampanel is a noncompetitive AMPA receptor antagonist and an FDA-approved anticonvulsant agent (Brigo et al. 2018), and emerging evidence suggests that it could be used to treat refractory and super-refractory SE. A retrospective analysis found that it was the last agent used in 61% of SE patients, and in 36% of the patients, response/resolution of SE on electroencephalography was attributed to it (Strzelczyk et al. 2019). In these cases, the median time to perampanel administration was 10 days, and the median time to the resolution of electrographic seizure activity was 72 hours. Other retrospective analyses of patient charts have also found that perampanel is efficacious in terminating refractory SE. In the study by Rohracher and colleagues (Rohracher et al. 2015), patients, mostly with nonconvulsive SE with or without coma, were treated with perampanel after using 2–7 other anticonvulsant agents after a median delay of 1.5 days. In 17% of these patients, clinical improvement was observed within 24 hours of perampanel treatment, and no adverse effects of the drug were observed, suggesting that its use may be safe. Findings of other case series also suggest that perampanel may be used to treat refractory and super-refractory SE (Ho et al. 2019; Hocker 2019; Redecker et al. 2015, 2018). Controlled, prospective studies are required to determine whether AMPA receptor antagonists can treat SE when the first-line agents are ineffective.

Conclusions

There is enhanced glutamatergic transmission during SE, due to increased release, receptor trafficking, and activation of second messenger systems. This potentiated glutamatergic transmission prolongs seizures and causes neuronal loss, and may contribute to epileptogenesis. We need to test the efficacy of NMDA and AMPA receptor antagonists in Phase 3 clinical trials.

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