X-Linked Bilateral Polymicrogyria With Epilepsy and Intellectual Disability Associated With a Novel KIF4A Variant.

We studied three brothers and a maternal half-brother featuring global developmental delay, mild to moderate intellectual disability, epilepsy, microcephaly, and strabismus. All had bilateral perisylvian and perirolandic polymicrogyria, while some also had malformations of the hippocampus (malrotation and dysplasia), cerebellum (heterotopias and asymmetric aplasia), corpus callosum dysgenesis, and brainstem asymmetric dysplasia. Exome sequencing showed that all four patients had a novel variant (c.1597C>T:p.Leu533Phe) on the KIF4A gene on chromosome X. We discuss how this variant is possibly pathogenic and could explain the reported phenotype.

Detection of focal to bilateral tonic-clonic seizures using a connected shirt.

OBJECTIVE: This study was undertaken to develop and evaluate a machine learning-based algorithm for the detection of focal to bilateral tonic-clonic seizures (FBTCS) using a novel multimodal connected shirt. METHODS: We prospectively recruited patients with epilepsy admitted to our epilepsy monitoring unit and asked them to wear the connected shirt while under simultaneous video-electroencephalographic monitoring. Electrocardiographic (ECG) and accelerometric (ACC) signals recorded with the connected shirt were used for the development of the seizure detection algorithm. First, we used a sliding window to extract linear and nonlinear features from both ECG and ACC signals. Then, we trained an extreme gradient boosting algorithm (XGBoost) to detect FBTCS according to seizure onset and offset annotated by three board-certified epileptologists. Finally, we applied a postprocessing step to regularize the classification output. A patientwise nested cross-validation was implemented to evaluate the performances in terms of sensitivity, false alarm rate (FAR), time in false warning (TiW), detection latency, and receiver operating characteristic area under the curve (ROC-AUC). RESULTS: We recorded 66 FBTCS from 42 patients who wore the connected shirt for a total of 8067 continuous hours. The XGBoost algorithm reached a sensitivity of 84.8% (56/66 seizures), with a median FAR of .55/24 h and a median TiW of 10 s/alarm. ROC-AUC was .90 (95% confidence interval = .88-.91). Median detection latency from the time of progression to the bilateral tonic-clonic phase was 25.5 s. SIGNIFICANCE: The novel connected shirt allowed accurate detection of FBTCS with a low false alarm rate in a hospital setting. Prospective studies in a residential setting with a real-time and online seizure detection algorithm are required to validate the performance and usability of this device.

Grading system for assessing the confidence in the epileptogenic zone reported in published studies: A Delphi consensus study.

OBJECTIVE: This study was undertaken to develop a standardized grading system based on expert consensus for evaluating the level of confidence in the localization of the epileptogenic zone (EZ) as reported in published studies, to harmonize and facilitate systematic reviews in the field of epilepsy surgery. METHODS: We conducted a Delphi study involving 22 experts from 18 countries, who were asked to rate their level of confidence in the localization of the EZ for various theoretical clinical scenarios, using different scales. Information provided in these scenarios included one or several of the following data: magnetic resonance imaging (MRI) findings, invasive electroencephalography summary, and postoperative seizure outcome. RESULTS: The first explorative phase showed an overall interrater agreement of .347, pointing to large heterogeneity among experts' assessments, with only 17% of the 42 proposed scenarios associated with a substantial level of agreement. A majority showed preferences for the simpler scale and single-item scenarios. The successive Delphi voting phases resulted in a majority consensus across experts, with more than two thirds of respondents agreeing on the rating of each of the tested single-item scenarios. High or very high levels of confidence were ascribed to patients with either an Engel class I or class IA postoperative seizure outcome, a well-delineated EZ according to all available invasive EEG (iEEG) data, or a well-delineated focal epileptogenic lesion on MRI. MRI signs of hippocampal sclerosis or atrophy were associated with a moderate level of confidence, whereas a low level was ascribed to other MRI findings, a poorly delineated EZ according to iEEG data, or an Engel class II-IV postoperative seizure outcome. SIGNIFICANCE: The proposed grading system, based on an expert consensus, provides a simple framework to rate the level of confidence in the EZ reported in published studies in a structured and harmonized way, offering an opportunity to facilitate and increase the quality of systematic reviews and guidelines in the field of epilepsy surgery.

Do we intervene less and slower in the epilepsy monitoring unit for psychogenic seizures?

PURPOSE: Individuals with psychogenic non-epileptic seizures (PNES) can be stigmatized in healthcare settings. We aimed to compare intervention rate (IR), intervention time (IT), and adverse event (AE) rate between PNES and epileptic seizures (ES) in the epilepsy monitoring unit (EMU). METHODS: We used a prospective database of consecutive admissions to our centre's EMU between August 2021 and September 2022. We excluded purely electric seizures and vague, minor spells with no EEG correlate. We therefore only included electroclinical seizures and PNES. We compared the IR, IT, and AE rate between PNES and ES, as diagnosed by an epileptologist during EEG monitoring. We performed the same comparisons between spells occurring in people admitted with a high vs low suspicion of PNES (HSP vs LSP). We also verified if ITs became longer with repeated PNES. RESULTS: We analyzed 586 spells: 43 PNES vs 543 ES, or 133 HSP vs 453 LSP. Our univariate analyses showed that IR was higher for PNES than for ES (93 % vs 61 %, p <.001) but that IT and AE rate were similar across groups. This higher IR was only apparent outside weekday daytime hours, when EEG technologists were not present. HSP did not differ from LSP in terms of IR, IT, and AE rate. As PNES accumulated in individual patients, IT tended to be longer (Spearman's correlation = 0.42; p =.012). SIGNIFICANCE: Our EMU staff did not intervene less or slower for PNES. Rather, IR was higher for PNES than for ES, but IT tended to be longer with repeat PNES.

Patient Safety in Canadian Epilepsy Monitoring Units: A Survey of Current Practices.

BACKGROUND: Guidelines on epilepsy monitoring unit (EMU) standards have been recently published. We aimed to survey Canadian EMUs to describe the landscape of safety practices and compare these to the recommendations from the new guidelines. METHODS: A 34-item survey was created by compiling questions on EMU structure, patient monitoring, equipment, personnel, standardized protocol use, and use of injury prevention tools. The questionnaire was distributed online to 24 Canadian hospital centers performing video-EEG monitoring (VEM) in EMUs. Responses were tabulated and descriptively summarized. RESULTS: In total, 26 EMUs responded (100% response rate), 50% of which were adult EMUs. EMUs were on average active for 23.4 years and had on average 3.6 beds. About 81% of respondents reported having a dedicated area for VEM, and 65% reported having designated EMU beds. Although a video monitoring station was available in 96% of EMUs, only 48% of EMUs provided continuous observation of patients (video and/or physical). A total of 65% of EMUs employed continuous heart monitoring. The technologist-to-patient ratio was 1:1-2 in 52% of EMUs during the day. No technologist supervision was most often reported in the evening and at night. Nurse-to-EMU-patient ratio was mostly 1:1-4 independent of the time of day. Consent forms were required before admission in 27% of EMUs. CONCLUSION: Canadian EMUs performed decently in terms of there being dedicated space for VEM, continuous heart monitoring, and adequate nurse-to-patient ratios. Other practices were quite variable, and adjustments should be made on a case-by-case basis to adhere to the latest guidelines.

Evaluation of Commercially Available Seizure Detection Wearables in Canada: Current Evidence.

Wearable-based seizure detection devices hold promise in reducing seizure-related adverse events and relieving the daily stress experienced by people with epilepsy. In this work, we present the latest evidence regarding the performance of three seizure detection wearables (eight studies) commercially available in Canada to provide guidance to clinicians. Overall, their ability to detect focal-to-bilateral and/or generalized tonic-clonic seizures ranges between 21.0% and 98.15% in sensitivity, with the 24h false alarm rates ranging from 0 to 1.28. While performance in epilepsy monitoring units show promise, the lack of evidence in outpatient settings precludes strong recommendations for their use in daily life.

Xanthine oxidase inhibition study of isolated secondary metabolites from Dolichandrone spathacea (Bignoniaceae): In vitro and in silico approach.

Xanthine oxidase (XO) has been widely recognized as a pivotal enzyme in developing hyperuricemia, primarily contributing to the excessive production of uric acid during purine metabolism in the liver. One of the standard treatment approaches involves reducing uric acid levels by inhibiting XO activity. In this study, the leaf extract of Dolichandrone spathacea, traditionally used in folk medicine, was found to inhibit XO activity in the ethyl acetate and butanol fractions at a concentration of 100 µg/mL, their values were 78.57 ± 3.85 % (IC50 = 55.93 ± 5.73 µg/ml) and 69.43 ± 8.68 % (IC50 = 70.17 ± 7.98 µg/ml), respectively. The potential XO inhibitory components were isolated by bioactivity assays and the HR-ESI-MS and NMR spectra system. The main constituents of leaf extracts of Dolichandrone spathacea, six compounds, namely trans-4-methoxycinnamic acid (3), trans-3,4-dimethoxycinnamic acid (4), p-coumaric acid (5), martynoside (6), 6-O-(p-methoxy-E-cinnamoyl)-ajugol (7), and scolymoside (17), were identified as potent XO inhibitors with IC50 values ranging from 19.34 ± 1.63 µM to 64.50 ± 0.94 µM. The enzyme kinetics indicated that compounds 3-5, 7, and 17 displayed competitive inhibition like allopurinol, while compound 6 displayed a mixed-type inhibition. Computational studies corroborated these experimental results, highlighting the interactions between potential metabolites and XO enzyme. The hydrogen bonds played crucial roles in the binding interaction, especially, scolymoside (17) forms a hydrogen bond with Mos3004, exhibited the lowest binding energy (-18.3286 kcal/mol) corresponding to the lowest IC50 (19.34 ± 1.63 µM). Furthermore, nine compounds were isolated for the first time from this plant. In conclusion, Dolichandrone spathacea and its constituents possess the potential to modulate the xanthine oxidase enzyme involved in metabolism.

SCA34 caused by ELOVL4 L168F mutation is a lysosomal lipid storage disease sharing pathology features with neuronal ceroid lipofuscinosis and peroxisomal disorders.

Spinocerebellar ataxia 34 (SCA34) is a late-onset progressive ataxia caused by a mutation in ELOVL4, a gene involved in the biosynthesis of very long-chain fatty acids (VLCFAs). We performed post-mortem neuropathological examinations on four SCA34 patients with the ELOVL4 L168F mutation and compared the findings to age-matched controls. Specific gross findings of SCA34 were limited to pontocerebellar atrophy. On light microscopy, pontine base showed neuronal loss and storage of an autofluorescent lipopigment positive on oil red O, PAS and Hale's colloidal iron and negative on Alcian blue and Luxol fast blue (LFB). Among the swollen neurons were abundant CD68+ /CD163+ /IBA1- macrophages laden with a material with similar histochemical profile as in neurons except for the lack of autofluorescence and oil red O positivity and the presence of needle-like birefringent inclusions. Normal resting IBA1 + microglia were generally absent from pontine base nuclei but present in normal numbers elsewhere in the pons. In dentate nucleus neurons, atrophy was milder than in the pontine base and the coarser storage material was LFB-positive, closely resembling lipofuscin. On electron microscopy, dentate nucleus neurons showed neuronal storage of tridimensionally organized trilaminar spicules within otherwise normal lipofuscin, while in the more affected pontine base neurons, lipofuscin was almost completely replaced by the storage material. Storage macrophages were tightly packed with stacks of unorganized trilaminar spicules, reminiscent of the storage material seen in peroxisomal disorders and thought to represent VLCFAs incorporated in complex polar lipids. In summary, we provide histochemical and ultrastructural evidence that SCA34 is a lipid storage disease, the first among the currently known SCAs, and that the storage lipid is accumulating within neuronal lipofuscin. Our findings suggest that the storage lipid is similar to the one accumulating in non-neuronal cells in peroxisomal disorders and provide the first ultrastructural description of this type of material within neurons.

Novel NALCN variant linked to temporal lobe epilepsy.

The sodium leak channel (NALCN) gene encodes a sodium leak channel that plays an important role in the regulation of the resting membrane potential and the control of neuronal excitability. Mutations in the NALCN gene have been reported in patients with infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF) and congenital contractures of the limbs and face with hypotonia and developmental delay (CLIFAHDD syndrome). We describe the case of a father with drug-resistant left temporo-orbitofrontal epilepsy and his son with mildly-symptomatic temporal epilepsy (only recurrent déjà vu auras) whose genetic panels identified a likely pathogenic deletion of exon 27 on the NALCN gene. Our study helps broaden the clinical spectrum of diseases associated with mutations in the NALCN gene.

Localizing and lateralizing value of auditory phenomena in seizures.

BACKGROUND: Auditory seizures (AS) are a rare type of focal seizures. AS are classically thought to involve a seizure onset zone (SOZ) in the temporal lobe, but there remain uncertainties about their localizing and lateralizing value. We conducted a narrative literature review with the aim of providing an up-to-date description of the lateralizing and localizing value of AS. METHODS: The databases PubMed, Scopus, and Google Scholar were searched for literature on AS in December 2022. All cortical stimulation studies, case reports, and case series were analyzed to assess for auditory phenomena that were suggestive of AS and to evaluate if the lateralization and/or localization of the SOZ could be determined. We classified AS according to their semiology (e.g., simple hallucination versus complex hallucination) and the level of evidence with which the SOZ could be predicted. RESULTS: A total of 174 cases comprising 200 AS were analyzed from 70 articles. Across all studies, the SOZ of AS were more often in the left (62%) than in the right (38%) hemisphere. AS heard bilaterally followed this trend. Unilaterally heard AS were more often due to a SOZ in the contralateral hemisphere (74%), although they could also be ipsilateral (26%). The SOZ for AS was not limited to the auditory cortex, nor to the temporal lobe. The areas more frequently involved in the temporal lobe were the superior temporal gyrus (STG) and mesiotemporal structures. Extratemporal locations included parietal, frontal, insular, and rarely occipital structures. CONCLUSION: Our review highlighted the complexity of AS and their importance in the identification of the SOZ. Due to the limited data and heterogeneous presentation of AS in the literature, the patterns associated with different AS semiologies warrant further research.

Usage of Genetic Panels in an Adult Epilepsy Clinic.

BACKGROUND: There is limited data on the utility, yield, and cost efficiency of genetic testing in adults with epilepsy. We aimed to describe the yield and utility of genetic panels in our adult epilepsy clinic. METHODS: We performed a retrospective, cross-sectional study of all patients followed by an epileptologist at a Canadian tertiary care centre's epilepsy clinic between January 2016 and August 2021 for whom a genetic panel was ordered. A panel was generally ordered when the etiology was unknown or in the presence of a malformation of cortical development. We determined the yield of panel positivity and of confirmed genetic diagnoses. We also estimated the proportion of these diagnoses that were clinically actionable. RESULTS: In total, 164 panels were ordered in 164 patients. Most had refractory epilepsy (80%), and few had comorbid intellectual disability (10%) or a positive family history of epilepsy (11%). The yield of panel positivity was 11%. Panel results were uncertain 49% of the time and negative 40% of the time. Genetic diagnoses were confirmed in 7 (4.3%) patients. These genetic conditions involved the following genes: SCARB2, DEPDC5, PCDH19, LGI1, SCN1A, MT-TL1, and CHRNA7. Of the seven genetic diagnoses, 5 (71%) were evaluated to be clinically actionable. CONCLUSION: We report a lower diagnostic yield for genetic panels in adults with epilepsy than what has so far been reported. Although the field of the genetics of epilepsy is a fast-moving one and more data is required, our findings suggest that guidelines for genetic testing in adults are warranted.

A Prospective Post-Marketing Observational Study of Brivaracetam in People With Focal Epilepsy.

We evaluated the effectiveness and tolerability of brivaracetam (BRV), an adjunctive antiseizure medication, as a treatment for focal epilepsy in adults. In this prospective study, we enrolled 51 participants from 3 sites across Canada. At 6 months, 68% (26/38) of participants were still taking BRV, among whom 35% (8/23) attained seizure freedom and 48% (11/23) saw their seizure frequency reduced by over 50%. We did not measure any significant change in irritability, quality of life, depression, and anxiety while treated with BRV. Our findings suggest BRV is effective in reducing seizure frequency among adults with focal epilepsy.

Fast Augmented Lagrangian Method in the convex regime with convergence guarantees for the iterates.

This work aims to minimize a continuously differentiable convex function with Lipschitz continuous gradient under linear equality constraints. The proposed inertial algorithm results from the discretization of the second-order primal-dual dynamical system with asymptotically vanishing damping term addressed by Bot and Nguyen (J. Differential Equations 303:369-406, 2021), and it is formulated in terms of the Augmented Lagrangian associated with the minimization problem. The general setting we consider for the inertial parameters covers the three classical rules by Nesterov, Chambolle-Dossal and Attouch-Cabot used in the literature to formulate fast gradient methods. For these rules, we obtain in the convex regime convergence rates of order O1/k2 for the primal-dual gap, the feasibility measure, and the objective function value. In addition, we prove that the generated sequence of primal-dual iterates converges to a primal-dual solution in a general setting that covers the two latter rules. This is the first result which provides the convergence of the sequence of iterates generated by a fast algorithm for linearly constrained convex optimization problems without additional assumptions such as strong convexity. We also emphasize that all convergence results of this paper are compatible with the ones obtained in Bot and Nguyen (J. Differential Equations 303:369-406, 2021) in the continuous setting.

Epilepsy and Pregnancy: An Audit of Specialized Care.

BACKGROUND: Caring for women with epilepsy (WWE) during pregnancy poses unique challenges. We conducted an audit of the care our epilepsy clinic provided to pregnant WWE. METHODS: We performed a retrospective study on all pregnancies followed by an epileptologist at a Canadian tertiary care centre's epilepsy clinic between January 2003 and March 2021. Among 81 pregnancies in 53 patients, 72 pregnancies in 50 patients were analyzed to determine patient-related, follow-up-related, antiseizure-medication-related, and child-related pregnancy characteristics. Univariate analyses were performed to explore if these characteristics were associated with disabling seizure occurrence during pregnancy. RESULTS: Most pregnancies were intended (72%) and occurred in women who used folic acid pre-pregnancy (76%) and who followed recommended blood tests for antiseizure medication (ASM) levels (71%). In 49% of pregnancies, ASM dosage was modified; 53% of these modifications were made in response to ASM blood levels. Most often used ASMs were lamotrigine (43%), followed by carbamazepine (32%) and levetiracetam (13%). One child was born with a thyroglossal duct cyst; our congenital malformation rate was thus 2%. Disabling seizures occurred in 24% of pregnancies. Exploratory analyses suggested that disabling seizure occurrence during pregnancy was associated with younger patient age (p = 0.018), higher number of ASMs used during pregnancy (p = 0.048), lamotrigine usage in polytherapy (p = 0.008), and disabling seizure occurrence pre-pregnancy (p = 0.027). CONCLUSION: This Canadian audit provides an in-depth description of pregnancies benefiting from specialized epilepsy care. Our results suggest an association between disabling seizure occurrence during pregnancy and lamotrigine usage in polytherapy that warrants further evaluation.

Superparamagnetic iron oxide nanoparticles-based detection of neuronal activity.

Precise detection of brain regions harboring heightened electrical activity plays a central role in the understanding and treatment of diseases such as epilepsy. Superparamagnetic iron oxide nanoparticles (SPIONs) react to magnetic fields by aggregating and represent interesting candidates as new sensors for neuronal magnetic activity. We hypothesized that SPIONs in aqueous solution close to active brain tissue would aggregate proportionally to neuronal activity. We tested this hypothesis using an in vitro model of rat brain slice with different levels of activity. Aggregation was assessed with dynamic light scattering (DLS) and magnetic resonance imaging (MRI). We found that increasing brain slice activity was associated with higher levels of aggregation as measured by DLS and MRI, suggesting that the magnetic fields from neuronal tissue could induce aggregation in nearby SPIONs in solution. MRI signal change induced by SPIONs aggregation could serve as a powerful new tool for detection of brain electrical activity.

Implication of Echinochrome A in the Plasticity and Damage of Intestinal Epithelium.

The diverse therapeutic feasibility of the sea urchin-derived naphthoquinone pigment, Echinochrome A (Ech A), has been studied. Simple and noninvasive administration routes should be explored, to obtain the feasibility. Although the therapeutic potential has been proven through several preclinical studies, the biosafety of orally administered Ech A and its direct influence on intestinal cells have not been evaluated. To estimate the bioavailability of Ech A as an oral administration drug, small intestinal and colonic epithelial organoids were developed from mice and humans. The morphology and cellular composition of intestinal organoids were evaluated after Ech A treatment. Ech A treatment significantly increased the expression of LGR5 (~2.38-fold change, p = 0.009) and MUC2 (~1.85-fold change, p = 0.08). Notably, in the presence of oxidative stress, Ech A attenuated oxidative stress up to 1.8-fold (p = 0.04), with a restored gene expression of LGR5 (~4.11-fold change, p = 0.0004), as well as an increased expression of Ly6a (~3.51-fold change, p = 0.005) and CLU (~2.5-fold change, p = 0.01), markers of revival stem cells. In conclusion, Ech A is harmless to intestinal tissues; rather, it promotes the maintenance and regeneration of the intestinal epithelium, suggesting possible beneficial effects on the intestine when used as an oral medication.

Insular seizures and epilepsies: Ictal semiology and minimal invasive surgery.

PURPOSE OF REVIEW: The increased identification of seizures with insular ictal onset, promoted by the international development of stereo-electroencephalography (SEEG), has led to the recent description of larger cohorts of patients with insular or insulo-opercular epilepsies than those previously available. These new series have consolidated and extended our knowledge of the rich ictal semiology and diverse anatomo-clinical correlations that characterized insular seizures. In parallel, some experiences have been gained in the surgical treatment of insular epilepsies using minimal invasive procedures. RECENT FINDINGS: The large majority of patients present with auras (mostly somatosensory and laryngeal) and motor signs (predominantly elementary and orofacial), an underlying focal cortical dysplasia, and an excellent postoperative seizure outcome. Many other subjective and objective ictal signs, known to occur in other forms of epilepsies, are also observed and clustered in five patterns, reflecting the functional anatomy of the insula and its overlying opercula, as well as preferential propagation pathways to frontal or temporal brain regions. A nocturnal predominance of seizure is frequently reported, whereas secondary generalization is infrequent. Some rare ictal signs are highly suggestive of an insular origin, including somatic pain, reflex seizures, choking spells, and vomiting. Minimal invasive surgical techniques have been applied to the treatment of insular epilepsies, including Magnetic Resonance Imaging-guided laser ablation (laser interstitial thermal therapy (LITT)), radiofrequency thermocoagulation (RFTC), gamma knife radiosurgery, and responsive neurostimulation. Rates of seizure freedom (about 50%) appear lower than that reported with open-surgery (about 80%) with yet a significant proportion of transient neurological deficit for LITT and RFTC. SUMMARY: Significant progress has been made in the identification and surgical treatment of insular and insulo-opercular epilepsies, including more precise anatomo-clinical correlations to optimally plan SEEG investigations, and experience in using minimal invasive surgery to reduce peri-operative morbidity.

How the Human Brain Sleeps: Direct Cortical Recordings of Normal Brain Activity.

OBJECTIVE: Regional variations in oscillatory activity during human sleep remain unknown. Using the unique ability of intracranial electroencephalography to study in situ brain physiology, this study assesses regional variations of electroencephalographic sleep activity and creates the first atlas of human sleep using recordings from the first sleep cycle. METHODS: Intracerebral electroencephalographic recordings with channels displaying physiological activity from nonlesional tissue were selected from 91 patients of 3 tertiary epilepsy centers. Sections during non-rapid eye movement sleep (stages N2 and N3) and rapid eye movement sleep (stage R) were selected from the first sleep cycle for oscillatory and nonoscillatory signal analysis. Results of 1,468 channels were grouped into 38 regions covering all cortical areas. RESULTS: We found regional differences in the distribution of sleep transients and spectral content during all sleep stages. There was a caudorostral gradient, with more slow frequencies and fewer spindles in temporoparieto-occipital than in frontal cortex. Moreover, deep-seated structures showed spectral peaks differing from the baseline electroencephalogram. The regions with >60% of channels presenting significant rhythmic activity were either mesial or temporal basal structures that contribute minimally to the scalp electroencephalogram. Finally, during deeper sleep stages, electroencephalographic analysis revealed a more homogeneous spatial distribution, with increased coupling between high and low frequencies. INTERPRETATION: This study provides a better understanding of the regional variability of sleep, and establishes a baseline for human sleep in all cortical regions during the first sleep cycle. Furthermore, the open-access atlas will be a unique resource for research (https://mni-open-ieegatlas. RESEARCH: mcgill.ca). ANN NEUROL 2020;87:289-301.

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

OBJECTIVE: 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). METHODS: 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. RESULTS: 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. SIGNIFICANCE: 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.

Uncommon case of complete loss of hunger following an isolated left insular stroke.

The insula has long been among the least understood regions of the human brain, in part due to its restricted accessibility. Mounting evidence suggests that the insula is a prominent player in gustatory, interoceptive, and emotional processing, and likely integrates these different functions to contribute to the homeostatic control of food intake. Here we report the case of a young adult patient who lost the subjective experience of hunger following an ischemic stroke localized in the posterior left insula. The loss of hunger was not attributable to medication, substance use, or a clinical disorder, and lasted for a period of 15 months. In line with the role attributed to the insula in gustation and interoception, we suggest that the insula integrates information about taste, interoception, and the hedonic value of food in the service of homeostatic regulation.