Search Results (2,998)

Sturge–Weber Syndrome (SWS) is a rare congenital disorder presenting with a vascular malformation in the upper face and brain, causing impaired blood–brain barrier function and perfusion, increased calcium signaling, inflammation, and seizures. All these neuropathologic processes result in injury to the brain. The somatic GNAQ R183Q variant, which accounts for the majority of SWS cases, increases signaling through MAPK, PI3K, mTOR, and inflammatory pathways, primarily in endothelial cells. The discovery of this variant enabled the creation of transgenic and genetic animal and cell culture models. Generating in vitro models has been challenging due to the mosaic nature of SWS, and attempts to separate unaffected from mutant cells in primary culture have failed, limiting the utility of in vitro work. Ongoing in vitro work seeks to overcome these limitations, shape our understanding of SWS, and lead to translational advances in treatment and prevention by studying the affected molecular pathways and identifying future targets for therapy. Full article

An encephalocele is a rare congenital or acquired cranial defect characterized by herniation of intracranial tissue through a defect in the skull base. In human and veterinary medicine, these lesions are frequently associated with abnormalities in neural tube development or structural weakness of the cranial bones, resulting in the protrusion of brain tissue and meninges through anatomical openings such as the cribriform plate. Although this condition has been extensively described in human neurosurgical research, reports on dogs remain limited, and the clinical significance of surgical intervention in cases with communication to the nasal cavity remains unclear. In this case, a young American Cocker Spaniel presented with seizures, prompting advanced diagnostic evaluation. Magnetic resonance imaging revealed a protrusion of the intracranial tissue through a defect in the cribriform plate extending into the nasal cavity. Surgical resection of the protruding tissue was performed, followed by skull base reconstruction. Histopathological examination demonstrated nervous tissue with chronic inflammatory changes without evidence of neoplasia. The patient recovered uneventfully after surgery and remained free of seizure recurrence during follow-up. Surgical management may represent a viable treatment option for seizure disorders in young dogs, particularly when persistent cranio-nasal communication is present, and provides a clinically relevant comparative model for similar cranial base defects described in human pathology. Full article

The limit of disease-modifying therapeutic strategies against epilepsy has prompted mainstream epilepsy research toward understanding the pathways contributing to epileptic seizures. Microglia, the powerhouse of the brain’s innate immune system, is known for its role in epileptic seizures, contributing via neuroinflammation, neuronal death, and neurogenesis. Therapeutic targeting of microglia with its inhibitor and therapeutic compounds modulating its activation reduces the development of spontaneous recurrent seizure after status epilepticus in a pre-clinical model. Herein, we review various aspects of microglia in epilepsy, including their contribution to seizure-induced neuronal death and neurogenesis, the outcome of depleting microglia (both pharmacologically and genetically), the aspects of microglia–astrocyte interaction, and promising therapeutic outcomes achieved by targeting microglia. Full article

Dravet syndrome (DS) is a severe, catastrophic childhood epilepsy predominantly caused by loss-of-function mutations in the SCN1A gene, which encodes the voltage-gated sodium channel Na_v1.1. In this study, we evaluated the therapeutic potential of 5-(Benzofuran-2-yl)-3-(2-chloro-4-fluorobenzyl)-1,3,4-oxadiazol-2(3H)-one (GM-90663), a novel small molecule designed to address the complex pathophysiology of DS. Using scn1lab knockout (KO) zebrafish larvae—a robust vertebrate model for DS—we demonstrated that GM-90663 significantly alleviates seizure-like behavioral movements and rescues deficit in cognitive-like functions. Whole-cell patch-clamp recordings in hippocampal slices revealed that GM-90663 modulates voltage-gated Na⁺ channel kinetics; specifically, it suppresses slow ramp-induced currents, thereby effectively attenuating neuronal hyperexcitability. Furthermore, neurochemical profiling indicated that GM-90663 treatment leads to a marked increase in endogenous serotonin (5-HT) levels in both wild-type and KO larvae. Molecular docking simulations and subsequent in vitro enzymatic assays confirmed that this elevation in serotonin is mediated through the potent inhibition of monoamine oxidase (MAO) activity. Collectively, our findings suggest that GM-90663 exerts its anti-seizure effects through a synergistic dual mechanism—stabilizing sodium channel conductance and elevating serotonergic activity—positioning it as a promising multi-target candidate for the treatment of DS. Full article

Childhood absence epilepsy (CAE) is one of the most common epilepsy syndromes in childhood and has traditionally been regarded as a condition with a favorable neurological prognosis. However, increasing evidence suggests that CAE is associated with functional disturbances in neuronal networks that extend beyond seizure generation and may involve sleep and wakefulness regulation. Methods: This narrative mini-review summarizes and critically discusses current clinical and neurophysiological evidence regarding alterations in sleep architecture and sleep electroencephalographic (EEG) microstructures in children with CAE, based on a focused analysis of selected clinical and observational studies. Results: The available data suggest that children with CAE, particularly before treatment initiation, may exhibit sleep macrostructure abnormalities, including reduced total sleep time, prolonged rapid eye movement sleep latency, increased arousal frequency, and decreased sleep efficiency. In addition, changes in sleep microstructure have been reported, most notably reduced sleep spindle density during stage-N2 sleep, especially in patients with concomitant cognitive impairment. These findings may reflect alterations in thalamocortical network function, although current evidence remains limited and heterogeneous. Conclusions: Sleep disturbances appear to represent an important component of the clinical phenotype of childhood absence epilepsy. Assessing the sleep architecture and sleep EEG microstructure, particularly sleep spindles, may provide insights into network dysfunction and cognitive vulnerability; however, further studies are needed to clarify their clinical utility. Full article

Background: We investigated whether common variants in SCN1A are associated with antiepileptic drug (AED) non-response in Jordanian patients with epilepsy. Methods: We recruited 114 patients (105 successfully genotyped) and Sanger-sequenced five loci spanning rs6432860 and its flanking region of rs1531380, rs1531379, rs1531378, and rs10198801. Genotype–response associations were tested using contingency analyses and multivariable logistic regression adjusting for age at the time of the interview, number of AEDs, and carbamazepine use. Pre-specified secondary analyses included (i) stratification by AED class (voltage-gated sodium channel [VGSC]-acting vs. non-VGSC agents) and (ii) sensitivity analyses using alternative non-response thresholds (seizures > 0/year and ≥4/year). Linkage disequilibrium (LD) and exact Hardy–Weinberg equilibrium (HWE) tests were evaluated. Cohort minor allele frequencies (MAFs) were compared with global population estimates. Results: The four upstream previously cataloged intronic variant SNPs (rs1531380, rs1531379, rs1531378, and rs6432860) were in a complete pattern of LD association in this population (D′ = 1; r^{2 =} 1) whereas each upstream variant with rs10198801 showed D′ = 1 with inverse correlation (r ≈ −0.53). All loci conformed to the exact HWE tests. Upstream variants had novel associations with a non-response in unadjusted analyses and remained significant after adjustment (genotype aOR = 2.8; 95% CI = 1.1–7.2; p value = 0.03), alongside independent effects of carbamazepine use (aOR = 3.3; 95% CI = 1.3–8.0; p value = 0.009) and a number of AEDs (aOR = 0.17; 95% CI = 0.06–0.50; p value = 0.002). In AED-class stratification, upstream additional intronic variants had novel associations with a non-response among VGSC-treated patients (OR = 3.8; 95% CI = 1.1–13.6; p value = 0.03) whereas rs10198801 was associated among non-VGSC patients (OR = 7.9; 95% CI = 0.9–70; p value = 0.04). Findings were robust using a ≥4 seizures/year threshold (recessive model significant) but not using any seizures > 0/year. Cohort MAFs for upstream variants (~48.6%) exceeded European, African, and Asian estimates. Significance: SCN1A upstream intronic variation has a novel association with AED non-response in the Jordanian cohort, shows mechanism-aligned patterns by AED class, persists after covariate adjustment and under a clinically used seizure-frequency threshold, and warrants ancestry-informed replication and functional validation. Full article

(1) Background: The characteristics of rare diseases (RDs) vary considerably—not only between different disease types but also between individual patients with the same condition. In the Roma community, we analyzed the most frequent rare genetic disorders related to the founder effect. (2) Methods: This retrospective study, conducted between January 2019 and January 2025 at the Clinical Genetics and Metabolics Outpatient Clinic in Košice, included 61 patients aged from infancy to 25 years diagnosed with hypomyelinating leukodystrophy 14, pontocerebellar hypoplasia type 1B, neuronal ceroid lipofuscinosis 7, or TMEM70 deficiency. (3) Results: This study includes the largest known cohort of patients with hypomyelinating leukodystrophy 14 caused by the UFM1 c.-273_-271delTCA mutation, predominantly affecting males (n = 17). The disorder is severe, with most patients dying before one year of age, and is characterized by inspiratory stridor, axial hypotonia, spastic quadriparesis, pseudobulbar signs, and microcephaly. In a separate group with pontocerebellar hypoplasia type 1B, six Roma patients (three males, three females) shared the same EXOSC3 mutation. Diagnosis occurred at an average age of 8.8 months, and most children did not survive beyond three years. Common features included microcephaly, severe hypotonia, and spastic quadriplegia. Thirteen children from eight families were diagnosed with neuronal ceroid lipofuscinosis 7, all carrying the same MFSD8 mutation. Symptoms typically began with psychomotor regression between ages 3 and 4, along with intellectual disability and seizures, which were more frequent in males. The mean age at diagnosis was 4.5 years, and eight children died before age nine. Finally, 25 patients with TMEM70 deficiency associated with Roma ancestry were identified, predominantly females, with a mean age of 9.95 years and the oldest patient aged 25. Four children died due to severe metabolic crises. Common findings included intellectual disability, global hypotonia, hypertrophic cardiomyopathy, epilepsy, and failure to thrive. (4) Conclusions: Most rare diseases are genetic and carry high morbidity and mortality, with no targeted therapies currently available. Their increased prevalence in the Roma population reflects founder effects and high consanguinity. Prenatal and newborn screening, along with voluntary carrier testing for couples, is essential for proactive health management. Full article

Explosive ordnance (EO), including AXO (abandoned explosive ordnance), IEDs (improvised explosives devices), and UXO (unexploded ordnance), are widely recognised for their blast and fragmentation hazards, but they also represent a persistent and under-addressed source of occupational chemical exposure for explosive ordnance disposal (EOD) personnel. EOD core activities liberate mixed metals and energetic chemicals, resulting in exposures that are multi-route (inhalation of dusts and fumes, dermal loading amplified by sweat and glove occlusion, and ingestion via hand-to-mouth transfer during eating, drinking, or smoking) and multi-temporal (repeated low-dose background plus task-driven spikes), as well as chemically complex. Clinically, this can present as syndromic overlap across acute and chronic domains, with symptoms that are easily misattributed to heat stress, dehydration, infection, or fatigue. Acute effects of concern include neurotoxic presentations (headache, dizziness, confusion, tremor, and seizure), respiratory and mucosal irritation following dust or fume events, gastrointestinal symptoms, and patterns suggestive of acute hepatic or renal stress, particularly when high-intensity tasks occur in hot environments that compound physiologic strain. Chronic outcomes relevant to repeatedly exposed EOD personnel include renal function decline, neurocognitive effects that can degrade operational decision making and safety, persistent haematologic abnormalities, and endocrine disruption signals, with long-latency risks requiring cautious interpretation given sparse longitudinal data and confounding co-exposures. This review synthesises the current evidence base through an EOD lens and translates it into pragmatic clinical and programmatic actions: task-based exposure characterisation; tiered biomonitoring and medical surveillance aligned to operational tempo; incident-triggered assessment pathways after high-residue events; and prevention strategies that work under field constraints, including contamination control zones, hygiene enforcement, glove and respiratory protection optimisation, tool and vehicle decontamination, and measures to prevent secondary transfer and take-home exposure. The central takeaway is practical: EOD programs can reduce morbidity and improve readiness by treating explosive ordnance as a chemical mixture exposure problem, adopting mixture-aware clinical triage, and embedding surveillance and controls that match how EOD work is actually performed. Full article

Cyclin-Dependent Kinase-Like 5 (CDKL5) Deficient Disorder (CDD) is a rare X-linked developmental and epileptic encephalopathy characterized by early-onset refractory epilepsy, severe neurodevelopmental impairment, and lifelong disability. Although more than thirty anti-seizure medications are available, most CDD patients remain pharmaco-resistant. Gene-based therapies are emerging, but therapeutic development is hindered by marked clinical heterogeneity, small patient populations, and the lack of robust, translatable brain-based biomarkers for clinical trials. Genetically engineered Cdkl5 mouse models recapitulate many cognitive, behavioral, and molecular features of CDD, yet their utility is limited by the absence of overt seizures, precluding seizure-based outcome measures. Here, we establish high-definition brain network (HDBN) biomarkers using advanced diffusion MRI tractography combined with graph-theoretical analysis to quantify whole-brain network organization in Cdkl5 knockout mice. Diffusion MRI enables non-invasive mapping of axonal connectivity by leveraging anisotropic water diffusion, while high-angular-resolution acquisition overcomes key limitations of conventional diffusion tensor imaging in regions with complex fiber architecture. We demonstrate that Cdkl5 knockout mice exhibit reproducible and region-specific disruptions in brain network organization, prominently affecting the somatosensory and somatomotor cortex, hippocampus, hypothalamus, amygdala, and superior colliculus—regions implicated in cognition, learning and memory, homeostasis, anxiety, and visual–motor function. In contrast, networks within the entorhinal cortex remain largely preserved. These findings identify HDBN metrics as sensitive, non-invasive biomarkers that capture clinically relevant circuit-level abnormalities in CDD. Because diffusion MRI–based network analyses are directly translatable across species, HDBN biomarkers provide a unified framework for therapeutic evaluation in mouse models, large animals, and human clinical trials, enabling longitudinal monitoring of disease progression and treatment response. Full article

Introduction: The relationship between epilepsy and alcohol use is complex and clinically significant. Alcohol acts as a neurochemical modulator capable of lowering the seizure threshold during both intoxication and withdrawal, while chronic misuse may contribute to epileptogenesis through neuronal injury, metabolic stress, and neurotransmitter dysregulation. However, the long-term impact of alcohol use on mortality among people with epilepsy (PWE) remains insufficiently characterized. The purpose of this study was to assess all-cause mortality risk among individuals with epilepsy based on alcohol use history, stratified by race/ethnicity. Methods: Data from the 2008–2018 National Health Interview Survey (NHIS) were linked to mortality outcomes on 31 December 2019 from the National Death Index (NDI) for U.S. adults aged 18 years and older. PWE and alcohol use were determined using self-reported data. Survival probabilities were estimated using weighted Kaplan–Meier methods, and hazard ratios were calculated using Cox proportional hazards models adjusted for demographic and clinical covariates. Results: Our results indicated that among PWE, alcohol use was associated with increased all-cause mortality. The unadjusted hazard ratio (HR) for alcohol use among individuals with epilepsy was 1.30, increasing to 1.40 after multivariable adjustment. In contrast, alcohol use alone without epilepsy was not associated with elevated mortality risk after adjustment. When stratified by race, the combined effect of epilepsy and alcohol use was significantly associated with increased mortality among Black individuals but not White individuals. Conclusions: In this nationally representative cohort, the combined presence of epilepsy and alcohol use was associated with higher all-cause mortality compared with alcohol use alone. Racial differences were observed, underscoring the need for integrated clinical care and further research into genetic, biological, and social determinants influencing epilepsy outcomes. Full article

Novel psychoactive substances (NPSs) exhibit extremely strong pharmaco-toxicological activity, often leading to severe adverse effects that pose a serious risk to consumers’ health. Among these, synthetic cannabinoids (SCs) currently represent the majority of drug seizures in Europe. One such compound, AKB-48 (also known as APINACA), was first identified in Japanese herbal smoking blends in 2012. Although it mimics the effects of Δ9-THC, the primary psychoactive component of Cannabis sativa, AKB-48 can induce more severe and potentially life-threatening outcomes. Several in vivo studies investigating the acute administration of AKB-48 have reported profound behavioral, neurological, and neurochemical alterations, including disruptions of neurotransmission across multiple brain regions, thus confirming its neurotoxic potential. Given the recognized vulnerability of the cerebellum to NPS, and its critical role in integrating neural circuits affected by psychostimulant drugs, the present study evaluated the toxic effects of repeated AKB-48 exposure on the cerebellar cortex of adult male and female ICR-CD1^® mice. Particular attention was paid to the modulation of cell death pathways, alongside assessments of sensorimotor responses. The results demonstrate, for the first time, that repeated AKB-48 administration induces significant morphological, immunohistochemical, and ultrastructural changes in both male and female mice. These alterations included pronounced disruption of cerebellar architecture and marked modulation of cell death pathways, further corroborated by TEM-detected ultrastructural damage and a substantial reduction in the basal visual placing response. Overall, the findings provide clear evidence of AKB-48’s sex-independent neurotoxicity, leading to cerebellar alterations that ultimately result in neuroplasticity impairment. Full article

SARS-CoV-2 infection is associated with not only acute respiratory symptoms but is also characterized by strong neurotropism which may contribute to the development of the multisystem post-COVID syndrome (PASC). Patients frequently report chronic neurocognitive disorders such as brain fog, significant attention deficits and increased susceptibility to epileptiform discharges. The aim of this review is to systematize the knowledge regarding deviations in quantitative electroencephalography (QEEG) recordings in convalescents and to evaluate the utility of this method as an objective biomarker. This work constitutes a comprehensive literature review integrating the latest data on neuroinflammation, blood-brain barrier damage and changes in cortical oscillatory dynamics induced by the infection. The literature analysis indicates that the virus may induce a pathological excitation and inhibition imbalance (E/I imbalance) in neuronal networks. In QEEG studies this manifests as excessive activity of slow bands (Theta, Delta), a deficit of rhythms responsible for attention and sensorimotor integration (SMR) and a pathologically elevated Theta to Beta ratio (TBR). In conclusion, QEEG can serve as an objective and highly sensitive tool supporting the diagnosis and stratification of patients with neurocognitive complications of Long COVID. The integration of precise electrophysiological phenotyping with targeted behavioral neuromodulation (e.g., EEG-Biofeedback) fits into the paradigm of personalized medicine and offers a prospective strategy for mitigating long-term neurological burdens. Full article

Background/Objectives: Epilepsy is a long-term condition that affects the brain and has a big impact on a person’s daily life, especially in areas where people do not have a lot of money or access to good healthcare. This study aimed to evaluate the relationship between medication adherence and QoL and to assess the role of seizure severity in the association between them among patients with epilepsy. Methods: A cross-sectional study of 1100 adult patients with epilepsy was conducted using registry data and structured interviews. The main outcomes that were assessed are quality of life (QoL), medication adherence, and seizure severity. Results: Reduced QoL was observed in 62% of patients. Low medication adherence was significantly associated with reduced QoL (OR = 4.33 [3.24–5.79] unadjusted; 3.90 [3.07–5.80] fully adjusted). Seizure severity was also associated with reduced QoL (OR = 1.62, p = 0.002; OR = 2.05, p < 0.001). Cognitive impairment showed the strongest association with reduced QoL, with ORs of 14.6 for mild and 80.8 for moderate-severe impairment in unadjusted models, remaining significant after adjustment. Medication adherence was significantly associated with seizure severity (OR = 1.18, p = 0.002), and attenuation of its effect after adjustment suggests that these variables are interrelated, although causality cannot be determined in this study. Additional factors associated with reduced QoL included lower education, longer disease duration, polytherapy, structural brain abnormalities, and comorbidities. Conclusions: Reduced QoL in epilepsy is strongly influenced by cognitive impairment and medication nonadherence, with seizure severity potentially contributing to this association, although causality cannot be inferred. These findings support integrated care strategies targeting adherence, cognition, and seizure control to improve patient outcomes. Full article

The WW domain-containing oxidoreductase (WWOX) gene, well-known as a tumor suppressor, also has a crucial role as a transcription factor in the developing brain. The bi-allelic loss of the WWOX gene causes a condition characterized by drug-resistant epilepsy, developmental delay, and neurological impairments, often resulting in mortality within the first year of life, known as WWOX-related epileptic encephalopathy (WOREE) syndrome (MIM: 616211). Whole Exome Sequencing (WES) analysis was performed on a female patient who died within three months of birth and was diagnosed with microcephaly, severe early-onset refractory seizures, and drug-resistant epileptic encephalopathy. WES revealed a 38 kb CNV deletion spanning WWOX exons 6–7, and a known frameshift variant in exon 8, impairing a highly clinically significant region of the encoded protein. Clinical and genetic features of reported WOREE patients with WWOX gene deletions similar to our patient were analyzed. Our case highlights the clinical heterogeneity of WWOX variants in WOREE syndrome and expands the spectrum of reported compound heterozygous deletions. Further research needs to elucidate WWOX pathophysiology and improve diagnostic and therapeutic strategies. Full article

Phenylketonuria (PKU) is an autosomal recessive disorder characterised by an inborn error of phenylalanine (Phe) metabolism. Such errors are attributed to pathogenic gene variants causing phenylalanine hydroxylase (PAH) deficiency, impairing the hydroxylation of phenylalanine to tyrosine in the Phe metabolic pathway. This defect leads to plasma Phe concentrations above the normal range. If untreated, hyperphenylalaninemia can adversely affect brain function, leading to severe intellectual disability and seizures. Since 1969, the newborn dried blood spot test has remained the main method of early screening and diagnosis for PKU. The primary therapeutic management is a lifelong phenylalanine-restricted diet with the aim of decreasing plasma Phe levels. The recommended diet consists of avoiding high-protein foods such as meat, fish, eggs and nuts, and can be supplemented with high-protein medical formulas which are low in phenylalanine. Pharmacological interventions such as sapropterin, sepiapterin and pegvaliase can also be used as treatment adjuncts in patients with PKU. Currently, small-molecule inhibitors reducing renal phenylalanine reabsorption are being explored as a potential therapeutic intervention. Furthermore, novel gene-editing techniques are under evaluation as potential curative strategies, with preclinical studies showing promising results in correcting pathogenic phenylalanine hydroxylase variants. This non-systematic review synthesises current literature on the management of PKU, with a focus on dietary interventions and recommendations. Full article