Neuroinflammation has been increasingly implicated in epileptogenesis and drug-resistant epilepsy, leading to growing research interest beyond the traditional focus on neuronal hyperexcitability. Despite the rapid expansion of research in this interdisciplinary field, a comprehensive structural mapping of its intellectual evolution and emerging frontiers is lacking. We performed a systematic bibliometric analysis of 1989 publications (2005-2026) retrieved from Web of Science Core Collection and Scopus. Analytical tools including CiteSpace, VOSviewer, and the Bibliometrix R package were employed to visualize collaboration networks, citation structures, and thematic transitions. The literature search was updated to include publications indexed up to January 4, 2026. Research output followed an exponential growth pattern (R2=0.97), peaking in 2025. China and the USA dominated the global landscape, with the Journal of Neuroinflammation and Epilepsia identified as core academic hubs. Highly cited works, led by pioneers such as Vezzani A and Aronica E, established a knowledge base centered on microglial activation and cytokine signaling. Keyword clustering identified several interconnected thematic domains. Long-standing topics included oxidative stress and hippocampal vulnerability, whereas recent citation bursts indicated increasing attention to autoimmune encephalitis, blood-brain barrier (BBB) dynamics, and the gut-brain axis. Furthermore, emerging trends highlight the ketogenic diet and network pharmacology as promising immunometabolic strategies for seizure control. This study provides the first systematic bibliometric landscape of neuroinflammation in epilepsy over the past two decades. Our findings suggest a gradual transition from studies of glial, cytokine, and vascular mechanisms toward translational interest in systemic immune-CNS interactions. These quantitative insights identify the gut-microbiota-inflammation axis and personalized immunotherapy as the next frontiers, offering a strategic roadmap for future disease-modifying interventions in refractory epilepsy.
Psychiatric comorbidities are highly prevalent in people with epilepsy, which adversely affect treatment outcomes. The proper choice of antiseizure medication (ASM) is therefore crucial because different ASMs have varying psychiatric safety profiles. This study investigates the psychiatric tolerability of commonly used ASMs in people with newly diagnosed focal epilepsy. This post hoc analysis included participants from the Human Epilepsy Project, an international, multicenter prospective cohort. Of 357 participants aged ≥12 years enrolled within 4 months of treatment initiation for focal epilepsy, those receiving levetiracetam, lamotrigine, or sodium channel blockers (SCBs, including carbamazepine, oxcarbazepine, and phenytoin) monotherapy who completed the Mini International Neuropsychiatric Interview at enrollment were included. Median doses at discontinuation for each treatment group were reported. Of 357 patients, 214 (60%) received levetiracetam, 69 (19%) lamotrigine, and 74 (21%) other SCBs. Treatment groups differed significantly by sex (p = 0.028) and education level (p = 0.001). During the 2-year follow-up, levetiracetam and other SCBs had a significantly higher risk of withdrawal because of psychiatric adverse events compared with lamotrigine (p = 0.001 and p = 0.024, respectively). Most withdrawals occurred early. Multivariable Cox regression showed a higher withdrawal risk for levetiracetam vs lamotrigine (adjusted HR 2.76; 95% CI 1.51-5.04; p ≤ 0.001) and for other SCBs vs lamotrigine (adjusted HR 2.25; 95% CI 1.13-4.47; p = 0.021). Discontinuation doses were substantially lower than maintenance doses across all groups (p < 0.001 for levetiracetam and lamotrigine; p = 0.0022 for other SCBs). Among patients without baseline depression or anxiety (n = 232), discontinuation occurred in 40% of those receiving levetiracetam, 40% receiving other SCBs, and 19% receiving lamotrigine. Consistent with the overall cohort, levetiracetam was associated with a higher risk of discontinuation (OR 2.40 [1.18-5.20], p = 0.020) compared with lamotrigine. People who were newly diagnosed with focal epilepsy on ASM monotherapy showed that levetiracetam was associated with approximately 2.8-fold risk of treatment withdrawal compared with lamotrigine because of psychiatric adverse events. Our analysis also demonstrated a better psychiatric tolerability profile for lamotrigine compared with other SCBs. Most discontinuations occurred at significantly lower doses than maintenance therapy, suggesting either failure to reach therapeutic dosing or dose tapering before discontinuation.
To evaluate treatment engagement and 12-month outcomes following structured diagnostic communication and individualized treatment planning in inpatients with the most common functional neurological disorder (FND) presentations encountered in epilepsy services and to explore the relationship between treatment engagement and adherence. In this prospective cohort study, adult inpatients with a diagnosis of functional/dissociative seizures (FDS) or functional movement disorder (FMD) received a multi-component psychotherapeutic consultation focused on psychoeducation and shared decision-making. Individualized treatment plans were developed collaboratively. Follow-up assessments were conducted over 12 months. Primary outcome was health-related quality of life (SF-36). Secondary outcomes included disorder-specific symptom burden and functional impairment (WSAS). Individual change was assessed using the Reliable Change Index. Of 55 FND inpatients, 58% (32) were admitted via the emergency department with acute presentations and 42% (23) electively for diagnostic evaluation; 37 were enrolled, while 18/55 (33%) could not be included. Twelve-month follow-up data were available for 25/37 patients (68%). Among completers, treatment engagement rates were high (>80%). Despite high rates of self-reported treatment adherence, no significant group-level improvements were observed. Only 8/25 patients (32%) showed reliable improvement in at least one major outcome domain without deterioration in another. Structured diagnostic communication combined with individualized treatment planning was associated with high treatment engagement rates. However, long-term outcomes remain unsatisfactory, suggesting treatment effectiveness as key limiting factor. Limitations include the uncontrolled design and incomplete follow-up. Our findings suggest that therapist specialization and closer integration between neurological and psychotherapeutic care may be important components of FND care.
Epidemiology, pathophysiology, clinical characteristics, established clinical- and experimental treatment options are discussed with regard to the lifespan. Attention is dedicated to special features of older patients. This narrative review was conducted in line with a structured literature search performed in the PubMed/MEDLINE database to identify relevant publications on post-traumatic epilepsy. Search terms included Medical Subject Headings (MeSH) and free-text keywords related to traumatic brain injury, post-traumatic seizures, epileptogenesis, epidemiology, and treatment. No restrictions on publication date were applied in order to include both seminal and contemporary studies. The literature was narratively synthesized to provide a concise and clinically relevant overview of post-traumatic epilepsy. Posttraumatic epilepsies of adults are frequently occurring in older patients. Little available data concerning age characteristics like TBI etiologies and PTE considerations by age groups with related management approaches exists. This review provides a condensed overview shedding also light on biological and clinical interlinks. TBI requires individual risk assessment for posttraumatic epilepsy and other neurological and psychiatric sequelae in the long-term course contributing to a "traumatic brain injury disease syndrome". Innovative approaches regarding diagnostics and approaches for interventions are discussed.
Nasal administration provides a favorable option for patients with a variety of disease conditions and their caregivers, including for acute treatment therapies in the community setting. This noninvasive route of administration allows for device portability and quick access, absorption, and bioavailability. Drug products should be developed with a detailed understanding of ideal formulation characteristics and device criteria to ensure high bioavailability, effectiveness, and tolerability. This narrative review examines how intranasal administration addresses limitations associated with some other routes of administration and how its own unique limitations can be addressed. There are numerous strategies to increase mucosal absorption, such as mucoadhesion and permeation enhancement. We searched PubMed about the role of the excipient dodecyl maltoside (DDM) in transmucosal absorption; those results were used for subsequent research. This narrative review discusses DDM use in formulations approved by several health authorities worldwide, including the US Food and Drug Administration, and in investigational drugs in development. DDM has demonstrated benefits in enhancing absorption in nasal spray formulations across a broad spectrum of medical conditions. These new treatment options offer effectiveness and ease of use for patients and caregivers. DDM and closely related excipients have many promising opportunities for future applications, facilitating absorption across nasal and other epithelia membranes.
Epilepsy is a common neurological disorder in the United States that disproportionately affects African Americans. Religious and spiritual practices are important coping mechanisms that may influence health beliefs and healthcare decisions, yet their influence on epilepsy outcomes in this population remains understudied. This narrative review examines how religious and spiritual practices contribute to health decision making behaviors among African Americans living with epilepsy. A literature search was conducted using PubMed, Google Scholar, Connected Papers, and the New York University Library system, focusing on religiosity and spirituality in chronic illness, epilepsy outcomes, racial disparities, stigma in faith-based settings, and church-based health interventions. Across the reviewed literature, findings showed that religiosity and spirituality were associated with coping, finding purpose, social support, and quality of life. In epilepsy-specific studies, positive religious and spiritual coping associated with better well-being, lower anxiety and depressive symptoms, and higher quality of life, while negative religious coping was associated with poorer psychosocial outcomes. Direct evidence among African Americans with epilepsy was limited; however, available findings suggest that Black patients relied more on religion, emotional support, positive reframing, and denial as coping strategies compared to White patients. Overall, this review highlights the need to better understand how African Americans with epilepsy use religious and spiritual frameworks to manage living with a chronic neurological condition.
Elucidating the internal representation of language in the brain has major implications for cognitive science, brain disorders, and artificial intelligence. A pillar of linguistic studies is the notion that words have defined functions, often referred to as parts of speech. Here, we recorded invasive neurophysiological responses from 1,801 electrodes in 20 patients with pharmacologically resistant epilepsy while they were presented with two-word phrases consisting of an adjective and a noun. We observed neural signals that distinguished between these two parts of speech. The representation of parts of speech showed invariance across visual and auditory presentation modalities; robustness to word properties such as length, order, frequency, and semantics; and even generalization across different languages. The selective signals were circumscribed within a small region in the left lateral orbitofrontal cortex. This selective, invariant, and localized representation of parts of speech extends classic fronto-temporal language models, providing a target for mechanistic and causal tests of how the brain represents the basic building blocks of language, and introduces a systematic approach to elucidate the orchestration of more complex aspects of language.
Acute symptomatic seizures (ASyS) are clinical seizures occurring at the time of a systemic insult or in close temporal association with a documented brain injury. We aimed to determine the 3-year mortality following a first ASyS. We previously conducted a prospective, population-based cohort comprising all individuals with a first seizure during 2017 from a defined geographic area. Individuals with ASyS were identified from this cohort using ILAE criteria and stratified by provoking factor. Mortality was assessed at 30 days, 1 year, and 3 years following the event, and age-standardized mortality ratios (SMRs) were calculated at 1 and 3 years using age-matched and sex-matched national mortality data. Among 207 cases of first ASyS, identified from a population of 542,868, there were 61 deaths (29.5%) during 3 years of follow-up. Mortality at 30 days, 1 year, and 3 years was 12.6%, 22.2%, and 29.5%, respectively. The SMR was 19.7 (95% CI 14.4-26.3) at 1 year and 10.4 (95% CI 7.9-13.4) at 3 years. Mean age at first ASyS was 52.1 years and at death 70.5 years. Excluding the substance use group, 3-year mortality rose to 45.5% (50/110). Pneumonia was the most frequent cause of death (17/61, 27.9%). ASyS is a common presentation and is associated with markedly increased mortality over 3 years. These findings underscore the prognostic importance of ASyS as a clinical indicator of increased long-term mortality, particularly in medically complex patients.
The ketogenic diet is used to treat drug-resistant epilepsy, yet the molecular mechanisms coupling metabolic state to seizure suppression remain understudied. β-Hydroxybutyrate (β-HB), a principal ketone body, exerts antiseizure effects, yet its downstream ionic mechanisms remain unclear. We used 69 C57BL/6 mice, including males and females (4-week-old for ex vivo electrophysiology and calcium imaging and 8-week-old for in vivo seizure experiments). β-HB or saline was administered after the onset of status epilepticus, induced in mice by continuous hippocampal stimulation. Intrinsic excitability and excitatory synaptic currents on hippocampal granule cells were measured using the patch clamp technique. Calcium imaging was performed after viral delivery of a genetically encoded calcium indicator into the hippocampus. In vivo, β-HB rapidly reduced the duration of status epilepticus. At the cellular level, patch-clamp recordings showed that β-HB hyperpolarized dentate granule cells (DGCs) increased action potential threshold and reduced firing frequency. Moreover, β-HB suppressed excitatory synaptic transmission onto DGCs. At the network-level, β-HB perfusion significantly decreased DGC population activity by reducing neuronal excitability and excitatory synaptic currents. Mechanistically, pharmacological blockade of G protein-gated inwardly rectifying potassium (GIRK) channels prevents the β-HB-induced suppression of DGC intrinsic excitability, excitatory synaptic transmission, and population-level activity. In contrast, inhibition of adenosine triphosphate-sensitive potassium channels had no detectable impact on β-HB-mediated modulation of DGC intrinsic excitability or network responses. These findings identify GIRK channels as a key downstream effector of β-HB signaling, providing a mechanistic link between ketogenic states and neuronal excitability, revealing a new mechanistic target for ketogenic therapies.
Anti-leucine-rich glioma-inactivated protein 1 (LGI1) encephalitis presents relapse risk and potential functional impairment, with no established maintenance treatment guidelines. The study aimed to uncover prognostic signatures, and identify predictors of relapse and poor outcome using real-world evidence. This multicenter retrospective study included anti-LGI1 encephalitis patients from five tertiary hospitals in Eastern China between January 2015 and January 2024, with ≥ 24-month follow-up. Relapse was defined as the presence of new or worsening clinical features after at least 3 months of stability or improvement. Poor outcome was defined as a modified Rankin Scale score > 2 at last follow-up. A total of 104 patients were included (median age 56.5 years, 60.6% male). Following the acute phase, the majority (66.3%) received prolonged corticosteroid treatment (≥6 months) without steroid-sparing maintenance immunotherapy (SSMI), whereas 16.3% received SSMI. Twelve patients (11.5%) experienced relapse. Hyponatremia at diagnosis was more common in relapsing patients (p = 0.017), and was significantly associated with an increased risk of relapse in Cox regression (hazard ratio = 4.67, 95% confidence interval [CI] = 1.41-15.53, p = 0.012). Poor outcome was observed in 17 patients (16.3%), with male sex (odds ratio [OR] = 5.12, 95% CI = 1.27-34.48, p = 0.041) and hyponatremia (OR = 4.69, 95% CI = 1.54-15.47, p = 0.008) as potential risk factors. This study suggests that hyponatremia is associated with an increased risk of relapse and poor outcome in anti-LGI1 encephalitis. These findings may facilitate individualized risk stratification, but further validation in larger prospective cohorts is needed. Anti-LGI1 encephalitis is an autoimmune brain disorder characterized by cognitive impairment, seizures, and psychiatric symptoms. While immunotherapy improves outcomes, relapses occur and long-term functional recovery varies. Risk factors for relapse and poor outcome remain inadequately defined. This multicenter study included 104 patients with minimum 24-month follow-up. Relapse occurred in 11.5% and poor functional outcome in 16.3%. Hyponatremia at diagnosis was significantly associated with a higher risk of relapse and poor outcome. These findings suggest hyponatremia may be a potential biomarker for risk stratification, thereby guiding individualized therapeutic strategies. However, further research is needed to confirm these observations.
Epilepsy is a chronic neurological disorder characterized by recurrent seizures, neuroinflammation, and epigenetic instability, with around one-third of patients experiencing drug-resistant epilepsy. While ion channels and neurotransmitter imbalances have been thoroughly examined in relation to epilepsy, the significance of piRNAs and their interaction with PIWI proteins in gene regulation, transposon silencing, and inflammatory signaling inside the epileptic brain is gaining recognition. This summary encapsulates the existing understanding of piRNA synthesis, the epigenetic control through PIWI-piRNA interactions, and their novel roles in epileptogenesis. PIWI-piRNA complexes target highly expressed genomic areas, such as LINE-1 retrotransposons, and mute them by recruiting chromatin modifiers such DNMT3A and H3K9 methyltransferase complexes, therefore influencing genome stability and neuronal excitability. Additionally, piRNAs initiate pathways associated with neuroinflammation, including the activation of the Toll-like receptor-4/NF-kB signaling pathway and the NLRP3 inflammasome, and indirectly influence GABAergic homeostasis through interactions with the extensive noncoding RNA regulatory network. Targeted modulation of kainic acid, pilocarpine, and hereditary epilepsy models has been documented to provide decreases in seizure load; however, the extent of this effect varies among the models and modulation techniques employed. The review critically evaluates emerging therapeutic strategies, including AAV9 vectors, lipid nanoparticles, exosome-based delivery systems, and antisense oligonucleotides, along with their associated challenges such as blood-brain barrier penetration, off-target effects, immune activation, and long-term safety. In conclusion, the PIWI-piRNA axis represents a potential yet nascent domain for biomarker creation and disease modulation in epilepsy.
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Ambulatory electroencephalography (aEEG) allows prolonged outpatient monitoring and improves seizure detection compared with routine EEG, particularly for subclinical seizures. aEEG is especially valuable in underserved populations, where socioeconomic barriers and comorbidities contribute to delayed diagnosis and poor seizure control. The objective of the study is to evaluate seizure-detection rate with aEEG in an underserved epilepsy population and to examine how it relates to self-reported seizure control. Clinical and socioeconomic factors influencing the discrepancy between actual vs perceived seizure control were examined. This is a retrospective, cross-sectional study of adult patients who underwent aEEG at the University of Illinois Hospital, Chicago, Illinois. Demographic and clinical data (seizure history, medications, aEEG findings, and presence of psychiatric and cognitive comorbidities) were extracted from electronic medical records. Participants were grouped according to the presence or absence of seizures on aEEG. Univariate analyses and multivariate logistic regression were used to identify predictors of seizures detected on aEEG, whereas secondary analyses examined discrepancies between reported seizure frequency and the presence of seizure on aEEG. Of 382 patients included, seizures were captured on aEEG in 46 patients (12%), the majority of which were subclinical (80%). Patients with seizures on aEEG were more likely to be unemployed or on disability, have focal epilepsy, be prescribed a greater number of anti-seizure medications (ASMs), and have mild cognitive impairment (MCI). In multivariate analysis, number of ASMs (odds ratio [OR] 2.10, 95% confidence interval [CI] 1.44-3.07) and presence of MCI (OR 6.13, 95% CI 3.04-12.38) independently predicted seizures on aEEG. MCI was present in ~70% of patients with subclinical seizures who were reporting rare seizures at home. aEEG detects subclinical seizures that often go unrecognized by patients. The presence of seizures has been shown to be associated with MCI. This highlights the importance of objective monitoring beyond patient self-report, particularly in vulnerable populations.
Functional/dissociative seizure (FDS) disorder presents diagnostic challenges due to its complex semiology and the lack of positive diagnostic biomarkers. Current evidence suggests that specific patterns of brain activity and distinct dynamics in the brain network may underlie the neurobiological mechanisms of FDS. We retrospectively analyzed ictal EEG recordings from 46 patients with FDS, in three different conditions: during resting wakefulness (RW), during resting while having eyes closed (EC), and during functional/dissociative seizures of variable semiology (FDS). The occipital EEG in the alpha band (8-13 Hz) was assessed in terms of power and functional connectivity, quantified by debiased weighted phase lag index (dwPLI). Heart rate was also analyzed across conditions. Statistical comparisons were performed via paired permutation testing with Benjamini-Hochberg correction for multiple comparisons, complemented by Bayes factors for the key FDS-EC comparisons. EEG during FDS exhibited significantly higher occipital alpha power than RW (p = 0.0003) and levels not significantly different from EC, with moderate Bayesian evidence for the absence of a difference (BF01 = 6.1). Alpha power was elevated across all FDS subtypes and was, paradoxically, numerically highest in hypermotor seizures, although subtype differences did not survive correction for multiple comparisons. Control analyses showed that the alpha power did not significantly differ across video-rated states of eyes during FDS (open, intermittently closed, closed), including when conditions were matched for eye state. Functional whole-brain connectivity in the alpha band was intermediate between the two resting conditions, being higher during FDS than during RW but lower than during EC. Heart rate was highest during FDS, with a non-significant tendency toward higher rates in hypermotor than atonic FDS. No significant correlation was found between occipital alpha power and heart rate during FDS. Our findings suggest that FDS are characterized by a paradoxical hypersynchronization in the EEG alpha band, similar to EC, despite concurrent motor activity. Increased functional alpha connectivity, simultaneous with elevated heart rate during FDS, suggests that FDSs involve altered brain network dynamics rather than simple alpha power suppression by voluntary motor activity. These findings may aid in developing positive biomarkers for FDS diagnosis.
Reliable detection of hippocampal engagement is critical in presurgical memory fMRI, yet the extent to which different paradigms differentially recruit anterior and posterior hippocampal regions at the individual level remains unclear. This study systematically compares hippocampal engagement across three commonly used memory fMRI tasks-autobiographical memory (AUT), picture encoding (PIC) and hometown walking (HTW)- at the individual level, with a particular emphasis on anterior versus posterior hippocampal regions. A total of 113 presurgical patients completed at least one memory fMRI task (AUT: n = 41; PIC: n = 53; HTW: n = 60). Hippocampal regions of interest were anatomically defined and subdivided into anterior/posterior and ipsilesional/contralesional segments. Individual-level suprathreshold activation detectability of hippocampal ROIs was assessed using standardized statistical criteria (p < 0.01, uncorrected). All tasks showed high global hippocampal detection rates. However, regional differences were observed in the anterior hippocampus, where AUT demonstrated higher detectability, particularly contralesionally (88.9 %), compared with PIC (60 %) and HTW (64.7 %) (Cramér's V = 0.259). In contrast, posterior hippocampal detection was high and comparable across tasks, with PIC showing the highest rates (80.6-97.8 %). Whole-brain analyses revealed stronger engagement of default mode network regions for AUT. Memory fMRI paradigms show distinct regional hippocampal engagement profiles and are not interchangeable for presurgical mapping at the individual level. These findings may inform task selection in presurgical memory fMRI depending on the anatomical region of interest and clinical context.
Brain physiological pulsations drive glymphatic clearance of neurotoxins from the brain. Neurodegenerative proteinopathies, including Parkinson's disease (PD), have altered glymphatic function. This study compares brain physiological pulsations important for glymphatic clearance in PD and healthy controls (HC). PD (N = 13) and HC (N = 20) participants were evaluated using magnetic resonance encephalography (MREG), an ultrafast, 3D spherical stack-of-spirals dynamic neuroimaging technique, to assess spectral power and optical flow in cardiovascular, respiratory, and low-frequency vasomotor bands as indirect proxies for glymphatic clearance. Group differences were analyzed with two-sample t-tests, controlling for age and sex. PD participants demonstrated significantly reduced power in the cardiovascular frequency band and reduced optical flow magnitude in the low-frequency vasomotor band in regions important for visual and cognitive processing and sensorimotor function. PD is associated with alterations in physiological pulsations important for glymphatic flow. Glymphatic clearance may represent a potential therapeutic target for neurodegenerative diseases.
Lennox-Gastaut syndrome (LGS) is a rare developmental and epileptic encephalopathy associated with treatment-resistant seizures, profound neurodevelopmental impairments, and high caregiver burden. While seizure control is often prioritized in clinical trials, caregivers emphasize the importance of assessing behavior, communication, and quality of life. This study explored the perspectives of caregivers, clinicians, and advocates on existing instruments for measuring these domains in individuals with LGS. We conducted four focus groups with caregivers (n = 22), epilepsy advocates (n = 5), and clinicians (n = 6). Participants reviewed pre-selected instruments for each domain before the sessions. Questions elicited feedback on instruments assessing the three domains, as well as other relevant domains for LGS. Discussions were recorded, transcribed, and thematically analyzed. Five themes emerged: (1) Behavior instruments - the Aberrant Behavior Checklist was favored for relevance and ease, while the Adaptive Behavior Assessment System-3 and Vineland Adaptive Behavior Scales-3 were viewed as lengthy or developmentally mismatched; (2) Communication instruments - the Communication Matrix was preferred for capturing nonverbal and alternative communication, while the Communication and Symbolic Behavior Scales lacked relevance; (3) Quality of life instruments - no clear preference emerged between Quality of Life Inventory-Disability and CDKL5 Deficiency Disorder Severity Assessment; (4) Impact on caregivers - negative language, time burden, and administration logistics posed challenges; and (5) Unaddressed gaps - sleep, gastrointestinal health, caregiver burden, socialization, and safety were noted as insufficiently captured. Participants identified strengths and limitations of existing instruments and highlighted several unmet measurement needs. These insights underscore the need for relevant, inclusive tools that are aligned with the lived experiences of individuals with LGS and their families.
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