Abstract

Clinical and preclinical studies have confirmed that neuroinflammation is a salient feature of the epileptic brain. The engagement of several neuroinflammatory pathways has been documented after epileptogenic injuries and in the aftermath of ongoing seizure activity. Preclinical research over the past decade has demonstrated that the ensuing neuroinflammation after epileptogenic triggers promotes seizures, neuronal injury, blood–brain barrier dysfunction, and behavioral comorbidities. Thus, successful modulation of the neuroinflammatory cascade is a potential therapeutic strategy. An overarching goal of anti-inflammatory approaches is to quench pathogenic neuroinflammation while maintaining, or promoting, the homeostatic effects. In this chapter we focus on treatments that are close to clinical translation, outlining the experimental evidence supporting the use of the anti-inflammatory therapy for both reducing drug-resistant seizures and for providing disease-modification effects. Approaches targeting IL-1β-IL-1R1 signaling, COX-2 pathways, immune-endothelial cell interations, statins, and dexamethasone are discussed. Recent combinatorial approaches with disease-modifying effects are highlighted. Successful development of anti-inflammatory therapies for epilepsy faces hurdles. The timing of therapeutic administration after epileptogenic triggers should, ideally, preserve the physiological roles of inflammation while opposing pathological ones. Biomarkers and consideration of epilepsy etiology can help identify patients who will best benefit from anti-inflammatory drugs. Clinical studies of anti-inflammatory treatments are underway in patients with drug-resistant seizures, and the results are described here. New clinical trial designs are likely needed to take into account the differences in mechanism of action between anti-inflammatory and conventional antiseizure medications.

Introduction

Preclinical and clinical evidence have demonstrated the presence of neuroinflammation in epileptogenic brain areas in structural epilepsies (Vezzani et al., 2015, 2019; Scheffer et al, 2017). Neuroinflammation is here defined by the presence of molecules with inflammatory properties in brain parenchymal cells, including neurons, glia, and cell components of brain microvasculature (Vezzani et al., 2019). The presence of neuroinflammation in epilepsy, together with the significant contribution of neuroinflammatory mediators to the mechanisms of seizure generation (van Vliet et al., 2018), set the ground for testing whether drugs modulating specific inflammatory pathways provide therapeutic effects in drug-resistant patients with epilepsy.

Initially, anti-inflammatory interventions have been attempted in models of acute seizures and status epilepticus, and in epileptic mice or rats with established chronic seizures. Subsequently, anti-inflammatory drugs have been administered in rodent models of acquired epilepsy, with intervention scheduled either between the epileptogenic injury and the onset of epilepsy, or early after the occurrence of the first spontaneous seizures (Ravizza et al., 2011; Fig. 74–1). Of note, specific anti-inflammatory drugs administered after epilepsy onset improved outcomes by blocking the progression of spontaneous seizures (Iori et al., 2017).

Figure 74–1.

Schematic representation of preclinical anti-inflammatory treatments at different stages of disease development in animal models of acquired epilepsy and the related therapeutic outcomes.

The therapeutic effects of anti-inflammatory treatments are not restricted to inhibition of seizures but also extend to reduction of neuropathology and comorbidities. The attainment of these effects, individually or in concert, depends on the specific inflammatory signaling targeted by the drug and the time of therapeutic intervention during the disease course.

Among neurological comorbidities, neuroinflammation plays a role in depression, which is a major risk factor for developing posttraumatic epilepsy and drug-resistant epilepsy (Kanner et al., 2014), and neuroinflammation contributes to cognitive deficits that develop in animals before epilepsy manifests (Ravizza et al., 2016). This evidence supports that neuroinflammation is a common pathogenic mechanism of mood and cognitive dysfunctions, although it remains to be determined which inflammatory pathways and mechanisms underlie comorbidities versus neuropathology and the development of epilepsy.

Thus, anti-inflammatory interventions may provide a broad therapeutic spectrum in epilepsy, and the tested drugs often mediate therapeutic effects that outlast treatment discontinuation, thus representing novel examples of disease-modification therapies (Clossen and Reddy, 2017; Varvel et al., 2015).

Animal studies have shown that neuroinflammation arising after an acute epileptogenic insult (e.g., status epilepticus, neurotrauma, stroke, central nervous system [CNS] infection) promotes neuronal cell loss in forebrain, microgliosis, astrogliosis, blood–brain barrier (BBB) dysfunction, neurological comorbidities, and seizures with different timelines. These findings underscore that in order to maximize a drug’s therapeutic efficacy, the dynamics of neuroinflammation, spanning from the initial epileptogenic injury to the establishment of the chronic disease, should be well characterized. This would allow for tailoring treatment initiation and discontinuation based on the “onset and offset” times of the specific inflammatory pathway.

The optimal time for intervention with anti-inflammatory drugs is a challenging aspect for human therapy. Specifically, treatments aimed at arresting disease development or preventing seizure progression or the onset of pharmacoresistance should include patients treated early after the epileptogenic injury, or newly diagnosed epilepsy patients. Moreover, although neuroinflammation acts overall as a pathogenic mechanism, some inflammatory processes are also involved in tissue repair and homeostatic plasticity after brain injury, as exemplified by involvement in neuroprotection of COX-2 early after status epilepticus or phagocytic activity of microglia for removal of cell debris. Thus, anti-inflammatory interventions outside the optimal target or therapeutic window might be ineffective or potentially harmful. Animal models are instrumental to elucidate the pathogenic inflammatory mechanisms and their dynamics during the disease development, thereby possibly informing human therapy (i.e., early post-injury, before or after disease onset, chronic epilepsy phase).

Another relevant aspect for human therapy is the selection of patients who might best benefit from anti-inflammatory drugs, which relies upon the availability of sensitive and specific biomarkers (Pitkanen et al., 2016).

Anti-inflammatory Treatments in Clinical Practice

Large-spectrum immunosuppressive steroids, the ketogenic diet, and vagal nerve stimulation were proven effective in some patients with drug-resistant seizures, particularly in pediatric epileptic encephalopathies. Although there is no clinical demonstration that their therapeutic effects are mediated by anti-inflammatory actions, this hypothesis is reinforced by recent case reports and proof-of-concept clinical studies showing that some anti-inflammatory drugs have therapeutic effects in drug-resistant epilepsies and in syndromes with acute unremitting status epilepticus (Table 74–1). Since these drugs are approved for autoinflammatory or autoimmune diseases, there is the concrete possibility of repurposing anti-inflammatory drugs with an acceptable safety profile, for testing their effects as add-on treatment in controlled clinical trials in drug-resistant epilepsies, or for preventive studies in patients at high risk of developing epilepsy after acute brain injuries (Klein et al., 2020).

Table 74–1

Off label use of anti-inflammatory drugs: clinical efficacy in patients with drug-resistant seizures.

One consideration is whether interference with the body inflammatory response increases the risk of infections. This is not of concern for some anti-inflammatory drugs chronically administered for other indications (e.g., NSAIDS). Experimental studies might also evaluate whether anti-inflammatory treatments can be administered intermittently rather than continuously to maintain control over the inflammatory pathways, a treatment strategy which may reduce potential adverse effects.

The reverberant and complex network of the inflammatory pathways implicated in epilepsy prompted preclinical research to use rationale combinations of anti-inflammatory drugs with different mechanisms of action, to test whether combined treatment is more effective than single drug alone.

This will be addressed in the following paragraphs, where we will report evidence for antiseizure and disease-modification effects of selected anti-inflammatory drugs, or their combination, targeting pathogenic inflammatory mechanisms in animal models. We will focus on treatments that are close to clinical translation or describe drugs used in initial clinical studies. For a broader overview of anti-inflammatory treatments in animal models of epilepsy, the reader should refer to recent review papers (Clossen and Reddy, 2017; van Vliet et al., 2018; Varvel et al., 2015; Vezzani et al., 2019).

Interference with the IL-1beta-IL-1R1 Axis

Clinical Studies with Anti-IL-1beta Treatments

The evidence that IL-1beta-IL-1R1 axis is activated in human epilepsy and contributes to seizures in animal models fostered clinical interest for attempting similar pharmacological interventions in patients with drug-resistant seizures.

Proof-of-concept clinical trials and case report studies have been recently developed with drugs targeting IL-1beta - IL-1R1 signaling. A 6-week phase IIA randomized, double-blind, placebo-controlled study was completed in patients with drug-resistant focal onset epilepsy administered with VX-765 (n = 48) or placebo (n = 12). Post-hoc analysis showed a delayed effect of VX-765 on reducing seizure recurrence that persisted for a few weeks after drug discontinuation (Bialer et al., 2013).

Anakinra currently dominates the field of IL-1beta therapeutics due to its safety profile, favorable PK, and route of administration. Anakinra is approved for various inflammatory disorders, including rheumatoid arthritis, neonatal-onset multisystem inflammatory disease, and other cryopyrin-associated periodic fever syndromes (Dinarello, 2018). Randomized phase II control studies have been developed with anakinra in various autoinflammatory and autoimmune diseases. In CNS, two phase II clinical studies in acute stroke (Emsley et al., 2005) and in TBI (Helmy et al., 2014) patients demonstrated the drug’s safety profile and showed improvements in neurological outcomes in patients, but epilepsy was not included in the outcome measures.

Recently, several case report studies have shown that anakinra drastically reduced drug-resistant seizures in super-refractory status epilepticus secondary to febrile infection-related epilepsy syndrome (FIRES), a rare but devastating neurological condition characterized by a febrile illness preceding days to weeks status epilepticus (DeSena et al., 2018; Dilena et al., 2019; Jyonouchi and Geng, 2016; Kenney-Jung et al., 2016; Sa et al., 2019; Westbrook et al., 2019). Notably, a recent retrospective study reported that anakinra was potentially safe, and earlier anakinra treatment initiation after seizure onset was associated with shorter duration of mechanical ventilation, ICU, and hospital length of stay. Eleven out of 15 children with available seizure frequency data exhibited 50% seizure reduction at 1 week of anakinra treatment, whereas large spectrum steroids and other immunotherapies were ineffective (Lai et al., 2020).

The add-on therapy of anakinra was also effective in controlling epileptic activity and improving cognitive skills in adolescents with drug-resistant epilepsy associated with autoinflammatory conditions (Jyonouchi and Geng, 2016). Anakinra followed by canakinumab, a monoclonal antibody against IL-1beta, also resolved seizures in a patient with a systemic inflammatory condition associated with chronic epilepsy (DeSena et al., 2018).

These initial and promising clinical observations support that anakinra may inhibit drug-resistant epileptic activity. Controlled clinical studies are therefore warranted to establish efficacy, doses, and treatment schedule not only in severe conditions such as FIRES and NORSE but also more broadly in pharmacoresistant forms of epilepsy, as suggested by animal studies.

Arachidonic Acid and COX-2 Signaling Pathways

Timing of Intervention

The cyclooxygenase signaling cascade (Fig. 74–2) produces both proinflammatory (e.g., prostanoids, particularly PGE2 acting on EP2) and inflammation-resolving molecules (e.g., lipoxins, resolvins, maresins, protectins, etc.). Moreover, in addition to metabolizing arachidonic acid, COX-2 also converts the two main endocannabinoids to eight lipid mediators (Fig. 74–2), the functions of which are poorly understood (Alhouayek and Muccioli, 2014). It is clear, then, that the overall effects of cyclooxygenase inhibition are certain to be complex.

Figure 74–2.

Cyclooxygenase signalling cascade. From Rojas et al. (2019).

In a well-designed early study, kainate treatment caused severe learning and memory deficits in both Morris water maze and object exploration in an open field. Administration of the COX-2 inhibitor, celecoxib, to rats 2 hours after kainate treatment improved performance in both tasks. By contrast, administration of celecoxib to rats 2 hours before kainate worsened seizure intensity, increased mortality, and did not improve memory deficits (Gobbo and O’Mara, 2004).

The selectivity of celecoxib as an inhibitor of COX-2 rather than COX-1 is only 10-fold (Grosser et al., 2006). Similar findings have been reported with other COX inhibitors of varying specificity, delivered before or after seizures produced by several convulsants (reviewed in Dhir, 2019; Rojas et al., 2019). These findings suggest that blocking homeostatic pathways mediated by COX-1 and to a lesser extent COX-2 exacerbates the pathologic consequences of seizures, whereas blocking pathways mediated by the delayed induction of COX-2 can ameliorate them. Indeed, the induction of COX-2 protein in hippocampus after status epilepticus is delayed by ~2 hours, which corresponds to the therapeutic window of a selective EP2 antagonist after status epilepticus (Jiang et al., 2015; Rojas et al., 2015). Further evaluation of this hypothesis will require careful PK-PD studies of the timing and extent of COX-1 and COX-2 inhibition in the brain. The realization that the early function of prostanoids is likely to be net beneficial in the peri-seizure setting, and later detrimental, represents a key challenge and opportunity for designing clinical trials of COX-2 or prostanoid synthase inhibitors, or prostanoid receptor antagonists.

Dexamethasone

Administration of glucocorticoids (GCs), such as dexamethasone or methylprednisolone, is a traditional treatment approach for patients presenting with refractory or super-refractory status epilepticus. GCs have diverse pleiotropic effects. One consequence of GC receptor agonism with dexamethasone (DEX), a synthetic GC, is the broad dampening of inflammation by inhibiting NF-kB and the subsequent block of proinflammatory mediator synthesis and release (Auphan et al., 1995; Gilmore, 2006).

DEX has been examined in several recent studies demonstrating suppression of proinflammatory cytokines in the pentylenetetrazole kindling (Guzzo et al., 2018) and the lithium-pilocarpine rat models (Borham et al., 2016; Vizuete et al., 2018). In the lithium-pilocarpine model, DEX dampened status epilepticus-induced elevation in the astrocyte proteins GFAP and S100B in the hippocampus. Inhibition of astrocytosis occurred one day post status epilepticus and was maintained up to 56 days (Vizuete et al., 2018). Microgliosis in the hippocampus was reduced after DEX treatment in an experimental febrile status epilepticus (eFSE) model (Brennan et al., 2021). Taken together, these findings indicate a broad anti-inflammatory effect of DEX treatment in seizure models.

The effect of DEX on hyperexcitability has also been examined in recent studies. Garcia-Curran and colleagues utilized the rat eFSE model to explore the protective effects of DEX, with aldosterone provided to support corticosterone production. Notably, DEX administration after eFSE in P10 rats reduced the percent of rats displaying spike series and the frequency of spikes per hour starting at P14 through P43, indicating a hyperexcitability-suppressing effect of DEX treatment in this model. One dose of DEX (3 mg/kg, i.p.) given 1 hour after eFSE suppressed hippocampal induction of mRNAs encoding IL-1β and IL-1R1, but not COX-2, measured 3 hours after DEX administration. DEX treatment also prevented extravasation of circulating FITC-albumin from the brain vasculature into the nearby cortical and thalamic parenchyma. Whereas nearly 60% of eFSE rats showed evidence of BBB dysfunction, this occurred in only 20% of eFSE rats treated with DEX (Garcia-Curran et al., 2019). These findings indicate DEX treatment is anti-inflammatory in the eFSE model, prevents deterioration of the BBB, and reduces epileptiform EEG activity in the days following eFSE in young rats.

The protective effects of DEX have also been investigated in a “two-hit,” early life seizure model to assess its potential to mitigate the consequences of a second seizure. Fox and colleagues exposed 25-day-old rats to systemic kainic acid and then provided DEX (1 mg/kg, i.p.) two times prior to a second systemic kainate injection at P39. DEX was effective at preventing microgliosis, and there was a trend for less cell death in rats. Notably, none of the rats given two doses of DEX entered status epilepticus after the second kainate injection, indicating that short-term DEX treatment dampens seizure activity after a second hit (Fox et al., 2020).

Finally, 3-day administration of DEX (3 mg/kg, i.p.) in adult epileptic mice reduced by 50% drug-resistant seizures, an effect that was reversible upon drug withdrawal (Maroso et al., 2011).

It is still unclear if the reduced seizure severity attributed to DEX treatment is solely due to its broad anti-inflammatory properties. Future studies should further investigate the disease-modifying antiepileptogenic potential of DEX treatment, and if DEX administration can attenuate seizure-induced cognitive impairments.

Interference with Leukocyte-Endothelial Cell Interaction by Natalizumab

Natalizumab is a humanized monoclonal anti-α4-integrin antibody, approved for the treatment of relapsing-remitting multiple sclerosis (Ransohoff, 2007). In a mouse model of pilocarpine-induced status epilepticus, circulating leukocytes have been shown to interact via α4-integrin with upregulated adhesion molecules, such as VCAM-1, p-selectin, ICAM in brain vessels. This interaction resulted in a breach of BBB (Fabene et al., 2008), likely due to endothelial cell activation and vessels inflammation. The consequent release of inflammatory cytokines and prostaglandins from endothelial cells can increase brain vessel permeability by enhancing transcytosis and by reducing the expression of tight junction proteins (Librizzi et al., 2007; Vezzani et al., 2019).

Genetic or pharmacological interference with leukocyte α4-integrin and adhesion molecules on brain vessels reduced spontaneous seizures in these mice, afforded neuroprotection (Fabene et al., 2008), and resolved the BBB leakage.

The contribution of BBB dysfunction to seizures is supported by various experimental findings, and one major mechanism contributing to neuronal hyperexcitability relies upon brain parenchymal extravasation of serum albumin (Löscher and Friedman, 2020). Albumin activates TGF-beta signaling in perivascular astrocytes that resulted in inflammatory genes induction and transcriptional down-regulation of GLT-1, Kir_4.1, and AQP-4 proteins. Thus, astrocytes may release inflammatory ictogenic molecules and showed a reduced ability to reuptake glutamate and to buffer extracellular K⁺ and water, thus generating an extracellular milieu permissive for seizures. This chain of events contributes to seizures, as shown in several animal models of acquired epilepsy (Vezzani et al., 2019).

The evidence that BBB dysfunction is a hallmark of drug-resistant epilepsies in humans, and the preclinical studies above mentioned, supported the first randomized clinical study (ClinicalTrials.gov: NCT03283371) with natalizumab, as adjunctive therapy in adults with drug-resistant focal epilepsy (French et al., 2021). The natalizumab-treated group did not achieve a 31% relative reduction in seizure frequency over the placebo group, which was the study’s predefined threshold for therapeutic success. However, a higher proportion of treated patients achieved ≥50% reduction in seizure frequency and displayed a greater number of seizure-free days versus the placebo group, although statistical significance was not attained. Additionally, patients with focal epilepsy and a structural etiology showed greater reduction in seizures versus placebo compared with participants without structural etiology. The study conclusion was to give further consideration to the signs of effect by including in a future trial only those patients with active neuroinflammation and BBB damage as assessed using imaging-associated markers (Vezzani et al., 2019; Vezzani and Friedman, 2011), and increasing the number of trial participants.

Statins

Several clinical studies indicate statin use might be protective against epileptogenesis or provide disease modification. A retrospective study of aged (>66 years) U.S. veterans revealed statin use was associated with lower new-onset epilepsy risk (Pugh et al., 2009). In a study of 1,832 patients, 3.4% of patients had poststroke seizures and 5.0% developed poststroke epilepsy. Statin use did not affect poststroke epilepsy overall, but in the 63 patients with early-onset poststroke seizures, there was a reduced risk for poststroke epilepsy in those using statins (Guo et al., 2015). In a cohort of 150,555 patients (aged 65 years) who had undergone coronary revascularization, statin use reduced the risk of hospitalization due to epilepsy in those currently taking statins and in patients who were past users of statins, although the risk reduction was not as great as in current statin users (Etminan et al., 2010).

There are conflicting preclinical reports on the protective effects of statin treatment. Oral treatment with atorvastatin, once a day for 7 days, before quinolinic acid–induced seizures in mice prevented cell death in the hippocampus (Piermartiri et al., 2009). However, a 14-day treatment with atorvastatin after pilocarpine-induced status epilepticus did not dampen pentylentetrazol seizure susceptibility nor provide neuroprotection (Oliveira et al., 2018). Notably, atorvastatin in combination therapy with levetiracetam and ceftriaxone reduced electrographic seizures developing post status epilepticus, suggesting a disease-modifying effect (Welzel et al., 2021; see below for details).

Statins reduce plasma cholesterol levels by reversibly inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, preventing de novo synthesis of cholesterol. Notably, statins also exhibit anti-inflammatory effects (Hussein et al., 2019; Ortego et al., 1999; Pahan et al., 1997) that are postulated to arise from the reduction of isoprenoid intermediates, such as farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), in cholesterol biosynthesis (Liao and Laufs, 2005). Thus, it remains unclear if the antiepileptogenic and disease-modifying potential of statins is solely attributed to their cholesterol-lowering capabilities or anti-inflammatory properties.

Combinatorial Anti-inflammatory Therapy

Inflammatory pathways activated during epileptogenesis and seizures are complex, redundant, and often simultaneously induced (Vezzani et al., 2019). This concept implies that blocking a single pathway may not be sufficient for efficient seizure reduction and neuroprotection, while a combinatorial approach targeting different inflammatory signaling with complementary mechanisms of action may be more effective (Table 74–2).

Table 74–2

Combinatorial Anti-inflammatory Therapy.

Based on these considerations, excellent therapeutic outcomes were reached in experimental models of epilepsy by anti-inflammatory treatments that simultaneously inhibited IL-beta - IL-1R1 and HMGB1-TLR4 activation. In particular, prevention of epilepsy progression leading to 90% reduction of carbamazepine-resistant seizures was achieved by combining the caspase-1 inhibitor VX-765 with cyanobacterial LPS, a selective antagonist of TLR4. This drug combination was administered to mice for 7 days after the onset of spontaneous seizures evoked by status epilepticus induced by intra-amygdala kainate injection (Iori et al., 2017). A similar outcome was attained with the same treatment schedule by injecting mice intracerebrally with the anti-inflammatory miR146a, which reduced the levels of the IRAK1/TRAF6 kinases downstream to both IL-1R1 and TLR4 receptors (Iori et al., 2017). Single-pathway blockade in different epilepsy models attained 50% seizure reduction (Iori et al., 2013; Maroso et al., 2011), thus suggesting that the drug combination provided additional benefit.

Drug combinations were also tested before the onset of epilepsy in rats exposed to electrical status epilepticus with a preventive study design, that is, starting treatment 1 hour after the induction of status epilepticus and for 7 additional days. In this model, spontaneous seizures typically occur around 10–15 days post status epilepticus (Terrone et al., 2019). The anti-inflammatory drug cocktail included anakinra and BoxA, a specific peptide antagonist of HMGB1 receptors. Ifenprodil, a NMDA-NR2B receptor blocker, was also added to block the NR2B subunit of the NMDA receptor, which is implicated in epileptogenesis (Frasca et al., 2011). This combinatorial treatment had neuroprotective effects and reduced significantly the occurrence and the progression of spontaneous seizures (Terrone et al., 2019; van Vliet et al., 2018). Notably, more limited effects were obtained in the same model by pharmacological inhibition of IL-beta - IL-1R1 axis since neuronal cell loss was reduced but chronic seizures were unaffected (Noé et al., 2013).

Similarly, a combination of anakinra and a COX-2 inhibitor injected systemically in adolescent rats for 10 days after pilocarpine-induced status epilepticus prolonged the latency to the first spontaneous seizure, reduced hippocampal neuronal cell loss, and decreased by 70% spontaneous seizures (Kwon et al., 2013). Cognitive deficit and anxiety-like behavior were also resolved. These improvements were not achieved when anakinra or the COX-2 inhibitor was injected in monotherapy.

A therapeutic synergism was also observed in a recent study aimed at aborting diazepam-resistant status epilepticus (Terrone et al., 2018). Mice injected with a selective monoacylglycerol lipase (MAGL) inhibitor, the major biosynthetic enzyme of arachidonic acid in the brain, showed an abrupt reduction of status epilepticus duration within 3 hours from drug administration. However, when the MAGL inhibitor was administered to mice under a ketogenic diet regimen, status epilepticus after kainate injection was virtually absent, whereas ketogenic diet alone was ineffective. Mice also showed neuroprotection in forebrain and rescue of cognitive deficits (Terrone et al., 2018). Each of the treatments alone was proven to be anti-inflammatory (Jeong et al., 2011; Terrone et al., 2018).

Notably, the administration of an anti-inflammatory drug may enhance the efficacy of a classical antiseizure drug. In fact, acute seizures induced by chemoconvulsive drugs or maximal electroshock test were prevented by a combining the NSAID diclofenac and retigabine, which activates voltage-gated Kv7 potassium channel, administered to mice at their respective ED50. Only partial reduction of seizures was attained with either drug given alone (Khattab et al., 2018).

Furthermore, anakinra together with a low dose of diazepam, but not either drug alone, terminated kainate-induced status epilepticus in mice (Xu et al., 2016). Similarly, coinjection of A438079, a P2X7 receptor antagonist, with lorazepam significantly reduced status epilepticus duration and severity and hippocampal CA3 damage, while weaker effects were observed after the administration of each drug alone (Engel et al., 2012; Beamer et al., 2022).

Synergistic effects of anti-inflammatory therapy with antiseizure drugs were also reported in a clinical study in newly diagnosed poststroke epilepsy patients treated with levetiracetam during a 1-year follow-up. The coadministration of atorvastatin and aspirin reduced the number of clinical seizures in patients and also allowed to reduce the dose of levetiracetam. The therapeutic effects were improved compared to levetiracetam alone (Zhao et al., 2020). The effect of this drug combination was apparently not due to PK interactions among the drugs. In a recent study, Welzel and colleagues reported that a combination therapy of levetiracetam (60 mg/kg) with two drugs with anti-inflammatory properties, namely atorvastatin (3 mg/kg) and ceftriaxone (60 mg/kg) initiated 6 hours after administration of intrahippocampal kainate and continuing for 5 days reduced the incidence of electrographic seizures by 60% and eliminated electroclinical seizures 12 weeks post status epilepticus (Welzel et al., 2021). Interestingly, a higher dose of each component of the cocktail was ineffective. These findings provide evidence that statin therapy in appropriate drug combinations might be effective for reducing seizure burden in epilepsy.

The early administration of an immunotherapy together with classical antiseizure drugs is an adjuvant treatment that improves the outcome in conditions such as FIRES and NORSE (Lin et al., 2018). In FIRES, the combination of immunoglobulins and methylprednisolone within 48 hours after hospitalization resulted in better neurological outcomes, decreased mortality, and reduced days of hospitalization compared to immunoglobulin monotherapy or no immunotherapy (Lin et al., 2018). Retrospective studies in NORSE patients provided similar results (Gall et al., 2013; Khawaja et al., 2015). Gall et al. showed that NORSE patients receiving combined immunotherapy did not develop significant neuropsychological decline and seizures were better controlled with antiseizure drugs. Prospective multicenter studies are necessary to assess the true efficacy of these immunotherapies in FIRES and NORSE.

These studies highlight that combinatorial anti-inflammatory approaches should be considered. A multidrug approach may be particularly useful for improving disease outcome if treatments are delivered during the early disease phases (before the onset of spontaneous seizures or early after epilepsy diagnosis) since animal studies showed that various inflammatory mechanisms dynamically contribute to disease onset and progression.

Summary and Conclusions

Clinical investigations confirmed the presence of neuroinflammation, originally described in animal models, in human drug-resistant epilepsies of various etiologies. Pharmacological interventions apt to resolve or prevent the neuroinflammatory response in animal models demonstrated that specific inflammatory pathways have pathogenic roles in seizures, brain neuropathology, and comorbidities. These studies support the notion that neuroinflammation lowers seizure threshold, thereby promoting seizure generation in concert with concomitant neuropathological events.

Overall, the available findings support that drugs modulating specific inflammatory pathways may both reduce drug-resistant seizures in human epilepsy and improve disease outcomes. Since some inflammatory pathways are commonly activated in various acquired epilepsies, they may represent targets for broad therapeutic applications. Moreover, anti-inflammatory drugs may offer neuroprotection and improve comorbidities, if treatment is initiated in a timely fashion after the epileptogenic injury (Mazarati et al., 2017).

Among the factors that potentially contribute to the outcomes of neuroinflammation, a key role is attributed to the extent and persistence of the neuroinflammatory response in individual patients. This may depend on their genetic background (Bartfai et al., 2007), intrinsic structural brain alterations (Iyer et al., 2010), environmental risk factors (Yuen et al., 2018), or their combination.

In the last decade, proof-of-concept clinical trials and several case report studies provided evidence of efficacy of some anti-inflammatory drugs in patients with drug-resistant seizures (Table 74–1). These encouraging results support starting controlled clinical trials in eligible patient populations. If these anti-inflammatory drugs are effective, they would offer new therapeutic opportunities for people at high risk of developing epilepsy or with established drug-resistant seizures. Several anti-inflammatory drugs with a safe profile are medically available for other indications and could be repurposed in epilepsy. Drug combinations may be required to maximize efficacy of anti-inflammatory treatments due to the complexity of the neuroinflammatory network. Alternatively, nodal points of control of the pathogenic inflammatory cascade are to be discovered and consequently targeted with new or repurposed drugs.

Biomarkers of neuroinflammation and consideration of the epilepsy etiology will help to stratify patients for clinical interventions. Finally, new clinical trial designs may be required since anti-inflammatory drugs have different mechanisms of action than clinically used antiseizure medications, and they may be endowed with disease-modifying effects.

Acknowledgments

Disclosure Statement

References

1. Alhouayek M, Muccioli GG.  COX-2-derived endocannabinoid metabolites as novel inflammatory mediators.  Trends Pharmacol. Sci.  2014;35:284–292. doi: 10.1016/j.tips.2014.03.001. PMID: 24684963. [PubMed: 24684963]
2. Arena A, Zimmer TS, van Scheppingen J, Korotkov A, Anink JJ, Mühlebner A, Jansen FE, van Hecke W, Spliet WG, van Rijen PC, Vezzani A, Baayen JC, Idema S, Iyer AM, Perluigi M, Mills JD, van Vliet EA, Aronica E.  Oxidative stress and inflammation in a spectrum of epileptogenic cortical malformations: molecular insights into their interdependence.  Brain Pathol.  2018;29(3):351–365. doi: 10.1111/bpa.12661. PMID: 30303592. [PMC free article: PMC8028690] [PubMed: 30303592]
3. Aronica E, Boer K, van Vliet EA, Redeker S, Baayen JC, Spliet WG, van Rijen PC, Troost D, da Silva FH, Wadman WJ, Gorter JA.  Complement activation in experimental and human temporal lobe epilepsy.  Neurobiol Dis.  2007;26:497–511. doi: 10.1016/j.nbd.2007.01.015. PMID: 17412602. [PubMed: 17412602]
4. Auphan N, Di Donato JA, Rosette C, Helmberg A, Karin M.  Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis.  Science.  1995;270:286–290. doi: 10.1126/science.270.5234.286. PMID: 7569976. [PubMed: 7569976]
5. Auvin S, Shin D, Mazarati A, Sankar R.  Inflammation induced by LPS enhances epileptogenesis in immature rat and may be partially reversed by IL1RA.  Epilepsia.  2010;51(3):34–8. doi: 10.1111/j.1528-1167.2010.02606.x. PMID: 20618397. [PMC free article: PMC2910518] [PubMed: 20618397]
6. Bartfai T, Sanchez-Alavez M, Andell-Jonsson S, Schultzberg M, Vezzani A, Danielsson E, Conti B.  Interleukin-1 system in CNS stress: seizures, fever, and neurotrauma.  Ann NY Acad Sci.  2007;1113:173–7. doi: 10.1196/annals.1391.022. PMID: 17656565. [PubMed: 17656565]
7. Bay MJ, Kossoff EH, Lehmann CU, Zabel TA, Comi AM. Survey of aspirin use in Sturge-Weber syndrome. J.  Child Neurol.  2011;26:692–702. doi: 10.1177/0883073810388646. -PMID: 21427442. [PubMed: 21427442]
8. Beamer E, Morgan J, Alves M, Menéndez Méndez A, Morris G, Zimmer B, Conte G, de Diego-Garcia L, Alarcón-Vila C, Yiu Ng NK, Madden S, Calzaferri F, de Los Ríos C, García AG, Hamacher M, Dinkel K, Pelegrín P, Henshall DC, Nicke A, Engel T.  Increased expression of the ATP-gated P2X7 receptor reduces responsiveness to anti-convulsants during status epilepticus in mice.  Br J Pharmacol. 2022 Jun;179(12):2986–3006. doi: 10.1111/bph.15785. [PubMed: 34962289]
9. Bialer M, Johannessen SI, Levy RH, Perucca E, Tomson T, White HS.  Progress report on new antiepileptic drugs: a summary of the Eleventh Eilat Conference (EILAT XI).  Epilepsy Res.  2013;103:2–30. doi: 10.1016/j.eplepsyres.2012.10.001. PMID: 23219031. [PubMed: 23219031]
10. Bittner S, Simon OJ, Gobel K, Bien CG, Meuth S., Wiendel H.  Rasmussen encephalitis treated with natalizumab.  Neurology.  2013;81:395–397. doi: 10.1212/WNL.0b013e31829c5ceb. PMID: 23794679. [PubMed: 23794679]
11. Borham LE, Mahfoz AM, Ibrahim IAA, Shahzad N, ALrefai AA, Labib AA, Bin Sef B, Alshareef A, Khan M, Milibary A, Al Ghamdi S.  The effect of some immunomodulatory and anti-inflammatory drugs on Li-pilocarpine-induced epileptic disorders in Wistar rats.  Brain Res.  2016;1648:418–424. doi: 10.1016/j.brainres.2016.07.046. PMID: 27498238. [PubMed: 27498238]
12. Brennan GP, Garcia-Curran MM, Patterson KP, Luo R, Baram TZ.  Multiple Disruptions of Glial-Neuronal Networks in Epileptogenesis That Follows Prolonged Febrile Seizures.  Front Neurol.  2021;12:615802. doi: 10.3389/fneur.2021.615802. PMID: 33679583. [PMC free article: PMC7930821] [PubMed: 33679583]
13. Cantarín-Extremera V, Jiménez-Legido M, Duat-Rodríguez A, García-Fernández M, Ortiz-Cabrera NV, Ruiz-Falcó-Rojas ML, González-Gutiérrez-Solana L. Tocilizumab in pediatric refractory status epilepticus and acute epilepsy: Experience in two patients. J Neuroimmunol.  2020;340:577142. doi: 10.1016/j.jneuroim.2019.577142. PMID: 31935626. [PubMed: 31935626]
14. Chee YC, Lim CH, Sanihah AH, Ong BH.  Extinguishing FIRES using tocilizumab.  Neurol Clin Neurosci.  2020;8:192–195. doi: 10.1111/ncn3.12385.
15. Clarkson BDS, LaFrance-Corey RG, Kahoud RJ, Farias-Moeller R, Payne ET, Howe CL.  Functional deficiency in endogenous interleukin-1 receptor antagonist in patients with febrile infection-related epilepsy syndrome.  Ann Neurol.  2019;85(4):526–537. doi: 10.1002/ana.25439. PMID: 30779222. [PMC free article: PMC6450741] [PubMed: 30779222]
16. Clossen BL, Reddy DS.  Novel therapeutic approaches for disease-modification of epileptogenesis for curing epilepsy.  Biochim Biophys Acta Mol Basis Dis.  2017;1863:1519–1538. doi: 10.1016/j.bbadis.2017.02.003. PMID: 28179120. [PMC free article: PMC5474195] [PubMed: 28179120]
17. De Simoni MG, Perego C, Ravizza T, Moneta D, Conti M, Marchesi F, De Luigi A, Garattini S, Vezzani A.  Inflammatory cytokines and related genes are induced in the rat hippocampus by limbic status epilepticus.  Eur J Neurosci.  2000;12:2623–33. doi: 10.1046/j.1460-9568.2000.00140.x. PMID: 10947836. [PubMed: 10947836]
18. DeSena AD, Do T, Schulert GS.  Systemic autoinflammation with intractable epilepsy managed with interleukin-1 blockade.  J Neuroinflammation.  2018;15(1):38. doi: 10.1186/s12974-018-1063-2. PMID: 29426321. [PMC free article: PMC5807745] [PubMed: 29426321]
19. Dhir A.  An update of cyclooxygenase (COX)-inhibitors in epilepsy disorders.  Expert Opin Investig Drugs.  2019;28:191–205. doi: 10.1080/13543784.2019.1557147. PMID: 30521407. [PubMed: 30521407]
20. Diamond ML, Ritter AC, Failla MD, Boles JA, Conley YP, Kochanek PM, Wagner AK. IL-1β associations with posttraumatic epilepsy development: a genetics and biomarker cohort study. Epilepsia.  2014;55:1109–19. doi: 10.1111/epi.12628. PMID: 24754437. [PMC free article: PMC4107119] [PubMed: 24754437]
21. Dilena R, Mauri E, Aronica E, Bernasconi P, Bana C, Cappelletti C, Carrabba G, Ferrero S, Giorda R, Guez S, Scalia Catenacci S, Triulzi F, Barbieri S, Calderini E, Vezzani A.  Therapeutic effect of Anakinra in the relapsing chronic phase of febrile infection-related epilepsy syndrome.  Epilepsia Open.  2019;4:344–350. doi: 10.1002/epi4.12317. PMID: 31168503. [PMC free article: PMC6546072] [PubMed: 31168503]
22. Dinarello CA.  Introduction to the interleukin-1 family of cytokines and receptors: Drivers of innate inflammation and acquired immunity.  Immunol Rev.  2018;281:5–7. doi: 10.1111/imr.12624. PMID: 29248001. [PMC free article: PMC5750395] [PubMed: 29248001]
23. Dinarello CA, Simon A, van der Meer JW.  Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases.  Nat Rev Drug Discov.  2012;11:633–52. doi: 10.1038/nrd3800. PMID: 22850787. [PMC free article: PMC3644509] [PubMed: 22850787]
24. Donnelly JP, Kasatwar N, Hafeez S, Seifi A, Gilbert A, Barthol C, Small C, Ákos Szabó C.  Resolution of cryptogenic new onset refractory status epilepticus with tocilizumab.  Epilepsy Behav Rep.  2021;15:100431. doi: 10.1016/j.ebr.2021.100431. PMID: 33748736. [PMC free article: PMC7972955] [PubMed: 33748736]
25. Dubé C, Vezzani A, Behrens M, Bartfai T, Baram TZ.  Interleukin-1beta contributes to the generation of experimental febrile seizures.  Ann Neurol.  2005;57:152–5. doi: 10.1002/ana.20358. PMID: 15622539. [PMC free article: PMC2909879] [PubMed: 15622539]
26. Emsley HC, Smith CJ, Georgiou RF, Vail A, Hopkins SJ, Rothwell NJ, Tyrrell PJ.  A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients.  J Neurol Neurosurg Psychiatry.  2005;76:1366–72. doi: 10.1136/jnnp.2004.054882. PMID: 16170078. [PMC free article: PMC1739363] [PubMed: 16170078]
27. Engel T, Gomez-Villafuertes R, Tanaka K, Mesuret G, Sanz-Rodriguez A, Garcia-Huerta P, Miras-Portugal MT, Henshall DC, Diaz-Hernandez M.  Seizure suppression and neuroprotection by targeting the purinergic P2X7 receptor during status epilepticus in mice.  FASEB J.  2012;26:1616–1628. doi: 10.1096/fj.11-196089. PMID: 22198387. [PubMed: 22198387]
28. Eriksson C, Tehranian R, Iverfeldt K, Winblad B, Schultzberg M.  Increased expression of mRNA encoding interleukin-1beta and caspase-1, and the secreted isoform of interleukin-1 receptor antagonist in the rat brain following systemic kainic acid administration.  J Neurosci Res.  2000;60:266–79. doi: 10.1002/(SICI)1097-4547(20000415)60:2<266::AID-JNR16>3.0.CO;2-P. PMID: 10740232. [PubMed: 10740232]
29. Eriksson C, Winblad B, Schultzberg M.  Kainic acid induced expression of interleukin-1 receptor antagonist mRNA in the rat brain.  Brain Res Mol Brain Res.  1998;58:195–208. doi: 10.1016/s0169-328x(98)00125-9. PMID: 9685640. [PubMed: 9685640]
30. Etminan M, Samii A, Brophy JM.  Statin use and risk of epilepsy: a nested case-control study.  Neurology.  2010;75:1496–1500. doi: 10.1016/s0169-328x(98)00125-9. PMID: 9685640. [PubMed: 20975051]
31. Fabene PF, Mora GN, Martinello M, Rossi B, Merigo F, Ottoboni L, Bach S, Angiari S, Benati D, Chakir A, Zanetti L, Schio F, Osculati A, Marzola P, Nicolato E, Homeister JW, Xia L, Lowe JB, McEver RP, Osculati F, Sbarbati A, Butcher EC, Constantin G.  A role for leukocyte-endothelial adhesion mechanisms in epilepsy.  Nat Med.  2008;14:1377–83. doi: 10.1038/nm.1878. PMID: 19029985. [PMC free article: PMC2710311] [PubMed: 19029985]
32. Fox P, Mithal DS, Somogyi JR, Vien AC, Sanchez RM, Koh S.  Dexamethasone after early-life seizures attenuates increased susceptibility to seizures, seizure-induced microglia activation and neuronal injury later in life.  Neurosci Lett.  2020;728:134953. doi: 10.1016/j.neulet.2020.134953. PMID: 3227894. [PubMed: 32278942]
33. Frasca A, Aalbers M, Frigerio F, Fiordaliso F, Salio M, Gobbi M, Cagnotto A, Gardoni F, Battaglia GS, Hoogland G, Di Luca M, Vezzani A.  Misplaced NMDA receptors in epileptogenesis contribute to excitotoxicity.  Neurobiol Dis.  2011;43(2):507–15. doi: 10.1016/j.nbd.2011.04.024. PMID: 21575722. [PubMed: 21575722]
34. French JA, Cole AJ, Faught E, Theodore WH, Vezzani A, Liow K, J Halford JJ, Armstrong R, Szaflarski JP, Hubbard S, Patel J, Chen K, Feng W, Rizzo M, Elkins J, Knafler G, Parkerson KA.  Safety and Efficacy of Natalizumab as Adjunctive Therapy for People With Drug-Resistant Epilepsy: A Phase 2 Study  Neurology.  2021;97(18):e1757–e1767. doi: 10.1212/WNL.0000000000012766. PMID: 34521687. [PMC free article: PMC8610627] [PubMed: 34521687]
35. Frigerio F, Flynn C, Han Y, Lyman K, Lugo JN, Ravizza T, Ghestem A, Pitsch J, Becker A, Anderson AE, Vezzani A, Chetkovich, D, Bernard C. Neuroinflammation Alters Integrative Properties of Rat Hippocampal Pyramidal Cells. Mol. Neurobiol. 2018a;55:7500–7511. doi: 10.1007/s12035-018-0915-1.  PMID: 29427087. [PMC free article: PMC6070409] [PubMed: 29427087]
36. Frigerio F, Pasqualini G, Craparotta I, Marchini S, van Vliet EA, Foerch P, Vandenplas C, Leclercq K, Aronica E, Porcu L, Pistorius K, Colas RA, Hansen TV, Perretti M, Kaminski RM, Dalli J, Vezzani A. n-3 Docosapentaenoic acid-derived protectin D1 promotes resolution of neuroinflammation and arrests epileptogenesis. Brain.  2018b;141:3130–3143. doi: 10.1093/brain/awy247. PMID: 30307467. [PMC free article: PMC6202571] [PubMed: 30307467]
37. Galic MA, Riazi K, Pittman QJ.  Cytokines and brain excitability.  Front Neuroendocrinol.  2012;33: 116–25. doi: 10.1016/j.yfrne. PMID: 22214786. [PMC free article: PMC3547977] [PubMed: 22214786]
38. Gall CRE, Jumma O, Mohanraj R.  Five cases of new onset refractory status epilepticus (NORSE) syndrome: outcomes with early immunotherapy.  Seizure.  2013;22:217–220. doi: 10.1016/j.seizure.2012.12.016. PMID: 23333762. [PubMed: 23333762]
39. Gallentine WB, Shinnar S, Hesdorffer DC, Epstein L, Nordli DR, Lewis DV, Frank LM, Seinfeld S, Shinnar RC, Cornett K, Liu B, Moshé SL, Sun S.  Plasma cytokines associated with febrile status epilepticus in children: A potential biomarker for acute hippocampal injury.  Epilepsia.  2017;58:1102–1111. doi: 10.1111/epi.13750. PMID: 28448686. [PMC free article: PMC5482499] [PubMed: 28448686]
40. Garcia-Curran MM, Hall AM, Patterson KP, Shao M, Eltom N, Chen K, Dubé CM, Baram TZ.  Dexamethasone Attenuates Hyperexcitability Provoked by Experimental Febrile Status Epilepticus.  eNeuro.  2019; 6(6):ENEURO.0430–19. doi: 10.1523/ENEURO.0430-19.2019. PMID: 31685676. [PMC free article: PMC6860985] [PubMed: 31685676]
41. Gilmore T.D.  Introduction to NF-kappaB: players, pathways, perspectives.  Oncogene.  2006;25: 6680–4. doi: 10.1038/sj.onc.1209954. PMID: 17072321. [PubMed: 17072321]
42. Gobbo OL, O’Mara SM.  Post-treatment, but not pre-treatment, with the selective cyclooxygenase-2 inhibitor celecoxib markedly enhances functional recovery from kainic acid-induced neurodegeneration.  Neuroscience.  2004;125:317–327. doi: 10.1016/j.neuroscience.2004.01.045. PMID: 15062975. [PubMed: 15062975]
43. Godfred RM, Parikh MS, Haltiner AM, Caylor LM, Sepkuty JP, Doherty MJ.  Does aspirin use make it harder to collect seizures during elective video-EEG telemetry?  Epilepsy Behav.  2013;27: 115–117. doi: 10.1016/j.yebeh.2012.12.031. PMID: 23399946. [PubMed: 23399946]
44. Grosser T, Fries S, FitzGerald GA.  Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities.  J Clin Invest.  2006;116:4–15. DOI: 10.1172/JCI27291. PMID: 16395396. [PMC free article: PMC1323269] [PubMed: 16395396]
45. Guo J, Guo J, Li J, Zhou M, Qin F, Zhang S, Wu B, He L, Zhou D. Statin treatment reduces the risk of poststroke seizures. Neurology.  2015;85:701–707. doi: 10.1212/WNL.0000000000001814. PMID: 26203092. [PubMed: 26203092]
46. Guzzo EFM, Lima KR, Vargas CR, Coitinho AS.  Effect of dexamethasone on seizures and inflammatory profile induced by Kindling Seizure Model.  J Neuroimmunol.  2018;325:92–98. doi: 10.1016/j.jneuroim.2018.10.005. PMID: 30316679. [PubMed: 30316679]
47. Hagberg H, Mallard C.  Effect of inflammation on central nervous system development and vulnerability.  Curr Opin Neurol.  2005:18:117–23. doi: 10.1097/01.wco.0000162851.44897.8f. PMID: 15791140. [PubMed: 15791140]
48. Helmy A, Guilfoyle MR, Carpenter KLH, Pickard JD, Menon DK, Hutchinson PJ.  Recombinant human interleukin-1 receptor antagonist in severe traumatic brain injury: a phase II randomized control trial.  J Cereb Blood Flow Metab.  2014;34:845–851. doi: 10.1038/jcbfm.2014.23. PMID: 24569690. [PMC free article: PMC4013762] [PubMed: 24569690]
49. Hussein HM, Al-Khoury DK, Abdelnoor AM, Rahal EA.  Atorvastatin increases the production of proinflammatory cytokines and decreases the survival of Escherichia coli-infected mice.  Sci Rep.  2019; 9:11717. doi: 10.1038/s41598-019-48282-2. PMID: 31406240. [PMC free article: PMC6690901] [PubMed: 31406240]
50. Iori V, Iyer AM, Ravizza T, Beltrame L, Paracchini L, Marchini S, Cerovic M, Hill C, Ferrari M, Zucchetti M, Molteni M, Rossetti C, Brambilla R, Steve White H, D’Incalci M, Aronica E, Vezzani A.  Blockade of the IL-1R1/TLR4 pathway mediates disease-modification therapeutic effects in a model of acquired epilepsy.  Neurobiol Dis.  2017;99:12–23. doi: 10.1016/j.nbd.2016.12.007. PMID: 27939857. [PubMed: 27939857]
51. Iori V, Maroso M, Rizzi M, Iyer AM, Vertemara R, Carli M, Agresti A, Antonelli A, Bianchi ME, Aronica E, Ravizza T, Vezzani A.  Receptor for Advanced Glycation Endproducts is upregulated in temporal lobe epilepsy and contributes to experimental seizures.  Neurobiol Dis.  2013;58:102–14. doi: 10.1016/j.nbd.2013.03.006. PMID: 23523633. [PubMed: 23523633]
52. Iyer, A., Zurolo, E., Spliet, W.G., van Rijen, P.C., Baayen, J.C., Gorter, J.A., Aronica, E.  Evaluation of the innate and adaptive immunity in type I and type II focal cortical dysplasias.  Epilepsia  2010;51(9):1736–73. doi: 10.1111/j.1528-1167.2010.02547.x. PMID: 20345941 [PubMed: 20345941]
53. Jeong EA, Jeon BT, Shin HJ, Kim N, Lee DH, Kim HJ, Kang SS, Cho GJ, Choi WS, Roh GS.  Ketogenic diet-induced peroxisome proliferator-activated receptor-gamma activation decreases neuroinflammation in the mouse hippocampus after kainic acid-induced seizures.  Exp Neurol.  2011;232:195–202. doi: 10.1016/j.expneurol.2011.09.001. PMID: 21939657. [PubMed: 21939657]
54. Jiang J, Quan Y, Ganesh T, Pouliot WA, Dudek FE, Dingledine R.  Inhibition of the prostaglandin receptor EP2 following status epilepticus reduces delayed mortality and brain PMID: 23401547 inflammation.  Proc Natl Acad Sci USA.  2013;110:3591–6. doi: 10.1073/pnas.1218498110. PMID: 23401547. [PMC free article: PMC3587237] [PubMed: 23401547]
55. Jiang J, Yang MS, Quan Y, Gueorguieva P, Ganesh T, Dingledine R.  Therapeutic window for cyclooxygenase-2 related anti-inflammatory therapy after status epilepticus.  Neurobiol Dis.  2015;76:126–36. doi: 10.1016/j.nbd.2014.12.032. PMID: 25600211 [PMC free article: PMC4408774] [PubMed: 25600211]
56. Jun JS, Lee ST, Kim R, Chu K, Lee SK. Tocilizumab treatment for new onset refractory status epilepticus. Ann.  Neurol.  2018;84(6):940–945. doi: 10.1002/ana.25374. PMID: 30408233. [PubMed: 30408233]
57. Jyonouchi H, Geng L.  Intractable Epilepsy (IE) and Responses to Anakinra, a Human RecombinantIL-1 Receptor Agonist (IL-1ra): Case Reports.  J of Clin and Cell Immunol.  2016;7:5. doi: 10.4172/2155-9899.1000456.
58. Kanner AM, Mazarati A, Koepp M. Biomarkers of epileptogenesis: psychiatric comorbidities (?). Neurotherapeutics 2014;11:358–72. doi: 10.1007/s13311-014-0271-4.  PMID: 24719199. [PMC free article: PMC3996129] [PubMed: 24719199]
59. Kenney-Jung DL, Vezzani A, Kahoud RJ, LaFrance-Corey RG, Ho ML, Muscardin TW, Wirrell EC, Howe CL, Payne ET.  Febrile infection-related epilepsy syndrome treated with anakinra.  Annals of Neurology.  2016;80:939–945. doi: 10.1002/ana.24806. PMID: 27770579. [PMC free article: PMC5225882] [PubMed: 27770579]
60. Khattab MI, Kamel ESM, Abbas NAT, Kaoud A.  Diclofenac Influence on the Anticonvulsant Effect of Retigabine: The Potential Role of KCNQ Channels.  Egyptian Journal of Basic and Clinical Pharmacology.  2018;8:17. doi:10.11131/2018/101384.
61. Khawaja AM, DeWolfe JL, Miller DW, Szaflarski JP.  New-onset refractory status epilepticus (NORSE) - The potential role for immunotherapy.  Epilepsy Behav.  2015;47:17–23. doi: 10.1016/j.yebeh.2015.04.054. PMID: 26010959. [PubMed: 26010959]
62. Klein P, Friedman A, Hameed MQ, Kaminski RM, Bar-Klein G, Klitgaard H, Koepp M, Jozwiak S, Prince DA, Rotenberg A, Twyman R, Vezzani A, Wong M, Löscher W.  Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?  Epilepsia.  2020;61:359–386. doi: 10.1111/epi.16450. PMID: 32196665. [PMC free article: PMC8317585] [PubMed: 32196665]
63. Kwon YS, Pineda E, Auvin S, Shin D, Mazarati A, Sankar R.  Neuroprotective and antiepileptogenic effects of combination of anti-inflammatory drugs in the immature brain.  J Neuroinflammation.  2013;10:30. doi: 10.1186/1742-2094-10-30. PMID: 23442201. [PMC free article: PMC3599749] [PubMed: 23442201]
64. Lagarde S, Villeneuve N, Trébuchon A, Kaphan E, Lepine A, McGonigal A, Roubertie A, Barthez MA, Trommsdorff V, LeFranc J, Wehbi S, des Portes V, Laguitton V, Scarvarda D, Giusiano B, Milh M, Bulteau C, Bartolomei F. Anti-tumor necrosis factor alpha therapy (adalimumab) in Rasmussen’s encephalitis. An open pilot study.  Epilepsia.  2016;57:956–966. doi: 10.1111/epi.13387. PMID: 27106864. [PubMed: 27106864]
65. Lai YC, Muscal E, Wells E, Shukla N, Eschbach K, Hyeong Lee K, Kaliakatsos M, Desai N, Wickström R, Viri M, Freri E, Granata T, Nangia S, Dilena R, Brunklaus A, Wainwright MS, Gorman MP, Stredny CM, Asiri A, Hundallah K, Doja A, Payne E, Wirrell E, Koh S, Carpenter JL, Riviello J.  Anakinra usage in febrile infection related epilepsy syndrome: an international cohort.  Ann Clin Transl Neurol.  2020;7:2467–2474. doi: 10.1002/acn3.51229. PMID: 33506622. [PMC free article: PMC7732241] [PubMed: 33506622]
66. Lance EI, Sreenivasan AK, Zabel TA, Kossoff EH, Comi AM. Aspirin use in Sturge-Weber syndrome: side effects and clinical outcomes. J.  Child Neurol.  2013;28:213–218. doi: 10.1177/0883073812463607. PMID: 23112247. [PMC free article: PMC4373084] [PubMed: 23112247]
67. Liao JK, Laufs U.  Pleiotropic effects of statins.  Annu Rev Pharmacol Toxicol.  2005;45:89–118. doi: 10.1146/annurev.pharmtox.45.120403.095748 PMID: 15822172. [PMC free article: PMC2694580] [PubMed: 15822172]
68. Librizzi L, Noè F, Vezzani A, de Curtis M, Ravizza T. Seizure-induced brain-borne inflammation sustains seizure recurrence and blood-brain barrier damage. Ann Neurol.  2012;72:82–90. doi: 10.1002/ana.23567. PMID: 22829270. [PubMed: 22829270]
69. Librizzi L, Regondi MC, Pastori C, Frigerio S, Frassoni C, de Curtis M.  Expression of adhesion factors induced by epileptiform activity in the endothelium of the isolated guinea pig brain in vitro.  Epilepsia.  2007;48:743–51. doi: 10.1111/j.1528-1167.2007.01047.x. PMID: 17386052. [PubMed: 17386052]
70. Lin JJ, Wang Y, Lan SY, Chan OW, Hsia SH, Chou ML, Hung PC, Hsieh MY, Chou IJ, Wang HS, Lin KL.  CHEESE Study Group. Combination of intravenous immunoglobulin and steroid pulse therapy improves outcomes of febrile refractory status epilepticus.  Epilepsy Res.  2018; 142:100–105. doi: 10.1016/j.eplepsyres.2018.03.017. PMID: 29609074. [PubMed: 29609074]
71. Löscher W, Friedman A.  Structural, Molecular, and Functional Alterations of the Blood-Brain Barrier during Epileptogenesis and Epilepsy: A Cause, Consequence, or Both?  Int J Mol Sci.  2020; 21(2):591–610. doi: 10.3390/ijms21020591. PMID: 31963328. [PMC free article: PMC7014122] [PubMed: 31963328]
72. Marchi N, Fan Q, Ghosh C, Fazio V, Bertolini F, Betto G, Batra A, Carlton E, Najm I, Granata T, Janigro D.  Antagonism of peripheral inflammation reduces the severity of status epilepticus.  Neurobiol Dis.  2009;33:171–81. doi: 10.1016/j.nbd.2008.10.002. PMID: 19010416. [PMC free article: PMC3045783] [PubMed: 19010416]
73. Marchi N, Granata T, Ghosh C, Janigro D.  Blood-brain barrier dysfunction and epilepsy: pathophysiologic role and therapeutic approaches.  Epilepsia.  2012;53:1877–1886. doi: 10.1111/j.1528-1167.2012.03637.x. PMID: 22905812. [PMC free article: PMC4842020] [PubMed: 22905812]
74. Maroso M, Balosso S, Ravizza T, Iori V, Wright CI, French J, Vezzani A.  Interleukin-1beta biosynthesis inhibition reduces acute seizures and drug resistant chronic epileptic activity in mice.  Neurotherapeutics.  2011;8:304–15. doi: 10.1007/s13311-011-0039-z. PMID: 21431948. [PMC free article: PMC3101825] [PubMed: 21431948]
75. Mazarati AM, Lewis ML, Pittman QJ. Neurobehavioral comorbidities of epilepsy: Role of inflammation. Epilepsia.  2017;58 (3):48–56. doi: 10.1111/epi.13786. PMID: 28675557. [PubMed: 28675557]
76. Meng XF, Tan L, Tan MS, Jiang T, Tan CC, Li MM, Wang HF, Yu JT.  Inhibition of the NLRP3 inflammasome provides neuroprotection in rats following amygdala kindling-induced status epilepticus.  J Neuroinflammation.  2014;11:212. doi: 10.1186/s12974-014-0212-5. PMID: 25516224. [PMC free article: PMC4275944] [PubMed: 25516224]
77. Noé FM, Polascheck N, Frigerio F, Bankstahl M, Ravizza T, Marchini S, Beltrame L, Bandero CR, Loscher W, Vezzani A.  Pharmacological blockade of IL-1beta/IL-1 receptor type 1 axis during epileptogenesis provides neuroprotection in two rat models of temporal lobe epilepsy.  Neurobiol Dis.  2013;59:183–93. doi: 10.1016/j.nbd.2013.07.015. PMID: 23938763. [PubMed: 23938763]
78. Nowak M, Strzelczyk A, Reif PS, Schrolemmer K, Bauer S, Norwood BA, Oertel WH, Rosenow F, Strik H, Hamer HM.  Minocycline as potent anticonvulsivant i a patient with astrocytoma and drug resistant epilepsy.  Seizure.  2012;21:227–228. doi: 10.1016/j.seizure.2011.12.009. PMID: 22265576. [PubMed: 22265576]
79. Oliveira CV, de Zorzi VN, Fighera MR, Royes LFF, Furian AF, Oliveira MS.  Subtle improvement of seizure susceptibility by atorvastatin treatment during epileptogenesis.  Pharmacol Rep.  2018;70:364–371. doi: 10.1016/j.pharep.2017.08.016. PMID: 29477945. [PubMed: 29477945]
80. Ortego M, Bustos C, Hernández-Presa MA, Tuñón J, Díaz C, Hernández G, Egido J.  Atorvastatin reduces NF-kappaB activation and chemokine expression in vascular smooth muscle cells and mononuclear cells.  Atherosclerosis.  1999;147:253–261. doi: 10.1016/s0021-9150(99)00193-8. PMID: 10559511. [PubMed: 10559511]
81. Pahan K, Sheikh FG, Namboodiri AM, Singh I.  Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microglia, and macrophages.  J Clin Invest.  1997;100:2671–2679. doi: 10.1172/JCI119812. PMID: 9389730. [PMC free article: PMC508470] [PubMed: 9389730]
82. Paudel YN, Shaikh MF, Shah S, Kumari Y, Othman I.  Role of inflammation in epilepsy and neurobehavioral comorbidities: Implication for therapy.  Eur J Pharmacol.  2018;837:145–155. doi: 10.1016/j.ejphar.2018.08.020. PMID: 30125565. [PubMed: 30125565]
83. Pernhorst K, Herms S, Hoffmann P, Cichon S, Schulz H, Sander T, Schoch S, Becker AJ, Grote A.  TLR4, ATF-3 and IL8 inflammation mediator expression correlates with seizure frequency in human epileptic brain tissue.  Seizure.  2013;8:675–8. doi: 10.1016/j.seizure.2013.04.023. PMID: 23706953. [PubMed: 23706953]
84. Piermartiri TCB, Vandresen-Filho S, de Araújo Herculano B, Martins WC, Dal’agnolo D, Stroeh E, Carqueja CL, Boeck CR, Tasca CI.  Atorvastatin prevents hippocampal cell death due to quinolinic acid-induced seizures in mice by increasing Akt phosphorylation and glutamate uptake.  Neurotox Res.  2009;16:106–115. doi: 10.1007/s12640-009-9057-6. PMID: 19526287. [PubMed: 19526287]
85. Pineda E, Shin D, You SJ, Auvin S, Sankar R, Mazarati A.  Maternal immune activation promotes hippocampal kindling epileptogenesis in mice.  Ann Neurol.  2013;74:11–19. doi: 101002/ana23898 PMID: 23907982 [PMC free article: PMC3775928] [PubMed: 23907982]
86. Pitkanen A, Loscher W, Vezzani A, Becker AJ, Simonato M, Lukasiuk K, Grohn O, Bankstahl JP, Friedman A, Aronica E, Gorter JA, Ravizza T, Sisodiya SM, Kokaia M, Beck H.  Advances in the development of biomarkers for epilepsy.  Lancet Neurol.  2016;15:843–56. doi: 10.1016/S1474-4422(16)00112-5. PMID: 27302363. [PubMed: 27302363]
87. Pohlentz MS, Müller P, Cases-Cunillera S, Opitz T, Surges R, Hamed M, Vatter H, Schoch S, Becker AJ, Pitsch J.  Characterisation of NLRP3 pathway-related neuroinflammation in temporal lobe epilepsy.  PLoS ONE.  2022;17(8):e0271995. https://doi​.org/10.1371/journal​.pone.0271995 [PMC free article: PMC9380933] [PubMed: 35972937]
88. Polascheck N, Bankstahl M, Loscher W.  The COX-2 inhibitor parecoxib is neuroprotective but not antiepileptogenic in the pilocarpine model of temporal lobe epilepsy.  Exp Neurol.  2010;224: 219–33. doi: 10.1016/j.expneurol.2010.03.014. PMID: 20353773. [PubMed: 20353773]
89. Pollard JR, Eidelman O, Mueller GP, Dalgard CL, Crino PB, Anderson CT, Brand EJ, Burakgazi E, Ivaturi SK, Pollard HB.  The TARC/sICAM5 Ratio in patient plasma is a candidate biomarker for drug resistant epilepsy.  Frontiers in Neurology.  2013;3:181. doi: 10.3389/fneur.2012.00181. PMID: 23293627. [PMC free article: PMC3535822] [PubMed: 23293627]
90. Pugh MJV, Knoefel JE, Mortensen EM, Amuan ME, Berlowitz DR, Van Cott AC.  New-onset epilepsy risk factors in older veterans.  J Am Geriatr Soc.  2009;57:237–242. doi: 10.1111/j.1532-5415.2008.02124.x. PMID: 19207140. [PubMed: 19207140]
91. Ramaswamy V, Walsh JG, Sinclair DB, Johnson E, Tang-Wai R, Wheatley BM, Branton W, Maingat F, Snyder T, Gross DW, Power C.  Inflammasome induction in Rasmussen’s encephalitis: cortical and associated white matter pathogenesis.  J Neuroinflammation.  2013;10:152. doi: 10.1186/1742-2094-10-152. PMID: 24330827. [PMC free article: PMC3881507] [PubMed: 24330827]
92. Rana A, Musto AE.  The role of inflammation in the development of epilepsy.  J Neuroinflammation.  2018;15(1):144. doi: 10.1186/s12974-018-1192-7. PMID: 29764485. [PMC free article: PMC5952578] [PubMed: 29764485]
93. Ransohoff RM.  Natalizumab for multiple sclerosis.  N Engl J Med.  2007;356(25):2622–2629. doi: 10.1056/NEJMct071462. PMID: 17582072. [PubMed: 17582072]
94. Ravizza T, Balosso S, Vezzani A.  Inflammation and prevention of epileptogenesis.  Neurosci Lett.  2011;497:223–30. doi: 10.1016/j.neulet.2011.02.040. PMID: 21362451. [PubMed: 21362451]
95. Ravizza T, Boer K, Redeker S, Spliet WG, van Rijen PC, Troost D, Vezzani A, Aronica E.  The IL-1beta system in epilepsy-associated malformations of cortical development.  Neurobiol Dis.  2006a;24:128–43. doi: 10.1016/j.nbd.2006.06.003. PMID: 16860990 [PubMed: 16860990]
96. Ravizza T, Gagliardi B, Noe F, Boer K, Aronica E, Vezzani A.  Innate and adaptive immunity during epileptogenesis and spontaneous seizures: evidence from experimental models and human temporal lobe epilepsy.  Neurobiol Dis.  2008;29:142–60. doi: 10.1016/j.nbd.2007.08.012. PMID: 17931873. [PubMed: 17931873]
97. Ravizza T, Lucas SM, Balosso S, Bernardino L, Ku G, Noe F, Malva J, Randle JC, Allan S, Vezzani A. Inactivation of caspase-1 in rodent brain: a novel anticonvulsive strategy. Epilepsia.  2006b;47(7):1160–8. doi: 10.1111/j.1528-1167.2006.00590.x. PMID: 16886979. [PubMed: 16886979]
98. Ravizza T, Onat FY, Brooks-Kayal AR, Depaulis A, Galanopoulou AS, Mazarati A, Numis AL, Sankar R, Friedman A. WONOEP appraisal: Biomarkers of epilepsy-associated comorbidities. Epilepsia. 2016;3:331–342. doi: 10.1111/epi.13652.  PMID: 28035782. [PMC free article: PMC6582945] [PubMed: 28035782]
99. Ravizza T, Vezzani A.  Status epilepticus induces time-dependent neuronal and astrocytic expression of interleukin-1 receptor type I in the rat limbic system.  Neuroscience.  2006;137:301–8. doi: 10.1016/j.neuroscience.2005.07.063. PMID: 16289587. [PubMed: 16289587]
100. Rees S, Harding R, Walker D.  An adverse intrauterine environment: implications for injury and altered development of the brain.  Int J Dev Neurosci.  2008;26:3–11. doi: 10.1016/j.ijdevneu.2007.08.020. PMID: 17981423. [PubMed: 17981423]
101. Riazi K.  Galic M.A.  Pittman Q.J.  Contributions of peripheral inflammation to seizure susceptibility: cytokines and brain excitability.  Epilepsy Res.  2010;89(1):34–42. doi: 10.1016/j.eplepsyres.2009.09.004. PMID: 19804959. [PubMed: 19804959]
102. Rodgers KM, Hutchinson MR, Northcutt A, Maier SF, Watkins LR, Barth DS.  The cortical innate immune response increases local neuronal excitability leading to seizures.  Brain.  2009;132: 2478–86. doi: 10.1093/brain/awp177. PMID: 19567702. [PMC free article: PMC2732268] [PubMed: 19567702]
103. Rojas A, Chen D, Ganesh T, Varvel N, Dingledine R.  The COX-2/prostanoid signalling cascades in seizure disorders.  Expert Opin Ther Targets.  2019;23:1–13. doi: 10.1080/14728222.2019.1554056. PMID: 30484341. [PMC free article: PMC6481174] [PubMed: 30484341]
104. Rojas A, Ganesh T, Lelutiu N, Gueorguieva P, Dingledine R.  Inhibition of the prostaglandin EP2 receptor is neuroprotective and accelerates functional recovery in a rat model of organophosphorus induced status epilepticus.  Neuropharmacology.  2015;93:15–27. doi: 10.1016/j.neuropharm.2015.01.017. PMID: 25656476. [PMC free article: PMC4387070] [PubMed: 25656476]
105. Rojas A, Ganesh T, Manji Z, O’neill T, Dingledine R.  Inhibition of the prostaglandin E2 receptor EP2 prevents status epilepticus-induced deficits in the novel object recognition task in rats.  Neuropharmacology.  2016;110:419–430. doi: 10.1016/j.neuropharm.2016.07.028. PMID: 27477533. [PMC free article: PMC5028311] [PubMed: 27477533]
106. Roseti C, van Vliet EA, Cifelli P, Ruffolo G, Baayen JC, Di Castro MA, Bertollini C, Limatola C, Aronica E, Vezzani A, Palma E.  GABA currents are decreased by IL-1beta in epileptogenic tissue of patients with temporal lobe epilepsy: implications for ictogenesis.  Neurobiol Dis.  2015;82:311–320. doi: 10.1016/j.nbd.2015.07.003. PMID: 26168875. [PubMed: 26168875]
107. Sa M, Singh R, Pujar S, D’Arco F, Desai N, Eltze C, Hughes E, Al Obaidi M, Eleftheriou D, Tisdall M, Selway R, Cross JH, Kaliakatsos M, Valentin A.  Centromedian thalamic nuclei deep brain stimulation and Anakinra treatment for FIRES - Two different outcomes.  Eur J Paediatr Neurol.  2019;23:749–754. doi: 10.1016/j.ejpn.2019.08.001. PMID: 31446001. [PubMed: 31446001]
108. Semple BD, O’Brien TJ, Gimlin K, Wright DK, Kim SE, Casillas-Espinosa PM, Webster KM, Petrou S, Noble-Haeusslein LJ.  Interleukin-1 Receptor in Seizure Susceptibility after Traumatic Injury to the Pediatric Brain.  J. Neurosci.  2017;37:7864–7877. doi: 10.1523/JNEUROSCI.0982-17.2017. PMID: 28724747. [PMC free article: PMC5559762] [PubMed: 28724747]
109. Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, Hirsch E, Jain S, Mathern GW, Moshé SL, Nordli DR, Perucca E, Tomson T, Wiebe S, Zhang YH, Zuberi SM.  ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology.  Epilepsia. 2017 Apr;58(4):512–521. doi: 10.1111/epi.13709. [PMC free article: PMC5386840] [PubMed: 28276062]
110. Sotgiu S, Murrighile MR, Constantin G. Treatment of refractory epilepsy with natalizumab in a apatient with multiple sclerosis. Case report. BMC Neurology.  2010;10:84. doi: 10.1186/1471-2377-10-84. PMID: 20863362. [PMC free article: PMC2954970] [PubMed: 20863362]
111. Stredny CM, Case S, Sansevere AJ, Son M, Henderson L, Gorman MP.  Interleukin-6 Blockade With Tocilizumab in Anakinra-Refractory Febrile Infection-Related Epilepsy Syndrome (FIRES).  Child Neurol Open.  2020;15:7:2329048X20979253., doi: 10.1177/2329048X20979253. PMID: 33403221. [PMC free article: PMC7745547] [PubMed: 33403221]
112. Sun FJ, Zhang CQ, Chen X, Wei YJ, Li S, Liu SY, Zang Z, He JJ, Guo W, Yang H.  Downregulation of CD47 and CD200 in patients with focal cortical dysplasia type IIb and tuberous sclerosis complex.  J Neuroinflammation.  2016;13(1):85. doi: 10.1186/s12974-016-0546-2. PMID: 27095555. [PMC free article: PMC4837553] [PubMed: 27095555]
113. Sun M, Brady RD, Wright DK, Kim HA, Zhang SR, Sobey CG, Johnstone MR, O’Brien TJ, Semple BD, McDonald SJ, Shultz SR.  Treatment with an interleukin-1 receptor antagonist mitigates neuroinflammation and brain damage after polytrauma.  Brain Behavior and Immunity.  2017;66:359–371. doi: 10.1016/j.bbi.2017.08.005. PMID: 28782716. [PubMed: 28782716]
114. Tan CC, Zhang JG, Tan MS, Chen H, Meng DW, Jiang T, Meng XF, Li Y, Sun Z, Li MM, Yu JT, Tan L.  NLRP1 inflammasome is activated in patients with medial temporal lobe epilepsy and contributes to neuronal pyroptosis in amygdala kindling-induced rat model.  J Neuroinflammation.  2015;12:18. doi: 10.1186/s12974-014-0233-0. PMID: 25626361. [PMC free article: PMC4314732] [PubMed: 25626361]
115. Taraschenko O, Fox HS, Zekeridou A, Pittock SJ, Eldridge E, Farukhuddin F, Al-Saleem F, Devi Kattala C, Dessain SK, Casale G, Willcockson G, Dingledine R.  Seizures and memory impairment induced by patient-derived anti-N-methyl-D-aspartate receptor antibodies in mice are attenuated by anakinra, an interleukin-1 receptor antagonist.  Epilepsia.  2021;62(3):671–682. doi: 10.1111/epi.16838. PMID: 33596332. [PMC free article: PMC8536397] [PubMed: 33596332]
116. Terrone G, Frigerio F, Balosso S, Ravizza T, Vezzani A.  Inflammation and reactive oxygen species in status epilepticus: Biomarkers and implications for therapy.  Epilepsy Behav.  2019;101(Pt B):106275. doi: 10.1016/j.yebeh.2019.04.028. PMID: 31171434. [PubMed: 31171434]
117. Terrone G, Pauletti A, Salamone A, Rizzi M, Villa BR, Porcu L, Sheehan MJ, Guilmette E, Butler CR, Piro JR, Samad TA, Vezzani A.  Inhibition of monoacylglycerol lipase terminates diazepam-resistant status epilepticus in mice and its effects are potentiated by a ketogenic diet.  Epilepsia.  2018;59:79–91. doi: 10.1111/epi.13950. PMID: 29171003. [PubMed: 29171003]
118. Udani V, Pujar S, Munot P, Maheshwari S, Mehta N. Natural history and magnetic resonance imaging follow-up in 9 Sturge-Weber Syndrome patients and clinical correlation. J Child Neurol. 2007;22:479–483. doi: 10.1177/0883073807300526.  PMID: 17621534. [PubMed: 17621534]
119. Vallecoccia MS, Martinotti A, Siddi C, Dominedò C, Cingolani E.  Use of Unconventional Therapies in Super-refractory Status Epilepticus: A Case Report and Literature Review.  Clin EEG Neurosci.  2022; 53(1):70–73. doi: 10.1177/1550059420975612. PMID: 33233961. [PubMed: 33233961]
120. van Stuijvenberg M, Derksen-Lubsen G, Steyerberg EW, Habbema JD, Moll HA.  Randomized, controlled trial of ibuprofen syrup administered during febrile illnesses to prevent febrile seizure recurrences.  Pediatrics.  1998;102(5):E51. doi: 10.1542/peds.102.5.e51. PMID: 9794981. [PubMed: 9794981]
121. van Vliet EA, Aronica E, Gorter JA.  Blood-brain barrier dysfunction seizures and epilepsy.  Semin Cell Dev Biol.  2015;38:26–34. doi: 10.1016/j.semcdb.2014.10.003. PMID: 25444846. [PubMed: 25444846]
122. van Vliet EA, Aronica E, Vezzani A, Ravizza T.  Review: Neuroinflammatory pathways as treatment targets and biomarker candidates in epilepsy: emerging evidence from preclinical and clinical studies.  Neuropathol Appl Neurobiol.  2018;44:91–111. doi: 10.1111/nan.12444. PMID: 28977690. [PubMed: 28977690]
123. Varvel NH, Amaradhi R, Espinosa-Garcia C, Duddy S, Franklin R, Banik A, Alemán-Ruiz C, Blackmar-Raynolds L, Wang W, Honore T, Ganesh T, Dingledine R.  Preclinical development of an EP2 antagonist for post-seizure cognitive deficits.  Neuropharmacology.  2023;224:109356. doi: 10.1016/j.neuropharm.2022.109356. PMID: 36460083. [PMC free article: PMC9894535] [PubMed: 36460083]
124. Varvel NH, Jiang J, Dingledine R.  Candidate drug targets for prevention or modification of epilepsy.  Annu Rev Pharmacol Toxicol.  2015;55:4.1–4.19. doi: 10.1146/annurev-pharmtox-010814-124607. PMID: 25196047. [PMC free article: PMC4427904] [PubMed: 25196047]
125. Vezzani A, Balosso S, Ravizza T.  Neuroinflammatory pathways as treatment targets and biomarkers in epilepsy.  Nat Rev Neurol.  2019;15:459–472. doi: 10.1038/s41582-019-0217-x PMID: 31263255. [PubMed: 31263255]
126. Vezzani A, Conti M, De Luigi A, Ravizza T, Moneta D, Marchesi F, De Simoni MG.  Interleukin-1beta immunoreactivity and microglia are enhanced in the rat hippocampus by focal kainate application: functional evidence for enhancement of electrographic seizures.  J Neurosci.  1999;19:5054–65. doi: 10.1523/JNEUROSCI.19-12-05054.1999. PMID: 10366638. [PMC free article: PMC6782637] [PubMed: 10366638]
127. Vezzani A, Friedman A.  Brain inflammation as a biomarker in epilepsy.  Biomark Med.  2011;5:607–14. doi: 10.2217/bmm.11.61. PMID: 22003909. [PMC free article: PMC3625731] [PubMed: 22003909]
128. Vezzani A, Lang B, Aronica E.  Immunity and Inflammation in Epilepsy.  Cold Spring Harb Perspect Med.  2015;6(2):a022699. doi: 10.1101/cshperspect.a022699. PMID: 26684336. [PMC free article: PMC4743070] [PubMed: 26684336]
129. Vezzani A, Moneta D, Conti M, Richichi C, Ravizza T, De Luigi A, De Simoni MG, Sperk G, Andell-Jonsson S, Lundkvist J, Iverfeldt K, Bartfai T.  Powerful anticonvulsant action of IL-1 receptor antagonist on intracerebral injection and astrocytic overexpression in mice.  Proc Natl Acad Sci U S A.  2000;97:11534–9. doi: 10.1073/pnas.190206797. PMID: 11016948. [PMC free article: PMC17235] [PubMed: 11016948]
130. Vezzani A, Moneta D, Richichi C, Aliprandi M, Burrows SJ, Ravizza T, Perego C, De Simoni MG. Functional role of inflammatory cytokines and antiinflammatory molecules in seizures and epileptogenesis. Epilepsia.  2002;43 (5):30–5. doi: 10.1046/j.1528-1157.43.s.5.14.x. PMID: 12121291. [PubMed: 12121291]
131. Vezzani A, Viviani B.  Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability.  Neuropharmacology.  2015;96:70–82. doi: 10.1016/j.neuropharm.2014.10.027. PMID: 25445483. [PubMed: 25445483]
132. Vizuete AFK, Hansen F, Negri E, Leite MC, de Oliveira DL, Gonçalves CA.  Effects of dexamethasone on the Li-pilocarpine model of epilepsy: protection against hippocampal inflammation and astrogliosis.  J Neuroinflammation.  2018;15(1):68. doi: 10.1186/s12974-018-1109-5. PMID: 29506554. [PMC free article: PMC5839012] [PubMed: 29506554]
133. Wang KY, Yu GF, Zhang ZY, Huang Q, Dong XQ.  Plasma high-mobility group box 1 levels and prediction of outcome in patients with traumatic brain injury.  Clin. Chim. Acta.  2012;413: 1737–1741. doi: 10.1016/j.cca.2012.07.002. PMID: 22789964. [PubMed: 22789964]
134. Welzel L, Bergin DH, Schidlitzki A, Twele F, Johne M, Klein P, Löscher W.  Systematic evaluation of rationally chosen multitargeted drug combinations: a combination of low doses of levetiracetam atorvastatin and ceftriaxone exerts antiepileptogenic effects in a mouse model of acquired epilepsy.  Neurobiol Dis.  2021;149:105227;1–19. doi: 10.1016/j.nbd.2020.105227. PMID: 33347976. [PubMed: 33347976]
135. Westbrook C, Subramaniam T, Seagren RM, Tarula E, Co D, Furstenberg-Knauff M, Wallace A, Hsu D, Payne E.  Febrile Infection-Related Epilepsy Syndrome Treated Successfully With Anakinra in a 21-Year-Old Woman.  WMJ.  2019;118:135–139. PMID: 31682750. [PMC free article: PMC7082129] [PubMed: 31682750]
136. Xu ZH, Wang Y, Tao AF, Yu J, Wang XY, Zu YY, Zhang SH, Chen Z.  Interleukin-1 receptor is a target for adjunctive control of diazepam-refractory status epilepticus in mice.  Neuroscience.  2016;328:22–29. doi: 10.1016/j.neuroscience.2016.04.036. PMID: 27133574. [PubMed: 27133574]
137. Yuen AWC, Keezer MR, Sander JW.  Epilepsy is a neurological and a systemic disorder.  Epilepsy Behav.  2018;78:57–61. doi: 10.1016/j.yebeh.2017.10.010. PMID: 29175221. [PubMed: 29175221]
138. Zhao T, Ding Y, Feng X, Zhou C, Lin W.  Effects of atorvastatin and aspirin on post-stroke epilepsy and usage of levetiracetam.  Medicine (Baltimore).  2020:99:e23577. doi: 10.1097/MD.0000000000023577. PMID: 33327318. [PMC free article: PMC7738023] [PubMed: 33327318]