We attempted to classify, according to the International Classification of Epilepsies and Epileptic Syndromes (1989), 302 patients at a tertiary epilepsy referral center. Proportion in categories as defined by the int...We attempted to classify, according to the International Classification of Epilepsies and Epileptic Syndromes (1989), 302 patients at a tertiary epilepsy referral center. Proportion in categories as defined by the international League Against Epilepsy (ILAE) were as follows: localization-related epilepsies: 62. 9 %,generalized epilepsies: 22. 2%,epilepsies undetermined whether focal or generalized: 14. 2%, special syndromes: 0. 7%. Only 26. 8 % cases were definitely classified in single diagnostic ILAE categories based on ictal CCTV/EEG recordings. The distribution of epileptic syndromes was different from the previous reports due to various methods of case ascertainment and inclusion criteria. Use of specific criteria for the reliability study of international classification has been proposed.展开更多
Description： The progressive myoclonus epilepsies （PME＇s） comprise a large group of genetically determined disorders characterized by myoclonus, generalized tonic-clonic seizures, cerebellar dysfunction and variab...Description： The progressive myoclonus epilepsies （PME＇s） comprise a large group of genetically determined disorders characterized by myoclonus, generalized tonic-clonic seizures, cerebellar dysfunction and variable degrees of cognitive impairment.展开更多
Objective To investigate the difference in interictal perfusion patterns between refractory and non-refractory temporal lobe epilepsies evaluated with flow-sensitive alternating inversion recovery (FAIR) magnetic reso...Objective To investigate the difference in interictal perfusion patterns between refractory and non-refractory temporal lobe epilepsies evaluated with flow-sensitive alternating inversion recovery (FAIR) magnetic resonance (MR) sequence. Methods Nine patients with refractory temporal lobe epilepsy, 21 patients with non-refractory temporal lobe epilepsy, and 13 normal volunteers underwent FAIR MR scanning. The relative cerebral blood flow (rCBF) in bilateral hemispheres and mesial temporal lobes were measured. And we also calculated the asymmetry index (AI) values. Results The AI values of bilateral hemispheres in refractory and non-refractory epilepsy patients were both significantly different from those of volunteers (P=0.012 and 0.029, respectively). There was significant difference in AI values of bilateral mesial temporal lobes between non-refractory epilepsy patients and volunteers (P=0.049), while no significant difference between refractory epilepsy patients and volunteers. Conclusions The hypoperfusion pattern of interictal refractory temporal lobe epilepsy patients is different from that of non-refractory patients. Although the hypoperfusion tends to extend out of temporal lobes in all patients, the refractory epilepsy patients have a preference of bilateral mesial temporal hypoperfusion, which may be valuable for evaluating prognosis.展开更多
Genetic factors are the major causes of epilepsies,such as developmental and epileptic encephalopathy(DEE)and idiopathic generalized epilepsy(IGE).However,the etiology of most patients remains elusive.This study perfo...Genetic factors are the major causes of epilepsies,such as developmental and epileptic encephalopathy(DEE)and idiopathic generalized epilepsy(IGE).However,the etiology of most patients remains elusive.This study performed exon sequencing in a cohort of 173 pa-tients with IGE.Additional cases were recruited from the matching platform in China.The excess and damaging effect of variants,the genotype-phenotype correlation,and the correlation be-tween gene expression and phenotype were studied to validate the geneedisease association.CSMD1 compound heterozygous variants were identified in four unrelated cases with IGE.Addi-tional CSMD1 variants were identified in five cases with DEE featured by generalized seizures from the matching platform,including two with de novo and three with compound heterozygous variants.Two patients were refractory to antiseizure medications and all patients were on long-term therapy.The CSMD1 variants presented a significantly high excess of variants in the case-cohort.Besides de novo origination,the DEE cases had each of the paired variants located closer to each other than the IGE cases or more significant alterations in hydrophobicity.The DEE-asso-ciated variants were all absent in the normal population and presented significantly lower minor allele frequency than the IGE-associated variants,suggesting a minor allele frequency-pheno-type severity correlation.Gene expression analysis showed that CSMD1 was extensively ex-pressed throughout the brain,particularly in the cortex.The CSMD1 temporal expression pattern correlated with the disease onset and outcomes.This study suggests that CSMD1 is asso-ciated with epilepsy and is a novel causative gene of DEE and generalized epilepsies.展开更多
The genetic generalized epilepsies(GGEs)have been proved to generate from genetic impact by twin studies and family studies.The genetic mechanisms of generalized epilepsies are always updating over time.Although the g...The genetic generalized epilepsies(GGEs)have been proved to generate from genetic impact by twin studies and family studies.The genetic mechanisms of generalized epilepsies are always updating over time.Although the genetics of GGE is complex,there are always new susceptibility genes coming up as well as copy number variations which can lead to important breakthroughs in exploring the problem.At the same time,the development of ClinGen fades out some of the candidate genes.This means we have to fgure out what accounts for a reliable gene for GGE,in another word,which gene has sufcient evidence for GGE.This will improve our understanding of the genetic mechanisms of GGE.In this review,important up-to-date genetic mechanisms of GGE were discussed.展开更多
Epilepsy is a leading cause of disability and mortality worldwide. However, despite the availability of more than 20 antiseizure medications, more than one-third of patients continue to experience seizures. Given the ...Epilepsy is a leading cause of disability and mortality worldwide. However, despite the availability of more than 20 antiseizure medications, more than one-third of patients continue to experience seizures. Given the urgent need to explore new treatment strategies for epilepsy, recent research has highlighted the potential of targeting gliosis, metabolic disturbances, and neural circuit abnormalities as therapeutic strategies. Astrocytes, the largest group of nonneuronal cells in the central nervous system, play several crucial roles in maintaining ionic and energy metabolic homeostasis in neurons, regulating neurotransmitter levels, and modulating synaptic plasticity. This article briefly reviews the critical role of astrocytes in maintaining balance within the central nervous system. Building on previous research, we discuss how astrocyte dysfunction contributes to the onset and progression of epilepsy through four key aspects: the imbalance between excitatory and inhibitory neuronal signaling, dysregulation of metabolic homeostasis in the neuronal microenvironment, neuroinflammation, and the formation of abnormal neural circuits. We summarize relevant basic research conducted over the past 5 years that has focused on modulating astrocytes as a therapeutic approach for epilepsy. We categorize the therapeutic targets proposed by these studies into four areas: restoration of the excitation–inhibition balance, reestablishment of metabolic homeostasis, modulation of immune and inflammatory responses, and reconstruction of abnormal neural circuits. These targets correspond to the pathophysiological mechanisms by which astrocytes contribute to epilepsy. Additionally, we need to consider the potential challenges and limitations of translating these identified therapeutic targets into clinical treatments. These limitations arise from interspecies differences between humans and animal models, as well as the complex comorbidities associated with epilepsy in humans. We also highlight valuable future research directions worth exploring in the treatment of epilepsy and the regulation of astrocytes, such as gene therapy and imaging strategies. The findings presented in this review may help open new therapeutic avenues for patients with drugresistant epilepsy and for those suffering from other central nervous system disorders associated with astrocytic dysfunction.展开更多
Epilepsy is one of the most prevalent and severe neurological disorders,and it is inadequately controlled with currently available medications.While cinnabar(mercury(II)sulfide)—a traditional Chinese medicine—has hi...Epilepsy is one of the most prevalent and severe neurological disorders,and it is inadequately controlled with currently available medications.While cinnabar(mercury(II)sulfide)—a traditional Chinese medicine—has historical application in epilepsy treatment,its therapeutic efficacy and underlying mechanisms are unclear.In this study,we find that cinnabar exerts model-dependent antiseizure efficacy in mice.Specifically,it significantly attenuates acute seizures,enhances the termination of diazepam-resistant status epilepticus,and reduces spontaneous seizures in the kainic acid(KA)-induced seizure model.Conversely,no therapeutic effect was found in the maximal electroshock-,pentylenetetrazole-,or kindling-induced seizure model.Fiber photometry revealed that cinnabar normalizes KA-induced hippocampal neurotransmission imbalances by simultaneously decreasing glutamate hyperactivity andγ-aminobutyric acid hypoactivity.Furthermore,cinnabar has neuroprotective effects and alleviates comorbid anxiety-like behaviors,while showing no alterations in motor function.Our findings suggest cinnabar's potential as a therapeutic agent for seizure management,via a mechanism associated with the reversal of the hippocampal excitatory/inhibitory imbalance.展开更多
Background:We performed this meta-analysis to investigate the association between GABRG2 rs211037polymorphism and the risk for idiopathic generalized epilepsies(IGEs).Methods:Medline,Embase,Cochrane Library and Chines...Background:We performed this meta-analysis to investigate the association between GABRG2 rs211037polymorphism and the risk for idiopathic generalized epilepsies(IGEs).Methods:Medline,Embase,Cochrane Library and Chinese National Knowledge Infrastructure(CNKI)databases were searched for eligible studies(until May 5,2020)on the association between GABRG2 rs211037 polymorphism and IGE.The odds ratios were calculated using a fixed or random model in STATA 15.0 software.Subgroup analyses for ethnicity,age,source of controls,type of seizure syndrome and therapeutic responses were conducted.Results:We found no significant associations between GABRG2 rs211037 polymorphism and the susceptibility to IGEs.In addition,no significant association was detected between GABRG2 rs211037 polymorphism and drug resistance in IGE patients.The results did not change after stratification by Asian population,healthy controls,children,juvenile myoclonic epilepsy,and childhood absence epilepsy.Conclusion:The current studies indicated that the GABRG2 rs211037 polymorphism was not related to susceptibility or drug resistance of IGE.Further well-designed studies are needed to verify the results.展开更多
For many decades,Alzheimer's disease research has primarily focused on impairments within cortical and hippocampal regions,which are thought to be related to cognitive dysfunctions such as memory and language defi...For many decades,Alzheimer's disease research has primarily focused on impairments within cortical and hippocampal regions,which are thought to be related to cognitive dysfunctions such as memory and language deficits.The exact cause of Alzheimer's disease is still under debate,making it challenging to establish an effective therapy or early diagnosis.It is widely accepted that the accumulation of amyloid-beta peptide in the brain parenchyma leads to synaptic dysfunction,a critical step in Alzheimer's disease development.The traditional amyloid cascade model is initiated by accumulating extracellular amyloid-beta in brain areas essential for memory and language.However,while it is possible to reduce the presence of amyloid-beta plaques in the brain with newer immunotherapies,cognitive symptoms do not necessarily improve.Interestingly,recent studies support the notion that early alterations in subcortical brain regions also contribute to brain damage and precognitive decline in Alzheimer's disease.A body of recent evidence suggests that early Alzheimer's disease is associated with alterations(e.g.,motivation,anxiety,and motor impairment)in subcortical areas,such as the striatum and amygdala,in both human and animal models.Also,recent data indicate that intracellular amyloid-beta appears early in subcortical regions such as the nucleus accumbens,locus coeruleus,and raphe nucleus,even without extracellular amyloid plaques.The reported effects are mainly excitatory,increasing glutamatergic transmission and neuronal excitability.In agreement,data in Alzheimer's disease patients and animal models show an increase in neuronal synchronization that leads to electroencephalogram disturbances and epilepsy.The data indicate that early subcortical brain dysfunctions might be associated with non-cognitive symptoms such as anxiety,irritability,and motivation deficits,which precede memory loss and language alterations.Overall,the evidence reviewed suggests that subcortical brain regions could explain early dysfunctions and perhaps be targets for therapies to slow disease progression.Future research should focus on these non-traditional brain regions to reveal early pathological alterations and underlying mechanisms to advance our understanding of Alzheimer's disease beyond the traditionally studied hippocampal and cortical circuits.展开更多
Complex genetic architecture is the major cause of heterogeneity in epilepsy,which poses challenges for accurate diagnosis and precise treatment.A large number of epilepsy candidate genes have been identified from cli...Complex genetic architecture is the major cause of heterogeneity in epilepsy,which poses challenges for accurate diagnosis and precise treatment.A large number of epilepsy candidate genes have been identified from clinical studies,particularly with the widespread use of next-generation sequencing.Validating these candidate genes is emerging as a valuable yet challenging task.Drosophila serves as an ideal animal model for validating candidate genes associated with neurogenetic disorders such as epilepsy,due to its rapid reproduction rate,powerful genetic tools,and efficient use of ethological and electrophysiological assays.Here,we systematically summarize the advantageous techniques of the Drosophila model used to investigate epilepsy genes,including genetic tools for manipulating target gene expression,ethological assays for seizure-like behaviors,electrophysiological techniques,and functional imaging for recording neural activity.We then introduce several typical strategies for identifying epilepsy genes and provide new insights into gene-gene interactions in epilepsy with polygenic causes.We summarize well-established precision medicine strategies for epilepsy and discuss prospective treatment options,including drug therapy and gene therapy for genetic epilepsy based on the Drosophila model.Finally,we also address genetic counseling and assisted reproductive technology as potential approaches for the prevention of genetic epilepsy.展开更多
Epilepsy is a prevalent neurological disorder in which hippocampal neuronal damage,particularly ferroptosis,plays a critical role.Previous studies have shown that hypoxia-inducible factor 1αis considered an important...Epilepsy is a prevalent neurological disorder in which hippocampal neuronal damage,particularly ferroptosis,plays a critical role.Previous studies have shown that hypoxia-inducible factor 1αis considered an important regulator of cellular stress responses and has been confirmed to play a critical role in the occurrence of various diseases.However,the mechanisms by which hypoxia-inducible factor 1αis related to epilepsy and neuronal ferroptosis remain unclear.In this study,we used a pentylentetrazole-induced chronic epilepsy mouse model and treated the mice with intraperitoneal administration of PX-478,a hypoxia-inducible factor-1αinhibitor.Our results showed that PX-478 significantly prolonged the latency of epilepsy,reduced seizure severity,and shortened seizure duration.PX-478 also alleviated neuronal damage in the hippocampal CA1 and CA2 regions,reduced levels of reactive oxygen species and malondialdehyde,and increased levels of superoxide dismutase,catalase,and glutathione peroxidase.Transmission electron microscopy showed that PX-478 treatment reduced mitochondrial damage in the hippocampal neurons of epileptic mice,and significantly improved mitochondrial length and area.Additionally,PX-478 preferentially reduced Fe^(2+)levels and the expression of cyclooxygenase-2,ferritin heavy chain 1 and transferrin in the hippocampus of epileptic mice.It also inhibited the activity of the hypoxia-inducible factor 1α/heme oxygenase-1 pathway.In summary,these findings suggest that PX-478 has the potential to treat epilepsy by inhibiting the hypoxia-inducible factor 1α/heme oxygenase-1 pathway,alleviating oxidative stress,and reducing ferroptosis in hippocampal neurons.展开更多
Voltage-gated sodium channels are essential ionic-conductance pathways in the nervous system,which play an irreplaceable role in modulating neuronal excitability and signal transduction.This review comprehensively ana...Voltage-gated sodium channels are essential ionic-conductance pathways in the nervous system,which play an irreplaceable role in modulating neuronal excitability and signal transduction.This review comprehensively analyzes the molecular mechanisms and pathophysiological significance of voltage-gated sodium channels,with particular emphasis on elucidating the molecular-action mechanisms of the distinct subtypes of these channels,including Nav1.1,Nav1.2,and Nav1.6,across various neurological disorders such as familial hemiplegic migraine,epilepsy,autism spectrum disorder,and retinal dysfunction.This review also provides a comprehensive overview of the pathogenic mechanisms associated with voltage-gated sodium channels,and systematically clarifies the evolutionary pathway of treatment strategies from conventional to innovative approaches.It analyzes two major categories of conventional sodium channel blockers and their applications:antiepileptic drugs(such as carbamazepine,lamotrigine,and phenytoin)and antiarrhythmic drugs(such as lidocaine,flecainide,and quinidine).However,these conventional blockers show limitations because of the lack of selectivity,driving research toward more precise therapeutic directions.Additionally,this review evaluates gabapentin,cannabidiol,and calcium channel blockers with different mechanisms of action.These drugs modulate neuronal excitability from multiple perspectives,providing diverse options for symptom relief.This review also highlights advances in gene therapy for specific diseases,such as STK-001,which promotes effective splicing of the sodium channel voltage-gated type 1 alpha subunit(SCN1A)gene,and ETX101,which utilizes adeno-associated virus 9 vectors to deliver engineered transcription factors.These two agents provide targeted therapeutic solutions for Dravet syndrome.Furthermore,this review summarizes some innovative therapeutic agents in clinical trials,including PRAX-222(for SCN2A gain-offunction mutation-related epilepsy),which has received Food and Drug Administration orphan drug designation,and the selective Nav1.6 inhibitor NBI-921352(for SCN8A-related epilepsy).Collectively,this review comprehensively compares the advantages and disadvantages of conventional drugs and gene therapy and envisions future treatment strategies that integrate the strengths of both approaches,facilitating personalized precision medicine to provide more accurate and effective treatment options for patients with ion channel diseases.展开更多
The voltage-gated sodium channel Nav1.6,encoded by the sodium voltage-gated channel alpha subunit 8 gene,is a crucial regulator of neuronal excitability,with widespread expression throughout the central and peripheral...The voltage-gated sodium channel Nav1.6,encoded by the sodium voltage-gated channel alpha subunit 8 gene,is a crucial regulator of neuronal excitability,with widespread expression throughout the central and peripheral nervous systems.Recent breakthroughs in structural biology,particularly the elucidation of the cryo-EM architecture of Nav1.6 at a resolution of 0.31 nm,have provided unprecedented insights into its molecular organization and functional modulation.As a key mediator of action potential initiation and propagation,Nav1.6 possesses unique biophysical properties,including persistent and resurgent sodium currents that critically influence neuronal firing patterns.This comprehensive review synthesizes current knowledge on the physiological functions and pathological roles of Nav1.6 in multiple neurological conditions.Key findings include the following:(1)Epilepsy studies reveal more than 250 sodium voltage-gated channel alpha subunit 8 mutations with distinct genotype-phenotype correlations,where gain-of-function variants lead to severe epileptic encephalopathies,while loss-of-function variants are associated with generalized epilepsy,highlighting the potential of Nav1.6-selective blockers such as XEN901 and GS967.(2)In Alzheimer’s disease,Nav1.6 mediates amyloid-βoligomer-induced neuronal hyperexcitability through amyloid precursor protein-dependent membrane trafficking and regulates beta-secretase 1 expression via nuclear factor of activated T cells 1 signaling,suggesting novel disease-modifying strategies.(3)Parkinson’s disease research has demonstrated that Nav1.6 upregulation in reactive astrocytes in the globus pallidus contributes to motor deficits through calcium-mediated abnormalities in neuronal synchronization.(4)Amyotrophic lateral sclerosis involves Nav1.6-dependent cortical hyperexcitability preceding motor neuron degeneration,with riluzole showing partial efficacy through sodium current modulation.(5)Multiple sclerosis pathophysiology features Nav1.6 redistribution in demyelinated axons,which drives calcium-dependent axonal injury via reverse Na+/Ca2+exchange.(6)Chronic pain mechanisms involve Nav1.6 overexpression in dorsal root ganglia neurons,regulated by the p38 mitogen-activated protein kinase and tumor necrosis factor-αsignaling pathways.(7)Traumatic brain injury models show that exercise-induced cognitive improvement is correlated with the normalization of Nav1.6-mediated excitability.Therapeutic development has progressed from nonselective sodium channel blockers to precision approaches,including state-dependent pore blockers designed using structural insights;allosteric modulators targeting specific conformations;gene therapy strategies using clustered regularly interspaced short palindromic repeats and antisense oligonucleotides;and miRNA-based regulation of channel expression.Current challenges include achieving sufficient subtype selectivity,optimizing blood-brain barrier penetration,and developing clinically relevant biomarkers for patient stratification.Future directions emphasize the integration of advanced technologies-such as single-cell multiomics to map neuronal subtype-specific expression patterns,patient-derived organoids for personalized drug testing,and machine learning-assisted drug design-to accelerate translation.Large-scale collaborative efforts will be essential to validate therapeutic candidates and establish genotype-guided treatment protocols for Nav1.6-related disorders.展开更多
Epilepsy is a serious neurological disorder;however,the effectiveness of current medications is often suboptimal.Recently,stem cell technology has demonstrated remarkable therapeutic potential in addressing various ne...Epilepsy is a serious neurological disorder;however,the effectiveness of current medications is often suboptimal.Recently,stem cell technology has demonstrated remarkable therapeutic potential in addressing various neurological diseases,igniting interest in its applicability for epilepsy treatment.This comprehensive review summarizes different therapeutic approaches utilizing various types of stem cells.Preclinical experiments have explored the use and potential therapeutic effects of mesenchymal stem cells,including genetically modified variants.Clinical trials involving patientderived mesenchymal stem cells have shown promising results,with reductions in the frequency of epileptic seizures and improvements in neurological,cognitive,and motor functions reported.Another promising therapeutic strategy involves neural stem cells.These cells can be cultured outside the body and directed to differentiate into specific cell types.The transplant of neural stem cells has the potential to replace lost inhibitory interneurons,providing a novel treatment avenue for epilepsy.Embryonic stem cells are characterized by their significant capacity for self-renewal and their ability to differentiate into any type of somatic cell.In epilepsy treatment,embryonic stem cells can serve three primary functions:neuron regeneration,the maintenance of cellular homeostasis,and restorative activity.One notable strategy involves differentiating embryonic stem cells intoγ-aminobutyric acidergic neurons for transplantation into lesion sites.This approach is currently undergoing clinical trials and could be a breakthrough in the treatment of refractory epilepsy.Induced pluripotent stem cells share the same genetic background as the donor,thereby reducing the risk of immune rejection and addressing ethical concerns.However,research on induced pluripotent stem cell therapy remains in the preclinical stage.Despite the promise of stem cell therapies for epilepsy,several limitations must be addressed.Safety concerns persist,including issues such as tumor formation,and the low survival rate of transplanted cells remains a significant challenge.Additionally,the high cost of these treatments may be prohibitive for some patients.In summary,stem cell therapy shows considerable promise in managing epilepsy,but further research is needed to overcome its existing limitations and enhance its clinical applicability.展开更多
The multiple PDZ domain crumbs cell polarity complex component gene(MPDZ;MIM:603785),is highly expressed in the brain across the whole lifespan.It encodes the multiple PDZ domain protein,which is a member of the NMDAR...The multiple PDZ domain crumbs cell polarity complex component gene(MPDZ;MIM:603785),is highly expressed in the brain across the whole lifespan.It encodes the multiple PDZ domain protein,which is a member of the NMDAR signaling complex that may play a role in the control of AMPAR potentiation and synaptic plasticity in excitatory synapses."Previously,MPDZ variants have been demonstrated to be associated with autosomal recessive congenital hydrocephalus-2(HYC2;MIM:615219)which is commonly complicated by brain abnormalities and developmental delay.Seizures were reported in only one case.The association between MPDz and epilepsy requires clarification.展开更多
Background:In 2012,the Ugandan Government declared an epidemic of Nodding Syndrome(NS)in the Northern districts of Gulu,Kitgum,Lamwo and Pader.Treatment guidelines were developed and NS treatment centres were establis...Background:In 2012,the Ugandan Government declared an epidemic of Nodding Syndrome(NS)in the Northern districts of Gulu,Kitgum,Lamwo and Pader.Treatment guidelines were developed and NS treatment centres were established to provide symptomatic control and rehabilitation.However,a wide gap remained between the predefined care standards and the quality of routine care provided to those affected.This study is to qualitatively assess adherence to accepted clinical care standards for NS;identify gaps in the care of affected children and offer Clinical Support Supervision(CSS)to Primary Health Care(PHC)staff at the treatment centres;and identify psychosocial challenges faced by affected children and their caregivers.Methods:This case study was carried out in the districts of Gulu,Kitgum,Lamwo and Pader in Uganda from September to December in 2015.Employing the 5-stage approach of Clinical Audit,data were collected through direct observations and interviews with PHC providers working in public and private-not-for-profit health facilities,as well as with caregivers and political leaders.The qualitative data was analysed using Seidel model of data processing.Results:Clinical Audit and CSS revealed poor adherence to treatment guidelines.Many affected children had suboptimal NS management resulting in poor seizure control and complications including severe burns.Root causes of these outcomes were frequent antiepileptic drugs stock outs,migration of health workers from their work stations and psychosocial issues.There was hardly any specialized multidisciplinary team(MDT)to provide for the complex rehabilitation needs of the patients and a task shifting model with inadequate support supervision was employed,leading to loss of skills learnt.Reported psychosocial and psychosexual issues associated with NS included early pregnancies,public display of sexual behaviours and child abuse.Conclusions:Despite involvement of relevant MDT members in the development of multidisciplinary NS guidelines,multidisciplinary care was not implemented in practice.There is urgent need to review the NS clinical guidelines.Quarterly CSS and consistent anticonvulsant medication are needed at health facilities in affected communities.Implementation of the existing policies and programs to deal with the psychosocial and psychosexual issues that affect children with NS and other chronic conditions is needed.展开更多
Background:The insula is a hidden part in the cerebral cortex.Insular epilepsy is underrecognized and it bears a special risk for misdiagnosis with regard to nonepileptic seizures or wrong localization of epileptic se...Background:The insula is a hidden part in the cerebral cortex.Insular epilepsy is underrecognized and it bears a special risk for misdiagnosis with regard to nonepileptic seizures or wrong localization of epileptic seizures.Case presentations:The manuscript describes 2 cases with ictal semiology of paresthesia and pain followed by hyperkinetic movements,noninvasive findings of source localization and/or invasive SEEG exploration.Conclusion:Magnetic source imaging,ictal SPECT as noninvasive and invasive recordings with depth electrodes(SEEG)can provide important preoperative information for the involvement of insular and periinsular regions in focal pharmacoresistant epilepsies.The optimal use of these methods presupposes extensive knowledge of ictal semiology and other clinical characteristics.The clinical localization hypothesis can be optimally proofed by SEEG exploration.展开更多
Background:For seizures emerging from the posterior cortex it can be a challenge to differentiate if they belong to temporal,parietal or occipital epilepsies.Sensoric auras like visual phenomena may occur in all of th...Background:For seizures emerging from the posterior cortex it can be a challenge to differentiate if they belong to temporal,parietal or occipital epilepsies.Sensoric auras like visual phenomena may occur in all of these focal epilepsies.Ictal signs may mimic non-epileptic seizures.Case presentations:Case 1:Patient suffering from a pharmacoresistent focal epilepsy.Focal seizures with sudden visual disturbance,later during the seizure epigastric aura,vertigo-nausea,involvement to bilateral tonic-clonic seizures.MEG detected interictal spikes,source localization indicated focal epileptic activity parietal right.Case 2:Patient with focal pharmacoresistent epilepsy,semiology with focal unaware seizures,feeling that something like a coat is imposed from behind on him,then feeling cold over the whole body,goose bumbs from both arms to head,then block of motoric activity,later focal unaware seizures with stare gaze,blinking of eyes,clouding of consciousness,elevation of arms and legs,sometimes tonic-clonic convulsions.EEG/MEG source localization and MRI detected an epileptogenic lesion parietal left.Case 3:Patient with pharmacoresistent focal epilepsy,focal aware seizures,a dark spot occurring in the left visual field,sometimes anxiety during seizures(leading to the suspicion of non-epileptic psychogenic pseudo seizures).MRI demonstrated an atrophy occipito-temporal right after sinus vein thrombosis.Ictal video-EEG showed a focal seizure onset occipital right.Conclusion:Contribution of noninvasive and/or invasive confirmation of the localization of the underlying focal epileptic activity in posterior cortex is illustrated.Characteristics of posterior cortex epilepsies are ventilated.展开更多
Epilepsy is a severe,relapsing,and multifactorial neurological disorder.Studies regarding the accurate diagnosis,prognosis,and in-depth pathogenesis are crucial for the precise and effective treatment of epilepsy.The ...Epilepsy is a severe,relapsing,and multifactorial neurological disorder.Studies regarding the accurate diagnosis,prognosis,and in-depth pathogenesis are crucial for the precise and effective treatment of epilepsy.The pathogenesis of epilepsy is complex and involves alterations in variables such as gene expression,protein expression,ion channel activity,energy metabolites,and gut microbiota composition.Satisfactory results are lacking for conventional treatments for epilepsy.Surgical resection of lesions,drug therapy,and non-drug interventions are mainly used in clinical practice to treat pain associated with epilepsy.Non-pharmacological treatments,such as a ketogenic diet,gene therapy for nerve regeneration,and neural regulation,are currently areas of research focus.This review provides a comprehensive overview of the pathogenesis,diagnostic methods,and treatments of epilepsy.It also elaborates on the theoretical basis,treatment modes,and effects of invasive nerve stimulation in neurotherapy,including percutaneous vagus nerve stimulation,deep brain electrical stimulation,repetitive nerve electrical stimulation,in addition to non-invasive transcranial magnetic stimulation and transcranial direct current stimulation.Numerous studies have shown that electromagnetic stimulation-mediated neuromodulation therapy can markedly improve neurological function and reduce the frequency of epileptic seizures.Additionally,many new technologies for the diagnosis and treatment of epilepsy are being explored.However,current research is mainly focused on analyzing patients’clinical manifestations and exploring relevant diagnostic and treatment methods to study the pathogenesis at a molecular level,which has led to a lack of consensus regarding the mechanisms related to the disease.展开更多
Epilepsy affects over 50 million people worldwide.Drug-resistant epilepsy(DRE)accounts for up to a third of these cases,and neuro-inflammation is thought to play a role in such cases.Despite being a long-debated issue...Epilepsy affects over 50 million people worldwide.Drug-resistant epilepsy(DRE)accounts for up to a third of these cases,and neuro-inflammation is thought to play a role in such cases.Despite being a long-debated issue in the field of DRE,the mechanisms underlying neuroinflammation have yet to be fully elucidated.The pro-inflammatory microenvironment within the brain tissue of people with DRE has been probed using single-cell multimodal transcriptomics.Evidence suggests that inflammatory cells and pro-inflammatory cytokines in the nervous system can lead to extensive biochemical changes,such as connexin hemichannel excitability and disruption of neurotransmitter homeostasis.The presence of inflammation may give rise to neuronal network abnormalities that suppress endogenous antiepileptic systems.We focus on the role of neuroinflammation and brain network anomalies in DRE from multiple perspectives to identify critical points for clinical application.We hope to provide an insightful overview to advance the quest for better DRE treatments.展开更多
文摘We attempted to classify, according to the International Classification of Epilepsies and Epileptic Syndromes (1989), 302 patients at a tertiary epilepsy referral center. Proportion in categories as defined by the international League Against Epilepsy (ILAE) were as follows: localization-related epilepsies: 62. 9 %,generalized epilepsies: 22. 2%,epilepsies undetermined whether focal or generalized: 14. 2%, special syndromes: 0. 7%. Only 26. 8 % cases were definitely classified in single diagnostic ILAE categories based on ictal CCTV/EEG recordings. The distribution of epileptic syndromes was different from the previous reports due to various methods of case ascertainment and inclusion criteria. Use of specific criteria for the reliability study of international classification has been proposed.
文摘Description： The progressive myoclonus epilepsies （PME＇s） comprise a large group of genetically determined disorders characterized by myoclonus, generalized tonic-clonic seizures, cerebellar dysfunction and variable degrees of cognitive impairment.
文摘Objective To investigate the difference in interictal perfusion patterns between refractory and non-refractory temporal lobe epilepsies evaluated with flow-sensitive alternating inversion recovery (FAIR) magnetic resonance (MR) sequence. Methods Nine patients with refractory temporal lobe epilepsy, 21 patients with non-refractory temporal lobe epilepsy, and 13 normal volunteers underwent FAIR MR scanning. The relative cerebral blood flow (rCBF) in bilateral hemispheres and mesial temporal lobes were measured. And we also calculated the asymmetry index (AI) values. Results The AI values of bilateral hemispheres in refractory and non-refractory epilepsy patients were both significantly different from those of volunteers (P=0.012 and 0.029, respectively). There was significant difference in AI values of bilateral mesial temporal lobes between non-refractory epilepsy patients and volunteers (P=0.049), while no significant difference between refractory epilepsy patients and volunteers. Conclusions The hypoperfusion pattern of interictal refractory temporal lobe epilepsy patients is different from that of non-refractory patients. Although the hypoperfusion tends to extend out of temporal lobes in all patients, the refractory epilepsy patients have a preference of bilateral mesial temporal hypoperfusion, which may be valuable for evaluating prognosis.
基金supported by the National Natural Science Foundation of China(No.82271505 to W.P.L.)the Multi-center Clinical Research Fund Project of the Second Affiliated Hospital of Guangzhou Medical University(No.010G271099,2020-LCYJ-DZX-03 to W.P.L.)the Science and Technology Project of Guangzhou,Guangdong,China(No.201904020028 to W.P.L.).
文摘Genetic factors are the major causes of epilepsies,such as developmental and epileptic encephalopathy(DEE)and idiopathic generalized epilepsy(IGE).However,the etiology of most patients remains elusive.This study performed exon sequencing in a cohort of 173 pa-tients with IGE.Additional cases were recruited from the matching platform in China.The excess and damaging effect of variants,the genotype-phenotype correlation,and the correlation be-tween gene expression and phenotype were studied to validate the geneedisease association.CSMD1 compound heterozygous variants were identified in four unrelated cases with IGE.Addi-tional CSMD1 variants were identified in five cases with DEE featured by generalized seizures from the matching platform,including two with de novo and three with compound heterozygous variants.Two patients were refractory to antiseizure medications and all patients were on long-term therapy.The CSMD1 variants presented a significantly high excess of variants in the case-cohort.Besides de novo origination,the DEE cases had each of the paired variants located closer to each other than the IGE cases or more significant alterations in hydrophobicity.The DEE-asso-ciated variants were all absent in the normal population and presented significantly lower minor allele frequency than the IGE-associated variants,suggesting a minor allele frequency-pheno-type severity correlation.Gene expression analysis showed that CSMD1 was extensively ex-pressed throughout the brain,particularly in the cortex.The CSMD1 temporal expression pattern correlated with the disease onset and outcomes.This study suggests that CSMD1 is asso-ciated with epilepsy and is a novel causative gene of DEE and generalized epilepsies.
基金Funding This work was supported by the National Natural Science Foundation of China(No.82071686)the Grant from Science and Technology Bureau of Sichuan province(No.2021YFS0093)+1 种基金the Grant from Research Fund of West China Second University Hospital(No.KL115,KL072)Graduate Education and Teaching Reform research project of Sichuan University(GSSCU2021156).
文摘The genetic generalized epilepsies(GGEs)have been proved to generate from genetic impact by twin studies and family studies.The genetic mechanisms of generalized epilepsies are always updating over time.Although the genetics of GGE is complex,there are always new susceptibility genes coming up as well as copy number variations which can lead to important breakthroughs in exploring the problem.At the same time,the development of ClinGen fades out some of the candidate genes.This means we have to fgure out what accounts for a reliable gene for GGE,in another word,which gene has sufcient evidence for GGE.This will improve our understanding of the genetic mechanisms of GGE.In this review,important up-to-date genetic mechanisms of GGE were discussed.
基金supported by the National Key Research and Development Program of China,No. 2023YFF0714200 (to CW)the National Natural Science Foundation of China,Nos. 82472038 and 82202224 (both to CW)+3 种基金the Shanghai Rising-Star Program,No. 23QA1407700 (to CW)the Construction Project of Shanghai Key Laboratory of Molecular Imaging,No. 18DZ2260400 (to CW)the National Science Foundation for Distinguished Young Scholars,No. 82025019 (to CL)the Greater Bay Area Institute of Precision Medicine (Guangzhou)(to CW)。
文摘Epilepsy is a leading cause of disability and mortality worldwide. However, despite the availability of more than 20 antiseizure medications, more than one-third of patients continue to experience seizures. Given the urgent need to explore new treatment strategies for epilepsy, recent research has highlighted the potential of targeting gliosis, metabolic disturbances, and neural circuit abnormalities as therapeutic strategies. Astrocytes, the largest group of nonneuronal cells in the central nervous system, play several crucial roles in maintaining ionic and energy metabolic homeostasis in neurons, regulating neurotransmitter levels, and modulating synaptic plasticity. This article briefly reviews the critical role of astrocytes in maintaining balance within the central nervous system. Building on previous research, we discuss how astrocyte dysfunction contributes to the onset and progression of epilepsy through four key aspects: the imbalance between excitatory and inhibitory neuronal signaling, dysregulation of metabolic homeostasis in the neuronal microenvironment, neuroinflammation, and the formation of abnormal neural circuits. We summarize relevant basic research conducted over the past 5 years that has focused on modulating astrocytes as a therapeutic approach for epilepsy. We categorize the therapeutic targets proposed by these studies into four areas: restoration of the excitation–inhibition balance, reestablishment of metabolic homeostasis, modulation of immune and inflammatory responses, and reconstruction of abnormal neural circuits. These targets correspond to the pathophysiological mechanisms by which astrocytes contribute to epilepsy. Additionally, we need to consider the potential challenges and limitations of translating these identified therapeutic targets into clinical treatments. These limitations arise from interspecies differences between humans and animal models, as well as the complex comorbidities associated with epilepsy in humans. We also highlight valuable future research directions worth exploring in the treatment of epilepsy and the regulation of astrocytes, such as gene therapy and imaging strategies. The findings presented in this review may help open new therapeutic avenues for patients with drugresistant epilepsy and for those suffering from other central nervous system disorders associated with astrocytic dysfunction.
基金supported by the National Natural Science Foundation of China(82204353,82330116)the Zhejiang Provincial Natural Science Foundation of China(LD24H310001,LY24H310002)+1 种基金the Research Project of Zhejiang Chinese Medical University(2023JKZDZC08)the Jinhua Municipal Science and Technology Projects(2023-3-118).
文摘Epilepsy is one of the most prevalent and severe neurological disorders,and it is inadequately controlled with currently available medications.While cinnabar(mercury(II)sulfide)—a traditional Chinese medicine—has historical application in epilepsy treatment,its therapeutic efficacy and underlying mechanisms are unclear.In this study,we find that cinnabar exerts model-dependent antiseizure efficacy in mice.Specifically,it significantly attenuates acute seizures,enhances the termination of diazepam-resistant status epilepticus,and reduces spontaneous seizures in the kainic acid(KA)-induced seizure model.Conversely,no therapeutic effect was found in the maximal electroshock-,pentylenetetrazole-,or kindling-induced seizure model.Fiber photometry revealed that cinnabar normalizes KA-induced hippocampal neurotransmission imbalances by simultaneously decreasing glutamate hyperactivity andγ-aminobutyric acid hypoactivity.Furthermore,cinnabar has neuroprotective effects and alleviates comorbid anxiety-like behaviors,while showing no alterations in motor function.Our findings suggest cinnabar's potential as a therapeutic agent for seizure management,via a mechanism associated with the reversal of the hippocampal excitatory/inhibitory imbalance.
基金supported by the National Natural Science Foundation of Shandong,China(item number ZR2019PH040)the National Natural Science Foundation of China(item number 81901321).
文摘Background:We performed this meta-analysis to investigate the association between GABRG2 rs211037polymorphism and the risk for idiopathic generalized epilepsies(IGEs).Methods:Medline,Embase,Cochrane Library and Chinese National Knowledge Infrastructure(CNKI)databases were searched for eligible studies(until May 5,2020)on the association between GABRG2 rs211037 polymorphism and IGE.The odds ratios were calculated using a fixed or random model in STATA 15.0 software.Subgroup analyses for ethnicity,age,source of controls,type of seizure syndrome and therapeutic responses were conducted.Results:We found no significant associations between GABRG2 rs211037 polymorphism and the susceptibility to IGEs.In addition,no significant association was detected between GABRG2 rs211037 polymorphism and drug resistance in IGE patients.The results did not change after stratification by Asian population,healthy controls,children,juvenile myoclonic epilepsy,and childhood absence epilepsy.Conclusion:The current studies indicated that the GABRG2 rs211037 polymorphism was not related to susceptibility or drug resistance of IGE.Further well-designed studies are needed to verify the results.
文摘For many decades,Alzheimer's disease research has primarily focused on impairments within cortical and hippocampal regions,which are thought to be related to cognitive dysfunctions such as memory and language deficits.The exact cause of Alzheimer's disease is still under debate,making it challenging to establish an effective therapy or early diagnosis.It is widely accepted that the accumulation of amyloid-beta peptide in the brain parenchyma leads to synaptic dysfunction,a critical step in Alzheimer's disease development.The traditional amyloid cascade model is initiated by accumulating extracellular amyloid-beta in brain areas essential for memory and language.However,while it is possible to reduce the presence of amyloid-beta plaques in the brain with newer immunotherapies,cognitive symptoms do not necessarily improve.Interestingly,recent studies support the notion that early alterations in subcortical brain regions also contribute to brain damage and precognitive decline in Alzheimer's disease.A body of recent evidence suggests that early Alzheimer's disease is associated with alterations(e.g.,motivation,anxiety,and motor impairment)in subcortical areas,such as the striatum and amygdala,in both human and animal models.Also,recent data indicate that intracellular amyloid-beta appears early in subcortical regions such as the nucleus accumbens,locus coeruleus,and raphe nucleus,even without extracellular amyloid plaques.The reported effects are mainly excitatory,increasing glutamatergic transmission and neuronal excitability.In agreement,data in Alzheimer's disease patients and animal models show an increase in neuronal synchronization that leads to electroencephalogram disturbances and epilepsy.The data indicate that early subcortical brain dysfunctions might be associated with non-cognitive symptoms such as anxiety,irritability,and motivation deficits,which precede memory loss and language alterations.Overall,the evidence reviewed suggests that subcortical brain regions could explain early dysfunctions and perhaps be targets for therapies to slow disease progression.Future research should focus on these non-traditional brain regions to reveal early pathological alterations and underlying mechanisms to advance our understanding of Alzheimer's disease beyond the traditionally studied hippocampal and cortical circuits.
基金supported by the Guangdong Basic and Applied Basic Research Foundation,No.2022A1515111123(to JQ)。
文摘Complex genetic architecture is the major cause of heterogeneity in epilepsy,which poses challenges for accurate diagnosis and precise treatment.A large number of epilepsy candidate genes have been identified from clinical studies,particularly with the widespread use of next-generation sequencing.Validating these candidate genes is emerging as a valuable yet challenging task.Drosophila serves as an ideal animal model for validating candidate genes associated with neurogenetic disorders such as epilepsy,due to its rapid reproduction rate,powerful genetic tools,and efficient use of ethological and electrophysiological assays.Here,we systematically summarize the advantageous techniques of the Drosophila model used to investigate epilepsy genes,including genetic tools for manipulating target gene expression,ethological assays for seizure-like behaviors,electrophysiological techniques,and functional imaging for recording neural activity.We then introduce several typical strategies for identifying epilepsy genes and provide new insights into gene-gene interactions in epilepsy with polygenic causes.We summarize well-established precision medicine strategies for epilepsy and discuss prospective treatment options,including drug therapy and gene therapy for genetic epilepsy based on the Drosophila model.Finally,we also address genetic counseling and assisted reproductive technology as potential approaches for the prevention of genetic epilepsy.
基金supported by the Science and Technology Development Plan Project of Jilin Province,No.YDZJ202401157ZYTS(to SL).
文摘Epilepsy is a prevalent neurological disorder in which hippocampal neuronal damage,particularly ferroptosis,plays a critical role.Previous studies have shown that hypoxia-inducible factor 1αis considered an important regulator of cellular stress responses and has been confirmed to play a critical role in the occurrence of various diseases.However,the mechanisms by which hypoxia-inducible factor 1αis related to epilepsy and neuronal ferroptosis remain unclear.In this study,we used a pentylentetrazole-induced chronic epilepsy mouse model and treated the mice with intraperitoneal administration of PX-478,a hypoxia-inducible factor-1αinhibitor.Our results showed that PX-478 significantly prolonged the latency of epilepsy,reduced seizure severity,and shortened seizure duration.PX-478 also alleviated neuronal damage in the hippocampal CA1 and CA2 regions,reduced levels of reactive oxygen species and malondialdehyde,and increased levels of superoxide dismutase,catalase,and glutathione peroxidase.Transmission electron microscopy showed that PX-478 treatment reduced mitochondrial damage in the hippocampal neurons of epileptic mice,and significantly improved mitochondrial length and area.Additionally,PX-478 preferentially reduced Fe^(2+)levels and the expression of cyclooxygenase-2,ferritin heavy chain 1 and transferrin in the hippocampus of epileptic mice.It also inhibited the activity of the hypoxia-inducible factor 1α/heme oxygenase-1 pathway.In summary,these findings suggest that PX-478 has the potential to treat epilepsy by inhibiting the hypoxia-inducible factor 1α/heme oxygenase-1 pathway,alleviating oxidative stress,and reducing ferroptosis in hippocampal neurons.
基金supported by the National Natural Science Foundation of China,Nos.82471107,31970930(both to KY)the National Key Research and Development Program of China,No.2024YFA1108701(to KY)+1 种基金the Natural Science Foundation of Hubei Province,Nos.2020CFA069(to KY),2018CFB434(to KY),2025AFB042(to HQ)the Neuroscience Team Development Project of Wuhan University of Science and Technology,Nos.1180002,1180030(both to KY)。
文摘Voltage-gated sodium channels are essential ionic-conductance pathways in the nervous system,which play an irreplaceable role in modulating neuronal excitability and signal transduction.This review comprehensively analyzes the molecular mechanisms and pathophysiological significance of voltage-gated sodium channels,with particular emphasis on elucidating the molecular-action mechanisms of the distinct subtypes of these channels,including Nav1.1,Nav1.2,and Nav1.6,across various neurological disorders such as familial hemiplegic migraine,epilepsy,autism spectrum disorder,and retinal dysfunction.This review also provides a comprehensive overview of the pathogenic mechanisms associated with voltage-gated sodium channels,and systematically clarifies the evolutionary pathway of treatment strategies from conventional to innovative approaches.It analyzes two major categories of conventional sodium channel blockers and their applications:antiepileptic drugs(such as carbamazepine,lamotrigine,and phenytoin)and antiarrhythmic drugs(such as lidocaine,flecainide,and quinidine).However,these conventional blockers show limitations because of the lack of selectivity,driving research toward more precise therapeutic directions.Additionally,this review evaluates gabapentin,cannabidiol,and calcium channel blockers with different mechanisms of action.These drugs modulate neuronal excitability from multiple perspectives,providing diverse options for symptom relief.This review also highlights advances in gene therapy for specific diseases,such as STK-001,which promotes effective splicing of the sodium channel voltage-gated type 1 alpha subunit(SCN1A)gene,and ETX101,which utilizes adeno-associated virus 9 vectors to deliver engineered transcription factors.These two agents provide targeted therapeutic solutions for Dravet syndrome.Furthermore,this review summarizes some innovative therapeutic agents in clinical trials,including PRAX-222(for SCN2A gain-offunction mutation-related epilepsy),which has received Food and Drug Administration orphan drug designation,and the selective Nav1.6 inhibitor NBI-921352(for SCN8A-related epilepsy).Collectively,this review comprehensively compares the advantages and disadvantages of conventional drugs and gene therapy and envisions future treatment strategies that integrate the strengths of both approaches,facilitating personalized precision medicine to provide more accurate and effective treatment options for patients with ion channel diseases.
基金supported by the Science and Technology Program Joint Program(Applied Basic Research Project)of Liaoning Province,China,No.2023JH2/101700079(to JunW).
文摘The voltage-gated sodium channel Nav1.6,encoded by the sodium voltage-gated channel alpha subunit 8 gene,is a crucial regulator of neuronal excitability,with widespread expression throughout the central and peripheral nervous systems.Recent breakthroughs in structural biology,particularly the elucidation of the cryo-EM architecture of Nav1.6 at a resolution of 0.31 nm,have provided unprecedented insights into its molecular organization and functional modulation.As a key mediator of action potential initiation and propagation,Nav1.6 possesses unique biophysical properties,including persistent and resurgent sodium currents that critically influence neuronal firing patterns.This comprehensive review synthesizes current knowledge on the physiological functions and pathological roles of Nav1.6 in multiple neurological conditions.Key findings include the following:(1)Epilepsy studies reveal more than 250 sodium voltage-gated channel alpha subunit 8 mutations with distinct genotype-phenotype correlations,where gain-of-function variants lead to severe epileptic encephalopathies,while loss-of-function variants are associated with generalized epilepsy,highlighting the potential of Nav1.6-selective blockers such as XEN901 and GS967.(2)In Alzheimer’s disease,Nav1.6 mediates amyloid-βoligomer-induced neuronal hyperexcitability through amyloid precursor protein-dependent membrane trafficking and regulates beta-secretase 1 expression via nuclear factor of activated T cells 1 signaling,suggesting novel disease-modifying strategies.(3)Parkinson’s disease research has demonstrated that Nav1.6 upregulation in reactive astrocytes in the globus pallidus contributes to motor deficits through calcium-mediated abnormalities in neuronal synchronization.(4)Amyotrophic lateral sclerosis involves Nav1.6-dependent cortical hyperexcitability preceding motor neuron degeneration,with riluzole showing partial efficacy through sodium current modulation.(5)Multiple sclerosis pathophysiology features Nav1.6 redistribution in demyelinated axons,which drives calcium-dependent axonal injury via reverse Na+/Ca2+exchange.(6)Chronic pain mechanisms involve Nav1.6 overexpression in dorsal root ganglia neurons,regulated by the p38 mitogen-activated protein kinase and tumor necrosis factor-αsignaling pathways.(7)Traumatic brain injury models show that exercise-induced cognitive improvement is correlated with the normalization of Nav1.6-mediated excitability.Therapeutic development has progressed from nonselective sodium channel blockers to precision approaches,including state-dependent pore blockers designed using structural insights;allosteric modulators targeting specific conformations;gene therapy strategies using clustered regularly interspaced short palindromic repeats and antisense oligonucleotides;and miRNA-based regulation of channel expression.Current challenges include achieving sufficient subtype selectivity,optimizing blood-brain barrier penetration,and developing clinically relevant biomarkers for patient stratification.Future directions emphasize the integration of advanced technologies-such as single-cell multiomics to map neuronal subtype-specific expression patterns,patient-derived organoids for personalized drug testing,and machine learning-assisted drug design-to accelerate translation.Large-scale collaborative efforts will be essential to validate therapeutic candidates and establish genotype-guided treatment protocols for Nav1.6-related disorders.
基金supported by the National Natural Science Foundation of China,Nos.82471471(to WJ),82471485(to FY)Shaanxi Province Special Support Program for Leading Talents in Scientific and Technological Innovation,No.tzjhjw(to WJ)+1 种基金Shaanxi Key Research and Development Plan Project,No.2023-YBSF-353(to XW)the Joint Fund Project of Innovation Research Institute of Xijing Hospital,No.LHJJ24JH13(to ZS)。
文摘Epilepsy is a serious neurological disorder;however,the effectiveness of current medications is often suboptimal.Recently,stem cell technology has demonstrated remarkable therapeutic potential in addressing various neurological diseases,igniting interest in its applicability for epilepsy treatment.This comprehensive review summarizes different therapeutic approaches utilizing various types of stem cells.Preclinical experiments have explored the use and potential therapeutic effects of mesenchymal stem cells,including genetically modified variants.Clinical trials involving patientderived mesenchymal stem cells have shown promising results,with reductions in the frequency of epileptic seizures and improvements in neurological,cognitive,and motor functions reported.Another promising therapeutic strategy involves neural stem cells.These cells can be cultured outside the body and directed to differentiate into specific cell types.The transplant of neural stem cells has the potential to replace lost inhibitory interneurons,providing a novel treatment avenue for epilepsy.Embryonic stem cells are characterized by their significant capacity for self-renewal and their ability to differentiate into any type of somatic cell.In epilepsy treatment,embryonic stem cells can serve three primary functions:neuron regeneration,the maintenance of cellular homeostasis,and restorative activity.One notable strategy involves differentiating embryonic stem cells intoγ-aminobutyric acidergic neurons for transplantation into lesion sites.This approach is currently undergoing clinical trials and could be a breakthrough in the treatment of refractory epilepsy.Induced pluripotent stem cells share the same genetic background as the donor,thereby reducing the risk of immune rejection and addressing ethical concerns.However,research on induced pluripotent stem cell therapy remains in the preclinical stage.Despite the promise of stem cell therapies for epilepsy,several limitations must be addressed.Safety concerns persist,including issues such as tumor formation,and the low survival rate of transplanted cells remains a significant challenge.Additionally,the high cost of these treatments may be prohibitive for some patients.In summary,stem cell therapy shows considerable promise in managing epilepsy,but further research is needed to overcome its existing limitations and enhance its clinical applicability.
基金funded by the National Natural Science Foundation of China(No.82201609)Shandong Medical and Health Science and Technology Development Plan(China)(No.202106010271)+2 种基金Scientific Research Project of Hunan Provincial Health Commission(China)(No.D202303077290)Guangdong Basic and Applied Basic Research Foundation(China)(No.2021A1515111064)Science and Technology Project of Guangzhou,Guangdong,China(No.202102021059,202201020106,202235395).
文摘The multiple PDZ domain crumbs cell polarity complex component gene(MPDZ;MIM:603785),is highly expressed in the brain across the whole lifespan.It encodes the multiple PDZ domain protein,which is a member of the NMDAR signaling complex that may play a role in the control of AMPAR potentiation and synaptic plasticity in excitatory synapses."Previously,MPDZ variants have been demonstrated to be associated with autosomal recessive congenital hydrocephalus-2(HYC2;MIM:615219)which is commonly complicated by brain abnormalities and developmental delay.Seizures were reported in only one case.The association between MPDz and epilepsy requires clarification.
文摘Background:In 2012,the Ugandan Government declared an epidemic of Nodding Syndrome(NS)in the Northern districts of Gulu,Kitgum,Lamwo and Pader.Treatment guidelines were developed and NS treatment centres were established to provide symptomatic control and rehabilitation.However,a wide gap remained between the predefined care standards and the quality of routine care provided to those affected.This study is to qualitatively assess adherence to accepted clinical care standards for NS;identify gaps in the care of affected children and offer Clinical Support Supervision(CSS)to Primary Health Care(PHC)staff at the treatment centres;and identify psychosocial challenges faced by affected children and their caregivers.Methods:This case study was carried out in the districts of Gulu,Kitgum,Lamwo and Pader in Uganda from September to December in 2015.Employing the 5-stage approach of Clinical Audit,data were collected through direct observations and interviews with PHC providers working in public and private-not-for-profit health facilities,as well as with caregivers and political leaders.The qualitative data was analysed using Seidel model of data processing.Results:Clinical Audit and CSS revealed poor adherence to treatment guidelines.Many affected children had suboptimal NS management resulting in poor seizure control and complications including severe burns.Root causes of these outcomes were frequent antiepileptic drugs stock outs,migration of health workers from their work stations and psychosocial issues.There was hardly any specialized multidisciplinary team(MDT)to provide for the complex rehabilitation needs of the patients and a task shifting model with inadequate support supervision was employed,leading to loss of skills learnt.Reported psychosocial and psychosexual issues associated with NS included early pregnancies,public display of sexual behaviours and child abuse.Conclusions:Despite involvement of relevant MDT members in the development of multidisciplinary NS guidelines,multidisciplinary care was not implemented in practice.There is urgent need to review the NS clinical guidelines.Quarterly CSS and consistent anticonvulsant medication are needed at health facilities in affected communities.Implementation of the existing policies and programs to deal with the psychosocial and psychosexual issues that affect children with NS and other chronic conditions is needed.
文摘Background:The insula is a hidden part in the cerebral cortex.Insular epilepsy is underrecognized and it bears a special risk for misdiagnosis with regard to nonepileptic seizures or wrong localization of epileptic seizures.Case presentations:The manuscript describes 2 cases with ictal semiology of paresthesia and pain followed by hyperkinetic movements,noninvasive findings of source localization and/or invasive SEEG exploration.Conclusion:Magnetic source imaging,ictal SPECT as noninvasive and invasive recordings with depth electrodes(SEEG)can provide important preoperative information for the involvement of insular and periinsular regions in focal pharmacoresistant epilepsies.The optimal use of these methods presupposes extensive knowledge of ictal semiology and other clinical characteristics.The clinical localization hypothesis can be optimally proofed by SEEG exploration.
文摘Background:For seizures emerging from the posterior cortex it can be a challenge to differentiate if they belong to temporal,parietal or occipital epilepsies.Sensoric auras like visual phenomena may occur in all of these focal epilepsies.Ictal signs may mimic non-epileptic seizures.Case presentations:Case 1:Patient suffering from a pharmacoresistent focal epilepsy.Focal seizures with sudden visual disturbance,later during the seizure epigastric aura,vertigo-nausea,involvement to bilateral tonic-clonic seizures.MEG detected interictal spikes,source localization indicated focal epileptic activity parietal right.Case 2:Patient with focal pharmacoresistent epilepsy,semiology with focal unaware seizures,feeling that something like a coat is imposed from behind on him,then feeling cold over the whole body,goose bumbs from both arms to head,then block of motoric activity,later focal unaware seizures with stare gaze,blinking of eyes,clouding of consciousness,elevation of arms and legs,sometimes tonic-clonic convulsions.EEG/MEG source localization and MRI detected an epileptogenic lesion parietal left.Case 3:Patient with pharmacoresistent focal epilepsy,focal aware seizures,a dark spot occurring in the left visual field,sometimes anxiety during seizures(leading to the suspicion of non-epileptic psychogenic pseudo seizures).MRI demonstrated an atrophy occipito-temporal right after sinus vein thrombosis.Ictal video-EEG showed a focal seizure onset occipital right.Conclusion:Contribution of noninvasive and/or invasive confirmation of the localization of the underlying focal epileptic activity in posterior cortex is illustrated.Characteristics of posterior cortex epilepsies are ventilated.
基金supported by the National Natural Science Foundation of China,No.32130060(to XG).
文摘Epilepsy is a severe,relapsing,and multifactorial neurological disorder.Studies regarding the accurate diagnosis,prognosis,and in-depth pathogenesis are crucial for the precise and effective treatment of epilepsy.The pathogenesis of epilepsy is complex and involves alterations in variables such as gene expression,protein expression,ion channel activity,energy metabolites,and gut microbiota composition.Satisfactory results are lacking for conventional treatments for epilepsy.Surgical resection of lesions,drug therapy,and non-drug interventions are mainly used in clinical practice to treat pain associated with epilepsy.Non-pharmacological treatments,such as a ketogenic diet,gene therapy for nerve regeneration,and neural regulation,are currently areas of research focus.This review provides a comprehensive overview of the pathogenesis,diagnostic methods,and treatments of epilepsy.It also elaborates on the theoretical basis,treatment modes,and effects of invasive nerve stimulation in neurotherapy,including percutaneous vagus nerve stimulation,deep brain electrical stimulation,repetitive nerve electrical stimulation,in addition to non-invasive transcranial magnetic stimulation and transcranial direct current stimulation.Numerous studies have shown that electromagnetic stimulation-mediated neuromodulation therapy can markedly improve neurological function and reduce the frequency of epileptic seizures.Additionally,many new technologies for the diagnosis and treatment of epilepsy are being explored.However,current research is mainly focused on analyzing patients’clinical manifestations and exploring relevant diagnostic and treatment methods to study the pathogenesis at a molecular level,which has led to a lack of consensus regarding the mechanisms related to the disease.
基金supported by the National Natural Science Foundation of China(82030037)the Translational and Application Project of Brain-inspired and Network Neuroscience on Brain Disorders(11000023T000002036286).
文摘Epilepsy affects over 50 million people worldwide.Drug-resistant epilepsy(DRE)accounts for up to a third of these cases,and neuro-inflammation is thought to play a role in such cases.Despite being a long-debated issue in the field of DRE,the mechanisms underlying neuroinflammation have yet to be fully elucidated.The pro-inflammatory microenvironment within the brain tissue of people with DRE has been probed using single-cell multimodal transcriptomics.Evidence suggests that inflammatory cells and pro-inflammatory cytokines in the nervous system can lead to extensive biochemical changes,such as connexin hemichannel excitability and disruption of neurotransmitter homeostasis.The presence of inflammation may give rise to neuronal network abnormalities that suppress endogenous antiepileptic systems.We focus on the role of neuroinflammation and brain network anomalies in DRE from multiple perspectives to identify critical points for clinical application.We hope to provide an insightful overview to advance the quest for better DRE treatments.
