Drug-resistant Epilepsy In Adults Research Articles

Contribution of automated hippocampal volume measurements to radiological diagnosis in cases of mesial temporal sclerosis

Aims: Epilepsy, particularly drug-resistant epilepsy in adults, is often caused by Mesial Temporal Sclerosis (MTS), which can develop after brain injury from febrile illnesses or trauma. Magnetic Resonance Imaging (MRI) is crucial for diagnosing MTS, although challenges such as patient movement and mild or bilateral hippocampal atrophy can complicate the diagnosis. T1-weighted hippocampal volume measurements are effective in detecting MTS, with recent software advancements enabling automatic hippocampal segmentation. This study compared the hippocampal volumes and indices between adults with MTS and a control group of similar age and sex in the Turkish population. This study aimed to highlight structural differences in the hippocampus associated with MTS. Methods: This study involved a retrospective review of cranial MRIs scans from patients with MTS, confirmed through histopathological examination after epilepsy surgery. To ensure unbiased comparisons, a control group was selected using propensity score matching by age and gender. Two experienced neuroradiologists independently assessed the MRIs findings for MTS without knowledge of hippocampal volumetric data. Hippocampal volumes were measured using FreeSurfer software and standardized using the hippocampal volume index (HVI) and hippocampal asymmetry index (HAI). Results: In our study of 38 patients, MTS was found in 55.2% of patients on the right side and in 44.8% of patients on the left side, with no bilateral cases. Visual MRI analysis identified MTS in 84.2% of patients, with an area under of curve (AUC) of 0.921. Automatic volumetry detected MTS in 23 patients with an AUC of 0.791. Combining both methods, MTS was diagnosed in 33 patients, with an AUC of 0.922. Conclusion: Automated volumetric analyses have been shown to enhance the detection of hippocampal volume loss in patients with MTS.

Stereotactic depth electrode placement for chronic subthreshold cortical stimulation: surgical technique video.

Neurostimulation is an increasingly common treatment option for medically intractable epilepsy. SANTE (Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy) and Responsive Neurostimulation (RNS) System are landmark neurostimulation trials that utilized either duty cycle or a responsive stimulation paradigm. A seizure-free outcome is rarely observed with responsive and duty cycle neurostimulation devices. Chronic subthreshold cortical stimulation (CSCS) is a promising treatment for adult drug-resistant epilepsy involving eloquent cortex and has demonstrated safety and efficacy. Herein, the authors describe the surgical technique as well as details of stimulation programming involved in CSCS placement to facilitate the adoption of this promising treatment. The video can be found here: https://stream.cadmore.media/r10.3171/2024.4.FOCVID2422.

The comparison of DBS and RNS for adult drug-resistant epilepsy: a systematic review and meta-analysis.

Neuromodulation has been proven to be a promising alternative treatment for adult patients with drug-resistant epilepsy (DRE). Deep brain stimulation (DBS) and responsive neurostimulation (RNS) were approved by many countries for the treatment of DRE. However, there is a lack of systematic studies illustrating the differences between them. This meta-analysis is performed to assess the efficacy and clinical characteristics of DBS and RNS in adult patients with DRE. PubMed, Web of Science, and Embase were retrieved to obtain related studies including adult DRE patients who accepted DBS or RNS. The clinical characteristics of these patients were compiled for the following statistical analysis. A total of 55 studies (32 of DBS and 23 of RNS) involving 1,568 adult patients with DRE were included in this meta-analysis. There was no significant difference in seizure reduction and responder rate between DBS and RNS for DRE. The seizure reduction of DBS and RNS were 56% (95% CI 50-62%, p > 0.05) and 61% (95% CI 54-68%, p > 0.05). The responder rate of DBS and RNS were 67% (95% CI 58-76%, p > 0.05) and 71% (95% CI 64-78%, p > 0.05). Different targets of DBS did not show significant effect on seizure reduction (p > 0.05). Patients with DRE who accepted DBS were younger than those of RNS (32.9 years old vs. 37.8 years old, p < 0.01). The mean follow-up time was 47.3 months for DBS and 39.5 months for RNS (p > 0.05). Both DBS and RNS are beneficial and alternative therapies for adult DRE patients who are not eligible to accept resection surgery. Further and larger studies are needed to clarify the characteristics of different targets and provide tailored treatment for patients with DRE.

Prospective study of the modified Atkins diet in adult drug-resistant epilepsy: effectiveness, tolerability, and adherence

IntroductionDrug-resistant epilepsy presents high worldwide prevalence and is difficult to control despite the wide variety of available antiepileptic drugs (AED). The modified Atkins diet (MAD) is an additional treatment alternative. Several studies have addressed the use of the ketogenic diet and MAD in children with drug-resistant epilepsy, but insufficient research has been conducted into adults with the same condition. ObjectiveTo evaluate the effectiveness and tolerability of, and adherence to, the MAD in adults with drug-resistant epilepsy. Material and methodsWe conducted a 6-month pre-post prospective study at a reference hospital. Patients were prescribed the MAD with limited carbohydrate intake and unlimited fat intake. We conducted clinical and electroencephalographic follow-up according to the relevant guidelines, and assessed adverse effects changes in laboratory findings, and adherence. ResultsThirty-two patients with drug-resistant epilepsy were included in the study. Patients’ mean age was 30 years, mean disease progression time was 22 years, and all patients had focal or multifocal epilepsy. Thirty-four percent of patients presented > 50% decreases in overall seizure frequency (P = .001); seizure control was greater in the first month and subsequently declined. These patients presented weight loss (RR: 7.2; 95% CI, 1.3–39.5; P = .02), good to fair adherence only in the first and third months (RR: 9.4; 95% CI, 0.9–93.6; P = .04 and RR: 0.4; 95% CI, 0.30−0.69; P = .02, respectively). Tolerability data showed that the MAD is safe: adverse effects were minor and short-lived in most cases, with the exception of mild to moderate hyperlipidaemia in one-third of patients. The adherence rate was 50% at the end of the study. ConclusionsIn adults with drug-resistant focal epilepsy, the MAD showed adequate tolerability and moderate but decreasing effectiveness and adherence, probably due to a preference for a carbohydrate-based diet.

Corpus Callosotomy for Drug Resistant Epilepsy. Long Term Outcome in Adult Population. (S44.005)

<h3>Objective:</h3> Favorable outcome of corpus callosotomy is reported in pediatric population with intractable epilepsy and it is considered standard of care for patients with drop attacks. Our objective is to compare the long term outcome of corpus callosotomy for drug resistant epilepsy in adult population. <h3>Background:</h3> Corpus callosotomy is a palliative neurosurgical procedure for patients with medically drug-resistant epilepsy who are not candidates for resective epilepsy surgery. Corpus callosotomy is most commonly performed in children with epilepsy, either as an anterior two-thirds disconnection of corpus callosum or as a complete disconnection. Good long-term outcomes against drop attacks have been reported in a population-based prospective study and the risk of a persistent complication is low. <h3>Design/Methods:</h3> 17 adults with idiopathic generalized epilepsy, frontal lobe epilepsy and Lennox Gastaut Syndrome (LGS) were followed for the outcome measures of seizure and antiepileptic drug (AED) burden and quality of life (QoL). Data was extracted from patients registered in our RedCap database. <h3>Results:</h3> 17 patients fulfill the inclusion criteria. 4 underwent conventional corpus callsotomy and 14 had laser interstitial thermal therapy (LITT). 7 had failed prior Vagal Nerve Stimulator and 10 did not have VNS. All patients who had conventional procedure had complications and none from the LITT group reported complications. 11 patients reported presence of seizures and 6 were seizure free. None of the patients had persistent drop attacks, while 4 had convulsive seizures and 11 had mild focal impaired awareness seizures. More than 70 % of the patients reported improvement in speech, social abilities and activities of daily living. <h3>Conclusions:</h3> Corpus callosotomy for drug resistant epilepsy in adults provide significant improvement when observed for decreasing in seizure burden, reduction in medication and improvement of quality of life. LITT carries a low risk for complication and similar efficacy when compared with conventional one and should be utilize more frequently. <b>Disclosure:</b> Miss Proteasa has nothing to disclose. Dr. Proteasa has nothing to disclose. Dr. Lado has a non-compensated relationship as a Board Member with American Epilepsy Society that is relevant to AAN interests or activities. Dr. Lado has a non-compensated relationship as a Officer with National Association of Epilepsy Centers that is relevant to AAN interests or activities.

Systematic Review of Cost-Effectiveness Analysis for Surgical and Neurostimulation Treatments for Drug-Resistant Epilepsy in Adults.

Surgical and neurostimulator treatments are effective for reducing seizure burden in selected individuals living with drug-resistant epilepsy (DRE). We aimed to determine the presence and key model determinants for cost-effectiveness of these interventions, compared with medical management alone, to assist with decisions about resource allocation. A systematic literature search was conducted on June 1, 2022, using MEDLINE, EMBASE, the NHS Economic Evaluation Database, and the Cost-Effectiveness Analysis database. Included studies were economic evaluations in adult DRE cohorts, comparing surgical and neurostimulator treatments (vagus nerve stimulation [VNS], responsive neurostimulation [RNS], and deep brain stimulation [DBS]) vs medical management alone and reporting cost-benefit analysis, cost-utility, or cost-effectiveness. Exclusion criteria were studies with pediatric cohorts and those published in a language other than English. Three independent reviewers screened, extracted, and assessed data against the Consolidated Health Economic Evaluation Reporting Standards checklist, and a fourth reviewer adjudicated discrepancies. Ten studies met inclusion criteria. Seven studies evaluated epilepsy surgery, and 3 evaluated neurostimulation treatments. All relevant studies established that epilepsy surgery is a cost-effective intervention compared with medical management alone, for quality-adjusted life-years and seizure freedom at 2 and 5 years. All relevant studies found neurostimulator treatments to be potentially cost-effective. The incremental cost-effectiveness ratio (ICER), with lower ICER indicating greater cost-effectiveness, was reported for 9 studies and varied between GBP £3,013 and US $61,333. Cost adaptation revealed ICERs from US $170 to US $121,726. Key model determinants included, but were not limited to, improved surgical outcomes and quality of life, reduced surgical and presurgical evaluation costs, higher rates of surgical eligibility after referral and evaluation, epilepsy subtype, less expensive neurostimulator devices with improved longevity, and cost analysis strategy used in the analysis. There is consistent evidence that epilepsy surgery is a cost-effective treatment of eligible candidates with DRE. Limited evidence suggests that VNS, RNS, and DBS may be cost-effective therapies for DRE, although more health economic evaluations alongside prospective clinical trials are needed to validate these findings. PROSPERO CRD42021278436.

Adjunctive Transdermal Cannabidiol for Adults With Focal Epilepsy

Cannabidiol has shown efficacy in randomized clinical trials for drug-resistant epilepsy in specific syndromes that predominantly affect children. However, high-level evidence for the efficacy and safety of cannabidiol in the most common form of drug-resistant epilepsy in adults, focal epilepsy, is lacking. To investigate the efficacy, safety, and tolerability of transdermally administered cannabidiol in adults with drug-resistant focal epilepsy. A randomized, double-blind, placebo-controlled, multicenter clinical trial at 14 epilepsy trial centers in Australia and New Zealand. Participants were adults with drug-resistant focal epilepsy receiving a stable regimen of up to 3 antiseizure medications. Data were analyzed from July 2017 to November 2018. Eligible participants were randomized (1:1:1) to 195-mg or 390-mg transdermal cannabidiol or placebo twice daily for 12 weeks, after which they could enroll in an open-label extension study for up to 2 years. Seizure frequency was self-reported using a daily diary. The primary efficacy end point was the least squares mean difference in the log-transformed total seizure frequency per 28-day period, adjusted to a common baseline log seizure rate, during the 12-week treatment period. A total of 188 patients (45% male [85 patients] and 54.8% female [103 patients]) with a mean (SD) age of 39.2 (12.78) years were randomized, treated, and analyzed (195-mg cannabidiol, 63 participants; 390-mg cannabidiol, 62 participants; placebo, 63 participants). At week 12 of the double-blind period, there was no difference in seizure frequency between placebo (mean [SD] 2.49 [1.31] seizures per 28 days) and 195-mg cannabidiol (mean [SD] 2.51 [1.15] seizures per 28 days; least squares mean difference, 0.014; 95% CI, -0.175 to 0.203; P = .89) or 390-mg cannabidiol (mean [SD] 2.59 [1.12] seizures per 28 days; least squares mean difference, 0.096; 95% CI, -0.093 to 0.285; P = .32). By month 6 of the open-label extension, 115 patients (60.8%) achieved a seizure reduction of at least 50%. Treatment-emergent adverse events occurred in 50.4% (63 of 125 participants) of the cannabidiol group vs 41.3% (26 of 63 participants) in the placebo group, with a treatment difference of 9.1% (95% CI, -6.0% to 23.6%), and occurred at similar rates in the cannabidiol groups. Few participants discontinued (7% [14 of 188 participants]), and most (98% [171 of 174 participants]) continued into the open-label extension. Both doses of transdermal cannabidiol were well tolerated and safe. No significant difference in efficacy was observed between cannabidiol and placebo during the double-blind treatment period. The open-label extension demonstrated the long-term safety, tolerability, and acceptability of transdermal cannabidiol delivery. ACTRN12616000510448 (double-blind); ACTRN12616001455459 (open-label).

Efficacy of supplemental MCT oil on seizure reduction of adult drug-resistant epilepsy – a single-center open-label pilot study

ABSTRACT Objective We set out to determine whether adding medium chain triglyceride (MCT) oil as a dietary supplement to standard diet in adult subjects with intractable epilepsy in a U.S. neurology clinical practice was associated with a reduction in number of seizures. We secondarily aimed to determine whether subjects experienced any side effects and whether there was a presence of urinary ketones while using MCT oil as a dietary supplement. Methods Adult patients with intractable epilepsy were recruited at standard of care clinical visits with their epileptologist. Once enrolled, subjects were instructed to supplement their diet with MCT oil as tolerated twice daily for three months (including a 1–2 week titration period, followed by a 1–2 week tapering off window) while keeping a seizure diary to record total number of seizures, presence of urinary ketones, and any side effects. Results Our data although limited by small sample size, shows that there is an estimated 42% reduction (p < 0.0001) in the rate of seizures. The MCT oil supplementation was well tolerated by most subjects except for minor GI side effects like nausea and loose stools. Most subjects developed ketones in their urine at some point during the trial. Conclusions MCT oil supplementation reduced seizure frequency in study participants. The reported side effects included mild nausea, stomachache, loose stools. A placebo-controlled study will be more informative.

Fibroblast growth factor 13 is involved in the pathogenesis of temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is the most common drug-resistant epilepsy in adults, with pathological mechanisms remaining to be fully elucidated. Fibroblast Growth Factor 13 (FGF13) encodes an intracellular protein involved in microtubule stabilization and regulation of voltage-gated sodium channels (VGSCs) function. FGF13 mutation has been identified in patients with inherent seizure, suggesting a potential association between FGF13 and the etiology of TLE. Here, we set to explore the pathological role of FGF13 in the etiology of TLE. We found that the expression of FGF13 was increased in the cortical lesions and CA1 region of sclerotic hippocampus and correlated with the seizure frequency in TLE patients. Also, Fgf13 expression was increased in the hippocampus of chronic TLE mice generated by kainic acid (KA) injection. Furthermore, Fgf13 knockdown or overexpression was respectively found to attenuate or potentiate the effects of KA on axonal length, somatic area and the VGSCs-mediated current in the hippocampal neurons. Taken together, these findings suggest that FGF13 is involved in the pathogenesis of TLE by modulating microtubule activity and neuronal excitability.

Long-term epilepsy-associated tumors

The goal of this review is to summarize data concerning radiological and histological diagnosis of epileptogenic tumors, as well as to discuss their surgical treatment. PubMed literature database was searched for relevant articles, we also used our own clinical experience. Benign glioneuronal tumors are the second most common cause of drug resistant epilepsy in adults after hippocampal sclerosis. Exceptionally slow growth (more than 2 years), localization in the brain cortex, presence of differentiated neuronal tissue in tumoral body and long history of epilepsy are the key features of these tumors called LEAT (long-term epilepsy-associated tumors). Management of LEAT requires epileptological as well as neurooncological approach. The epileptogenic zone commonly spreads beyond the tumor borders and simple lesionectomy alone may not be sufficient for achieving seizure freedom. LEAT typically exhibit low proliferative activity, however they should be thoroughly differentiated from more aggressive glial tumors; while this task is sometimes quite challenging, it's achievable by means of histological and immunohistochemical examination.

Topographic divergence of atypical cortical asymmetry and atrophy patterns in temporal lobe epilepsy.

Temporal lobe epilepsy, a common drug-resistant epilepsy in adults, is primarily a limbic network disorder associated with predominant unilateral hippocampal pathology. Structural MRI has provided an in vivo window into whole-brain grey matter structural alterations in temporal lobe epilepsy relative to controls, by either mapping (i) atypical inter-hemispheric asymmetry; or (ii) regional atrophy. However, similarities and differences of both atypical asymmetry and regional atrophy measures have not been systematically investigated.Here, we addressed this gap using the multisite ENIGMA-Epilepsy dataset comprising MRI brain morphological measures in 732 temporal lobe epilepsy patients and 1418 healthy controls. We compared spatial distributions of grey matter asymmetry and atrophy in temporal lobe epilepsy, contextualized their topographies relative to spatial gradients in cortical microstructure and functional connectivity calculated using 207 healthy controls obtained from Human Connectome Project and an independent dataset containing 23 temporal lobe epilepsy patients and 53 healthy controls and examined clinical associations using machine learning.We identified a marked divergence in the spatial distribution of atypical inter-hemispheric asymmetry and regional atrophy mapping. The former revealed a temporo-limbic disease signature while the latter showed diffuse and bilateral patterns. Our findings were robust across individual sites and patients. Cortical atrophy was significantly correlated with disease duration and age at seizure onset, while degrees of asymmetry did not show a significant relationship to these clinical variables.Our findings highlight that the mapping of atypical inter-hemispheric asymmetry and regional atrophy tap into two complementary aspects of temporal lobe epilepsy-related pathology, with the former revealing primary substrates in ipsilateral limbic circuits and the latter capturing bilateral disease effects. These findings refine our notion of the neuropathology of temporal lobe epilepsy and may inform future discovery and validation of complementary MRI biomarkers in temporal lobe epilepsy.

Associations of overweight and obesity with drug-resistant epilepsy

BackgroundObesity and overweight have been well established as comorbidities of epilepsy in adults. However, the effects of overweight and obesity on the risk of adult drug-resistant epilepsy (DRE) has not been fully assessed. Thus, the objective of this study was to investigate the relationships between categories of body mass index (BMI) and DRE. MethodsThis was a case-control study. Patients with epilepsy hospitalized for Video electroencephalogram were included in the study from 2015 to 2020. Low/normal weight, overweight, and obesity were defined as BMI<23 and 23-24.9 and ≥25 kg/m2, respectively. The proportions of patients diagnosed with DRE in each category were calculated. ResultsA total of 1272 patients with drug-responsive epilepsy and 345 patients with DRE were included in this study. More men than women had DRE (P=0.012). Higher proportions of patients with DRE had a history of status epilepticus (P<0.001), CNS infection (P=0.027), developmental delay (P=0.001), and comorbidity (P<0.001). Obesity (BMI≥25 kg/m2) was associated with an increased risk of DRE (adjusted OR, 2.339; 95% CI, 1.724-3.171). No significant increase in the risk of DRE was found to be associated with overweight. Further stratified analyses by valproic acid (VPA) treatment attenuated the obesity-DRE relationship, but the associations remained statistically significant (adjusted OR, 1.79; 95% CI, 1.15-2.80). ConclusionObesity, but not overweight, potentially plays a role in DRE, although confounders, such as antiseizure medications (ASMs) use, need to be explored. In the future, well-designed trials are needed to elucidate this issue.

How much can medical management alone improve the outcome of adult drug-resistant epilepsy? An exploratory study on possibilities and limitations of combining multiple therapeutic actions

PurposeFailure to control epileptic seizures with two medications, adequately chosen and dosed, indicates drug-resistant epilepsy (DRE). The chance of pharmacologically controlling seizures is low for patients with DRE and uncontrolled seizures who are not candidates for surgery, who have already undergone surgery, or who already had a vagus nerve stimulator (VNS) placed. Patients experiencing these conditions must instead rely on medical management of their seizures, and there is no breakthrough solution on the horizon.Medical care of DRE might be optimized by systematically considering factors that promote and inhibit breakthrough seizures. For example, seizure control could be enhanced through measures such as increasing the frequency of follow-up visits, tracking treatment plan compliance, treating sleep disorders, rational polypharmacy, adjusting drug administration to achieve higher levels when seizures are more likely and educating patients on seizure triggers. A systematic and simultaneous implementation of all of these measures is likely to yield a sizable, clinically relevant, improvement.This paper presents an exploratory study on the effects of implementing such an approach, specifically evaluating this method’s impact on seizure frequency. MethodsI performed a retrospective chart review of 659 consecutive adult patients with epilepsy followed up at the University of Utah and at the Salt Lake City VA Medical center using the multimodal approach described above. I identified 27 patients who had DRE and uncontrolled seizures and in whom a medical management optimization protocol was implemented. I measured these patients’ seizure frequency at the beginning and the end of the study period and compared the results with those of a matching control group of 48 patients. ResultsThe optimization protocol did not increase the number of seizure-free patients with DRE; however, it was effective in minimizing seizure frequency in patients whose seizures remained uncontrolled. Among these patients, the median seizure frequency dropped by 64% in the optimization group but did not change in the control group. ConclusionsDespite the high occurrence of DRE, there is no accepted protocol for the related medical management. This paper describes an effective approach that can be implemented in a clinically relevant and readily achievable manner.

41502 Does dietary fat composition predict short-term elevations in lipid levels in adults on a modified Atkins diet?

ABSTRACT IMPACT: Our work provides guidance on whether dietary fat intake influences serum cholesterol levels in response to ketogenic diet therapy in adults with epilepsy. OBJECTIVES/GOALS: The modified Atkins diet (MAD) is used in the management of drug-resistant epilepsy in adults. Some patients on MAD show an increase in serum levels of total cholesterol and low-density lipoprotein (LDL) cholesterol. We explored whether dietary fat composition predicts short-term elevations in serum lipid levels in diet-naive adults who begin MAD. METHODS/STUDY POPULATION: Participants self-reported their diet intake with 3-day food records at baseline, 1 month and 2 months. Food records were analyzed using Nutrition Data System for Research software. Fasting serum levels of total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, and triglycerides were also collected and LDL level calculated at baseline, 1 month, and 2 months. RESULTS/ANTICIPATED RESULTS: 38 patients submitted complete food records at each study visit (baseline, 1 month, and 2 month). Compared to baseline diet intake, there was a significant reduction in daily carbohydrate intake at 1 and 2 months (p&lt;0.001) and a significant increase in daily fat intake at 1 and 2 months (p&lt;0.001). There was also a significant increase in daily saturated fatty acid (SFA) intake at 1 and 2 months (p&lt;0.001), daily mono-unsaturated fatty acid (MUFA) intake at 1 and 2 months (p&lt;0.001), and daily cholesterol intake at 1 month (p&lt;0.05) and 2 months (p&lt;0.001), but no change in daily poly-unsaturated fatty acid (PUFA) intake over time. Compared to baseline, there was a significant increase in serum LDL at 1 month (p&lt;0.001) and 2 months (p&lt;0.01) and an increase in serum TC at 1 month (p&lt;0.01) but not 2 months. DISCUSSION/SIGNIFICANCE OF FINDINGS: Despite a significant increase in total fat, saturated fat and mono-unsaturated fat intake as well as an increase in total cholesterol and LDL levels following MAD initiation, dietary fat composition appears to minimally predict serum lipid values in the short term.

D-Serine Intervention In The Medial Entorhinal Area Alters TLE-Related Pathology In CA1 Hippocampus Via The Temporoammonic Pathway

Entrainment of the hippocampus by the medial entorhinal area (MEA) in Temporal Lobe Epilepsy (TLE), the most common type of drug-resistant epilepsy in adults, is believed to be mediated primarily through the perforant pathway (PP), which connects stellate cells in layer (L) II of the MEA with granule cells of the dentate gyrus (DG) to drive the hippocampal tri-synaptic circuit. Using immunohistochemistry, high-resolution confocal microscopy and the rat pilocarpine model of TLE, we show here that the lesser known temporoammonic pathway (TAP) plays a significant role in transferring MEA pathology to the CA1 region of the hippocampus independently of the PP. The pathology observed was region-specific and restricted primarily to the CA1c subfield of the hippocampus. As shown previously, daily intracranial infusion of d-serine (100 μm), an antagonist of GluN3-containing triheteromeric N-Methyl d-aspartate receptors (t-NMDARs), into the MEA prevented loss of LIII neurons and epileptogenesis. This intervention in the MEA led to the rescue of hippocampal CA1 neurons that would have otherwise perished in the epileptic animals, and down regulation of the expression of astrocytes and microglia thereby mitigating the effects of neuroinflammation. Interestingly, these changes were not observed to a similar extent in other regions of vulnerability like the hilus, DG or CA3, suggesting that the pathology manifest in CA1 is driven predominantly through the TAP. This work highlights TAP’s role in the entrainment of the hippocampus and identifies specific areas for therapeutic intervention in dealing with TLE.

Increased frequency of proinflammatory CD4 T cells and pathological levels of serum neurofilament light chain in adult drug-resistant epilepsy.

Adult drug-resistant epilepsy (DRE) is associated with significant morbidity. Infiltration of immune cells is observed in DRE epileptic foci; however, the relation between DRE and the peripheral immune cell compartment remains only partially understood. We aimed to investigate differences in immune cell populations, cytokines, and neurodegenerative biomarkers in the peripheral blood of subjects with epilepsy versus healthy controls, and in DRE compared to well-controlled epilepsy (WCE). Peripheral blood mononuclear cells and serum from >120 age- and sex-matched adults suffering from focal onset epilepsy and controls were analyzed by multipanel flow cytometry, multiplex immunoassays, and ultrasensitive single molecule array. Using a data-driven analytical approach, we identified that CD4 T cells in the peripheral blood are present in a higher proportion in DRE patients. Moreover, we observed that the frequency of CD4 T cells expressing proinflammatory cytokines interleukin (IL)-17A, IL-22, tumor necrosis factor, interferon-γ, and granulocyte-macrophage colony-stimulating factor, but not anti-inflammatory cytokines IL-10 and IL-4, is elevated in the peripheral blood of DRE subjects compared to WCE. In parallel, we found that Th17-related circulating proinflammatory cytokines are elevated, but Th2-related cytokine IL-4 is reduced, in the serum of epilepsy and DRE subjects. As Th17 cells can exert neurotoxicity, we measured levels of serum neurofilament light chain (sNfL), a marker of neuronal injury. We found significantly elevated levels of sNfL in DRE compared to controls, especially among older individuals. Our data support that DRE is associated with an expansion of the CD4 Tcell subset in the peripheral blood and with a shift toward a proinflammatory Th17/Th1 CD4 Tcell immune profile. Our results further show that pathological levels of sNfL are more frequent in DRE, supporting a potential neurodegenerative component in adult DRE. With this work, we provide evidence for novel potential inflammatory and degenerative biomarkers in DRE.

D-serine mitigates cell loss associated with temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is the most common type of drug-resistant epilepsy in adults, with an unknown etiology. A hallmark of TLE is the characteristic loss of layer 3 neurons in the medial entorhinal area (MEA) that underlies seizure development. One approach to intervention is preventing loss of these neurons through better understanding of underlying pathophysiological mechanisms. Here, we show that both neurons and glia together give rise to the pathology that is mitigated by the amino acid D-serine whose levels are potentially diminished under epileptic conditions. Focal administration of D-serine to the MEA attenuates neuronal loss in this region thereby preventing epileptogenesis in an animal model of TLE. Additionally, treatment with D-serine reduces astrocyte counts in the MEA, alters their reactive status, and attenuates proliferation and/or infiltration of microglia to the region thereby curtailing the deleterious consequences of neuroinflammation. Given the paucity of compounds that reduce hyperexcitability and neuron loss, have anti-inflammatory properties, and are well tolerated by the brain, D-serine, an endogenous amino acid, offers new hope as a therapeutic agent for refractory TLE.

4013 Does dietary fat composition predict short-term elevations in lipid levels in adults on a modified Atkins diet?

OBJECTIVES/GOALS: The modified Atkins diet (MAD) is used in the management of drug-resistant epilepsy in adults. Some patients on MAD show an increase in serum levels of total cholesterol and low-density lipoprotein (LDL) cholesterol. We explored whether dietary fat composition predicts short-term elevations in serum lipid levels in diet-naïve adults who begin MAD. METHODS/STUDY POPULATION: Participants self-reported their diet intake with 3-day food records at baseline, 1 month and 2 months. Food records were analyzed using Nutrition Data System for Research software. Fasting serum levels of total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, and triglycerides were also collected and LDL level calculated at baseline, 1 month, and 2 months. RESULTS/ANTICIPATED RESULTS: 38 patients submitted complete food records at each study visit (baseline, 1 month, and 2 month). Compared to baseline diet intake, there was a significant reduction in daily carbohydrate intake at 1 and 2 months months (p&lt;0.001). There was also a significant increase in daily saturated fatty acid (SFA) intake at 1 and 2 months (p&lt;0.001), daily mono-unsaturated fatty acid (MUFA) intake at 1 and 2 months (p&lt;0.001), and daily cholesterol intake at 1 month (p&lt;0.05) and 2 months (p&lt;0.001), but no change in daily poly-unsaturated fatty acid (PUFA) intake over time. Compared to baseline, there was a significant increase in serum LDL at 1 month (p&lt;0.001) and 2 months (p&lt;0.01) and an increase in serum TC at 1 month (p&lt;0.01) but not 2 months. DISCUSSION/SIGNIFICANCE OF IMPACT : Despite a significant increase in total fat, saturated fat and mono-unsaturated fat intake as well as an increase in total cholesterol and LDL levels following MAD initiation, dietary fat composition appears to minimally predict serum lipid values in the short term. CONFLICT OF INTEREST DESCRIPTION: Tanya McDonald has received speaking honoraria from Nutricia North America. Bobbie Henry-Barron receives grants from Johns Hopkins Institute for Clinical and Translational Research (ICTR) which is funded in part by Grant Number UL1 TR 001079 from the National Center for Advancing Translational Sciences (NCATS) a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research, Nutricia and Vitaflo. Diane Vizthum receives grants from the Johns Hopkins Institute for Clinical and Translational Research (ICTR) which is funded in part by Grant Number UL1 TR 001079 from the National Center for Advancing Translational Sciences (NCATS) a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Mackenzie C. Cervenka has received grant support from Nutricia North America, Vitaflo, Army Research Laboratory, The William and Ella Owens Medical Research Foundation and BrightFocus Foundation. She receives speaking honoraria from LivaNova, Epigenix, Nutricia North America and the Glut1 Deficiency Foundation and performs consulting with Nutricia North America and Sage Therapeutics and receives Royalties from Demos Health.

Functional connectome contractions in temporal lobe epilepsy: Microstructural underpinnings and predictors of surgical outcome.

Temporal lobe epilepsy (TLE) is the most common drug-resistant epilepsy in adults. Although it is commonly related to hippocampal pathology, increasing evidence suggests structural changes beyond the mesiotemporal lobe. Functional anomalies and their link to underlying structural alterations, however, remain incompletely understood. We studied 30 drug-resistant TLE patients and 57 healthy controls using multimodal magnetic resonance imaging (MRI) analyses. All patients had histologically verified hippocampal sclerosis and underwent postoperative imaging to outline the extent of their surgical resection. Our analysis leveraged a novel resting-state functional MRI framework that parameterizes functional connectivity distance, consolidating topological and physical properties of macroscale brain networks. Functional findings were integrated with morphological and microstructural metrics, and utility for surgical outcome prediction was assessed using machine learning techniques. Compared to controls, TLE patients showed connectivity distance reductions in temporoinsular and prefrontal networks, indicating topological segregation of functional networks. Testing for morphological and microstructural associations, we observed that functional connectivity contractions occurred independently from TLE-related cortical atrophy but were mediated by microstructural changes in the underlying white matter. Following our imaging study, all patients underwent an anterior temporal lobectomy as a treatment of their seizures, and postsurgical seizure outcome was determined at a follow-up at least 1year after surgery. Using a regularized supervised machine learning paradigm with fivefold cross-validation, we demonstrated that patient-specific functional anomalies predicted postsurgical seizure outcome with 76±4% accuracy, outperforming classifiers operating on clinical and structural imaging features. Our findings suggest connectivity distance contractions as a macroscale substrate of TLE. Functional topological isolation may represent a microstructurally mediated network mechanism that tilts the balance toward epileptogenesis in affected networks and that may assist in patient-specific surgical prognostication.

Epidemiology of drug resistant epilepsy in adults

This review examines the epidemiology of drug resistant epilepsy in adults in Russia and abroad. References were taken from Russian and foreign databases for the period from 2010–2017. Only full-text publications (66) were included in this review. We concluded that the despite the achievements of clinical pharmacology and the development of new antiepileptic drugs, the problem of drug resistant epilepsy remains not fully resolved today. The worldwide high prevalence rate of patients with drug resistant epilepsy substantiates the problem. Thus, the average incidence of this disease varies from 30% to 70%, depending on the type of epilepsy and background pathology, which is the cause of symptomatic epilepsy. However, we have faced the problem of the absence both in Russia and abroad of large multicenter studies on the epidemiology of drug resistant epilepsy in the analyzed period of time. We have also revealed the lack of a unified definition of the disease, which is probably one of the reasons for the insufficient number of epidemiological studies of drug resistant epilepsy in different countries of the world.