In a recent study, we analyzed interictal quantitative levels of IFN-γ in the different clinical settings of childhood epilepsies.   No significant differences were found among the groups. However, the results indicate a considerable heterogeneity in IFN-γ levels among different types of epilepsy. These findings could highlight the potential involvement of IFN-γ in the epileptogenesis and clinical characteristics of different clinical settings of epilepsy.

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The dual nature of IFN- reveals its complex role in modulating seizure susceptibility and emphasizes its therapeutic potential. IFN-γ is typically considered a pro-inflammatory cytokine primarily associated with immune responses and neuroinflammation. In the developing brain, neuroinflammation can persist even after the initial trigger has resolved and can contribute to the development and progression of epilepsy. (15)

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IFN-γ promotes neuroinflammation by activating microglia and astrocytes, producing additional pro-inflammatory cytokines and chemokines. (16) However, recent studies have revealed that IFN-γ possesses multifaceted properties, including potential neuroprotective and anticonvulsant effects.

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IFN-γ has been shown to promote the clearance of cellular debris and apoptotic cells, which may limit neuronal damage following seizures. (17) Furthermore, IFN-γ has been implicated in regulating blood-brain barrier integrity, which could have implications for entering inflammatory cells and molecules into the brain. (18)

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IFN-γ is typically pro-inflammatory and can exert anti-inflammatory effects in specific contexts. Several studies have reported alterations in IFN-γ levels in animal models and patients with epilepsy. Studies using animal models have shown increased IFN-γ expression in the brain following seizures, suggesting its association with epileptogenesis. (19) Furthermore, experimental manipulations that attenuate IFN-γ signaling pathways have reduced seizure frequency and severity, indicating a potential proconvulsant role for IFN-γ. (20)

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In human studies, alterations in IFN-γ levels have been observed in different epilepsies. Some studies have reported elevated levels of IFN-γ in the serum or cerebrospinal fluid of patients with epilepsy compared to healthy controls. (21) These findings suggest that increased IFN-γ production may contribute to the inflammatory response in epilepsy. Moreover, higher IFN-γ levels have been associated with increased seizure frequency and disease severity in specific epilepsy subtypes, (22) indicating a potential correlation between IFN-γ dysregulation and disease progression.

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The exact mechanisms through which IFN-γ exerts its effects in epilepsies are not fully understood. However, several hypotheses have been proposed. One possibility is that IFN-γ promotes neuroinflammation by activating microglia and astrocytes, producing additional pro-inflammatory cytokines and chemokines. This cascade of inflammatory events may contribute to the maintenance and propagation of seizures. (22) Additionally, IFN-γ has been shown to modulate the excitability of neurons by altering ion channel expression and synaptic plasticity, potentially enhancing seizure susceptibility. IFN-γ can modulate immune responses by promoting the production of anti-inflammatory cytokines, such as interleukin-10 (IL-10), which may dampen neuroinflammatory processes associated with seizures. IFN-γ may indirectly contribute to seizure resistance by mitigating the pro-convulsive effects of neuroinflammation. (10)

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IFN-γ has been shown to influence neuronal excitability, potentially affecting seizure susceptibility directly. Studies suggest that IFN-γ can modulate the expression and function of ion channels and neurotransmitter receptors, including GABA receptors. (23) GABA is the primary inhibitory neurotransmitter in the brain, and enhancing its inhibitory effects can reduce seizure activity. IFN-γ may promote inhibitory neurotransmission and neuroprotective properties in various neurological conditions. It can promote neuronal survival, enhance synaptic plasticity, and exert antioxidant effects. These neuroprotective mechanisms may help maintain the integrity of neuronal networks and prevent excessive excitability. Thus, low IFN-γ levels could contribute to seizure resistance. (24)

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The potential role of IFN-γ in promoting seizure resistance opens up new avenues for therapeutic interventions. (25) Harnessing the protective effects of IFN-γ or developing strategies to enhance its activity could represent novel therapeutic approaches for epilepsy. Modulating IFN-γ levels or its downstream signaling pathways may offer neuroprotective benefits and reduce seizure frequency and severity. Targeting neuroinflammation and immune pathways has emerged as a potential approach for managing drug-resistant epilepsy in preclinical and clinical studies as adjunctive treatments to improve seizure control and overcome drug resistance. (26)

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Despite the growing evidence implicating IFN-γ in epilepsies, several questions and challenges remain. The precise cellular sources of IFN-γ and the specific signaling pathways involved in its actions within the epileptic brain require further investigation. Moreover, the factors contributing to the dysregulation of IFN-γ in epilepsy, such as genetic predisposition or environmental triggers, need to be elucidated. While the precise role of IFN-γ in childhood epilepsy still warrants exploration, further research is needed to explore the current understanding of the relationship between IFN-γ and childhood epilepsy. The findings from this study may contribute to a better understanding of the role of cytokines in the pathogenesis of epilepsy. They could potentially support the development of novel therapeutic approaches targeting cytokine dysregulation in epilepsy.

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Several limitations were acknowledged in this study. Firstly, the sample size was relatively small, which may limit the generalizability of the findings. Additionally, the study design was cross-sectional, restricting the ability to establish a causal relationship between cytokines and epilepsy. Further longitudinal studies with larger sample sizes are needed to confirm and expand upon these findings.