Excessively high or synchronized neuronal activity in the brain is the underlying cause of epilepsy, a condition of the central nervous system. Epilepsy is caused mostly by an imbalance in the activity of inhibitory and excitatory neural networks. Recurrent or prolonged seizures lead to neuronal death, which in turn promotes epileptogenesis and epileptic seizures. Ferrous ion-mediated cell death is known as ferroptosis, which is due to the accumulation of lipid peroxidation products resulting from compromise of the glutathione (GSH)-dependent antioxidant system. The pathophysiology of epilepsy has been linked to anomalies in the glutathione peroxidase 4 (GPX4)/GSH redox pathway, lipid peroxidation, and iron metabolism. Studies have shown that inhibiting ferroptosis may alleviate cognitive impairment and decrease seizures, indicating that it is neuroprotective. With the hope of aiding the development of more novel approaches for the management of epilepsy, this research aimed to examine the role of ferroptosis in this disease.

A central role for neuroinflammation in epileptogenesis has recently been suggested by several investigations. This systematic review explores the role of inflammatory mediators in epileptogenesis, its association with seizure severity, and its correlation with drug-resistant epilepsy (DRE). The study analysed articles published in JCR journals from 2019 to 2024. The search strategy comprised the MESH, free terms of \"Neuroinflammation\", and selective searches for the following single biomarkers that had previously been selected from the relevant literature: \"High mobility group box 1/HMGB1\", \"Toll-Like-Receptor 4/TLR-4\", \"Interleukin-1/IL-1\", \"Interleukin-6/IL-6\", \"Transforming growth factor beta/TGF-β\", and \"Tumour necrosis factor-alpha/TNF-α\". These queries were all combined with the MESH terms \"Epileptogenesis\" and \"Epilepsy\". We found 243 articles related to epileptogenesis and neuroinflammation, with 356 articles from selective searches by biomarker type. After eliminating duplicates, 324 articles were evaluated, with 272 excluded and 55 evaluated by the authors. A total of 21 articles were included in the qualitative evaluation, including 18 case-control studies, 2 case series, and 1 prospective study. As conclusion, this systematic review provides acceptable support for five biomarkers, including TNF-α and some of its soluble receptors (sTNFr2), HMGB1, TLR-4, CCL2 and IL-33. Certain receptors, cytokines, and chemokines are examples of neuroinflammation-related biomarkers that may be crucial for the early diagnosis of refractory epilepsy or may be connected to the control of epileptic seizures. Their value will be better defined by future studies.

An epilepsy diagnosis reduces a patient\'s quality of life tremendously, and it is a fate shared by over 50 million people worldwide. Temporal lobe epilepsy (TLE) is largely considered a nongenetic or acquired form of epilepsy that develops in consequence of neuronal trauma by injury, malformations, inflammation, or a prolonged (febrile) seizure. Although extensive research has been conducted to understand the process of epileptogenesis, a therapeutic approach to stop its manifestation or to reliably cure the disease has yet to be developed. In this review, we briefly summarize the current literature predominately based on data from excitotoxic rodent models on the cellular events proposed to drive epileptogenesis and thoroughly discuss the major molecular pathways involved, with a focus on neurogenesis-related processes and transcription factors. Furthermore, recent investigations emphasized the role of the genetic background for the acquisition of epilepsy, including variants of neurodevelopmental genes. Mutations in associated transcription factors may have the potential to innately increase the vulnerability of the hippocampus to develop epilepsy following an injury-an emerging perspective on the epileptogenic process in acquired forms of epilepsy.

The aim of the present study was to review the current knowledge on the neuropathological spectrum of late onset epilepsies. Several terms including \'neuropathology*\' AND \'late onset epilepsy\' (LOE) combined with distinct neuropathological diagnostic terms were used to search PubMed until November 15, 2023. We report on the relevance of definitional aspects of LOE with implications for the diagnostic spectrum of epilepsies. The neuropathological spectrum in patients with LOE is described and includes vascular lesions, low-grade neuroepithelial neoplasms and focal cortical dysplasias (FCD). Among the latter, the frequency of the FCD subtypes appears to differ between LOE patients and those with seizure onset at a younger age. Neurodegenerative neuropathological changes in the seizure foci of LOE patients require careful interdisciplinary interpretation with respect to the differential diagnosis of primary neurodegenerative changes or epilepsy-related changes. Innate and adaptive neuroinflammation represents an important cause of LOE with intriguing therapeutic options.

Epilepsy is one of the most prevalent and serious brain disorders and affects over 70 million people globally. Antiseizure medications (ASMs) relieve symptoms and prevent the occurrence of future seizures in epileptic patients but have a limited effect on epileptogenesis. Addressing the multifaceted nature of epileptogenesis and its association with the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated neuroinflammation requires a comprehensive understanding of the underlying mechanisms of these medications for the development of targeted therapeutic strategies beyond conventional antiseizure treatments. Several types of NLRP3 inhibitors have been developed and their effect has been validated both in in vitro and in vivo models of epileptogenesis. In this review, we discuss the advances in understanding the regulatory mechanisms of NLRP3 activation as well as progress made, and challenges faced in the development of NLRP3 inhibitors for the treatment of epilepsy.

Phagocytes maintain homeostasis in a healthy brain. Upon injury, they are essential for repairing damaged tissue, recruiting other immune cells, and releasing cytokines as the first line of defense. However, there seems to be a delicate balance between the beneficial and detrimental effects of their activation in a seizing brain. Blocking the infiltration of peripheral phagocytes (macrophages) or their depletion can partially alleviate epileptic seizures and prevent the death of neurons in experimental models of epilepsy. However, the depletion of resident phagocytes in the brain (microglia) can aggravate disease outcomes. This review describes the role of resident microglia and peripheral infiltrating monocytes in animal models of acutely triggered seizures and epilepsy. Understanding the roles of phagocytes in ictogenesis and the time course of their activation and involvement in epileptogenesis and disease progression can offer us new biomarkers to identify patients at risk of developing epilepsy after a brain insult, as well as provide novel therapeutic targets for treating epilepsy.

Traumatic brain injury (TBI) is often followed by post-traumatic epilepsy (PTE), a condition often difficult to treat and leading to a substantial decline in quality of life as well as increased long-term mortality. The latent period between TBI and the emergence of spontaneous recurrent seizures provides an opportunity for pharmacological intervention to prevent epileptogenesis. Biomarkers capable of predicting PTE development are urgently needed to facilitate clinical trials of putative anti-epileptogenic drugs. EEG is a widely available and flexible diagnostic modality that plays a fundamental role in epileptology. We systematically review the advances in the field of the discovery of EEG biomarkers for the prediction of PTE in humans. Despite recent progress, the field faces several challenges including short observation periods, a focus on early post-injury monitoring, difficulties in translating findings from animal models to scalp EEG, and emerging evidence indicating the importance of assessing altered background scalp EEG activity alongside epileptiform activity using quantitative EEG methods while also considering sleep abnormalities in future studies.

BACKGROUND: Seizures are a common complication of subarachnoid hemorrhage (SAH) in both acute and late stages: 10-20 % acute symptomatic seizures, 12-25 % epilepsy rate at five years. Our aim was to identify early electroencephalogram (EEG) and computed tomography (CT) findings that could predict long-term epilepsy after SAH.
METHODS: This is a multicenter, retrospective, longitudinal study of adult patients with aneurysmal SAH admitted to two tertiary care hospitals between January 2011 to December 2022. Routine 30-minute EEG recording was performed in all subjects during admission period. Exclusion criteria were the presence of prior structural brain lesions and/or known epilepsy. We documented the presence of SAH-related cortical involvement in brain CT and focal electrographic abnormalities (epileptiform and non-epileptiform). Post-SAH epilepsy was defined as the occurrence of remote unprovoked seizures ≥ 7 days from the bleeding.
RESULTS: We included 278 patients with a median follow-up of 2.4 years. The mean age was 57 (+/-12) years, 188 (68 %) were female and 49 (17.6 %) developed epilepsy with a median latency of 174 days (IQR 49-479). Cortical brain lesions were present in 189 (68 %) and focal EEG abnormalities were detected in 158 patients (39 epileptiform discharges, 119 non-epileptiform abnormalities). The median delay to the first EEG recording was 6 days (IQR 2-12). Multiple Cox regression analysis showed higher risk of long-term epilepsy in those patients with CT cortical involvement (HR 2.6 [1.3-5.2], p 0.009), EEG focal non-epileptiform abnormalities (HR 3.7 [1.6-8.2], p 0.002) and epileptiform discharges (HR 6.7 [2.8-15.8], p < 0.001). Concomitant use of anesthetics and/or antiseizure medication during EEG recording had no influence over its predictive capacity. ROC-curve analysis of the model showed good predictive capability at 5 years (AUC 0.80, 95 %CI 0.74-0.87).
CONCLUSIONS: Focal electrographic abnormalities (both epileptiform and non-epileptiform abnormalities) and cortical involvement in neuroimaging predict the development of long-term epilepsy. In-patient EEG and CT findings could allow an early risk stratification and facilitate a personalized follow-up and management of SAH patients.

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Alpha-synuclein (α-Syn) is a specific neuronal protein that regulates neurotransmitter release and trafficking of synaptic vesicles. Exosome-associated α-Syn which is specific to the central nervous system (CNS) is involved in the pathogenesis of epilepsy. Therefore, this review aimed to elucidate the possible link between α-Syn and epilepsy, and how it affects the pathophysiology of epilepsy. A neurodegenerative protein such as α-Syn is implicated in the pathogenesis of epilepsy. Evidence from preclinical and clinical studies revealed that upregulation of α-Syn induces progressive neuronal dysfunctions through induction of oxidative stress, neuroinflammation, and inhibition of autophagy in a vicious cycle with subsequent development of severe epilepsy. In addition, accumulation of α-Syn in epilepsy could be secondary to the different cellular alterations including oxidative stress, neuroinflammation, reduction of brain-derived neurotrophic factor (BDNF) and progranulin (PGN), and failure of the autophagy pathway. However, the mechanism of α-Syn-induced-epileptogenesis is not well elucidated. Therefore, α-Syn could be a secondary consequence of epilepsy. Preclinical and clinical studies are warranted to confirm this causal relationship.