Targeting inflammation as a therapeutic strategy for drug-resistant epilepsies

Abstract

An increasing body of literature data suggests that inflammation, and in particular neuroinflammation, is involved in the pathophysiology of particular forms of epilepsy and convulsive disorders.

Animal models have been used to identify inflammatory triggers in epileptogenesis and inflammation has recently been shown to enhance seizures. For example, pharmacological blockade of the IL-1beta/IL-1 receptor type 1 axis during epileptogenesis has been demonstrated to provide neuroprotection in temporal lobe epilepsy. Furthermore, experimental models have suggested that neural damage and the onset of spontaneous recurrent seizures are modulated via complex interactions between innate and adaptive immunity. However, it has also been suggested that inflammation can occur as a result of epilepsy, since animal models have also shown that seizure activity can induce neuroinflammation, and that recurrent seizures maintain chronic inflammation, thereby perpetuating seizures.

On the basis of these observations, it has been suggested that immune-mediated therapeutic strategies may be beneficial for treating some drug resistant epilepsies with an underlying demonstrable inflammatory process. Although the potential mechanisms of immunotherapeutic strategies in drug-resistant seizures have been extensively discussed, evidence on the efficacy of such therapy is limited. However, recent research efforts have been directed toward utilizing the potential therapeutic benefits of anti-inflammatory agents in neurological disease and these are now considered prime candidates in the ongoing search for novel anti-epileptic drugs.

The objective of our review is to highlight the immunological features of the pathogenesis of seizures and to analyze possible immunotherapeutic approaches for drug resistant epilepsies that can alter the immune-mediated pathogenesis.

Keywords: :

• immunophlogosis
• drug resistent epilepsy
• immunotherapeutic approaches
• childhood

Introduction

An increasing body of data suggests that inflammation, and in particular neuroinflammation is involved in the pathophysiology of certain types of epilepsy and convulsive disorders. Several epileptic and seizure-inducing disorders such as FIRES, temporal lobe epilepsy and Rasmussen encephalitis are associated with an increase in inflammatory markers within the cerebral spinal fluid (CSF), central nervous system (CNS) and the blood-brain barrier (BBB). Further evidence comes from efficacy studies of anti-inflammatory and immunomodulatory therapies for the treatment of some epileptic disorders, from genetic studies and from evidence of high levels of stress hormones and BBB disruption in epileptic patients.^1-3 Moreover, epilepsy has been shown to be a feature of systemic autoimmune disorders including systemic lupus erythematosus, Sjogren syndrome, and antiphospholipid syndrome.^4-8

Animal models used to identify inflammatory triggers in epileptogenesis have recently shown an enhancement of seizures with inflammation in the developing rat brain⁹ with pharmacological blockade of the IL-1beta/IL-1 receptor type 1 axis during epileptogenesis providing neuroprotection in 2 rat models of temporal lobe epilepsy.¹⁰ Furthermore, experimental models have suggested that neural damage and the onset of spontaneous recurrent seizures are modulated via complex interactions between innate and adaptive immunity.^11,12 However, it has also been suggested that inflammation can occur as a result of epilepsy, since animal models have shown that seizure activity can induce neuroinflammation and that recurrent seizures maintain chronic inflammation.¹³

The objective of our review is to highlight the immunological features mediating the pathogenesis of epileptic seizures and to analyze possible immunotherapeutic approaches for drug resistant epilepsies that modulate the immune-mediated pathogenesis.

Materials and Methods

Articles reporting evidence of the immunological and inflammatory mechanisms in epileptic disorders were selected. Those reporting the evidence of the presence of immune-mediated inflammation in epileptic patients and the subsequent trial of immunotherapy for intractable epileptic disorders were also included.

Given the lack of an electronic database that contains all publications for all medical journals and the fact that the restriction of only one database could be associated with a systematic bias, it was necessary to combine multiple databases for a comprehensive literature search. For this reason, an electronic literature search was performed in¹ MEDLINE via PubMed interface,² SCOPUS,³ Google Scholar,⁴ and the Cochrane Library for all articles published from inception to October 2013. Database specific search strings were developed and included search terms describing epilepsies or epileptic syndromes (population/exposure) and neuroinflammation, and immunotherapy for drug-resistant seizures (study design/description of cases). A combination of medical subject headings (MeSH) and keywords were used.

Titles and abstracts of identified papers were screened by 2 independent reviewers to determine whether they met the eligibility criteria of interest to develop our review. Subsequently, full texts of the remaining articles were independently retrieved for eligibility by the 2 reviewers.

Inflammatory mediators in epilepsy

The hypothesis of an immune-mediated pathogenesis for epileptic syndromes arose from evidence of inflammation in seizures linked to Rasmussen encephalitis. This disorder is characterized by severe seizures and progressive degeneration of a single brain hemisphere associated with the presence of glutamate receptor subunit R3 (GlutR3) autoimmune antibodies.¹⁴ The pathological examination of 45 hemispherectomies revealed the presence of inflammatory cells ranging from T-cell infiltration and neuroglial reactions to extensive neuronal death.¹⁵ Furthermore, Bien et al.¹⁶ found evidence of T-cell-mediated cytotoxicity in specimens of 11 patients. This evidence suggests a role for inflammatory components in the pathogenesis and ongoing progression of Rasmussen encephalitis. In addition, there are some specific epileptic syndromes characterized by immunological features that could be considered as targets of immunomodulatory or anti-inflammatory therapy when recognized. In this regard, inflammation has been described in West Syndrome, temporal lobe epilepsy, seizures characterizing cortical dysplasia, and in idiopathic tonic-clonic seizures. Moreover, a distinction has been made between the inflammatory response occurring in single seizure events and in epilepsy where convulsive episodes are repetitive or can show different semiologies.

First an autoimmune disorder has been demonstrated in West syndrome, with observation of elevated interleukin-2 (IL-2), Tumor Necrosis Factor alpha (TNF-alpha), and Interferon alpha (IFN-alpha) levels compared with matched controls in 23 Chinese patients.¹⁷ Furthermore a link to viral infections was observed in 25 of 29 Japanese patients exhibiting remission of West syndrome over a 30-y period.¹⁸

In temporal lobe epilepsy (TLE) the inflammatory process is characterized by increased levels of beta-amyloid precursor and IL-1.¹⁹ Increased levels of IL-1 and IL-1 receptor 1 (IL-1R1) were also found in specimens from patients with drug-resistant TLE undergoing surgery for focal cortical dysplasia or glioneural tumors (causes of epilepsy), and levels of IL-1beta and IL-1R1 directly correlated with the frequency of seizures.²⁰ Another study demonstrated overexpression of nuclear factor-kB (NfkB), a mediator of acute inflammation, in areas of neural loss from hippocampi of 18 patients with medial temporal lobe epilepsy and hippocampal sclerosis, compared with tissue from 7 hippocampi from non-epileptic patients or those with cryptogenic medial temporal lobe epilepsy without hippocampal sclerosis (P < 0.01).²¹

High levels of pro-inflammatory cytokines were also demonstrated in patients affected by focal cortical dysplasia with seizures. In 2013, He JJ et al.¹ demonstrated protein levels of IL-17, IL-17 receptor (IL-17R) as well as downstream factors of the IL-17 pathway (such as nuclear factor-κB activator 1), and pro-inflammatory cytokine activity, were all markedly elevated in focal cortical dysplasia type Ia, IIa, and IIb. Moreover, protein levels of IL-17 and IL-17R positively correlated with the frequency of seizures in these patients. The authors found, by immunostaining, that IL-17 and IL-17R were highly expressed in neuronal microcolumns, dysmorphic neurons, balloon cells, astrocytes, and vascular endothelial cells, while NFkB activator 1 and NFkB-p65 were diffusely expressed in focal cortical dysplasia patients. Thus, the authors concluded that overexpression of the IL-17 system and activation of the IL-17 signal transduction pathway may be involved in the epileptogenicity of cortical lesions in focal cortical dysplasia.

Finally, a group of Finnish investigators demonstrated significant elevation in both CSF and plasma levels of IL-6 in 22 patients within 24 h following tonic-clonic seizures, compared with 18 controls (P < 0.01).²² Moreover, the same research group demonstrated that increased IL-6 levels in plasma were correlated with increased leukocyte counts and C-reactive protein levels after tonic-clonic seizures in 37 patients vs. 40 controls (P < 0.001).²² The group also observed a pro-inflammatory cytokine profile, characterized by elevated IL-6, low levels of IL-1 receptor antagonist (IL-1Ra), and low IL-1Ra:IL-1beta ratio in the plasma of 10 patients with drug-resistant epilepsy vs. controls, with no evidence of increased production from peripheral blood mononuclear cells suggesting the most likely origin of the cytokines to be in the brain.^23,24

Mechanism of molecular inflammation in epilepsy

As discussed above, much of the early evidence supporting a role for inflammation in epilepsy arose from studies on the levels of cytokines such as IL-1beta, its receptor (IL-1R) and the antagonist of its receptor (IL-1Ra). All 3 are upregulated in rodent brain following chemically and electrically induced seizures,²⁵ with IL-1beta expression in glial cells remaining elevated for up 60 d after experimental status epilepticus.²⁶ IL-1beta overexpression has been observed in other epileptic diseases involving hippocampal sclerosis and focal cortical dysplasia. However overexpression is not the only mechanism of neuroinflammation predisposing to epileptic seizures in these patients. In fact, IL-1beta and IL-1Ra can also modulate susceptibility to seizure-inducing stimuli. IL-1beta injected directly in the CNS exacerbates seizures induced by kainic acid and bicuculine²⁷ and lowers the seizure threshold in models of febrile convulsions.^28,29 The pro-convulsive effects of IL-1beta are thought to be linked to a IL-1R1-dependent activation of neuronal sphingomyelinase and Src kinases. These cause the phosphorylation of the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor, stabilization of the receptor at the cell surface, enhanced NMDA-mediated calcium conductance, and an increase in glutamatergic neurotransmission with consequent propensity for excitotoxicity.^30,31 Another hypothesized pathogenic pattern for IL-1beta involves a decrease in glutamate uptake within astrocytes,³² an increased release of glutamate from glial cells, possibly via enhanced secretion of TNF-alfa³³ and the generation of acquired channelopathies.³⁴ Moreover, the involvement of IL-1beta in immune-mediated inflammation in seizures is confirmed by the fact that IL-1Ra has anticonvulsant activity, distinct from the anticonvulsant properties of IL-1beta, following intracerebral expression in transgenic mice that overexpress this protein in astrocytes and thereby have reduced seizure susceptibility.^35,36

Recent research has highlighted alternative mechanisms for the onset of neuroinflammation, involving various Toll Like Receptors (TLRs), that form part of the inflammatory pathways associated with epilepsy.³⁷ TLRs play a key role in pathogen recognition, binding molecules of microbial origin and triggering localized inflammation, leading to an increase in pro-inflammatory cytokines secretion, among with IL-1beta.³⁸ However, TLRs are also activated by various hyper-acetylated molecules released by necrotic cells, immune cells and other cells following immune challenge or biological stress.³⁹ Among these TLR activating proteins, “high mobility box 1 group protein” (HMGB), a chromatin component released by necrotic cells, acts as a “danger signal” and alerts the immune system to damaged or dying cells. Hyperacetylated HMGB regulates the transcription of different pro-inflammatory cytokines such as IL-1beta, binding to TLR2 and TLR4 and also to the receptor for advanced glycation end products (RAGE).^39-41 Therefore, HMGB-1-TLR-RAGE may represent a novel inflammatory axis that increases the secretion of IL-1beta by the traditional immunological pathway following sterile brain injury and without requiring microglial activation.³⁸

Apart from IL-1beta, other pro-inflammatory cytokines have been proposed to contribute to inflammatory events associated with seizures and epileptogenesis, such as TNF-alfa, Transforming Growth Factor beta (TGF-beta), Cyclo-oxygenase 2, as well as blood-brain barrier (BBB) disruption.^42-45 It is pertinent to mention the latest studies on the role of BBB disruption in epileptogenesis, as a major cause of CNS involvement in systemic inflammation is linked to the loss of BBB integrity, affecting leukocyte endothelial permeability⁴⁶ in a phenomenon described as “immunological barrier to electrical storms”⁴⁷. According to this theory mast cells are considered “the immune gate of the brain”⁴⁸, present in a high number in the human BBB as well as in the hypothalamus. When these cells are critically activated by any stress, such as oxidative and/or inflammatory stress, they lead to BBB disruption.⁴⁹ Moreover, it seems that stress hormones, such as corticotropin-releasing factor (CRF) are able to activate mast cells in the BBB,⁵⁰ causing a mast-cell dependent BBB disruption.^49,50 Furthermore, Histamine-1 receptor is also involved in BBB disruption by activation of mast cells.⁵¹

As a consequence of BBB disruption local neural inflammation, mediated by mast cells, can be noticed and this may constitute the initial focus of an epileptogenic area. Moreover, this process has been shown to worsen through activation of Fc-gamma receptors (FcgRI) on neurons that contribute to brain cell death after injection of epileptogenic kainic acid.⁵² Furthermore it has been demonstrated that a type of Fc receptor called Fc-epsilon receptors (FceRI), are typically present on neurons and it seems possible that systemic inflammatory triggers may directly affect neurons through the activation of these specific receptors.^53,54

It is important to note that all the above-described pathogenic mechanisms are not mutually exclusive. In fact HMGB1 enhances the expression of IL-1beta via an effect on TLRs³⁹ and increases the expression of vascular cell adhesion proteins in the cerebrovascular endothelium.⁵⁵ Furthermore IL-1beta promotes the nuclear to cytoplasmic transfer of HMGB1,⁵⁶ while several inflammatory mediators disrupt the BBB barrier perpetuating the immune-mediated pathogenesis⁵⁷ and, on the basis of current evidence, ultimately impact excitatory transmission and excitotoxicity mediated by glutamate.^40,41

Taken together, the described pathogenic mechanisms for epileptogenesis could lead to new therapeutic interventions. Furthermore any therapeutic strategy undertaken to alleviate the unresolved inflammation associated with ongoing seizure activity, needs to consider this interplay between various mechanisms and apparent points of redundancy in the cascade,⁵⁸ aiming to target a common upstream initiator (i.e., IL-1/TLR signaling) rather than more downstream pathways (i.e., BBB disruption, TNF-alfa production).

In 2006, Takemiya T et al.⁵⁹ found that KA microinjection into animal model brain hippocampus induced a delayed overexpression of COX-2 in non-neuronal cells, such as endothelial cells and astrocytes. This increase was associated with a paired increase of PGE2 in the injected side that reflected the pattern of non-neural COX-2 overexpression. Selective COX2- inhibitor NS398 treatment abolished this PGE2 increase, as well as blocking hippocampal neuronal death after KA treatment. Moreover, pre-treatment with the COX-2 inhibitor restored the anticonvulsant activity of phenobarbital in rats that failed to exhibit a relevant response before celecoxib treatment.⁶⁰

It has been suggested that a peripheral inflammatory state can impact a central nervous system inflammatory process.⁴² However in patients affected by drug-resistant epilepsy it seems that pro-inflammatory plasma cytokines are absent and there is no evidence of any increase in peripheral blood mononuclear cells,⁶¹ suggesting that the most likely origin for these cytokines is the brain, where cytokines can exert neuromodulatory functions. In support of this, Yu N demonstrated pro-inflammatory cytokine profile-high IL-6 and low IL-1Ra in the plasma from epileptic patients.⁶² Furthermore Hirvonen J. et al.⁶³ found a marker of inflammation-translocator protein that was increased both in vitro in surgical samples from patients with TLE and in the seizure focus of living TLE patients.

Different pathogenic mechanisms have been described for pro-inflammatory factors predisposing to drug-resistant epilepsies. First, the reduction of astrocytic glutamate reuptake via the inhibition of astrocytic glutamate synthetase and causing increase of the extracellular glutamate concentration. This induces glutamate release⁶⁴ that is mediated via the TNF-alpha-induced-production of PGE2 in astrocytes, upon the TNF-alpha release from activated microglia, and mediates astrocyte Ca2-dependent glutamate release.⁶⁵ Second, the rapid alteration of neurotransmitter functions by modulation of their receptor assembly and phosphorylation at neuronal membranes.⁶⁶ It has been demonstrated that the activation of IL-1R/TLR signaling mediates rapid post-translational changes in NMDA-gated inward Ca-dependent channels in pyramidal neurons.⁶⁷

It is important to note that inflammatory mediators are also responsible for promoting angiogenesis and increased vascular permeability. Therefore, their overexpression in perivascular astrocytes and endothelial cells after epileptogenic challenges may affect BBB properties, promoting excitability in surrounding neurons.⁶⁸ They are also involved in different cascades mediating cell death and neurogenesis, as well as synaptic reorganization (i.e., via NF-kB activation of chemokines, adhesion molecules, growth factors, and free radicals), that seem to be increased during epileptogenic processes in several animal models and humans, including in post-traumatic epilepsy.^69,70

The involvement of pro-inflammatory cytokines in epileptogenesis is also confirmed by the evidence that pharmacological targeting of these pro-inflammatory pathways, using selective receptor antagonists, or the use of transgenic mice with perturbed cell signaling, demonstrates the activation of IL-1R and TLR4 by endogenous IL-1beta and HMGB1, in the precipitation and recurrence of experimentally induced seizures in rodents.^40,41

All this evidence highlights how inflammation may be a new target for pharmacological interventions in drug-resistant epilepsies, by interfering with the inflammatory process predisposing to epileptogenesis and recurrent seizures.

Immunotherapeutic strategy in epilepsy—A focus on inflammation

The evidence that inflammatory mediators significantly contribute to the onset and recurrence of seizures in experimental seizure models, as well as the presence of inflammatory molecules in human epileptogenic tissue, highlights the possibility of targeting specific inflammation-related pathways to control seizures that are otherwise resistant to the available anticonvulsant drugs.⁷¹ Although the potential effect of immunotherapeutic strategies in drug-resistant seizures has been extensively discussed, evidence on the efficacy of this kind of therapy is limited. However, recent research efforts have been directed toward its potential therapeutic benefits in neurological diseases. Thus, anti-inflammatory agents have been considered as potential candidates in the ongoing search for novel anti-epileptic drugs.

Historically, corticosteroids were first used in certain childhood epilepsy syndromes. Among them, adrenocorticotropic hormone (ACTH) has often been employed as a viable anti-epileptic treatment option. Improvement was also reported in some severe seizure cases secondary to CNS viral infections with IVIG treatment,⁷² as well as other autoimmune diseases with neurological involvement such as Thrombotic thrombocytopenic purpura (TTP). In the latter a study of metallo-protease ADAMST 13 showed a low value (<10%) with positive anti-ADAMTS 13 IgG and inhibitor, strengthening the hypothesis of an autoimmune process.⁷³ In addition, Corticosteroids have been widely used in infantile spasms and West Syndrome, and there is still a debate on their efficacy when compared with the historical used Vigabatrin therapy⁷⁴

On the basis of the large involvement of IL-1beta in immune-mediated epileptogenesis, the compounds showing greatest promise belong to the group of inhibitors known as interleukin converting enzyme (ICE)/caspase-1, the proteases that catalyzes the conversion of the inactive precursor pro-IL-1beta to active IL-1beta.⁷⁵ This kind of inhibitor acts to reduce the release of IL-1beta in organotypic hippocampal slices following exposure to pro-inflammatory stimuli,⁷⁶ decreasing acute seizure activity following intra-hippocampal kainate in rats,⁷⁶ and restricts the generalization of seizures in a rapid kindling model.⁷⁷ All these effects are closely linked to a decrease in the production of IL-1beta in hippocampal astrocytes that acts as the main pro-inflammatory agent in epileptogenesis. These effects are absent in IL-1beta gene knockout mice, that consequently show an inherent resistance to experimentally-induced seizures.⁷⁶

In mouse models, systemic administration of VX-756, a prototypic ICE/caspase-1 inhibitor, increased the time to seizure onset and decreased cumulative duration of electrographic seizures induced by acute intra-hippocampal kainate.^40,41 Furthermore use of VX-765 in the chronic model decreased the time of spontaneous epileptic activity by up to 75% with a concomitant reduction of IL-1beta in hyppocampal astrocytes and microglia.^40,41 Therefore, laboratory efficacy has been demonstrated for VX-765, proposing this class of compounds for further evaluation as putative anti-epileptic drugs. Moreover VX-765 was originally developed for the treatment of inflammatory and autoimmune conditions,⁷⁸ with good oral bioavailability, whose active metabolite is able to cross the BBB following systemic administration. Recently, a phase IIa trial in drug-resistant partial epilepsy has been undertaken,⁷⁹ with preliminary unpublished results suggesting goof tolerance and safety when administered over a 6-wk-period of time.

Therefore, drugs blocking the IL-1beta pro-inflammatory actions have entered clinical trials as potential therapeutics for autoimmune and inflammatory pathologies, and may have therapeutic potential for epilepsies associated with pro-inflammatory processes in the brain.^80,81

Recently other classes of drugs, such as TLR antagonists have been used as anticonvulsant drugs, including Resveratrol, a TLR3 antagonist. This has shown to reduce the frequency of video-monitored spontaneous seizures in rats after daily administration from day 1 to day 10 after KA-induced status epilepticus (SE).⁸² This effect was associated with a reduction of neuronal cell loss, and inhibition of mossy fiber sprouting. Jiang et al.⁸³ also found that pharmacological inhibition of PGE2 receptor subtype EP2 is neuroprotective in a pilocarpine model of SE.

Further strategies against convulsive inflammation

Antibody antagonists

Several studies have demonstrated the involvement of serum auto-antibodies in epileptogenesis.⁸⁴ This autoimmune mechanism could potentially be targeted by monoclonal antibodies such as efalizumab and natalizumab, commonly used for inflammatory disorders such as psoriasis, multiple sclerosis and Crohn's disease.⁸⁵ At least 2 such antagonists are in clinic trials at the time of writing. One is bimosiamose (TBC1269), a pan-selectin antagonist and another is YSPSL, a fusion protein of PSGL-1 and human IgG1 acting as a SELP antagonist. YSPLS is being evaluated in preclinical epilepsy models in collaboration with Constantin and colleagues.⁸⁶

Immunosuppressants

In epileptogenesis, cyclosporine A, FK-506 (also known as Tacrolimus), and rapamycin have been used.⁸⁷ Among their various mechanisms of action, one of the best characterized is the inhibition of T-lymphocyte activation. It has been shown that daily systemic injection of cyclosporine A or FK-506 during electrical amygdala kindling prevented the acquisition of stage 5 seizures in rats.⁸⁸ However, after drug withdrawal, stimulated animals showed stage 5 seizures, indicating that the treatments failed to inhibit long-term epileptogenesis while providing limited anticonvulsant effects.⁸⁹ Opposite effects were reported by Suzuki et al. (2001),⁹⁰ who showed an acceleration of pentylenetetrazole kindling in rats treated with FK-506. These data indicate the conflicting efficacies of immunosuppressant therapy, which is still a topic of debate requiring further investigation.

Anti-inflammatory treatments

Studies have shown that adult mice exposed to traumatic brain injury (TBI) showed a reduced threshold to electroconvulsive shock-induced seizures, assessing a putative link between injury-induced inflammation, microglia activation, and seizure threshold.⁹¹ The important finding was that this effect was reversed using Minozac, an inhibitor of microglia activation and the concomitant production of pro-inflammatory cytokines. Moreover this treatment also prevented the ensuing cognitive dysfunction seen in mice exposed to TBI and affected by seizures. Minozac anticonvulsant effects were also demonstrated in RN15-treated rats affected by status epilepticus, whose seizures reversed after the administration of this drug, with a consequent decreased susceptibility to kainic acid-induced seizures. Furthermore it has been shown that this drug decreases microglia activation and pro-inflammatory cytokines in the hippocampus.⁹²

Future perspectives

Immunity and inflammation are an integral part of epileptogenesis and their central role in the pathogenesis of epilepsy has raised the prospect of new therapeutic approaches to counteract epilepsy. However the relationship between the immune system and the drug-resistant epileptic brain is still rudimentary and not sufficient to guide therapeutic interventions that in some cases have failed.

Modulation of adaptive immunity may afford the opportunity to treat drug-resistant epilepsies, even if this field is still poorly understood and needs further discovery of novel inflammatory molecules and pathways in multiple epileptic models. Moreover further studies are necessary to develop new strategies to target inflammatory factors in order to inhibit seizures or prevent epileptogenesis particularly in the clinical setting. In addition, it is also speculative as to whether modulation of the innate immunity may prevent the development of seizures. Further strategies may therefore redirect us toward understanding the role of anti-inflammatory T cells, such as Treg cells, rather than T cells with a pro-inflammatory activity. In regards, a recent paper of Li C et al. showed the presence of lower percentages of peripheral blood CD4+ CD25+ Foxp3+ Tregs and CD4+ T cells and the ratio of CD4+ T cells to CD8+ T cells in 41 epileptic children with respect to 38 healthy controls (P < 0.05). In contrast, the percentages of CD8+ T cells, NK cells, and B cells in lymphocytes in epileptic children were significantly higher than those in healthy children (P < 0.05).⁹³ This finding may represent a starting point to open new therapeutic topics on immunomodulation since early stages of life, improving innate immunity toward an efficient increase of CD4+ CD25+ Foxp3+ Treg cells with an anti-inflammatory effect in perypheral blood as therapeutic strategy for immuno-mediated epilepsies.⁹⁴

Targeting inflammation to treat epileptic seizures rather than targeting neural function has the advantage potentially less side effects than traditional anticonvulsant therapies, and further this allows action on a pathogenic cause of epilepsy rather than modifying the disease. Another advantage would be the potential prophylactic aspect, which could help prevent the development of seizures in patients at risk of epilepsy, including victims of traumatic brain injury, stroke, and cerebral infection.

Taken together the presented evidence suggests that future therapeutic anti-epileptic interventions should focus on targeting the inflammatory factors predisposing to epilepsy, investigating further anti-inflammatory agents used for the treatment of drug-resistant epilepsies.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

10.4161/hv.28400