Epileptic Lesions Research Articles

Dapagliflozin alleviated seizures and cognition impairment in pilocarpine induced status epilepticus via suppressing microglia-mediated neuroinflammation and oxidative stress.

Status epilepticus (SE) is a neurological emergency with prolonged seizures leading to chronic epilepsy, cognitive impairment, and neuronal damage. Microglial activation, subsequent neuroinflammation and oxidative stress contribute to SE-induced neuronal injury. Single-cell sequencing has delineated the pro-inflammatory microenvironment in epileptic lesions, characterized by widespread microglial activation. Dapagliflozin, an inhibitor of sodium-glucose cotransporter 2 (SGLT2), has shown potential in modulating neuroinflammatory responses. This study aimed to investigate the effects of Dapagliflozin on seizure and cognitive impairment by alleviating microglia-mediated neuroinflammation, oxidative stress. Single-Cell Transcriptomic Analysis were used to reveal SLC5A2 cellular heterogeneity and subtype-specific signatures of Temporal lobe Epilepsy. Male C57BL/6 mice were administered pilocarpine. Dapagliflozin were injected immediately after the termination of SE and at 24-hour intervals after SE until sacrifice. The latency and seizure score were recorded. Morris water maze were used to evaluate cognitive function of mouse. The neuroinflammation cell model was induced by lipopolysaccharide(LPS) in BV2 cell. Immunofluorescent staining, immunohistochemistry, flow cytometry, western blot, RT-qPCR, ELISA etc were used to examine the activation of microglia, evaluate neuroinflammation and oxidative stress. The expression of SLC5A2 is up-regulated in microglia of epileptic patients. Administration of Dapagliflozin significantly reduced seizure activity and improved cognitive performance in SE mouse. Dapagliflozin reduced microglial activation, as indicated by downregulation of CD86, iNOS expression and increased CD206, Arg-1 level. Dapagliflozin decreased oxidative stress, as evidenced by reduced levels of malondialdehyde (MDA), reactive oxygen species (ROS), increased superoxide dismutase (SOD) and Glutathione (GSH) activity. In addition, Dapagliflozin treatment can rescured the neuronal damage and suppressed the release of inflammatory cytokines such as IL-6, IL-18 and IL-1β. Our findings suggest that Dapagliflozin exerts neuroprotective effects by modulating microglia-mediated neuroinflammation and oxidative stress. The inhibition of SGLT2 may represent a novel therapeutic strategy for the treatment of SE and associated cognitive impairments.

High-field MRI findings in epileptic dogs with a normal inter-ictal neurological examination.

Epilepsy is one of the most common chronic neurological conditions affecting dogs. Previous research exploring the likelihood of a structural cause of epilepsy specifically in dogs with a normal inter-ictal examination is limited to a small population of dogs using low-field MRI. The aims of this study were to establish high-field (1.0T and 1.5T) MRI findings in dogs presenting with epileptic seizures and a normal inter-ictal examination. Medical records were retrospectively searched for dogs presenting with at least two epileptic seizure events more than 24 h apart. To be included in the study, patients had to have a normal neurological examination, high-field MRI of the brain and have had metabolic and toxic causes excluded. Four hundred and twelve dogs were eligible for inclusion. Crossbreeds were most commonly affected (n = 63, 15.3%) followed by Border collies (n = 39, 9.5%) and Labrador retrievers (n = 26, 6.3%). Seventy-six dogs (18.5%) had abnormalities detected on MRI, 60 (78.9%) of which were considered to be incidental. Overall, 16 dogs (3.9%) had a structural cause of their epileptic seizures including neoplasia (n = 13, 81.3%), anomalous (n = 2, 12.5%) and meningoencephalitis of unknown origin (MUO) (n = 1, 6.3%). When split into age group at first epileptic seizure structural lesions were documented in 0/66 dogs aged <1 year, 4/256 (1.6%) dogs aged ≥1 year ≤6 years (three neoplastic and one anomalous), 3/51 (5.9%) aged >6 years ≤8 years (two neoplastic and one MUO), and 9/39 (23.1%) dogs aged >8 years (eight neoplastic, one anomalous). Multivariate analysis identified two risk factors for structural disease: increasing age at first epileptic seizure (p < 0.001, OR = 4.390, CI 2.338-8.072) and a history of status epilepticus (p = 0.049, OR = 4.389, CI 1.010-19.078). Structural lesions are an uncommon cause of epilepsy at any age in dogs with a normal inter-ictal examination.

Stimuli-responsive nanoscale drug delivery system for epilepsy theranostics.

Epilepsy is a common neurological disease characterized by distinct pathological changes in the epileptogenic zone. Antiseizure drugs (ASDs) are widely used as the primary treatment for epilepsy. To improve the efficiency of ASDs medication, stimuli-responsive nanoscale drug delivery systems (nanoDDSs), triggered by either endogenous or exogenous factors, have been developed and been considered as a noninvasive and spatial-temporal approach to epilepsy theranostics. In this review, we introduce the pathological variations observed in epileptic lesions such as dysregulated neurotransmitter systems, disrupted ion homeostasis, and dynamic inflammatory cytokine networks. Furthermore, we summarize the recent advances in functional nano-assemblies that could be activated by endogenous stimuli of pathological alterations or exogenous stimuli such as electricity, light, and other interventions. Finally, we discuss the remaining challenges and prospect the insight into perspective of future development in this field. In summary, this review aims to highlight the potential of stimuli-responsive nanoDDSs as precise, controllable and efficient strategies for addressing unresolved issues in epilepsy theranostics. STATEMENT OF SIGNIFICANCE: This review summarizes recent progress in pathological changes such as dysregulated neurotransmitter system, disrupted ion homeostasis and dynamic inflammatory cytokine network, and emphasizes endogenous/exogenous stimuli-responsive nanoscale platforms including neurotransmitter-, ion-, and other stimuli-responsive nanoDDSs, providing the prospects of smart nanoDDSs applications and discussing the challenges to offer generalized guideline for further development of epilepsy theranostics.

Self-other voice discrimination task: A potential neuropsychological tool for clinical assessment of self-related deficits

BackgroundDeficits in self are commonly described through different neuro-pathologies, based on clinical evaluations and experimental paradigms. However, currently available approaches lack appropriate clinical validation, making objective evaluation and discrimination of self-related deficits challenging. MethodsWe applied a statistical standardized method to assess the clinical discriminatory capacity of a Self-Other Voice Discrimination (SOVD) task. This task, validated experimentally as a marker for self-related deficits, was administered to 17 patients eligible for neurosurgery due to focal hemispheric brain tumors or epileptic lesions. ResultsThe clinical discriminatory capacity of the SOVD task was evident in three patients who exhibited impairments for self-voice perception that could not be predicted by other neuropsychological deficits. Impairments in other-voice perception were linked to inhibitory neuropsychological deficits, suggesting a potential association with executive deficits in voice recognition. ConclusionsThis exploratory study highlights the clinical discriminatory potential of the SOVD task and suggests that it could complement the standard neuropsychological assessment, paving the way for enhanced diagnoses and tailored treatments for self-related deficits.

Altered expression of the Plexin-B2 system in tuberous sclerosis complex and focal cortical dysplasia IIb lesions.

Tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) type IIb are the predominant causes of drug-refractory epilepsy in children. Dysmorphic neurons (DNs), giant cells (GCs), and balloon cells (BCs) are the most typical pathogenic profiles in cortical lesions of TSC and FCD IIb patients. However, mechanisms underlying the pathological processes of TSC and FCD IIb remain obscure. The Plexin-B2-Sema4C signalling pathway plays critical roles in neuronal morphogenesis and corticogenesis during the development of the central nervous system. However, the role of the Plexin-B2 system in the pathogenic process of TSC and FCD IIb has not been identified. In the present study, we investigated the expression and cell distribution characteristics of Plexin-B2 and Sema4C in TSC and FCD IIb lesions with molecular technologies. Our results showed that the mRNA and protein levels of Plexin-B2 expression were significantly increased both in TSC and FCD IIb lesions versus that in the control cortex. Notably, Plexin-B2 was also predominantly observed in GCs in TSC epileptic lesions and BCs in FCD IIb lesions. In contrast, the expression of Sema4C, the ligand of Plexin-B2, was significantly decreased in DNs, GCs, and BCs in TSC and FCD IIb epileptic lesions. Additionally, Plexin-B2 and Sema4C were expressed in astrocytes and microglia cells in TSC and FCD IIb lesions. Furthermore, the expression of Plexin-B2 was positively correlated with seizure frequency in TSC and FCD IIb patients. In conclusion, our results showed the Plexin-B2-Sema4C system was abnormally expressed in cortical lesions of TSC and FCD IIb patients, signifying that the Plexin-B2-Sema4C system may play a role in the pathogenic development of TSC and FCD IIb.

Robot-assisted treatment of secondary epilepsy caused by parasitic infection: a case report

BackgroundCerebral sparganosis represents the most severe manifestation of sparganosis, with a relatively low global incidence. For cases of secondary epileptic seizures caused by sparganosis infection in the functional areas of the brain, what advanced neurosurgical techniques should be employed to precisely identify and excise the epileptic lesions in the deep functional areas of the brain, aiming to achieve maximal removal while minimising the risk of neurological deficits? This remains a current challenge for epilepsy surgeons.Case presentationA 24-year-old Chinese male was admitted to our hospital, presenting with a history of left limb twitching persisting for over a year. His main clinical symptoms presented twitching and numbness of his left limb without loss of consciousness. Under the premise of inappropriate anti-seizure treatment, recurrent epilepsy attacked persist. The patient's diagnosis was considered as “space-occupying lesions in the several lobes of brain, secondary epilepsy” after comprehensive assessment and discussion. And experts considered that the patient's space-occupying lesions in the right frontal and parietal lobes were highly suspected to be infected by parasites. This report delved into the application of neurosurgery robot-assisted frameless stereotaxic technology and intraoperative stereotactic electroencephalography (SEEG) monitoring technology to accurately locate and optimize removal of parasite-related epileptic lesions situated in functional areas of the brain. As a result, the patient had achieved seizure freedom, leaving no symptoms of neurological deficit.ConclusionsWith the highly integrated development of imaging technology, mechanical technology, computer control technology, and artificial intelligence, surgical robots are poised to play a larger role across various neurosurgical specialties in the future. Considering benefits for patients and the promising application of this technology, its utilization holds significant value.

Intrahippocampal Supramolecular Assemblies Directed Bioorthogonal Liberation of Neurotransmitters to Suppress Seizures in Freely Moving Mice.

The precise delivery of anti-seizure medications (ASM) to epileptic loci remains the major challenge to treat epilepsy without causing adverse drug reactions. The unprovoked nature of epileptic seizures raises the additional need to release ASMs in a spatiotemporal controlled manner. Targeting the oxidative stress in epileptic lesions, here the reactive oxygen species (ROS) induced in situ supramolecular assemblies that synergized bioorthogonal reactions to deliver inhibitory neurotransmitter (GABA) on-demand, are developed. Tetrazine-bearing assembly precursors undergo oxidation and selectively self-assemble under pathological conditions inside primary neurons and mice brains. Assemblies induce local accumulation of tetrazine in the hippocampus CA3 region, which allows the subsequent bioorthogonal release of inhibitory neurotransmitters. For induced acute seizures, the sustained release of GABA extends the suppression than the direct supply of GABA. In the model of permanent damage of CA3, bioorthogonal ligation on assemblies provides a reservoir of GABA that behaves prompt release upon 365nm irradiation. Incorporated with the state-of-the-art microelectrode arrays, it is elucidated that the bioorthogonal release of GABA shifts the neuron spike waveforms to suppress seizures at the single-neuron precision. The strategy of in situ supramolecular assemblies-directed bioorthogonal prodrug activation shall be promising for the effective delivery of ASMs to treat epilepsy.

Multimodal non-invasive evaluation in MRI-negative epilepsy patients.

Presurgical evaluation is still challenging for MRI-negative epilepsy patients. As non-invasive modalities are the easiest acceptable and economic methods in determining the epileptogenic zone, we analyzed the localization value of common non-invasive methods in MRI-negative epilepsy patients. In this study, we included epilepsy patients undergoing presurgical evaluation with presurgical negative MRI. MRI post-processing was performed using a Morphometric Analysis Program (MAP) on T1-weighted volumetric MRI. The relationship between MAP, magnetoencephalography (MEG), scalp electroencephalogram (EEG), and seizure outcomes was analyzed to figure out the localization value of different non-invasive methods. Eighty-six patients were included in this study. Complete resection of the MAP-positive regions or the MEG-positive regions was positively associated with seizure freedom (p = 0.028 and 0.007, respectively). When an area is co-localized by MAP and MEG, the resection of the area was significantly associated with seizure freedom (p = 0.006). However, neither the EEG lateralization nor the EEG localization showed statistical association with the surgical outcome (p = 0.683 and 0.505, respectively). In conclusion, scalp EEG had a limited role in presurgical localization and predicting seizure outcome, combining MAP and MEG results can significantly improve the localization of epileptogenic lesions and have a positive association with seizure-free outcome. PLAIN LANGUAGE SUMMARY: Due to the lack of obvious structure abnormalities on neuroimaging examinations, the identification of epilepsy lesions in MRI-negative epilepsy patients can be difficult. In this study, we intended to use non-invasive examinations to explore the potential epileptic lesions in MRI-negative epilepsy patients and to determine the results accuracy by comparing the neuroimaging results with the epilepsy surgery outcomes. A total of 86 epilepsy patients without obvious structure lesions on MRI were included, and we found that the combinations of different non-invasive examinations and neuroimaging post-processing methods are significantly associated with the seizure freedom results of epilepsy surgery.

Association Of Electroencephalogram Patterns With Ammonia Levels In Hepatic Encephalopathy Patients

Objective: To find out the association between electroencephalogram (EEG) and hepatic encephalopathy.&#x0D; Methodology: This cross-sectional study included 100 patients (with the age of52.5±6.09years for males and 51.7 ± 6.10 years for females) of reported hepatic encephalopathy, visiting the medical department (indoor and OPD) at Federal Government Polyclinic Hospital, Islamabad. The study was conducted from January 2020 to May 2021. Patients who had known epileptic and structural brain lesions or strokes were excluded from the study. Statistical analysis was done using GraphPad Prism software. The significance of data (p-value or R2 value) was calculated through a two-tailed test or correlation coefficient.&#x0D; Results: All the patients in hepatic encephalopathy grade IV reported abnormal EEG representing triphasic waves and flattening of EEG pattern. There was no correlation observed between age, gender and hepatic encephalopathy grades. However, a significant correlation (R2= 0.9032) was observed between serum ammonia levels and hepatic encephalopathy grades. Elevated serum ammonia levels depicted the severity of hepatic encephalopathy. Overall, the percentage of patients with abnormal EEG increased with increasing grade of hepatic encephalopathy. It was quite intriguing to note that EEG, being the common method to diagnose hepatic encephalopathy grades, is not dependent on patients’ socio-economic status.&#x0D; Conclusion: Data concluded that serum ammonia levels are well associated with the progression of hepatic encephalopathy. Moreover, the EEG patter provides the appropriate information about the neurological abnormalities associated with the severity of hepatic encephalopathy. Hence, serum ammonia levels and EEG both should accurately be used as indicators for diagnosis and monitoring the response to the treatment of various grades of hepatic encephalopathy. Data warrant further investigations to get a better insight into hepatic encephalopathy's relationship with EEG patterns through the inclusion of molecular parameters.

Meningioangiomatosis with Skull Erosion

Meningioangiomatosis (MA) is a rare, poorly studied brain hamartomatous lesion, the etiology of which is not fully elucidated. It typically involves the leptomeninges, extending to the underlying cortex, characterized by small vessel proliferation, perivascular cuffing, and scattered calcifications. Given its close proximity to, or direct involvement of, the cerebral cortex, MA lesions typically manifest in younger patients as recurrent episodes of refractory seizures, comprising approximately 0.6% of operated-on intractable epileptic lesions. Due to the absence of characteristic radiological features, MA lesions constitute a significant radiological challenge, making them easy to miss or misinterpret. Although MA lesions are rarely reported with still-unknown etiology, it is prudent to be aware of these lesions for prompt diagnosis and management to avoid morbidity and mortality associated with delayed diagnosis and treatment. We present a case of a young patient with a first-time seizure caused by a right parieto-occipital MA lesion that was successfully excised via an awake craniotomy, achieving 100% seizure control.

ROS/Electro Dual-Reactive Nanogel for Targeting Epileptic Foci to Remodel Aberrant Circuits and Inflammatory Microenvironment.

Medicinal treatment against epilepsy is faced with intractable problems, especially epileptogenesis that cannot be blocked by clinical antiepileptic drugs (AEDs) during the latency of epilepsy. Abnormal circuits of neurons interact with the inflammatory microenvironment of glial cells in epileptic foci, resulting in recurrent seizures and refractory epilepsy. Herein, we have selected phenytoin (PHT) as a model drug to derive a ROS-responsive and consuming prodrug, which is combined with an electro-responsive group (sulfonate sodium, SS) and an epileptic focus-recognizing group (α-methyl-l-tryptophan, AMT) to form hydrogel nanoparticles (i.e., a nanogel). The nanogel will target epileptic foci, release PHT in response to a high concentration of reactive oxygen species (ROS) in the microenvironment, and inhibit overexcited circuits. Meanwhile, with the clearance of ROS, the nanogel can also reduce oxidative stress and alleviate microenvironment inflammation. Thus, a synergistic regulation of epileptic lesions will be achieved. Our nanogel is expected to provide a more comprehensive strategy for antiepileptic treatment.

Metabolic profiles and correlation with surgical outcomes in mesial versus neocortical temporal lobe epilepsy.

Differentiating mesial temporal lobe epilepsy (MTLE) and neocortical temporal lobe epilepsy (NTLE) remains challenging. Our study characterized the metabolic profiles between MTLE and NTLE and their correlation with surgical prognosis using 18 F-FDG-PET. A total of 137 patients with intractable temporal lobe epilepsy (TLE) and 40 age-matched healthy controls were recruited. Patients were divided into the MTLE group (N = 91) and the NTLE group (N = 46). 18 F-FDG-PET was used to measure the metabolism of regional cerebra, which was analyzed using statistical parametric mapping. The volume of abnormal metabolism in cerebral regions and their relationship with surgical prognosis were calculated for each surgical patient. The cerebral hypometabolism of MTLE was limited to the ipsilateral temporal and insular lobes (p < 0.001, uncorrected). The NTLE patients showed hypometabolism in the ipsilateral temporal, frontal, and parietal lobes (p < 0.001, uncorrected). The MTLE patients showed extensive hypermetabolism in cerebral regions (p < 0.001, uncorrected). Hypermetabolism in NTLE was limited to the contralateral temporal lobe and cerebellum, ipsilateral frontal lobe, occipital lobe, and bilateral thalamus (p < 0.001, uncorrected). Among patients who underwent resection of epileptic lesions, 51 (67.1%) patients in the MTLE group and 10 (43.5%) in the NTLE group achieved Engel class IA outcome (p = 0.041). The volumes of metabolic increase for the frontal lobe or thalamus in the MTLE group were larger in non-Engel class IA patients than Engel class IA patients (p < 0.05). The spatial metabolic profile discriminated NTLE from MTLE. Hypermetabolism of the thalamus and frontal lobe in MTLE may facilitate preoperative counseling and surgical planning.

Anterior temporal lobectomy improved mood status and quality of life in Chinese patients with mesial temporal lobe epilepsy: a single-arm cohort study.

Many studies have emphasized that selective resection of epileptic lesions in temoral lobe is associated with better preservation of cognition function; whether this applies to patients with refractory mesial temporal lobe epilepsy (MTLE) remains unknown. The objective of this study was to evaluate changes in cognitive functions, mood status, and quality of life after anterior temporal lobectomy in patients with refractory MTLE. This single-arm cohort study assessed cognitive function, mood status, and quality of life, as well as electroencephalography findings, in patients with refractory MTLE who underwent anterior temporal lobectomy at Xuanwu Hospital from January 2018 to March 2019. Pre- and post-operative characteristics were compared to evaluate the effects of surgery. Anterior temporal lobectomy significantly reduced the frequencies of epileptiform discharges. The overall success rate of surgery was acceptable. Anterior temporal lobectomy did not result in significant changes in overall cognitive functions (P > 0.05), although changes in certain domains, including visuospatial ability, executive ability, and abstract thinking, were detected. Anterior temporal lobectomy resulted in improvements in anxiety and depression symptoms and quality of life. Anterior temporal lobectomy reduced epileptiform discharges and incidence of post-operative seizures as well as resulted in improved mood status and quality of life without causing significant changes in cognitive function.

A Potent Antagonist of Smoothened in Hedgehog Signaling for Epilepsy.

Epilepsy is one of the common encephalopathies caused by sudden abnormal discharges of neurons in the brain. About 30% of patients with epilepsy are insensitive and refractory to existing antiseizure medications. The sonic hedgehog signaling pathway is essential to the development and homeostasis of brain. Aberrant sonic hedgehog signaling is increased in refractory epileptic lesions and may involve the etiology of epilepsy. Thus, new inhibitors of Smoothened, a key signal transducer of this signaling pathway are urgently need for refractory epilepsy. We have established a high-throughput screening platform and discovered several active small molecules targeting Smoothened including TT22. Here we show that the novel Smoothened inhibitor TT22 could block the translocation of βarrestin2-GFP to Smoothened, reduce the accumulation of Smoothened on primary cilia, displace Bodipy-cyclopamine binding to Smoothened, and inhibit the expression of downstream Gli transcription factor. Moreover, TT22 inhibits the abnormal seizure-like activity in neurons. Furthermore, we demonstrated that FDA-approved Smoothened inhibitor GDC-0449 and LDE-225 are able to inhibit abnormal seizure-like activity in neurons. Thus, our study suggests that targeting the sonic hedgehog signaling with new small-molecule Smoothened inhibitors might provide a potential new therapeutic avenue for refractory epilepsy.

The genomic landscape across 474 surgically accessible epileptogenic human brain lesions.

Understanding the exact molecular mechanisms involved in the etiology of epileptogenic pathologies with or without tumor activity is essential for improving treatment of drug-resistant focal epilepsy. Here, we characterize the landscape of somatic genetic variants in resected brain specimens from 474 individuals with drug-resistant focal epilepsy using deep whole-exome sequencing (>350×) and whole-genome genotyping. Across the exome, we observe a greater number of somatic single-nucleotide variants (SNV) in low-grade epilepsy-associated tumors (LEAT; 7.92 ± 5.65 SNV) than in brain tissue from malformations of cortical development (MCD; 6.11 ± 4 SNV) or hippocampal sclerosis (HS; 5.1 ± 3.04 SNV). Tumor tissues also had the largest number of likely pathogenic variant carrying cells. LEAT had the highest proportion of samples with one or more somatic copy number variants (CNV; 24.7%), followed by MCD (5.4%) and HS (4.1%). Recurring somatic whole chromosome duplications affecting Chromosome 7 (16.8%), chromosome 5 (10.9%), and chromosome 20 (9.9%) were observed among LEAT. For germline variant-associated MCD genes such as TSC2, DEPDC5, and PTEN, germline SNV were frequently identified within large loss of heterozygosity regions, supporting the recently proposed 'second hit' disease mechanism in these genes. We detect somatic variants in twelve established lesional epilepsy genes and demonstrate exome-wide statistical support for three of these in the etiology of LEAT (e.g., BRAF) and MCD (e.g., SLC35A2 and MTOR). We also identify novel significant associations for PTPN11 with LEAT and NRAS Q61 mutated protein with a complex MCD characterized by polymicrogyria and nodular heterotopia. The variants identified in NRAS are known from cancer studies to lead to hyperactivation of NRAS, which can be targeted pharmacologically. We identify large recurrent 1q21-q44 duplication including AKT3 in association with focal cortical dysplasia type 2a with hyaline astrocytic inclusions, another rare and possibly under-recognized brain lesion. The clinical genetic analyses showed that the numbers of somatic SNV across the exome and the fraction of affected cells were positively correlated with the age at seizure onset and surgery in individuals with LEAT. In summary, our comprehensive genetic screen sheds light on the genome-scale landscape of genetic variants in epileptic brain lesions, informs the design of gene panels for clinical diagnostic screening, and guides future directions for clinical implementation of epilepsy surgery genetics.

Surgery for Epilepsy Involving Rolandic and Perirolandic Cortex: A Case Series Assessing Complications and Efficacy.

Surgical removal of lesions around the rolandic cortex remains a challenge for neurosurgeons owing to the high risk of neurological deficits. Evaluating the risk factors associated with motor deficits after surgery in this region may help reduce the occurrence of motor deficits. To report our surgical experience in treating epileptic lesions involving the rolandic and perirolandic cortices. We performed a single-center retrospective review of patients undergoing epilepsy surgeries with lesions located in the rolandic and perirolandic cortices. Patients with detailed follow-up information were included. The lesion locations, resected regions, and invasive exploration techniques were studied to assess their relationship with postoperative motor deficits. Forty-one patients were included. Twenty-three patients suffered from a transient motor deficit, and 2 had permanent disabilities after surgery. Six patients with lesions at the posterior bank of the precentral sulcus underwent resection, and 5 experienced short-term motor deficits. Two patients with lesions adjacent to the anterior part of the precentral gyrus, in whom the adjacent precentral gyrus was removed, experienced permanent motor deficits. Lesions located at the bottom of the central sulcus and invading the anterior bank of the central sulcus were observed in 3 patients. The patients did not experience permanent motor deficits after surgery. The anterior bank of the central sulcus is indispensable for motor function, and destruction of this region would inevitably cause motor deficits. The anterior bank of the precentral gyrus can also be removed without motor impairment if there is a preexisting epileptogenic lesion.

Single cell transcriptomics of human brain epileptic lesions identifies pro-inflammatory signaling based on interlacing cellular immune networks

Single cell transcriptomics of human brain epileptic lesions identifies pro-inflammatory signaling based on interlacing cellular immune networks

Single-cell transcriptomics and surface epitope detection in human brain epileptic lesions identifies pro-inflammatory signaling

Epileptogenic triggers are multifactorial and not well understood. Here we aimed to address the hypothesis that inappropriate pro-inflammatory mechanisms contribute to the pathogenesis of refractory epilepsy (non-responsiveness to antiepileptic drugs) in human patients. We used single-cell cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to reveal the immunotranscriptome of surgically resected epileptic lesion tissues. Our approach uncovered a pro-inflammatory microenvironment, including extensive activation of microglia and infiltration of other pro-inflammatory immune cells. These findings were supported by ligand–receptor (LR) interactome analysis, which demonstrated potential mechanisms of infiltration and evidence of direct physical interactions between microglia and T cells. Together, these data provide insight into the immune microenvironment in epileptic tissue, which may aid the development of new therapeutics.

Guiding Epilepsy Surgery with an LRP1-Targeted SPECT/SERRS Dual-Mode Imaging Probe.

Accurate identification of the resectable epileptic lesion is a precondition of operative intervention to drug-resistant epilepsy (DRE) patients. However, even when multiple diagnostic modalities are combined, epileptic foci cannot be accurately identified in ∼30% of DRE patients. Inflammation-associated low-density lipoprotein receptor-related protein-1 (LRP1) has been validated to be a surrogate target for imaging epileptic foci. Here, we reported an LRP1-targeted dual-mode probe that is capable of providing comprehensive epilepsy information preoperatively with SPECT imaging while intraoperatively delineating epileptic margins in a sensitive high-contrast manner with surface-enhanced resonance Raman scattering (SERRS) imaging. Notably, a novel and universal strategy for constructing self-assembled monolayer (SAM)-based Raman reporters was proposed for boosting the sensitivity, stability, reproducibility, and quantifiability of the SERRS signal. The probe showed high efficacy to penetrate the blood-brain barrier. SPECT imaging showed the probe could delineate the epileptic foci clearly with a high target-to-background ratio (4.11 ± 0.71, 2 h). Further, with the assistance of the probe, attenuated seizure frequency in the epileptic mouse models was achieved by using SPECT together with Raman images before and during operation, respectively. Overall, this work highlights a new strategy to develop a SPECT/SERRS dual-mode probe for comprehensive epilepsy surgery that can overcome the brain shift by the co-registration of preoperative SPECT and SERRS intraoperative images.

Profiling PI3K-AKT-MTOR variants in focal brain malformations reveals new insights for diagnostic care.

Focal malformations of cortical development including focal cortical dysplasia, hemimegalencephaly and megalencephaly, are a spectrum of neurodevelopmental disorders associated with brain overgrowth, cellular and architectural dysplasia, intractable epilepsy, autism and intellectual disability. Importantly, focal cortical dysplasia is the most common cause of focal intractable paediatric epilepsy. Gain and loss of function variants in the PI3K-AKT-MTOR pathway have been identified in this spectrum, with variable levels of mosaicism and tissue distribution. In this study, we performed deep molecular profiling of common PI3K-AKT-MTOR pathway variants in surgically resected tissues using droplet digital polymerase chain reaction (ddPCR), combined with analysis of key phenotype data. A total of 159 samples, including 124 brain tissue samples, were collected from 58 children with focal malformations of cortical development. We designed an ultra-sensitive and highly targeted molecular diagnostic panel using ddPCR for six mutational hotspots in three PI3K-AKT-MTOR pathway genes, namely PIK3CA (p.E542K, p.E545K, p.H1047R), AKT3 (p.E17K) and MTOR (p.S2215F, p.S2215Y). We quantified the level of mosaicism across all samples and correlated genotypes with key clinical, neuroimaging and histopathological data. Pathogenic variants were identified in 17 individuals, with an overall molecular solve rate of 29.31%. Variant allele fractions ranged from 0.14 to 22.67% across all mutation-positive samples. Our data show that pathogenic MTOR variants are mostly associated with focal cortical dysplasia, whereas pathogenic PIK3CA variants are more frequent in hemimegalencephaly. Further, the presence of one of these hotspot mutations correlated with earlier onset of epilepsy. However, levels of mosaicism did not correlate with the severity of the cortical malformation by neuroimaging or histopathology. Importantly, we could not identify these mutational hotspots in other types of surgically resected epileptic lesions (e.g. polymicrogyria or mesial temporal sclerosis) suggesting that PI3K-AKT-MTOR mutations are specifically causal in the focal cortical dysplasia-hemimegalencephaly spectrum. Finally, our data suggest that ultra-sensitive molecular profiling of the most common PI3K-AKT-MTOR mutations by targeted sequencing droplet digital polymerase chain reaction is an effective molecular approach for these disorders with a good diagnostic yield when paired with neuroimaging and histopathology.