Search Results (99)

Background and Objectives: Infantile spasms (ISs), or West syndrome (WS), represent an early-onset epileptic encephalopathy in which diverse structural, genetic, metabolic, infectious, and neurocutaneous conditions converge on a shared pattern of hypsarrhythmia, clustered spasms, and later developmental impairment. Growing use of genomic diagnostics has revealed that variants in STXBP1, KCNQ2, GRIN2A, GRIN2B, and TSC-related genes are more common than previously recognized and can be linked to partially actionable pathways. This review aimed to synthesize current evidence on the multifactorial etiology, network-based pathogenesis, and evolving targeted therapies for ISs, with particular attention to TSC-related forms. Materials and Methods: A structured narrative review was undertaken of publications from 1990 to 2025 in PubMed, Scopus, Web of Science, and Embase using terms related to ISs, WS, genetics, mTOR, ACTH, vigabatrin, ketogenic diet, and precision therapies. Authoritative guidance from ILAE and AAN was incorporated. Clinical, molecular, and therapeutic data were grouped under etiological, pathogenetic, and management domains. Results: Structural causes remained the largest group, but combined genetic, genetic–structural, and metabolic etiologies accounted for about one third of contemporary cohorts. Early network disruption involving cortex, thalamus, basal ganglia, and brainstem, together with imbalances in NGF, BDNF, and IGF-1, explained why distinct primary insults produce a uniform electroclinical phenotype. Early treatment with ACTH or high dose prednisolone, with or without vigabatrin, was consistently associated with higher electroclinical remission and better developmental outcome. Everolimus and related mTOR inhibitors showed benefit in TSC-associated ISs, while agents directed at NMDA receptors or KCNQ channels are emerging for genotype defined subgroups. Conclusions: ISs should be approached as a heterogeneous but mechanistically convergent disorder in which rapid diagnosis, parallel genetic testing, and early disease modifying therapy improve prognosis. Integration of molecular profiling with standardized outcome monitoring is likely to move management from symptomatic seizure control to pathway-specific intervention. Full article

Lafora disease is a fatal neurodegenerative disorder caused by loss-of-function mutations in the EPM2A or EPM2B genes, which encode laforin and malin, respectively. These mutations lead to the accumulation of intracellular inclusions of abnormal glycogen, known as Lafora bodies, the hallmark of the disease. Symptoms typically begin in early adolescence with seizures and rapidly progress to cognitive and motor decline, ultimately resulting in dementia and death within a decade of onset. Disruption of Epm2a or Epm2b in mice causes neuronal degeneration and Lafora body accumulation in the brain and other tissues. Epm2a^−/− and Epm2b^−/− mice exhibit motor and memory impairments, epileptic activity, and molecular and histological abnormalities. We previously demonstrated that intracerebroventricular delivery of a recombinant adeno-associated virus carrying EPM2A significantly improved pathology in Epm2a^−/− mice. In this study, we tested recombinant adeno-associated virus-mediated delivery of the human EPM2B gene in Epm2b^−/− mice. The treatment partially improved neurological, molecular, and histopathological outcomes, although some pathological features persisted. Importantly, our findings reveal differences between EPM2A- and EPM2B-based gene therapies, highlighting the need to better understand their distinct mechanisms. Despite limitations, our study provides new insights into the complexity of targeting EPM2B mutations in Lafora disease. Full article

Epilepsy affects approximately 50 million people worldwide, with nearly one-third of patients experiencing inadequate seizure control with conventional anti-epileptic drugs. The GABAergic system, responsible for inhibitory neurotransmission in the central nervous system, represents a critical target for seizure management. GABA aminotransferase (GABA-T), the enzyme responsible for GABA catabolism, has emerged as a particularly attractive therapeutic target. Inhibition of GABA-T increases synaptic GABA availability, enhancing inhibitory neurotransmission and raising the seizure threshold. Vigabatrin, an irreversible GABA-T inhibitor, has demonstrated remarkable efficacy in specific epilepsy syndromes, particularly infantile spasms and refractory partial seizures. However, its clinical utility is tempered by the risk of irreversible visual field defects, necessitating careful patient selection and monitoring. This review examines the molecular biology of GABA-T, the mechanisms of action of its inhibitors, clinical applications, safety considerations, and emerging developments in this therapeutic area. We discuss the structure–function relationships of GABA-T, the pharmacology of vigabatrin and experimental inhibitors, clinical efficacy across various epilepsy syndromes, adverse effect profiles, and future directions including novel inhibitors with improved safety profiles. Understanding the role of GABA-T in epilepsy pathophysiology and the therapeutic potential of its inhibitors provides insights into rational drug design and personalized treatment strategies for epilepsy management. Full article

Background: Cryoglobulinemia is a rare immune-mediated condition, in which abnormal proteins (cryoglobulins) precipitate at cold temperatures, leading to blood vessel inflammation. It affects approximately 1 in 100,000 individuals globally and often goes undiagnosed due to its overlapping symptoms with common conditions such as stroke. When the central nervous system (CNS) is involved—primarily in Type 2 cryoglobulinemia—it can cause serious neurological events, including seizures, confusion, and stroke-like episodes. Despite this, there is limited awareness and minimal research on this condition in South Africa. Objective: The aims of this study were to describe neurological manifestations of cryoglobulinemia using global case reports, evaluate outcomes associated with delayed diagnosis, and highlight the importance of early detection in patients with unexplained neurological symptoms. Methods: A qualitative systematic review of published case reports (2015–2024) was conducted. The study focused on adults (≥18 years) who were diagnosed with cryoglobulinemia involving CNS manifestations. Reports from hospital-based studies in Europe, North America, and Asia were retrieved from medical databases. Data on symptoms, diagnosis, treatment, and outcomes were summarized numerically and by identifying common patterns. Results: Seventeen relevant cases were identified. The most common neurological symptoms were ischemic stroke (35%), reversible posterior encephalopathy syndrome (24%), seizures (18%), and intracranial hemorrhage (12%). Most cases were associated with Type 2 cryoglobulinemia. Neuroimaging frequently revealed vasculitis, infarcts, or cerebral edema. All patients received immunosuppressive therapy, mainly corticosteroids. Outcomes showed that 76% improved, 12% partially recovered, and 12% died—mostly due to delayed diagnosis. Conclusions: Neurological involvement in cryoglobulinemia is uncommon but potentially fatal. Stroke-like presentations dominate due to vasculitis injury and vascular occlusion. Early diagnosis significantly improves outcomes, while delays can be deadly. Increased clinical awareness is essential in South Africa, where this condition is rarely reported. Clinicians should consider cryoglobulinemia as a possible cause in patients presenting with unexplained neurological symptoms. Full article

Background/Objectives: Very early pediatric-onset multiple sclerosis (POMS) is rare; clinical studies using disease-modifying treatments (DMTs) have not been performed. Clinicians rely on studies performed at older ages. This review resulted from difficulties faced by clinicians and the off-label use of DMTs at this age. Methods: A literature review of studies dated between 1982 and 2025 on very early POMS, specifically with onset before age 5, has been performed, searching for outcomes without or with DMTs. The curated database of the selected patients was analyzed using computed descriptive and integrated cohort-level estimates. The clinical, paraclinical, treatment, and outcome characteristics were analyzed. Statistical analysis used JASP, with GenAI-assisted verification. The treatment outcome of a 16-year-old patient with very early POMS starting at 2 years 4 months that consecutively received interferon, immunoglobulin, and Natalizumab is presented. Results: A total of 101 patients with very early POMS presented, at onset, with ataxic syndrome (57.4%), pyramidal syndrome (41.4%), ophthalmoplegia (10.3%), and optic neuritis (6.9%). In evolution, 22.7% had seizures. Half of the patients were not treated. Among those treated, acute steroid therapy was administered; 11 received the DMTs interferon, Glatiramer acetate, Dimethyl fumarate, and Azathioprine (three), with only two high-efficacy therapies (Natalizumab and Rituximab). Our patient had partial remission under interferon, relapses when stopped and replaced by immunoglobulin and 9 years relapse-free interval when Natalizumab was introduced. Conclusions: Early treatment with high-efficiency DMTs should be considered in very early POMS; association with known increased neuroplasticity at this age may improve prognosis, allowing good recovery of acquired disability. Full article

Epilepsy affects over 50 million people globally, with accurate seizure type classification directly influencing treatment selection as different seizure types respond to specific antiepileptic medications. Manual electroencephalogram (EEG) interpretation remains time-intensive and requires specialized expertise, creating clinical workflow bottlenecks. This work presents EEG-ARCNet, an attention-residual convolutional network integrating residual connections with channel attention mechanisms to extract discriminative temporal and spectral features from multi-channel EEG recordings. The model combines nine statistical temporal features with five frequency-band power measures through Welch’s spectral decomposition, processed through attention-enhanced convolutional pathways. Evaluated on the Temple University Hospital Seizure Corpus, EEG-ARCNet achieved 99.65% accuracy with 99.59% macro-averaged F1-score across five seizure types (absence, focal non-specific, simple partial, tonic-clonic, and tonic). To validate practical deployment, the model was implemented on Raspberry Pi 4, achieving a 2.06 ms average inference time per 10 s segment with 35.4% CPU utilization and 499.4 MB memory consumption. The combination of high classification accuracy and efficient edge deployment demonstrates technical feasibility for resource-constrained seizure-monitoring applications. Full article

While syncope is characterized by a sudden and temporary loss of consciousness caused by decreased blood flow to the brain and is easily recognized by its clinical features, presyncope involves a sensation of impending fainting, often accompanied by autonomic symptoms. Presyncope is less characterized and studied than syncope, presenting a particular diagnostic challenge in neurology clinics. Neurologists commonly encounter patients with presyncope in outpatient settings or during consultation at the emergency department after cardiopulmonary causes have been excluded. Differential diagnosis of recurrent presyncope is broad but from a neurologic standpoint falls into multiple neurologic categories, including complex partial seizures, basilar or vestibular migraine, dysautonomia, cataplexy, alteration in cerebrospinal fluid flow, Meniere’s disease, posterior circulation transient ischemic attacks and others. Here, we review presyncope as a feature of dysautonomia and common autonomic disorders, such as neurocardiogenic syncope, postural orthostatic tachycardia syndrome, orthostatic hypotension and orthostatic intolerance. We discuss clinical and neurologic exam findings, diagnostic tests, differential diagnosis and treatment of presyncope as a manifestation of common autonomic disorders. Full article

Background/Objectives: Ferroptosis, an iron-dependent form of regulated cell death characterized by excessive lipid peroxidation, has been implicated in various acute and chronic brain disorders, including epilepsy. Although 1,4-naphthoquinone derivatives have been reported to regulate ferroptosis, their mechanistic roles in the nervous system remain underexplored. Here, we investigated the protective effects of 8-hydroxy-2-anilino-1,4-naphthoquinone (8-HANQ) on ferroptotic neuronal death in vitro and seizure behaviors in vivo. Methods: HT22 hippocampal cells were exposed to ferroptosis inducers including glutamate, glutamate plus iron, or RSL3. Lipid reactive oxygen species (ROS), ferroptosis markers, and its related molecules were assessed by flow cytometry and Western blotting. In a kainate (KA)-induced seizure model, 8-HANQ was delivered intracerebroventricularly, followed by behavioral seizure scoring and analysis of hippocampal levels of PSD95, cathepsin-B, and FGFR1 at 72 h post-seizure. Results: 8-HANQ attenuated ferroptotic death in HT22 cells, reducing lipid ROS accumulation and abnormal acyl-coA synthetase long chain family member 4 (ACSL4), suggesting 8-HANQ’s anti-ferroptotic action. Moreover, 8-HANQ also prevented aberrant STAT3-dependent cathepsin-B overexpression while modulating soluble N-cadherin-mediated FGFR1 activation. In vivo, 8-HANQ decreased KA-induced seizure behavior, restored hippocampal cathepsin-B and PSD95 expression, and partially alleviated dysregulation of FGFR1 activation. Conclusions: 8-HANQ prevents ferroptotic neuronal death and synaptic deficits involving FGFR1/STAT3/cathepsin-B-driven ferroptosis while lowering seizure severity, suggesting that 8-HANQ may serve as a potential anti-ferroptotic and anti-seizure agent. Full article

The IQSEC2 protein is a guanine nucleotide exchange factor for Arf6. Pathogenic variants in the X-linked IQSEC2 gene are associated with drug-resistant epilepsy, severe intellectual disability, and autism. The vast majority of disease-causing variants introduce premature termination codons into the IQSEC2 gene, resulting in little or no IQSEC2 protein being produced. Approximately 20% of cases are missense variants in the seven functional domains of the IQSEC2 protein. We sought to determine whether an adeno-associated virus (AAV) containing the IQSEC2 gene could rescue abnormal phenotypes in mice in two different Iqsec2 mouse models with premature Iqsec2 termination codons resulting in a knockout of the Iqsec2 gene expression and in mice with an A350V Iqsec2 missense mutation. In the Iqsec2 knockout mice, the AAV significantly improved growth, corrected behavioral abnormalities, and normalized the seizure threshold. Behavioral abnormalities were partially rescued in A350V mice, which expression studies suggest may have been due to the feedback inhibition of the endogenous Iqsec2 allele by viral IQSEC2. We propose that the success in the Iqsec2 knockout mice warrants a proof-of-concept study for gene replacement therapy in boys with IQSEC2 premature termination variants. Full article

Background: Functional Neurological Disorder (FND) encompasses conditions with neurological symptoms inconsistent with structural pathology, arising instead from complex interactions between psychological, biological, and social factors. Despite growing research, the etiological and risk factor landscape remains only partially understood, complicating diagnosis and treatment. Objective: This systematic review maps risk factors for major FND subtypes such as functional seizures (psychogenic non-epileptic seizures or PNES), functional cognitive disorder (FCD), functional movement disorders (FMD), functional weakness and sensory disturbances, functional visual symptoms, and functional gait abnormalities by categorizing predisposing, precipitating, and perpetuating influences. Methods: A systematic search of PubMed, PsycINFO, Scopus, and Web of Science initially identified 245 records. After removal of 64 duplicates, 181 studies were screened by title and abstract. Of these, 96 full texts were examined in detail, and finally 23 studies met the predefined inclusion criteria. Data were extracted and analyzed thematically within a biopsychosocial framework, with results summarized in subtype-specific profiles. Results: Childhood adversity, especially emotional, physical, or sexual abuse, emerged as a robust and consistent predisposing factor across PNES cohorts. Psychiatric history (notably anxiety, depression, and PTSD), neurodevelopmental traits (more frequent in FCD), and personality patterns such as alexithymia and somatization also contributed to vulnerability. Precipitating influences included acute psychological stress, intrapersonal conflict, or concurrent medical illness. Perpetuating factors comprise maladaptive illness beliefs, avoidance behaviors, insufficient explanation or validation by healthcare providers, and secondary gains related to disability. While several risk factors were shared across subtypes, others appeared subtype-specific (trauma was especially associated with PNES, whereas neurodevelopmental traits were more characteristic of FCD). Conclusions: FND arises from a dynamic interplay of predisposing, precipitating, and perpetuating factors, with both shared and subtype-specific influences. Recognizing this heterogeneity can enhance diagnostic precision, guide tailored intervention, and inform future research into the neurobiological and psychosocial mechanisms underlying FND. Full article

Oxidative stress and membrane damage are believed to be principally involved in the pathogenesis of epilepsy. This study aimed to assess the effects of phenosanic acid (PA), an antioxidant and membrane protector, in acute pentylenetetrazole and chronic lithium–pilocarpine seizure models in male Wistar rats. PA was administered acutely (ip, 120 mg/kg BW ip, or 240 mg/kg BW per os) or chronically (80 mg/kg BW/day per os). Indices of free radical oxidation, the hypothalamo–pituitary–adrenocortical axis, and the nitrergic system were assessed in blood and brain regions. Morphological analysis of the hippocampus was performed in the lithium–pilocarpine model. PA exerted an acute anti-seizure effect in the pentylenetetrazole model. In the lithium–pilocarpine model, acute PA treatment decreased the death rate and corticosterone levels in the neocortex and brainstem. In contrast, the level of free radical oxidation products reacting with thiobarbituric acid declined in the brain stem in response to chronic PA treatment. In the lithium–pilocarpine model, the neuronal density in the dentate gyrus was elevated, and the proliferating cell nuclear antigen positive (PCNA+) cell counts in the subgranular zone did not differ between groups. Doublecortin positive (DCX+) cell count was significantly increased after chronic PA treatment. PA-induced reduction in mortality in the lithium–pilocarpine epilepsy model may be partially mediated by decreasing the lipid peroxidation and corticosterone levels in different brain regions. Chronic PA treatment may affect adult hippocampal neurogenesis by either prolonging the action of factors that increase neurogenesis after status epilepticus or by slowing down the neuronal differentiation rate. These data suggest that PA may be a disease-modifying AED able to hamper epileptogenesis. Full article

Background and clinical significance: Functional/dissociative seizures (FDSs) in adolescents are paroxysmal events which superficially resemble epileptic seizures or syncope. This study evaluated the effectiveness of brief cognitive analytic therapy (CAT). Case presentation: The patient was a 17-year-old white cisgender male with a diagnosis of non-epileptic attack disorder. The functional/dissociative seizures were treated with 8-session CAT, with follow-up at 5 weeks. Two target problems (TPs) and associated target problem procedures (TPPs) were rated for recognition and revision at each session and at follow-up. An A-B-C-FU single-case experimental evaluation of the TP/TPPs was conducted. Nomothetic outcome measures (DES-2 and RCADS) were administered at session 1, session 8, and at follow-up, and the YP-CORE and the Session Rating Scale were completed at each session. The patient was independently interviewed using the Change Interview 13 weeks after completing therapy. The results show that CAT effectively increased the recognition and revision of TPs/TPPs, four specific changes occurred (including cessation of functional seizures). There were pre–post reliable and clinically significant improvements to psychological wellbeing, but these were not maintained at follow-up. Conclusions: This study indicates that CAT was a partially effective intervention. The use of CAT as a treatment for FND in adolescents holds promise, but more research is needed. Full article

Background/Objectives: Pathogenic variants in the growth differentiation factor 2 (GDF2) gene have been linked to a hereditary hemorrhagic telangiectasia (HHT)-like syndrome, yet their clinical significance remains under investigation. This study reports seven pediatric patients with GDF2 variants from a single center. Methods: We identified children with GDF2 pathogenic variants and variants of uncertain significance (VUS) from the Children’s Hospital of Philadelphia Comprehensive HHT Program and cross-referenced the list with a full-text query by GDF2 gene name on >53,000,000 visits to ensure complete ascertainment. Medical records were reviewed retrospectively, and variables of interest were abstracted. Results: The median age at genetic testing was 12 years (range 1.75–16). Reasons for genetic testing included telangiectasias, pulmonary hypertension, familial testing, respiratory symptoms, seizures, developmental disabilities, and lung arteriovenous malformations (AVMs). Four patients had missense VUS, including two novel VUS (c.34C>G; p.Leu12Val, c.41C>T; p.Ser14Phe), while three had pathogenic deletions. All patients experienced epistaxis, starting at a median age of 6 years (range 2–12). Three had telangiectasias. One patient had both a GDF2 VUS and a de novo partial endoglin (ENG) gene deletion. While this patient’s symptoms of HHT are likely related to her ENG variant, synergy cannot be excluded, and two first-degree family members with clinically significant epistaxis also have the same GDF2 VUS. Notably, two patients had visceral AVMs—one with a lung AVM and another with a vein of Galen malformation. Conclusions: Interpretation of GDF2 VUS and their relationship to clinical symptoms is challenging given the rarity of these genetic variants and the inadequate diagnostic utility of the current clinical criteria for HHT in the pediatric population. Further research with larger cohorts is necessary to improve the genotype–phenotype correlation in GDF2-related HHT. Carefully collected clinical information with longitudinal follow-up may also assist in refining classification of GDF2 VUS as benign or pathogenic in the future. Full article

A 7-year-old, 6.5 kg, neutered male toy poodle presented with tetraparesis, characterized by lower motor neuron signs in the forelimbs and upper motor neuron signs in the hindlimbs, along with seizures. Diagnostic imaging using magnetic resonance imaging (MRI) and computed tomography (CT) revealed a 1.4 cm × 1.4 cm × 2.2 cm mass in the fourth ventricle and caudal part of the brainstem. The surgical objective was to precisely remove masses compressing the cerebellum and brainstem. Using the telovelar approach, the tumor was partially excised, contrary to the goal of complete removal. Histopathological analysis confirmed the diagnosis of glioma. By the third postoperative day, the patient began to walk independently, and tetra-ataxia symptoms gradually decreased. Postoperative imaging confirmed the successful debulking of the tumor. By postoperative day 15, the patient showed normal gait, and adjuvant radiation therapy (RT) was initiated 2 weeks later. Unfortunately, the patient died 91 days after surgery, though the precise cause of death remains undetermined. Full article

Chemokine (CXC motif) ligand 8 (CXCL8) is a pro-inflammatory chemokine binding to CXC motif receptors 1/2 (CXCR1/2). Patients with temporal lobe epilepsy (TLE) exhibit increased serum CXCL8 levels. CXC motif ligand 1 (CXCL1), a murine ortholog of CXCL8, has been implicated in seizure generation and neuronal loss. This study evaluated the antiepileptogenic and antiseizure effects of reparixin in amygdaloid kindling rat model of TLE. Reparixin was administered during the kindling period for 14 days, and seizures were induced twice daily via electrical stimulation. To assess the antiseizure effects, reparixin was administered to fully kindled animals, and stimulations were performed 24 and 48 h later. Levetiracetam, a broad-spectrum antiseizure drug, was administered intraperitoneally (i.p.) as positive control 1 h before each stimulation. Reparixin delayed secondary seizure generalization during kindling. Reparixin reduced seizure severity and after-discharge duration in fully kindled animals at 24 h from treatment initiation. CXCR1/2 and protein kinase B pathway proteins exhibited no significant changes; reparixin reduced the phospho-extracellular signal-regulated kinase (pERK)/ERK ratio in the cortex and hippocampus. CXCL1 expression was significantly decreased in the cortex. Reparixin exhibited antiepileptogenic and partial antiseizure effects by modulating the CXCL1–CXCR1/2 axis and reducing ERK signaling. Already in clinical trials on respiratory diseases, reparixin could be repurposed for epilepsy therapy. Full article