Seizures are symptoms of epilepsy but spontaneous seizure recurrence can also be considered a biomarker of disease progression. The temporary imbalance between excitatory and inhibitory drive that culminates in a hyperexcitable, hypersynchronous state clinically observed as seizure, initiates an insidious cascade of neurochemical, structural, genetic, epigenetic, and neuroinflammatory processes that increases seizure frequency, duration, and severity. As seizure activity increases, the hyperexcitable and hypersynchronous states entrain neuronal networks, leading to a further reduction in seizure threshold and further increases in seizure frequency, duration, and severity over time. The pathological circuitry generated and sustained by epileptic events not only drive hyperexcitable states within the seizure circuit but also can affect wider network connections. These effects lead to altered network physiology, which is associated with neuropsychiatric comorbidities, such as cognitive decline and psychiatric disorders, and can impact the operation of other organ systems. Here, we review the current understanding of how seizures can hijack normal brain function and set off a cascade of pathobiological events that support continued seizure activity and epilepsy progression. Understanding the neurobiology of seizure progression is fundamental to building comprehensive treatment strategies and developing new pharmacotherapies that aim to retrain seizure circuitry, with the goal of reducing overall seizure burden, improving quality of life, and limiting disease progression.

Dengue is a major mosquito-borne viral illness affecting tropical and subtropical regions worldwide and remains an important cause of critical care admissions. Although most infections are self-limited, a subset progresses to severe dengue characterized by plasma leakage, shock, severe bleeding, and end-organ dysfunction. Neurological manifestations are uncommon but increasingly recognized under the spectrum of expanded dengue syndrome, including seizures, encephalopathy, cerebral edema, ischemic stroke, and intracranial hemorrhage. We report a fatal case of a 29-year-old previously healthy man with significant occupational and environmental heat exposure in a tropical setting. He presented after two generalized tonic-clonic seizures followed by profound unconsciousness. He had experienced four days of continuous fever, retro-orbital pain, myalgia, and arthralgia and had been diagnosed one day earlier with NS1-positive dengue fever without warning signs. On arrival, his temperature was 41°C, and his skin was hot and dry; shortly afterward, he developed respiratory arrest requiring emergency intubation, making environmental heat stroke an important initial differential diagnosis. Brain imaging demonstrated subarachnoid hemorrhage and diffuse cerebral edema. During intensive care, he developed progressive hemoconcentration, dengue shock syndrome, coagulopathy suggestive of disseminated intravascular coagulation, acute kidney injury, hepatic dysfunction, lactic acidosis, and refractory shock despite fluid resuscitation, vasopressor support, neurocritical care, and blood product replacement, ultimately resulting in death. This case highlights the diagnostic challenge posed by the overlap between severe dengue and heat-stroke-like presentations, particularly in individuals with significant exposure to environmental heat.

The structure-function gradient along the hippocampal long axis is recognized but poorly understood. Rodent recordings mainly sample the dorsal hippocampus (posterior), while surgical recordings in epilepsy patients typically sample from the ventral hippocampus (anterior), because of greater known involvement in seizure networks. These divergent recording practices imply that the mechanisms of rodent spatial navigation may not directly apply to human episodic memory. In general, the role of the posterior hippocampus in human memory and seizure networks is under-appreciated. We survey the basic, translational, and clinical research accounting for long-axis differentiation and outline future research directions.

Epilepsy is a prevalent neurological disorder characterized by recurrent seizures and significant impacts on quality of life. This case report describes a 2-year-old male patient presenting with epilepsy associated with fever, in whom whole-exome sequencing (WES) revealed a novel de novo variant in the KCNMA1 gene, resulting in the amino acid substitution p.Leu187His. This variant is classified as likely pathogenic and is situated within a key functional domain of the BK channel, a crucial regulator of neuronal excitability. In silico analyses suggest that the substitution alters the local hydrophobicity and may disrupt the channel's function, potentially contributing to the patient's seizure activity. Additionally, the identification of this genetic variant underscores the importance of genetic factors in epilepsy, particularly in cases of drug-resistant epilepsy (DRE) or those with unclear etiology. The findings highlight the utility of WES in diagnosing genetically mediated epilepsy and the need for further research to establish comprehensive genotype-phenotype correlations, ultimately guiding personalized treatment strategies for affected individuals.

Epileptic seizures and interictal epileptiform discharges are strongly influenced by sleep and circadian rhythms. However, human data on the effect of sleep on neuronal behaviour during interictal activity have been lacking. We analysed EEG from eight epileptic patients implanted with macro and micro electrodes in mesial temporal structures. Sleep staging was performed on polysomnography and video-EEG. Automated detection identified thousands of interictal epileptiform discharges per patient. Both their rate and amplitude increased with deeper stages of non-rapid eye movement sleep. Single- and multi-unit firing rates were often temporally coupled with local field potentials, exhibiting increased firing during the spike and decreased activity during the following slow wave. These time-locked firing rate modulations were shown to increase during deeper stages of non-rapid eye movement sleep. Furthermore, neuronal background activity showed a decrease in firing rate, bursting and regularity with deeper stages of non-rapid eye movement sleep.

Examination of cause of death patterns among disabled people is shrouded by death patterns in the general population. To remove this shroud, we focus on multiple causes of death (MCOD) comorbidity patterns between decedents with and without Down syndrome with Alzheimer's disease or unspecified dementia. Using 2005 to 2019 U.S. MCOD data, we examined comorbidity profiles of adults with (N = 7,936) and without (N = 4,593,118) Down syndrome using the broadest International Classification of Diseases (ICD-10) "List of 113 Selected Causes of Death" (selected cause groups) of death classification scheme as well as the ICD-10 "Specific Conditions" (specific causes). Comparison of these classification schemes revealed that the use of selected cause groups veiled comorbidities common among adults with Down syndrome-choking-related deaths, seizures and hypothyroidism. Results from this study underscore the necessity to change cause of death classifications schemes and/or the reporting of this information to account for differences and to mitigate data inequities.

IntroductionBipolar depression is disabling and often inadequately responsive to medication alone. The current efficacy evidence of transcranial magnetic stimulation (TMS) for bipolar depression is conflicting. Therefore, we synthesized randomized controlled trials (RCTs) that tested the efficacy, safety, and tolerability of TMS for bipolar depression.MethodsWe searched MEDLINE/EMBASE/Cochrane/PsycINFO/gray literature (01/10/2025) for RCTs comparing any TMS protocol with sham. Co-primary outcomes were depressive symptoms, all-cause discontinuation; secondary outcomes were response, remission. Risk of bias (RoB) was assessed with RoB-2. Random-effects models estimated standardized mean differences (SMDs) and risk ratios (RRs) with 95% confidence intervals (95%CI), alongside sensitivity, subgroup, and meta-regression analyses.ResultsNineteen comparisons from 17 RCTs (N = 563; TMS = 293, sham = 270; mean N TMS = 15.4, sham = 15.9; mean duration = 2.40 weeks; RoB "low" = 35%, "some concerns" = 65%) were included. Among trials reporting subtypes (k = 13), 41.8% of participants had bipolar I disorder, and 58.2% had bipolar II disorder. The left dorsolateral prefrontal cortex was the most common target (k = 12). TMS reduced depressive symptoms versus sham (SMD = -0.34; 95%CI = -0.58 to -0.11), with no difference in all-cause discontinuation. TMS was favoured for response (RR = 1.41; 95%CI = 1.10 to 1.80) and remission (RR = 1.54; 95%CI = 1.06 to 2.23). However, these effects were not consistently confirmed in sensitivity or subgroup analyses by RoB, TMS type, stimulation site, or treatment resistance. Overall, 15 comparisons (88.2%) did not show superiority of TMS over sham for depressive symptoms at the individual trial level. No seizures or serious adverse events occurred; adverse events did not differ from sham. Meta-regression suggested a greater number of total pulses was associated with greater depressive symptom reduction (β = -0.018; p = .00017).ConclusionsTMS shows a small meta-analytic antidepressant effect and acceptable tolerability in bipolar depression despite most individual trials being negative. However, subgroups and sensitivity findings did not support TMS as an efficacious treatment at current doses. Further testing via larger RCTs with higher-dose protocols is warranted.

Drug-resistant epilepsy (DRE) represents a major clinical hazard, characterised by persistent uncontrolled seizures that elevate risks of trauma, cognitive deterioration, psychiatric comorbidity, and sudden unexpected death in epilepsy, while cumulative medication exposure, healthcare burden, and functional impairment substantially worsen long-term morbidity and quality of life. In DRE, disruptions in GABAA receptors (GABAAR) function through altered subunit composition, receptor mislocalisation, or impaired trafficking, undermine inhibitory control and contribute to persistent seizures. The regulation of intracellular chloride by NKCC1 and KCC2 further shapes GABAAR-mediated inhibition, where imbalances in these transporters exacerbate network hyperexcitability. Structural studies, including high-resolution cryo-EM, reveal how ligand binding, receptor conformation, and interactions with auxiliary proteins modulate GABAAR activity, offering insights into why some subtypes respond differently to benzodiazepines or neurosteroids. Emerging evidence suggests that targeting receptor-associated proteins, trafficking pathways, or specific subunit combinations may offer novel ways to restore inhibitory tone and overcome pharmacoresistance. Understanding how these molecular, structural, and cellular factors converge to alter GABAAR function provides a roadmap for designing therapies that are both effective and precise, especially for DRE. By unravelling the mechanisms behind GABAAR dysfunction in DRE, new avenues open for restoring network stability and improving outcomes for patients living with DRE.

Epilepsy, a neurological condition, is characterized by frequent, spontaneous seizures. Both apolipoprotein E (ApoE) and TAM (Tyro3, Axl and MerTK) receptors, the key efferocytosis receptors, have been associated with the pathological mechanisms underlying epilepsy. Nevertheless, little is known about how they interact or the molecular mechanisms. Here, we explored how ApoE and microglial efferocytosis interact in a mouse model of acute seizures caused by kainic acid (KA). KA exposure reduced microglial efferocytosis that is dependent on growth arrest-specific protein 6 (Gas6)/MER proto-oncogene tyrosine kinase (MerTK). Additionally, KA treatment increased microglial ApoE expression, whereas ApoE knockout restored Gas6/MerTK-mediated microglial efferocytosis and alleviated KA-induced seizures and neuronal injury. Furthermore, KA exposure promoted ApoE immunoprecipitation with nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3). ApoE knockout suppressed KA-induced NLRP3 inflammasome activation. Interestingly, KA-induced seizures and neuronal injury were lessened by hippocampal NLRP3 knockdown, which further preserved Gas6/MerTK-dependent microglial efferocytosis. Furthermore, exogenous delivery of recombinant Gas6 had anti-seizure and neuroprotective benefits in addition to restoring microglial efferocytosis function. Collectively, ApoE stimulates NLRP3 inflammasome activation and targets Gas6/MerTK in seizure-prone mice, thereby impairing microglial efferocytosis. For the treatment of seizures, the ApoE-NLRP3-Gas6/MerTK axis may represent a potential therapeutic target.

Translational large-animal models that can accommodate human-scale implantable devices are essential for advancing neuromodulation therapies in epilepsy. This study establishes a kainic acid (KA)-induced porcine model of mesial temporal lobe epilepsy (mTLE) using clinical imaging, stereotactic surgery, and a fully implantable neural stimulator-recorder (INSR) device designed for humans. Seven pigs (six KA-treated and one saline control) underwent MRI-guided stereotactic implantation of electrodes targeting bilateral hippocampus (HPC) and anterior thalamus (ANT), followed by intra-hippocampal KA or saline infusion. Local field potentials (LFP) were recorded continuously with synchronized video monitoring. Seizures and LFP interictal epileptiform-like discharges (IEDs) were quantified using validated automated detectors. Histology was performed in the saline control and the longest surviving KA-treated pig. Intra-hippocampal KA infusion induced acute status epilepticus in all treated pigs (6/6). Four animals survived to chronic monitoring with spontaneous seizures observed in three pigs (2,733 seizures; mean duration of 27.2 ± 17.6 s). IEDs were observed in bilateral HPC of all animals, including saline control, with higher rates in the lesioned HPC (p < 0.0001). While the IED morphology is consistent with epileptiform activity, IEDs alone are not specific for epilepsy and physiological transients (e.g. sharp-wave ripples) and injury-related hyperexcitability or strain-specific hyperexcitability cannot be excluded. Histological analysis revealed patchy neuronal loss and cytoarchitectural changes in HPC. This porcine model reproduces electrophysiological features of human mTLE. This approach provides a powerful translational bridge for developing and testing next-generation INSR and neuromodulation strategies in freely behaving large animals.