INTRODUCTION
Epilepsy is among the most prevalent disorders of the central nervous system (CNS), affecting approximately 1% of individuals across all age groups. It is characterized by spontaneous recurrent seizures, frequently accompanied by neuropsychiatric and cognitive comorbidities. Notably, at least 30% of epilepsy patients exhibit resistance to current anti-seizure medications (ASMs)[1]. It is now well established that inflammation plays an integral and critical role in epileptogenesis and its associated neuropsychiatric comorbidities. Recent years have witnessed a paradigm shift in understanding the role of immuno-modulatory and neuro-inflammatory activity in the epileptogenesis and progression of epilepsy, underscoring their pivotal influence on the chronicity and severity of the disease. Interleukin (IL)-6 is widely regarded as a crucial cytokine within the IL family and has been extensively studied in inflammation-related diseases. Nevertheless, its function in epilepsy and related disorders remains inadequately understood. Elevated levels of IL-6 are positively correlated with both the frequency and severity of seizures, suggesting its potential role as a biomarker for disease activity[2]. Additionally, IL-6 has been associated with the development of psychiatric and neurological comorbidities, including depression, anxiety, and cognitive impairment in individuals with epilepsy, indicating a broader impact on neurological function[3]. This dual role of IL-6 in exacerbating epileptic episodes while simultaneously affecting emotional and cognitive processes underscores the necessity for a thorough understanding of its underlying mechanisms.
A Mendelian randomization study employing a cis-IL-6R instrument, conducted by Yu et al[4] and recently published, has provided preliminary evidence indicating that inhibition of the IL-6 receptor pathway may be associated with a decreased risk of epilepsy and related neuropsychiatric conditions. The objective of this editorial is to synthesize the current knowledge regarding the complex role of IL-6 in epilepsy and its neuropsychiatric comorbidities. By critically analyzing the empirical evidence and theoretical frameworks, we seek to elucidate the mechanisms through which IL-6 influences epileptogenesis and neuropsychiatric outcomes.
IL-6 IN EPILEPSY AND ITS NEUROPSYCHIATRIC COMORBIDITIES
The role of IL-6 in epilepsy and related disorders
Numerous studies have demonstrated that IL-6 may exhibit both pro-inflammatory and anti-inflammatory properties through distinct signal transduction pathways mediated by various receptors[5]. In certain CNS disorders, the immunostimulation of astrocytes and microglia can lead to elevated expression of IL-6[6]. The expression of IL-6 is also modulated by other cytokines, including IL-1β, IL-17 and tumor necrosis factor-alpha (TNF-α). An increased level of IL-6 is reported to inhibit long-term potentiation and neurogenesis in the hippocampus, facilitating epileptogenesis. Clinical research has indicated increased serum levels of IL-6 in specific types of epilepsy, suggesting the presence of chronic systemic inflammation in these patients[7].
Autoimmune epilepsy, particularly antibody-mediated epilepsy, is characterized by a well-established mechanism involving IL-6. IL-6 signaling may represent a promising anti-inflammatory therapeutic target for the treatment of autoimmune epilepsy induced by glutamic acid decarboxylase (GAD) antibodies[8] and contactin-associated protein-like 2 (Caspr2) antibodies[9]. GAD is an enzyme responsible for the synthesis of γ-aminobutyric acid (GABA), while Caspr2 antibodies can impair the function of voltage-gated potassium Kv1 channels. Autoimmunity against GAD and Caspr2 disrupts the balance between excitation and inhibition within neural circuits, contributing to the pathophysiology of autoimmune epilepsy.
In the context of neuropsychological patterns, autoimmune epilepsies, particularly those associated with Caspr2 and GABA receptor antibodies, frequently exhibit distinct cognitive and behavioral impairments. This observation implies that IL-6 and other cytokines may play a role in these neuropsychiatric manifestations. However, further research is required to establish consistent correlations and delineate specific profiles.
New-onset refractory status epilepticus (NORSE) is a severe and rare neurological condition characterized by continuous or highly frequent seizures that are unresponsive to standard ASMs. The etiology of NORSE is often idiopathic, although it may be associated with elevated levels of pro-inflammatory molecules in the brain, potentially triggered by a systemic infection. A clinical study conducted by Wang et al[10] investigated patients with NORSE attributed to anti-NMDAR encephalitis and cryptogenic NORSE. The study found that cerebrospinal fluid (CSF) IL-6 levels correlated with an elevated proteomic score, which has been proposed as a promising biomarker for assessing the severity of NORSE.
Several studies have confirmed that the elevated expression of IL-6 is particularly notable in febrile seizures. Liang et al's research[11], utilizing hyperthermia-induced zebrafish models exhibiting the febrile seizure phenotype, demonstrated that neuroinflammation is induced during febrile seizures. This study suggests that the increased expression of IL-6 may play a role in epileptogenesis, indicating that both IL-6 and IL-1β could serve as potential therapeutic targets for fever-associated epilepsy[11]. However, a case study reported that tocilizumab, an IL-6 receptor antagonist, may be more effective than anakinra, an IL-1β receptor antagonist, for the treatment of refractory febrile infection-related epilepsy syndrome (FIRES)[12]. Consequently, tocilizumab may be considered for patients with FIRES and elevated IL-6 levels[13]. However, a cross-sectional study indicated that, in contrast to FIRES, chronic epilepsy and afebrile status epilepticus generally did not exhibit significant elevation of CSF cytokines/chemokines, including IL-6, despite frequent daily seizures[14]. This finding suggests that there may be differential regulation of IL-6 in different epileptic seizure states, such as acute seizures, FIRES, afebrile status epilepticus, and chronic epilepsy. Elevated levels of IL-6 have been reported to inhibit long-term potentiation and neurogenesis in the hippocampus, thereby facilitating epileptogenesis. Nevertheless, a prospective study involving 364 patients with epilepsy and 91 healthy controls found that plasma levels of IL-6 were lower in patients compared to controls[15]. Overall, these studies underscore the critical role IL-6 homeostasis plays in epilepsy, suggesting that both IL-6 deficiency and excess may exacerbate the disease.
IL-6 receptor blockade in the treatment of epilepsy
Considering the involvement of neuroinflammation and oxidative stress in specific forms of status epilepticus and epilepsy, numerous anti-inflammatory and antioxidant compounds are currently undergoing preclinical or early clinical development[16]. Notably, IL-6 receptor blockade via tocilizumab has exhibited anti-absence seizure and anti-epileptogenic properties in the WAG/Rij rat model of absence epilepsy[17]. Furthermore, as previously discussed, clinical case reports indicate that the IL-6 antagonist tocilizumab can effectively treat and significantly mitigate refractory status epilepticus associated with FIRES, characterized by elevated IL-6 levels[13]. Yu et al[4] conducted a Mendelian randomization study that shed light on the potential benefits of IL-6R blockade in mitigating epilepsy risk. Their findings suggested that genetic simulation targeting IL-6R inhibition led to a notable decrease in the overall risk of developing epilepsy, albeit with varying efficacy across different epilepsy subtypes. This highlights the complexity of IL-6's involvement in epileptogenesis and underscores the necessity for tailored therapeutic approaches.
Furthermore, IL-6 antagonists have demonstrated disease-modifying effects in patients with epilepsy[18]. A phase 3 clinical trial is currently recruiting subjects to investigate the potential efficacy of tocilizumab in refractory status epilepticus (NCT05346666). Tocilizumab represents the first IL-6-targeting drug to enter clinical trials for anti-epileptic purposes, suggesting significant potential for IL-6 as a therapeutic target in the clinical management of epilepsy.
Nevertheless, the clinical application of IL-6 receptor blockers in epilepsy presents several challenges. Firstly, the optimal timing and duration of treatment require elucidation. Secondly, the identification of patient subgroups most likely to benefit from this therapy remains elusive. Thirdly, the long-term safety profile of IL-6R antagonists necessitates comprehensive investigation, given the potential risks associated with chronic immunosuppression.
The role of IL-6 in depression
Clinical depression and somatic symptom disorders frequently arise in response to physiological stressors and exhibit a high degree of interconnection.
The behavior associated with somatic symptom disorders has been demonstrated to be mediated by pro-inflammatory cytokines, including IL-1, IL-6, and TNF-α[19]. Among these cytokines, both preclinical and clinical studies indicate that IL-6 plays a pivotal role in the pathogenesis of depression[20]. Preclinical research has provided evidence that sustained elevations of IL-6 in the brain contribute to depressive and anxiety-like behaviors in animal models[21,22]. This elevation is not merely coincidental but rather reflects a fundamental mechanism linking inflammation and depression. IL-6 activates the hypothalamic-pituitary-adrenal axis, leading to increased cortisol production, which has been implicated in the development of depressive symptoms[23]. Additionally, a meta-analysis of cytokines in major depression, encompassing 136 studies, revealed that 24 of these studies reported elevated IL-6 levels in individuals with depression compared to non-depressed controls[24].
The role of IL-6 in neuropsychiatric comorbidities of epilepsy
Depression, a complicated disorder with a variety of etiologies, has been linked to an elevated risk of developing epilepsy. Conversely, epilepsy characterized by seizure foci in the temporal lobe may present a heightened risk of subsequent depression, particularly when seizures remain focal and do not generalize[25]. Inflammatory mediators and cytokines are believed to play a pivotal role in the interplay between seizures and neuropsychiatric comorbidities in individuals with epilepsy[26]. For instance, IL-6 has been associated with an increased prevalence of attention deficit hyperactivity disorder in pediatric epilepsy patients[27]. Furthermore, IL-6 influences neurotransmitter systems, particularly serotonin, dopamine, and norepinephrine, which are crucial for mood regulation. Chronic exposure to elevated IL-6 levels in epilepsy patients can induce structural changes in the brain, including hippocampal atrophy and reduced neurogenesis, further exacerbating the interplay between IL-6, epilepsy, and depression.
In a pentylenetetrazole-induced seizure model, the administration of serotonin and treatment with fluoxetine were observed to ameliorate seizures and reduce levels of IL-1β and IL-6 in both circulating and CNS tissues in rats[28]. Neuroinflammatory mechanisms have been identified in studies of coexisting chronic epilepsy and depression, suggesting that IL-6 and other pleiotropic cytokines may represent a causal link between these disorders[17]. This could potentially explain the high degree of comorbidity between epilepsy and neuropsychiatric disorders[29].
Moreover, research indicates that stress-induced elevation of IL-6 may be a critical factor in the etiology of a wide range of hyperexcitable CNS conditions, such as epilepsy, schizophrenia, anxiety, and autism spectrum disorders[30]. A Mendelian randomization study incorporating gene expression correlation and connectivity analyses identified an association between IL-6 and alterations in brain structure. The most pronounced associations were observed in the middle temporal gyrus, where several genes exhibit differential overexpression relative to the entire brain. These genes constitute a highly interconnected protein-protein interaction network with IL-6 and functionally contribute to diseases and phenotypes related to schizophrenia, autism spectrum disorder, and epilepsy[31]. Accordingly, a study examining interictal levels of 25 cytokines and immunoproteins in the serum of patients with temporal lobe epilepsy (TLE), frontal lobe epilepsy (FLE), and psychogenic non-epileptic seizures revealed that IL-6 levels were significantly elevated in TLE and FLE patients compared to those with psychogenic non-epileptic seizures[32]. Notably, IL-6 levels transiently increased further within hours postictally in TLE patients, but not in FLE patients. Additionally, higher serum concentrations of IL-6 were more frequently observed in patients with epileptogenic TLE[33]. Patients with TLE exhibit an increased susceptibility to cognitive impairment and neuropsychiatric complications. This observation suggests that IL-6 may play a contributory role in the pathophysiological mechanisms underlying the development of neuropsychological comorbidities in individuals with TLE.
The relationship between IL-6 and electroencephalograms
Previous research has demonstrated that elevated IL-6 levels frequently correlate with increased seizure frequency and severity, as observed on electroencephalograms (EEG), potentially indicating inflammatory processes that contribute to epileptogenesis[34]. Furthermore, there is evidence suggesting that elevated IL-6 levels in febrile seizures are associated with the progression to epilepsy and are linked to increased background slow rhythms and epileptiform discharges on EEG[35].
The effect of antiseizure medications on IL-6
In relation to ASMs and their impact on IL-6, it is known that certain ASMs can influence cytokine levels, although the effects are medication-specific. Emerging evidence indicates that some ASMs can affect not only seizure activity but also neuropsychiatric conditions and cognitive function, which are frequently compromised in individuals with epilepsy. Nevertheless, certain ASMs (i.e. valproic acid) may inadvertently elevate IL-6 levels due to their neurotoxic properties, potentially aggravating cognitive and behavioral disturbances[36]. Consequently, the relationship between IL-6 modulation and epilepsy management merits further exploration. Given that inflammation significantly contributes to the pathogenesis of neuropsychiatric comorbidities in epilepsy, ASMs that influence inflammatory pathways may also exert consequential effects.
CONCLUSION
The identification of IL-6 as a critical factor in the pathophysiology of epilepsy and its associated neuropsychiatric comorbidities has catalyzed new therapeutic investigations. Advancing research is expected to elucidate the mechanisms by which IL-6 contributes to epileptogenesis and neuropsychiatric manifestations, thereby facilitating the development of more efficacious and individualized treatment modalities. The continued investigation into IL-6 receptor antagonism holds promise for a future in which epilepsy and its comorbid conditions are managed more holistically, ultimately improving patient outcomes and quality of life.
Understanding the precise mechanisms by which IL-6 influences the development and progression of neuropsychiatric comorbidities in epilepsy is essential for the advancement of targeted therapeutic interventions. The complex interplay between IL-6, inflammation, and neuropsychiatric outcomes necessitates a multidisciplinary approach, incorporating perspectives from neurology, psychiatry and immunology. By examining IL-6 within both autoimmune and general epilepsy contexts, the editorial suggests a direction for tailoring therapy based on the immunologic characteristics of patients, possibly bridging the gap between epilepsy management and immunological insights. This integrative approach may influence future research and clinical practices around neuropsychiatric and epileptic disorders. As ongoing research continues to elucidate the multifaceted role of IL-6 in neuropsychiatric disorders, the development of personalized treatment strategies that address both epilepsy and its comorbid conditions holds significant promise for enhancing the quality of life for affected individuals.
Future research should prioritize the refinement of IL-6 inhibitor utilization in clinical settings, taking into account patient-specific inflammation profiles and comorbid conditions. Additionally, identifying patient subgroups that would derive the greatest benefit from IL-6-targeted therapies is crucial for optimizing treatment outcomes. The potential of IL-6 as a biomarker for disease activity and prognosis in epilepsy and its associated comorbidities also merits further investigation. Further studies will be of great importance in elucidating the mechanisms by which IL-6 modulates seizure activity and its association with cognitive and behavioral comorbidities. By elucidating the multifaceted role of IL-6 in the neuropsychiatric comorbidities associated with epilepsy, we advance towards the objective of personalized medicine. This approach aims to tailor treatments to epilepsy patients based on their unique disease profiles and comorbid conditions.
