Refractory Epilepsy Research Articles

Macrocephaly and developmental delay caused by missense variants in RAB5C.

Rab GTPases are important regulators of intracellular vesicular trafficking. RAB5C is a member of the Rab GTPase family that plays an important role in the endocytic pathway, membrane protein recycling and signaling. Here we report on 12 individuals with nine different heterozygous de novo variants in RAB5C. All but one patient with missense variants (n= 9) exhibited macrocephaly, combined with mild-to-moderate developmental delay. Patients with loss of function variants (n= 2) had an apparently more severe clinical phenotype with refractory epilepsy and intellectual disability but a normal head circumference. Four missense variants were investigated experimentally. In vitro biochemical studies revealed that all four variants were damaging, resulting in increased nucleotide exchange rate, attenuated responsivity to guanine exchange factors and heterogeneous effects on interactions with effector proteins. Studies in C. elegans confirmed that all four variants were damaging in vivo and showed defects in endocytic pathway function. The variant heterozygotes displayed phenotypes that were not observed in null heterozygotes, with two shown to be through a dominant negative mechanism. Expression of the human RAB5C variants in zebrafish embryos resulted in defective development, further underscoring the damaging effects of the RAB5C variants. Our combined bioinformatic, in vitro and in vivo experimental studies and clinical data support the association of RAB5C missense variants with a neurodevelopmental disorder characterized by macrocephaly and mild-to-moderate developmental delay through disruption of the endocytic pathway.

MYT1L variant inherited by a mosaic father in a case of severe developmental and epileptic encephalopathy.

The MYT1L gene plays a critical role in brain development, promoting the differentiation and proliferation of cells, important for the formation of brain connections. MYT1L is also involved in regulating the development of the hypothalamus, which is a crucial actor in weight regulation. Genetic variants in the MYT1L are associated with a range of developmental disorders, including intellectual disability, autism spectrum disorder, facial dysmorphisms, and epilepsy. The specific role of MYT1L in epilepsy remains elusive and no patients with developmental and epileptic encephalopathy (DEE) have been described so far. In this study, we report a patient with DEE presenting with severe refractory epilepsy, obesity and behavioral abnormalities. Exome sequencing led to the identification of the heterozygous variant NM_001303052.2: c.1717G>A, p.(Gly573Arg) (chr2-1910340-C-T; GRCh38.p14) in the MYT1L gene. This variant was found to be inherited by the father, who was a mosaic and did not suffer from any neuropsychiatric disorders. Our observations expand the molecular and phenotype spectrum of MYT1L related disorders, suggesting that affected individuals may present with severe epileptic phenotype leading to neurocognitive deterioration. Furthermore, we show that mosaic parents may not display the disease phenotype, with relevant implications for genetic counseling.

Everolimus precision therapy for the GATOR1-related epilepsies: a case series.

Pathogenic variants in the GAP activity towards RAGs 1 (GATOR1) complex genes (DEPDC5, NPRL2, NPRL3) cause focal epilepsy through hyperactivation of the mechanistic target of rapamycin pathway. We report our experience using everolimus in patients with refractory GATOR1-related epilepsy. We performed an open-label observational study of everolimus for drug-resistant epilepsy caused by variants in DEPDC5, NPRL2 and NPRL3. Everolimus was titrated to a target serum concentration (5-15ng/mL). The primary outcome measure was change in mean monthly seizure frequency compared with baseline. Five patients were treated with everolimus. All had highly active (median baseline seizure frequency, 18/month) and refractory focal epilepsy (failed 5-16 prior anti-seizure medications). Four had DEPDC5 variants (three loss-of-function, one missense) and one had a NPRL3 splice-site variant. All patients with DEPDC5 loss-of-function variants had significantly reduced seizures (74.3-86.1%), although one stopped everolimus after 12 months due to psychiatric symptoms. Everolimus was less effective in the patient with a DEPDC5 missense variant (43.9% seizure frequency reduction). The patient with NPRL3-related epilepsy had seizure worsening. The most common adverse event was stomatitis. Our study provides the first human data on the potential benefit of everolimus precision therapy for epilepsy caused by DEPDC5 loss-of-function variants. Further studies are needed to support our findings.

Feasibility of ketogenic diet therapy variants for refractory epilepsy in neonates to infants under 2 years old

BackgroundKetogenic diet Therapy (KDT) has been reported as a possible beneficial management strategy for controlling seizures in infants aged <2 years, but the safety and efficacy of this therapy remain to be investigated. We investigated the achievability, tolerability, efficacy, and safety of KDT for patients under 2 years old. Materials and methodsInfants younger than 2 years old with pharmacoresistant epilepsy were enrolled in this prospective study. We divided cases into three age groups: I) neonates; II) infants aged 1–12 months; III) infants aged 12–24 months. KDT initiation protocol were administration through parenteral route, enteral route or oral feeding. Seizure reduction rate, physical growth, and adverse effects were assessed at monthly visit. ResultsThirteen patients who completed 6 months of KDT were recruited. There was one neonate in group I, 9 infants in group II, and 3 infants in group III. Eleven of them (11/13, 84.6%) were responders to KDT. All infants with underlying genetic etiology were seizure free after treating with KDT. The starting keto ratio was 1.1 mmol/L in group I, 2.3 mmol/L in group II, and 2.8 mmol/L in group III, which gradually approached 3:1–4:1 over 5–7 days. There were no symptomatic adverse effects or growth retardation in any of the study subjects. ConclusionsKDT is a promising alternative therapy with high feasibility, safety, and efficacy for pharmacoresistant epilepsy in infants under 2 years old, especially for those with genetic etiology. The starting keto ratio should be lower, and the keto ratio titration period should be longer than for children older than 2 years.

Cenobamate in patients with highly refractory focal epilepsy: A retrospective real-world study

PurposeTo determine the effectiveness and safety outcomes of cenobamate in a cohort of patients with highly refractory focal epilepsy in routine clinical practice. MethodsObservational, retrospective, phase 4 study on subjects receiving cenobamate in three Spanish centers. The primary endpoint was the retention rate at the last follow-up. The main secondary endpoints were the 50%-responder and seizure-free rates at three months and the last follow-up. Other secondary endpoints were Global Clinical Impressions-Improvement (CGI-I) scores and treatment-emergent adverse events (TEAEs). ResultsFifty-one patients with highly refractory focal epilepsy with 24.7 years of disease evolution, ten previously tried ASM, and a 23.5% of previous epilepsy surgery were included. The retention rate at the last follow-up was 80.4%. The 50% responder rate in focal seizures at three months was 56.5% (median reduction per month 51%, 0–74.6; p < 0.0001) and in focal to bilateral tonic-clonic seizures was 63.6% (median reduction per month 89%, 0–100; p = 0.022). A total of 54.3% of subjects reported a reduction in the intensity of focal seizures, and 66% manifested clinically significant satisfaction. Cenobamate allowed a significant decrease in concomitant ASM, especially sodium channel blockers. TEAEs were reported in 43.1% of individuals, 85% of whom resolved or improved, with no new safety findings. ConclusionIn this analysis of patients with highly refractory focal epilepsy treated with cenobamate according to standard clinical practice, there was evidence of a high reduction in both seizure frequency and intensity, with a manageable safety profile.

Functional brain connectivity indexes derived from low-density EEG of pre-implanted patients as VNS outcome predictors

Objective. In 1/3 of patients, anti-seizure medications may be insufficient, and resective surgery may be offered whenever the seizure onset is localized and situated in a non-eloquent brain region. When surgery is not feasible or fails, vagus nerve stimulation (VNS) therapy can be used as an add-on treatment to reduce seizure frequency and/or severity. However, screening tools or methods for predicting patient response to VNS and avoiding unnecessary implantation are unavailable, and confident biomarkers of clinical efficacy are unclear. Approach. To predict the response of patients to VNS, functional brain connectivity measures in combination with graph measures have been primarily used with respect to imaging techniques such as functional magnetic resonance imaging, but connectivity graph-based analysis based on electrophysiological signals such as electroencephalogram, have been barely explored. Although the study of the influence of VNS on functional connectivity is not new, this work is distinguished by using preimplantation low-density EEG data to analyze discriminative measures between responders and non-responder patients using functional connectivity and graph theory metrics. Main results. By calculating five functional brain connectivity indexes per frequency band upon partial directed coherence and direct transform function connectivity matrices in a population of 37 refractory epilepsy patients, we found significant differences (p < 0.05) between the global efficiency, average clustering coefficient, and modularity of responders and non-responders using the Mann–Whitney U test with Benjamini–Hochberg correction procedure and use of a false discovery rate of 5%. Significance. Our results indicate that these measures may potentially be used as biomarkers to predict responsiveness to VNS therapy.

Determinants of epileptogenic zone identification and seizure outcome in children with refractory epilepsy undergoing stereoelectroencephalography.

The objective of this paper was to investigate the factors associated with successful epileptogenic zone (EZ) identification and postsurgical seizure freedom in pediatric patients with drug-resistant epilepsy who underwent first-time stereoelectroencephalography (SEEG). The authors conducted a retrospective cohort study of all consecutive patients younger than 18 years of age at the time of recommendation for invasive evaluation with SEEG who were treated from July 2009 to June 2020. The authors excluded patients who had undergone failed prior resective epilepsy surgery or prior intracranial electrode evaluation for seizure localization. For their primary outcome, the authors evaluated the relationship between clinical and radiographic factors and successful identification of a putative EZ. For their secondary outcome, the authors investigated whether these factors had a significant relationship with seizure freedom (according to the Engel classification) at last follow-up. The authors included 101 patients in this study. SEEG was safe, with no major morbidity or mortality experienced. The population was complex, with an MRI lesion present in less than 40% of patients and patients as young as 2.9 years included. A proposed EZ was identified in 88 (87%) patients. Patients with an older onset of epilepsy (OR 1.20/year, p = 0.04) or epilepsy etiology suspected to be due to a developmental lesion (OR 8.38, p = 0.02) were more likely to have proposed EZ identification. Patients with a preimplantation bilateral seizure-onset hypothesis (OR 0.29, p = 0.047) and those who underwent longer periods of monitoring (OR 0.86/day, p = 0.006) were somewhat less likely to have proposed EZ identification. The presence of an MRI lesion was a positive factor on secondary analyses (OR 4.18, p = 0.049; 1-tailed test). Fifty percent of patients who underwent surgical treatment with resection or laser ablation achieved Engel class I outcomes, in contrast to 0% of patients who underwent neuromodulation. Patients with a preimplantation hypothesis in the frontal/parietal lobes had increased odds of seizure freedom compared with patients with a hypothesis in other locations (OR 3.64, p = 0.01). Pediatric SEEG is safe and often identifies a proposed resectable EZ. These results suggest that SEEG is effective in patients with frontal/parietal preimplantation hypothesis, with or without identified lesions on MRI.

Effects of ketogenic diet on the classification and functional composition of intestinal flora in children with mitochondrial epilepsy.

The ketogenic diet (KD) has shown excellent performance in the treatment of refractory epilepsy, but how it works is not yet fully understood. Gut microbiota is associated with various neurological disorders through the brain-gut axis. Different dietary patterns have different effects on the composition and function of gut microbiota. Here, by analyzing fecal samples from some patients with mitochondrial epilepsy before and after KD treatment through 16SrRNA sequencing, we found that KD intervention reduced the abundance of Firmicutes in the patient's gut, while the abundance of Bacteroidota increased in the KD group. LefSe analysis showed that Actinobacteriota, Phascolarctobacterium had significant advantages in the control group, while Bacteroides increased significantly after KD intervention, especially Bacteroides fragilis. Functional analysis showed that there were significant differences in 12 pathways in level 3. These changes suggest that KD can change the composition and diversity of the gut microbiota in patients and affect their function. Changes in specific bacterial groups in the gut may serve as biomarkers for the therapeutic effects of KD on epilepsy.

Altered functional connectivity and network excitability in a model of cortical dysplasia

Focal cortical dysplasias (FCDs) are malformations of cortical development that often result in medically refractory epilepsy, with a greater incidence in the pediatric population. The relationship between the disturbed cortical morphology and epileptogenic activity of FCDs remains unclear. We used the BCNU (carmustine 1-3-bis-chloroethyl-nitrosourea) animal model of cortical dysplasia to evaluate neuronal and laminar alterations and how these result in altered activity of intracortical networks in early life. We corroborated the previously reported morphological anomalies characteristic of the BCNU model, comprising slightly larger and rounder neurons and abnormal cortical lamination. Next, the neuronal activity of live cortical slices was evaluated through large field-of-view calcium imaging as well as the neuronal response to a stimulus that leads to cortical hyperexcitability (pilocarpine). Examination of the joint activity of neuronal calcium time series allowed us to identify intracortical communication patterns and their response to pilocarpine. The baseline power density distribution of neurons in the cortex of BCNU-treated animals was different from that of control animals, with the former showing no modulation after stimulus. Moreover, the intracortical communication pattern differed between the two groups, with cortexes from BCNU-treated animals displaying decreased inter-layer connectivity as compared to control animals. Our results indicate that the altered anatomical organization of the cortex of BCNU-treated rats translates into altered functional networks that respond abnormally to a hyperexcitable stimulus and highlight the role of network dysfunction in the pathophysiology of cortical dysplasia.

Cenobamate (YKP3089) and Drug-Resistant Epilepsy: A Review of the Literature.

Cenobamate (CNB), ([(R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl], is a novel tetrazole alkyl carbamate derivative. In November 2019, the Food and Drug Administration approved Xcopri®, marketed by SK Life Science Inc., (Paramus, NJ, USA) for adult focal seizures. The European Medicines Agency approved Ontozry® by Arvelle Therapeutics Netherlands B.V.(Amsterdam, The Neatherlands) in March 2021. Cenobamate is a medication that could potentially change the perspectives regarding the management and prognosis of refractory epilepsy. In this way, this study aims to review the literature on CNB's pharmacological properties, pharmacokinetics, efficacy, and safety. CNB is a highly effective drug in managing focal onset seizures, with more than twenty percent of individuals with drug-resistant epilepsy achieving seizure freedom. This finding is remarkable in the antiseizure medication literature. The mechanism of action of CNB is still poorly understood, but it is associated with transient and persistent sodium currents and GABAergic neurotransmission. In animal studies, CNB showed sustained efficacy and potency in the 6 Hz test regardless of the stimulus intensity. CNB was revealed to be the most cost-effective drug among different third-generation antiseizure medications. Also, CNB could have neuroprotective effects. However, there are still concerns regarding its potential for abuse and suicidality risk, which future studies should clearly assess, after which protocols should be changed. The major drawback of CNB therapy is the slow and complex titration and maintenance phases preventing the wide use of this new agent in clinical practice.

Depicting and defining sleep disturbed breathing associated with vagal nerve stimulation

BackgroundVagal nerve stimulators (VNS), which have been approved for management of refractory epilepsy and depression, induce unique disturbances of breathing during sleep (SDBVNS) that are not captured well using standard criteria. The primary purpose of this retrospective study was to compare AASM definitions with alternative criteria to more accurately measure SDBVNS We also sought to assess outcome variables that may be clinically relevant and response to positive airway pressure therapy. MethodsWe analyzed the electronic medical records and comprehensive polysomnography results of all adult subjects with active VNS for epilepsy who were referred to the sleep center for suspected sleep apnea (2015–2020). We compared standard AASM criteria for defining apneas/hypopnea index (AHIAASM) with three novel scoring criteria for hypopnea according to degree of oxygen desaturation associated with VNS events: AHIVNS0 (none required); AHIVNS2 (2% required); and AHIVNS3 (3% required). ResultsTwenty-six subjects were included in the final analysis with 35 PSGs (14 females/12 males). The mean age was 33.6 years and mean body mass index (BMI) of 32.2 kg/m2. AHIAASM measured ≥ 15/hour in 7 (26.9%) subjects versus 21 (80.8%) by AHIVNS0; 15 (70.0%) by AHIVNS2; and 5 (19.2%) by AHIVNS3. Clinically significant hypoxemia was not present. The mean time SpO2<89% was 7 (20.8) minutes. Oximetry tracings often showed a desaturation pattern that resembled a sawfish rather than sawtooth. Arousals specifically linked to VNS activation were not elevated (2.9/hour). The baseline AHIVNS0 was 27.7/hour with a lowest AHIVNS0 on PAP of 27.9/hr. ConclusionsAASM scoring criteria significantly underestimated the degree of VNS induced respiratory disturbances. VNS events were not associated with increased arousals or significant hypoxemia. PAP therapy was an ineffective treatment in this population. This study adds to the increasing body of evidence of sleep disordered breathing related to VNS and questions the clinical significance of this finding.

The efficacy and safety of patent Foramen Ovale Closure for Refractory Epilepsy (PFOC-RE): a prospectively randomized control trial of an innovative surgical therapy for refractory epilepsy patients with PFO of high-grade right-to-left shunt

BackgroundA significant proportion of patients with epilepsy have an unknown etiology and lack effective targeted therapeutic drugs. Patent Foramen Ovale (PFO) induces hypoxia and microembolism, leading to cerebral neurological dysfunction and increased epilepsy risk. This study aims to assess the efficacy and safety of PFO closure for relieving epileptic seizures in patients with refractory epilepsy associated with PFO.Methods/designRecruitment takes place at the West China Hospital of Sichuan University, China, for an open-label, randomized controlled clinical trial. The trial will include 110 patients with refractory epilepsy and PFO. Disease diagnoses will conform to the diagnostic criteria of the International League Against Epilepsy (ILAE) for refractory epilepsy and the American Society of Echocardiography (ASE) for PFO. Refractory epilepsy and high-grade right-to-left shunt (RLS) of the PFO will be further diagnosed using 24-hour video electroencephalogram and transthoracic echocardiography with contrast injection, respectively. Eligible participants require a secondary or higher volume of RLS.Trial registrationChinese Clinical Trial Registry (ChiCTR2200065681). Registered on November 11, 2022.

Predictive factors for successful vagus nerve stimulation in patients with refractory epilepsy: real-life insights from a multicenter study.

Vagus nerve stimulation (VNS) therapy is an established treatment for patients with drug-resistant epilepsy that reduces seizure frequency by at least 50% in approximately half of patients; however, the characteristics of the patients with the best response have not yet been identified. Thus, it is important to identify the profile of patients who would have the best response to guide early indications and better patient selection. This retrospective study evaluated vagus nerve stimulation (VNS) as an adjuvant therapy for patients with drug-resistant epilepsy from six epilepsy centers in Brazil. Data from 192 patients aged 2-66 years were analyzed, and all patients received at least 6 months of therapy to be included. Included patients were aged 2-66 years (25.6 ± 14.3), 105 (54.7%) males and 87 (45.8%) females. Median follow-up interval was 5 years (range, 2005-2018). Overall, the response rate (≥50% seizure reduction) after VNS implantation was 65.6% (126/192 patients). Most patients had 50-90% seizure reduction (60.9%) and nine patients became seizure-free. There were no serious complications associated with VNS implantation. The rate of a ≥ 50% seizure reduction response was significantly higher in patients with no history of neurosurgery. The presence of focal without generalized seizures and focal discharges on interictal EEG was associated with better response. Overall, etiological predictors of a better VNS response profile were tumors while a worse response to VNS was related to the presence of vascular malformations and Lennox-Gastaut Syndrome. We observed an association between a better response to VNS therapy no history of neurosurgery, focal interictal epileptiform activity, and focal seizure pattern. Additionally, it is important to highlight that age was not a determinant factor of the response, as children and adults had similar response rates. Thus, VNS therapy should be considered in both adults and children with DRE.

Closed-Loop Deep Brain Stimulation Using a Type of Fixed-Time Sliding Mode Controller for Avoiding Epileptiform Discharge in a Human Cortical Model

The cortical excitability rate correlates with epileptic seizures, which should be modulated in a finite time to prevent brain damage. Deep brain stimulation (DBS) is a successful treatment for patients with refractory epilepsy. This study proposes a closed-loop DBS control method that uses a Fixed-Time Integral Super-Twisting Sliding Mode Controller (FTISTSMC) to stop simulated epileptiform discharges within a limited time by modifying cortical excitability in the human Cortical Model (CM). First, the simulated stimulus current in the DBS method is injected into the state variable of the excitatory neurons population in CM. Then, the FTISTSMC is applied to the state variable described above to regulate the stimulus current value during the stimulation process to reduce the possible destructive effects of electrical pulses on the behavior of the healthy neurons. The proposed controller has some characteristics causing the simulated epileptic activity to become normal and the tracking error of the healthy state to be completely zero after 4.7[Formula: see text]s. In addition, it is possible to resolve the chattering and singularity problems and completely control epileptic seizures within a fixed and finite time frame.

Discovery and characterization of a specific inhibitor of serine-threonine kinase cyclin-dependent kinase-like 5 (CDKL5) demonstrates role in hippocampal CA1 physiology.

Pathological loss-of-function mutations in cyclin-dependent kinase-like 5 (CDKL5) cause CDKL5 deficiency disorder (CDD), a rare and severe neurodevelopmental disorder associated with severe and medically refractory early-life epilepsy, motor, cognitive, visual, and autonomic disturbances in the absence of any structural brain pathology. Analysis of genetic variants in CDD has indicated that CDKL5 kinase function is central to disease pathology. CDKL5 encodes a serine-threonine kinase with significant homology to GSK3β, which has also been linked to synaptic function. Further, Cdkl5 knock-out rodents have increased GSK3β activity and often increased long-term potentiation (LTP). Thus, development of a specific CDKL5 inhibitor must be careful to exclude cross-talk with GSK3β activity. We synthesized and characterized specific, high-affinity inhibitors of CDKL5 that do not have detectable activity for GSK3β. These compounds are very soluble in water but blood-brain barrier penetration is low. In rat hippocampal brain slices, acute inhibition of CDKL5 selectively reduces postsynaptic function of AMPA-type glutamate receptors in a dose-dependent manner. Acute inhibition of CDKL5 reduces hippocampal LTP. These studies provide new tools and insights into the role of CDKL5 as a newly appreciated key kinase necessary for synaptic plasticity. Comparisons to rodent knock-out studies suggest that compensatory changes have limited the understanding of the roles of CDKL5 in synaptic physiology, plasticity, and human neuropathology.

Evaluation of connectivity measures to identify Seizure Onset and Propagation Zones in Refractory Epilepsy: A Case study with two different Post- Surgical Outcomes.

High Frequency Oscillations (HFO) have been found very useful in refractory epilepsy. They have been used to identify the epileptogenic zone and as a promising clinical biomarker for presurgical evaluation in childhood epilepsy. There is controversy about whether there is a spread of HFOs and their propagation. Some researchers reinforce the idea of dealing with epilepsy as a network disorder, so the fact of propagation can promote this research. The hypothesis of this study is that connectivity methods can be useful to detect the seizure onset and propagation zones. Methodology has been applied to two cases where the clinical outcomes after surgery were free of seizures and not free. Promising results were obtained to understand both situations. A future study with more cases is necessary to obtain strong conclusions.Clinical Relevance- This exploratory study shows the relationship between connectivity measures and the propagation of HFOs and this can be useful to know the epileptogenic function of these waves that, nowadays, are unknown. Connectivity features in conjunction with other multivariate estimators can be a tool to help in identifying the regions of interest in refractory epilepsy.

The probability of achieving remission after correction of therapy in patients with pharmacoresistant focal epilepsy

Drug-resistant forms of epilepsy are an important medical and social problem.Goal of the work. Evaluation of the probability of achieving remission after correction of therapy in patients with drug-resistant focal epilepsy.Material and methods. The study included 309 patients divided into three heterogeneous groups: a group of patients with focal pharmacoresistant epilepsy; a group of patients with super refractory focal epilepsy; control group – patients who had not previously received treatment. The examination included history taking, clinical and neurological examination, routine EEG and/or EEG video monitoring, MRI of the brain, and analysis of medical records. Therapy was adjusted.Results. After correction of therapy, remission in patients in Group 1 was achieved in 27.8% of patients, improvement – in 27.1%, no effect – in 45.1%; in Group 2, remission was achieved in 13.2% of patients, improvement – in 28.6%, no effect – in 58.2%; in Group 3, remission was achieved in 41.2% of patients, improvement – in 32.9%, no effect – in 25.9%. Negative prognostic factors did not show a significant correlation with the lack of effect of therapy.Conclusion. After correction of therapy, remission was achieved in several patients with drug-resistant focal epilepsy, while negative prognostic factors do not exclude the possibility of achieving remission.

Histopathological characterization of cerebral small vessel disease in epilepsy patients with temporal lobe epilepsy submitted to surgery - a case-control study.

Cerebrovascular disease (CVD) is a major contributor to epilepsy. However, patients with epilepsy also have a significantly increased risk of stroke. The way epilepsy contributes to the increased risk of stroke is still uncertain and is ill characterized in neuropathological studies. A neuropathological characterization of cerebral small vessel disease (cSVD) in patients with chronic epilepsy was performed. Thirty-three patients with refractory epilepsy and hippocampal sclerosis (HS) submitted to epilepsy surgery from a reference centre were selected between 2010 and 2020 and compared to 19 autopsy controls. Five randomly selected arterioles from each patient were analysed using a previously validated scale for cerebral small vessel disease (cSVD). The presence of CVD disease imaging markers in pre-surgical brain MRI was studied. There were no differences in age (43,8 vs 41,6; p=0,547) or gender distribution (female gender 60,6% vs 52,6%; p=0,575) between groups. Most CVD findings in brain MRI were mild. Patients had a mean time between the epilepsy onset and surgery of 26±14,7 years and were medicated with a median number of 3 antiseizure medication (ASMs) [inter-quartile range 2-3]. Patients had higher median scores in arteriolosclerosis (3 vs 1; p<0,0001), microhemorrhages (4 vs 1; p<0,0001) and total score value (12 vs 8,9; p=0,031) in comparison with controls. No correlation was found between age, number of years until surgery, number of ASMs or cumulative defined daily dosage of ASM. The present study provided evidence supporting the increased burden of cSVD in the neuropathological samples of patients with chronic epilepsy.

Association of serum magnesium levels with seizure disorder; experience from central India

Magnesium is the fourth most abundant cation in the body. It has several functions in the human body including its role as a cofactor for more than 300 enzymatic reactions. Mg is a potential modulator of seizure activity because of its ability to antagonize the excitatory calcium influx through the N-methyl-D-aspartate receptor. Low magnesium levels in people with refractory epilepsy can increase the frequency of seizures. Hence in our study we aim to study the association of serum magnesium levels with seizure disorders and compare it with matched controls. In our study 154 adult individuals were included with seizure patients to control ratio of 1:1. Serum Magnesium levels was estimated in all individuals and levels were compared between patients of seizure disorder and healthy controls. Mean serum magnesium level was significantly lower in patients of seizure disorder as compared to controls (p&amp;#60;0.01). We, also observed significantly lower calcium level amongst cases as compared to controls (p&amp;#60;0.05). The mean magnesium level within 24 hours of seizures was 1.47±0.50 mg/dl whereas as the duration since seizures increased, mean magnesium level increased. In our study we found significant association between seizures and serum magnesium levels, as low magnesium has been implicated in refractory seizures which are resistant to anti-epileptic drugs and magnesium supplementation in such patients may result in decrease in number of anti-epileptic drugs and better control of seizures.

Additional Effect of High-output Current and/or High-duty Cycle in Vagus Nerve Stimulation for Adolescent/Adult Intractable Epilepsy.

A vagus nerve stimulation (VNS) device delivers electrical pulses to the vagus nerve at a rhythm defined by the duty cycle. The standard therapeutic range is advocated for an output current of 1.5-2.25 mA and a duty cycle of 10%. As the optimal settings vary from patient to patient, some patients may benefit from additional seizure reduction when stimulated beyond the standard range. A total of 74 patients (15 children aged <12 years and 59 adolescents/adults) who underwent VNS implantation between 2011 and 2020 and who were followed up for at least 2 years were included in this retrospective study. Stimulation parameters exceeding 2.25 mA of output current, 25% of duty cycle, and 0.5625 (2.25 mA × 25%) of current × duty cycle were defined as high stimulation. The proportion achieved an additional seizure reduction of 20%, and the 50% seizure reduction rate at the last follow-up was compared between adolescents/adults and children. Approximately 40% of patients in adolescents/adults treated with high stimulation experienced an additional acute effect, resulting in a 50% or greater reduction in seizures in almost all patients. Moreover, in adolescents/adults, 22.2%-41.9% of the patients were treated with high stimulation, and the responder rate was 69.5%. Conversely, the responder rate in children was 26.7%, significantly worse than that in adolescents/adults, despite higher stimulation. VNS with high-stimulation settings is effective for adolescent and adult patients with intractable epilepsy. Even high stimulation may not be effective in extremely refractory pediatric epilepsy with a high seizure frequency.