Short-term effectiveness and side effects of ketogenic diet for drug-resistant epilepsy in children with genetic epilepsy syndromes.

Background: Drug-resistant epilepsy (DRE) impacts a significant portion, one-third, of individuals diagnosed with epilepsy. In such cases, exploring non-pharmacological interventions are crucial, with the ketogenic diet (KD) standing out as a valuable option. KD, a high-fat and low-carb dietary approach with roots dating back to the 1920s for managing DRE, triggers the formation of ketone bodies and modifies biochemistry to aid in seizure control. Recent studies have increasingly supported the efficacy of KD in addressing DRE, showcasing positive outcomes. Furthermore, while more research is needed, limited data suggests that KD May also be beneficial for specific genetic epilepsy syndromes (GESs). Objective: This study aimed to assess the short-term efficacy of KD among pediatric patients diagnosed with GESs. Materials and methods: This is a multi-center retrospective analysis of pediatric patients with GESs diagnosed using next-generation sequencing. The enrolled patients followed the keto-clinic protocol, and the KD efficacy was evaluated at 3, 6, and 12-month intervals based on seizure control and compliance. The collection instrument included demographic, baseline, and prognostic data. The collected data was coded and analyzed promptly. Results: We enrolled a cohort of 77 patients with a mean current age of 7.94 ± 3.83 years. The mean age of seizure onset was 15.5 months. Notably, patients experienced seizures at a younger age tended to have less positive response to diet. Overall, 55 patients responded favorably to the diet (71.4%) while 22 patients (28.6%) showed no improvement. Patients with genetic etiology showed a significantly more favorable responses to the dietary intervention. Patients with Lennox-Gastaut syndrome showed the most significant improvement (14/15) followed by patients with Dravet syndrome (6/8), and West syndrome (3/4). The number of used anti-seizure medications also played a significant role in determining their response to the diet. While some patients experienced mild adverse events, the most common being constipation, these occurrences were not serious enough to necessitate discontinuation of the diet. Conclusion: The study revealed a high improvement rate in seizure control, especially among younger patients and those with later seizure onset. The success of dietary treatment hinges greatly on early intervention and the patient's age. Certain genetic mutations responded favorably to the KD, while efficacy varied among various genetic profiles.

Long-term trends in total administered radiation dose from brain [18F]FDG-PET in children with drug-resistant epilepsy.

PURPOSE: To assess the trends in administered 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) doses, computed tomography (CT) radiation doses, and image quality over the last 15 years in children with drug-resistant epilepsy (DRE) undergoing hybrid positron emission tomography (PET) brain scans. METHODS: We retrospectively analyzed data from children with DRE who had [18F]FDG-PET/CT or magnetic resonance scans for presurgical evaluation between 2005 and 2021. We evaluated changes in injected [18F]FDG doses, administered activity per body weight, CT dose index volume (CTDIvol), and dose length product (DLP). PET image quality was assessed visually by four trained raters. Conversely, CT image quality was measured using region-of-interest analysis, normalized by signal-to-noise (SNR) and contrast-to-noise ratio (CNR). RESULTS: We included 55 children (30 male, mean age: 9 ± 6 years) who underwent 61 [18F]FDG-PET scans (71% as PET/CT). Annually, the injected [18F]FDG dose decreased by ~ 1% (95% CI: 0.92%-0.98%, p < 0.001), with no significant changes in administered activity per body weight (p = 0.51). CTDIvol and DLP decreased annually by 16% (95% CI: 9%-23%) and 15% (95% CI: 8%-21%, both p < 0.001), respectively. PET image quality improved by 9% year-over-year (95% CI: 6%-13%, p < 0.001), while CT-associated SNR and CNR decreased annually by 7% (95% CI: 3%-11%, p = 0.001) and 6% (95% CI: 2%-10%, p = 0.008), respectively. CONCLUSION: Our findings indicate stability in [18F]FDG administered activity per body weight alongside improvements in PET image quality. Conversely, CT-associated radiation doses reduced. These results reaffirm [18F]FDG-PET as an increasingly safer and higher-resolution auxiliary imaging modality for children with DRE. These improvements, driven by technological advancements, may enhance the diagnostic precision and patient outcomes in pediatric epilepsy surgery.

Long-term effects of vagus nerve stimulation on EEG aperiodic components in patients with drug-resistant epilepsy.

Background: Drug-resistant epilepsy (DRE) affects approximately one-third of epilepsy patients who do not achieve adequate seizure control with medication. Vagus nerve stimulation (VNS) is an adjunctive therapy for DRE, but its long-term effects on cortical excitability remain unclear. Objectives: This study aims to elucidate the long-term effects of VNS on electroencephalography (EEG) aperiodic components in patients with DRE. Our objective is to identify biomarkers that can serve as indicators of therapeutic efficacy and provide mechanistic insights into the underlying neural processes. Design: This longitudinal observational study focused on patients with DRE undergoing VNS therapy at Sanbo Brain Hospital. The reduction in seizure frequency rates was quantified over short-term (⩽1 year), medium-term (1-3 years), and long-term (⩾3 years) intervals to assess the therapeutic efficacy of VNS. Both the periodic and aperiodic components of EEG data were analyzed. Methods: Advanced signal processing techniques were utilized to parameterize the periodic and aperiodic components of EEG data, focusing particularly on "offset" and "exponent." These measures were compared before and after VNS therapy. Correlation analyses were conducted to explore the relationship between these EEG parameters and clinical outcomes. Results: In all, 18 patients with DRE participated in this study. During the long-term follow-up period, the responder rate was 55.56%. Significant decreases were observed in aperiodic offset (p = 0.022) and exponent (p = 0.039) among responders. The impact of age on these results was not significant. Correlation analyses revealed a negative association between therapeutic efficacy and a decrease in offset (R = -0.546, p = 0.019) and exponent (R = -0.636, p = 0.019). Conclusion: EEG aperiodic parameters, including offset and exponent, have the potential to serve as promising biomarkers for evaluating the efficacy of VNS. An understanding of the regulatory influence of VNS on cortical excitability through these aperiodic parameters could provide a basis for the development of more effective stimulation parameters and therapeutic strategies.

Advanced tractography-guided laser ablation of a perirolandic long-term epilepsy-associated tumor: illustrative case.

BACKGROUND: Microsurgical resection of drug-resistant epilepsy-associated perirolandic lesions can lead to postoperative motor impairment. Magnetic resonance imaging (MRI)-guided laser interstitial thermal therapy (MRgLITT) has emerged as a less invasive alternative, offering reduced surgical risks and improved neurological outcomes. Electrophysiological tools routinely used for motor mapping in resective microsurgery are incompatible with intraoperative MRI. The utilization of advanced neuroimaging adjuncts for eloquent brain mapping during MRgLITT is imperative. The authors present the case of a 17-year-old athlete who underwent MRgLITT for a perirolandic long-term epilepsy-associated tumor (LEAT). They performed probabilistic multi-tissue constrained spherical deconvolution (MT-CSD) tractography to delineate the corticospinal tract (CST) for presurgical planning and intraoperative image guidance. The CST tractography was integrated into neuronavigation and MRgLITT workstation software to guide the ablation while monitoring the CST throughout the procedure. OBSERVATIONS: The integration of CST tractography into neuronavigation workstation planning and laser ablation workstation thermoablation is feasible and practical, facilitating complete ablation of a deep-seated perirolandic LEAT while preserving motor function. LESSONS: Probabilistic MT-CSD tractography enhanced MRgLITT planning as well as intraprocedural CST visualization and preservation, leading to a favorable functional outcome. The limitations of tractography and the predictability of thermal output distribution compared to the gold standard of microsurgical resection merit further discussion. https://thejns.org/doi/10.3171/CASE24139.

Therapeutic potential of ketamine in management of epilepsy: Clinical implications and mechanistic insights.

Epilepsy, a widespread neurological disorder, affects approximately 50 million people worldwide. This disorder is typified by recurring seizures due to abnormal neuron communication in the brain. The seizures can lead to severe ischemia and hypoxia, potentially threatening patients' lives. However, with proper diagnosis and treatment, up to 70 % of patients can live without seizures. The causes of epilepsy are complex and multifactorial, encompassing genetic abnormalities, structural brain anomalies, ion channel dysfunctions, neurotransmitter imbalances, neuroinflammation, and immune system involvement. These factors collectively disrupt the crucial balance between excitation and inhibition within the brain, leading to epileptic seizures. The management of treatment-resistant epilepsy remains a considerable challenge, necessitating innovative therapeutic approaches. Among emerging potential treatments, ketamine-a drug traditionally employed for anesthesia and depression-has demonstrated efficacy in reducing seizures. It is noteworthy that, independent of its anti-epileptic effects, ketamine has been found to improve the balance between excitatory and inhibitory (E/I) activities in the brain. The balance is crucial for maintaining normal neural function, and its disruption is widely considered a key driver of epileptic seizures. By acting on N-methyl-D-aspartate (NMDA) receptors and other potential mechanisms, ketamine may regulate neuronal excitability, reduce excessive synchronized neural activity, and counteract epileptic seizures. This positive impact on E/I balance reinforces the potential of ketamine as a promising drug for treating epilepsy, especially in patients who are insensitive to traditional anti-epileptic drugs. This review aims to consolidate the current understanding of ketamine's therapeutic role in epilepsy. It will focus its impact on neuronal excitability and synaptic plasticity, its neuroprotective qualities, and elucidate the drug's potential mechanisms of action in treating epilepsy. By scrutinizing ketamine's impact and mechanisms in various types of epilepsy, we aspire to contribute to a more comprehensive and holistic approach to epilepsy management.

Targeting heterozygous dominant negative variant of KCNA2 using Gapmer ASO for the treatment of drug-resistant epilepsy.

A missense mutation c.1220C>G of KCN2A gene was recently identified in an infant with epilepsy. KCNA2 encodes KV1.2 subunits that form voltage-gated potassium channels (VGKC) via tetrameric assembly. The mutation results in amino acid change P407R at the highly conserved PVP motif. Functional characterization revealed that mutant KV1.2_P407R subunits formed loss-of-function channels and suppressed both KV1.2 and KV1.1 channel activities. Hetero-tetrameric assembly of the KV1.2_P407R subunits with other neuronal voltage-gated potassium channels of Shaker subfamily could lead to general deficit of repolarizing potassium current and potentially underlie the enhanced seizure susceptibility. Indeed, expression of human KV1.2_P407R in early postnatal rat cortical neurons or genetically engineered hESC-derived neurons disclosed broadening of action potential duration and early afterdepolarization (EAD), associating with reduced potassium current. We hypothesize that Gapmer antisense oligonucleotides (ASOs) targeted to c.1220C>G mutation will selectively degrade the mutant mRNA while allowing the remaining wild-type (WT) subunits to form functional channels. As a proof of principle, delivery of Gapmer packaged in lipid nanoparticle into cortical neurons selectively suppressed KV1.2_P407R over the WT protein expression, reversing the broadening of action potential duration, abrogating the EAD and leading to overall increase in potassium current.

Ketogenic diet effectiveness is superior for drug resistant epilepsy with causative genetic mutation than those without genetic etiology.

AIM: Epilepsy with genetic etiology is high prevalence of DRE, which is reported responsive to ketogenic diet therapy (KDT). Our retrospective cohort study attempted to investigate the KD responsiveness between DRE with genetic and non-genetic etiology. METHOD: Non-fasting gradual KD initiation protocol (GRAD-KD) and five-day diet program was implemented. Participants were categorized into genetic epilepsy or non-genetic epilepsy groups based on genetic tests. Monthly seizure frequencies and seizure reduction rate after KDT 3 months and 6 months were compared between two groups. RESULTS: Forty-six patients with genetic epilepsy and ninety-four patients with non-genetic epilepsy were recruited. Among 46 patients with genetic epilepsy, 12 patients withdrew from diet before 3 months of KDT, and 7 patients withdrew from diet before 6 months of KDT, thus, 27 patients retained the diet. Among 94 patients with non-genetic epilepsy, 20 patients withdrew from diet before 3 months of KDT, and 21 patients withdrew from diet before 6 months of KDT, 53 patients retained the diet. For the 46 patients with genetic epilepsy, 12 patients had pathogenic variants related to developmental and epileptic encephalopathy (DEE), whereas other 34 patients had disease-causing variants other than DEE. The mean monthly seizure frequencies showed significantly decreased both in patient with genetic-and non-genetic epilepsy after 6 months of KDT, however, the seizure reduction rate was significantly higher in patients with genetic epilepsy than patients with non-genetic epilepsy after 6 months of KDT. In addition, our data demonstrated that KDT could significantly reduce seizure burden in patients with non-DEE than patients with DEE. In addition, the patients with non-DEE significantly achieved greater seizure reduction rate than patients with DEE after 6 months of KDT. INTERPRETATION: Our data highlighted that KD effectiveness is more outstanding in decreasing seizure burdens for epileptic patients with genetic etiology than those without causative gene mutation. Additionally, KDT is also significantly effective for decreasing more seizure burdens for non-DEE patients than for DEE patients. We suggested epileptic patients caused by genetic mutation should implement KDT as early as possible.

Review of pharmacogenetics of antiseizure medications: focusing on genetic variants of mechanistic targets.

Antiseizure medications (ASMs) play a central role in seizure management, however, unpredictability in the response to treatment persists, even among patients with similar seizure manifestations and clinical backgrounds. An objective biomarker capable of reliably predicting the response to ASMs would profoundly impact epilepsy treatment. Presently, clinicians rely on a trial-and-error approach when selecting ASMs, a time-consuming process that can result in delays in receiving alternative non-pharmacological therapies such as a ketogenetic diet, epilepsy surgery, and neuromodulation therapies. Pharmacogenetic studies investigating the correlation between ASMs and genetic variants regarding their mechanistic targets offer promise in predicting the response to treatment. Sodium channel subunit genes have been extensively studied along with other ion channels and receptors as targets, however, the results have been conflicting, possibly due to methodological disparities including inconsistent definitions of drug response, variations in ASM combinations, and diversity of genetic variants/genes studied. Nonetheless, these studies underscore the potential effect of genetic variants on the mechanism of ASMs and consequently the prediction of treatment response. Recent advances in sequencing technology have led to the generation of large genetic datasets, which may be able to enhance the predictive accuracy of the response to ASMs.

A Revolutionary Approach for Combating Efflux Transporter-mediated Resistant Epilepsy: Advanced Drug Delivery Systems.

Epilepsy is a persistent neurological condition that affects 60 million individuals globally, with recurrent spontaneous seizures affecting 80% of patients. Antiepileptic drugs (AEDs) are the main course of therapy for approximately 65% of epileptic patients, and the remaining 35% develop resistance to medication, which leads to Drug-Resistant Epilepsy (DRE). DRE continues to be an important challenge in clinical epileptology. There are several theories that attempt to explain the neurological causes of pharmacoresistance in epilepsy. The theory that has been studied the most is the transporter hypothesis. Therefore, it is believed that upregulation of multidrug efflux transporters at the blood-brain barrier (BBB), such as P-glycoprotein (P-gp), which extrudes AEDs from their target location, is the major cause, leading to pharmacoresistance in epilepsy. The most effective strategies for managing this DRE are peripheral and central inhibition of P-gp and maintaining an effective concentration of the drug in the brain parenchyma. Presently, no medicinal product that inhibits P-gp is being used in clinical practice. In this review, several innovative and promising treatment methods, including gene therapy, intracranial injections, Pgp inhibitors, nanocarriers, and precision medicine, are discussed. The primary goal of this work is to review the P-gp transporter, its substrates, and the latest novel treatment methods for the management of DRE.

Simultaneous robotic-assisted laser thermal ablation of multiple cortical tubers for drug-resistant epilepsy in a 17-year-old patient with Tuberous Sclerosis Complex.

Magnetic resonance guided laser interstitial thermal therapy (MRgLITT) is a new minimally invasive treatment for Tuberous Sclerosis Complex (TSC) associated epilepsy in children. This video describes a case of a 17-year-old girl with TSC-associated drug resistant epilepsy treated with robotic-assisted MRgLITT. In our case, MRgLITT was safe and effective in simultaneous targeting multiple epileptic tubers in one single procedure, leading to a marked decrease in seizure frequency. MRgLITT could be a promising and more appealing treatment option for children who may need multiple surgeries over their lifetime due to the progressive nature of TSC.

Quantitative phenotyping of verbal and non-verbal cognitive impairment using diffusion-weighted MRI connectome: Preliminary study of the crowding effect in children with left hemispheric epilepsy.

The "crowding" effect (CE), wherein verbal functions are preserved presumably at the expense of nonverbal functions, which diminish following inter-hemispheric transfer of language functions, is recognized as a specific aspect of functional reorganization, offering an insight about neural plasticity in children with neural insult to the dominant hemisphere. CE is hypothesized as a marker for language preservation or improvement after left-hemispheric injury, yet it remains challenging to fully discern it in preoperative evaluation. We present a novel DWI connectome (DWIC) approach to predict the presence of CE in 24 drug-resistant epilepsy (DRE) patients with a left-hemispheric focus and 29 young healthy controls. Psychometry-driven DWIC analysis was applied to create verbal and non-verbal modular networks. Local efficiency (LE) was assessed at individual regions of the two networks and its Z-score was compared to predict the presence of CE. Compared with a traditional organization (TO) group, wherein verbal functions are adversely affected, while non-verbal functions are preserved, the CE group showed significantly higher Z-scores in verbal network and significantly lower Z-scores in non-verbal network, corresponding to network reorganization in CE. A larger number of antiseizure drugs was significantly associated with more decreased Z-score in the right non-verbal network of the CE group and left verbal network of the TO group. These findings hold great potential to identify DRE patients whose verbal/language skills may over time be preserved due to effective inter-hemispheric reorganization and identify those whose verbal/language impairments may persist due to lack of inter-hemispheric reorganization.

Focal cortical dysplasia lesion segmentation using multiscale transformer.

OBJECTIVES: Accurate segmentation of focal cortical dysplasia (FCD) lesions from MR images plays an important role in surgical planning and decision but is still challenging for radiologists and clinicians. In this study, we introduce a novel transformer-based model, designed for the end-to-end segmentation of FCD lesions from multi-channel MR images. METHODS: The core innovation of our proposed model is the integration of a convolutional neural network-based encoder-decoder structure with a multiscale transformer to augment the feature representation of lesions in the global field of view. Transformer pathways, composed of memory- and computation-efficient dual-self-attention modules, leverage feature maps from varying depths of the encoder to discern long-range interdependencies among feature positions and channels, thereby emphasizing areas and channels relevant to lesions. The proposed model was trained and evaluated on a public-open dataset including MR images of 85 patients using both subject-level and voxel-level metrics. RESULTS: Experimental results indicate that our model offers superior performance both quantitatively and qualitatively. It successfully identified lesions in 82.4% of patients, with a low false-positive lesion cluster rate of 0.176 ± 0.381 per patient. Furthermore, the model achieved an average Dice coefficient of 0.410 ± 0.288, outperforming five established methods. CONCLUSION: Integration of the transformer could enhance the feature presentation and segmentation performance of FCD lesions. The proposed model has the potential to serve as a valuable assistive tool for physicians, enabling rapid and accurate identification of FCD lesions. The source code and pre-trained model weights are available at https://github.com/zhangxd0530/MS-DSA-NET . CRITICAL RELEVANCE STATEMENT: This multiscale transformer-based model performs segmentation of focal cortical dysplasia lesions, aiming to help radiologists and clinicians make accurate and efficient preoperative evaluations of focal cortical dysplasia patients from MR images. KEY POINTS: The first transformer-based model was built to explore focal cortical dysplasia lesion segmentation. Integration of global and local features enhances the segmentation performance of lesions. A valuable benchmark for model development and comparative analyses was provided.

Role of Responsive Neurostimulation in Managing Drug-Resistant Epilepsy: A Systematic Review of Clinical Outcomes.

Drug-resistant epilepsy remains a substantial challenge in neurology, affecting patients who do not respond to conventional antiepileptic drugs. Responsive neurostimulation (RNS) has emerged as a promising therapeutic approach, yet comprehensive reviews synthesizing its clinical outcomes are sparse. This systematic review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and involved a comprehensive database search through PubMed, Medline, Embase, the Cochrane Library, and Scopus, covering literature up to April 2024. The review targeted peer-reviewed articles evaluating the efficacy, safety, and quality of life impacts of RNS in patients with drug-resistant epilepsy. Key inclusion criteria encompassed clinical trials, cohort studies, and meta-analyses, while exclusion criteria included non-peer-reviewed and irrelevant studies. We identified five studies meeting our inclusion criteria. These studies collectively demonstrated that RNS significantly reduces seizure frequency and improves quality of life, while maintaining a favorable safety profile. Despite small sample sizes and potential selection biases, the benefits of RNS appeared consistent across diverse patient demographics. RNS represents a viable and effective treatment option for drug-resistant epilepsy, offering significant improvements in seizure control and patient quality of life. Future research should focus on long-term outcomes and refining patient selection to optimize the therapeutic benefits of RNS. The integration of RNS into standard epilepsy management protocols is recommended based on current evidence.

Synergistic Effect between the APOE ε4 Allele with Genetic Variants of GSK3B and MAPT: Differential Profile between Refractory Epilepsy and Alzheimer Disease.

Temporal Lobe Epilepsy (TLE) is a chronic neurological disorder characterized by recurrent focal seizures originating in the temporal lobe. Despite the variety of antiseizure drugs currently available to treat TLE, about 30% of cases continue to have seizures. The etiology of TLE is complex and multifactorial. Increasing evidence indicates that Alzheimer's disease (AD) and drug-resistant TLE present common pathological features that may induce hyperexcitability, especially aberrant hyperphosphorylation of tau protein. Genetic polymorphic variants located in genes of the microtubule-associated protein tau (MAPT) and glycogen synthase kinase-3ß (GSK3B) have been associated with the risk of developing AD. The APOE ε4 allele is a major genetic risk factor for AD. Likewise, a gene-dose-dependent effect of ε4 seems to influence TLE. The present study aimed to investigate whether the APOE ɛ4 allele and genetic variants located in the MAPT and GSK3B genes are associated with the risk of developing AD and drug-resistant TLE in a cohort of the Mexican population. A significant association with the APOE ε4 allele was observed in patients with AD and TLE. Additional genetic interactions were identified between this allele and variants of the MAPT and GSK3B genes.

Epilepsy surgery below the age of 5 years: Are we still in time to preserve developmental and intellectual functions?

OBJECTIVE: The aim of this study is to describe the pre- and post-operative developmental and intellectual functions in a cohort of patients who underwent surgery for drug-resistant epilepsy (DRE) before the age of 5 years. METHOD: We retrospectively reviewed the medical records and neurodevelopmental assessments of a cohort of 80 surgically treated pediatric patients with DRE. We included patients if they had at least one pre- and one post-surgical neuropsychological assessments; 27 met the inclusion criteria. We evaluated Developmental Quotient (DQ) and Intelligence Quotient (IQ) before and after surgery. We identified two groups based on psychological evaluation outcome: Group 1, with stable or improved developmental and intellectual functions, and Group 2, experiencing developmental and intellectual loss. RESULTS: The mean age at seizure onset was 1.2 ± 1.0 years, and the mean age at surgery was 2.9 ± 1.2 years. At the last follow-up (mean 4 years, SD ± 2), 19/27 (70%) patients were seizure- and drug-free; 18/27 patients (67%) fit in Group 1, and 9/27 (33%) fit in Group 2. The mean age at surgery was 2.6 years (SD ± 1.1; range 1.2-5.1) in Group 1 and 3.4 years in Group 2 (SD ± 1.1; range 1.6-5.0). Group 1 had a lower pre-operative DQ/IQ total score than Group 2 (median DQ/IQ respectively 82 vs 108, p = 0.05). Between pre- and post-assessments, we found that in Group 1, Performance scores improved (82.7 vs 102, p = 0.001), while in Group 2, the Total and Verbal scores worsened (respectively 108 vs 75, p = 0.008, and 100 vs 76, p = 0.021). SIGNIFICANCE: Our study's results emphasize the positive impact of surgery before the age of 5 years on developmental and intellectual outcomes. Despite limitations such as a small sample size, lack of a control group, and diverse etiologies, our findings support the crucial role of early intervention in preserving or enhancing developmental and intellectual functions in young patients with DRE. PLAIN LANGUAGE SUMMARY: This retrospective study, conducted at the Bambino Gesù Children Hospital in Italy, reports neuropsychological and developmental and/or cognitive data for children undergoing early epilepsy surgery (before the age of 5). It found that children with lower developmental or cognitive profiles gained the highest scores on post-operative neuropsychological evaluations. This study provides information on the potential benefits of early surgery in shortening the duration of epilepsy, preventing or arresting deterioration, and enhancing plasticity and recovery.

Seizure outcome in drug-resistant epilepsy in the setting of polymicrogyria.

OBJECTIVE: We aimed to analyze seizure outcomes and define ictal onset with intracranial electroencephalography (ICEEG) in patients with polymicrogyria (PMG)-related drug-resistant epilepsy (DRE), considering surrounding cortex and extent of surgical resection. METHODS: Retrospective study of PMG-diagnosed patients (2001 to June 2018) at a single epilepsy center was performed. Primary outcome was complete seizure freedom (SF), based on Engel classification with follow-up of ≥ 1 year. Univariate analyses identified predictive clinical variables, later integrated into multivariate Cox proportional hazards models. RESULTS: Thirty-five patients with PMG-related DRE (19 adults/16 pediatric: 20 unilateral/15 bilateral) were studied. In surgical group (n = 23), 52 % achieved SF (mean follow-up:47 months), whereas none in non-resective treatment group (n = 12) attained SF (mean follow-up:39.3 months) (p = 0.002). In surgical group, there were no significant differences in SF, based on the laterality of the PMG [uni or bilateral,p = 0.35], involvement of perisylvian region(p = 0.714), and extent of the PMG resection [total vs. partial,p = 0.159]. Patients with ictal ICEEG onset in both PMG and non-PMG cortices, and those limited to non- PMG cortices had a greater chance of achieving SF compared to those limited to the PMG cortices. CONCLUSION: Resective surgery guided by ICEEG for defining the epileptogenic zone (EZ), in DRE patients with PMG, leads to favorable seizure outcomes. ICEEG-guided focal surgical resection(s) may lead to SF in patients with bilateral or extensive unilateral PMG. ICEEG aids in EZ localization within and/or outside the MRI-identified PMG. Complete removal of PMG identified on MRI does not guarantee SF. Hence, developing preimplantation hypotheses based on epileptogenic networks evaluation during presurgical assessment is crucial in this patient population.

PPP3CA gene-related developmental and epileptic encephalopathy: Expanding the electro-clinical phenotype.

PURPOSE: The objective of this study is to characterize the electro-clinical phenotype of individuals affected by the rare PPP3CA gene-related developmental and epileptic encephalopathy (DEE). METHODS: We provide a detailed electro-clinical description of four previously unreported subjects, with unremarkable structural brain MRI and a normal screening for inborn errors of metabolism, who carry pathogenic variants within the regulatory domain of the PPP3CA gene, which encodes for calcineurin. We also conducted a literature review via PubMed and SCOPUS (up to December 2023) to collect all the studies reporting clinical details of subjects with PPP3CA pathogenic variants within the regulatory domain. RESULTS: Our in-depth investigation reveals two distinct electro-clinical phenotypes with unique interictal and ictal patterns. Pathogenic variants within the calmodulin-binding domain result in childhood-onset epilepsy with focal and generalized seizures, developmental and intellectual impairments. Pathogenic variants within the regulatory domain lead to early onset drug-resistant severe epilepsy and potentially fatal outcomes. Comparative analysis with existing literature corroborates the notion that truncating mutations, prevalent in the regulatory domain but also possible in the calmodulin-binding domain, consistently associate with more profound disabilities and drug-resistant epilepsy. CONCLUSION: Our study emphasizes the critical role of pathogenic variants' type and location on the severity of PPP3CA-related DEE. We also speculate, based on peculiar EEG patterns, on potential pathophysiological mechanisms involving calcineurin dysfunction and calcium homeostasis. In order to improve our understanding of this rare DEE, we need both collaborative efforts to gather larger cohorts and further experimental studies.

Role of antioxidants in reducing oxidative stress and seizure frequency in drug-resistant epileptic patients.

Drug-resistant epilepsy presents significant challenges in treating epileptic patients, leading to recurrent seizures and necessitating the use of polypharmacy with anti-epileptic drugs. Both of these conditions contribute to increased oxidative stress, which is detrimental to the brain. The aim of this study was to determine the role of vitamins C and E in reducing oxidative stress and seizure frequency in drug-resistant epileptic patients. This was a double-blinded, randomized clinical trial with a placebo, parallel design, and block randomization. The subjects were drug-resistant epileptic patients aged 1-18 years who received routine treatment. Randomization was performed on 100 patients who were divided into the treatment or placebo groups. The patients received a combination of vitamin C (100 mg/day) and vitamin E (200 IU/day for those <5 years or 400 IU/day for those ≥5 years) or a placebo for eight weeks. Malondialdehyde (MDA) levels and seizure frequency were measured prior to and after the intervention. A total of 42 and 46 patients were followed till the end of the study in the intervention and placebo groups, respectively. Our data indicated that the MDA levels prior to treatment were not significantly different between the treatment and placebo groups (0.901 vs 0.890 mmol/mL, p=0.920) and were significantly reduced after the treatment in both the treatment group (p<0.001) and placebo group (p=0.028). The changes in MDA levels (between post- and pre-treatment) were also not significantly different between the two groups (p=0.181). Our per-protocol analysis indicated that the reduction in seizure frequency was significantly higher in the treatment group compared to the placebo group (95% vs 35%, p<0.001), with 92% and 60% relative and absolute risk reduction, respectively. The intention-to-treat analysis also indicated that the reduction in seizure frequency was significantly higher in the intervention group than in the control group (80% vs 32%, p<0.001), with relative and absolute risk reduction of 70% and 48%, respectively. There was no significant relationship between changes in MDA levels and seizure frequency in either group. In conclusion, vitamins C and E could reduce seizure frequency and, therefore, could be considered as adjuvant therapy in drug-resistant epileptic patients.

Machine learning algorithm for predicting seizure control after temporal lobe resection using peri-ictal electroencephalography.

Brain resection is curative for a subset of patients with drug resistant epilepsy but up to half will fail to achieve sustained seizure freedom in the long term. There is a critical need for accurate prediction tools to identify patients likely to have recurrent postoperative seizures. Results from preclinical models and intracranial EEG in humans suggest that the window of time immediately before and after a seizure ("peri-ictal") represents a unique brain state with implications for clinical outcome prediction. Using a dataset of 294 patients who underwent temporal lobe resection for seizures, we show that machine learning classifiers can make accurate predictions of postoperative seizure outcome using 5 min of peri-ictal scalp EEG data that is part of universal presurgical evaluation (AUC 0.98, out-of-group testing accuracy > 90%). This is the first approach to seizure outcome prediction that employs a routine non-invasive preoperative study (scalp EEG) with accuracy range likely to translate into a clinical tool. Decision curve analysis (DCA) shows that compared to the prevalent clinical-variable based nomogram, use of the EEG-augmented approach could decrease the rate of unsuccessful brain resections by 20%.

Total posterior quadrant disconnection for drug-resistant epilepsy in children.

OBJECTIVE: To assess seizure outcomes, prognostic factors, and developmental changes in children undergoing total posterior quadrant disconnection (PQD) for drug-resistant epilepsy (DRE). METHODS: We conducted a retrospective analysis of the clinical data of children with DRE who underwent total PQD surgery. The study focused on Engel's classification for seizure outcomes, exploring correlation of preoperative data and surgical effectiveness, and predictors of seizure prognosis. It involved a comparative analysis of developmental levels pre- and 3 months postoperatively using Griffiths Mental Development Scales-China (GMDS-C), and the correlation between clinical characteristics and GMDS-C results. RESULTS: Out of 61 pediatric patients, 70.5% showed no seizure recurrence postoperatively. In the univariate analysis, interictal electroencephalogram (EEG), magnetic resonance imaging (MRI), fluorodeoxyglucose positron emission tomography (FDG-PET), and acute postoperative seizure (APOS) were significantly related to surgical prognosis. In multivariate analysis, interictal EEG and APOS were identified as predictors of seizure prognosis. Survival analysis indicated significant associations between MRI, interictal EEG, FDG-PET, APOS and postoperative seizure occurrence. Preoperative GMDS-C levels were significantly correlated with epilepsy duration, seizure frequency, interictal EEG, and FDG-PET. GMDS-C scores improved postoperatively, while developmental quotients remained stable. SIGNIFICANCE: For patients with structural abnormalities in the entire posterior quadrant, thorough preoperative assessment and timely total PQD surgery can effectively control seizures without causing neurological development deterioration. APOS and interictal EEG abnormalities beyond the posterior quadrant are predictors for seizure prognosis but should not be deemed contraindications for surgery. PLAIN LANGUAGE SUMMARY: Due to lack of analysis on pediatric total PQD cases, 61 pediatric patients who underwent total PQD surgery were retrospectively enrolled. Seizure and development results were collected and analyzed as dependent variables. The study found that 70.5% of patients were seizure-free and showed development improvement, with no deaths or severe complications reported. Prognosis predictors included APOS and interictal EEG abnormalities beyond the posterior quadrant.