Serotonin 2C receptor in a rat model of temporal lobe epilepsy: From brainstem expression to pharmacological blockade in relation to ventilatory function.

Because of its involvement in breathing control and neuronal excitability, dysregulation of the serotonin (5-HT) 2C receptor (5-HT2C) might play a key role in sudden unexpected death in epilepsy. Seizure-induced respiratory arrest is thus prevented by a 5-HT2B/C agonist in different seizure model. However, the specific contribution of 5-HT2C in chronic epilepsy-related respiratory dysfunction remains unknown. In a rat model of temporal lobe epilepsy (EPI rats), in which we previously reported interictal respiratory dysfunctions and a reduction of brainstem 5-HT tone, quantitative reverse transcriptase polymerase chain reaction showed overexpression of TPH2 (5-HT synthesis enzyme), SERT (5-HT reuptake transporter), and 5-HT2C transcript levels in the brainstem of EPI rats, and of RNA-specific adenosine deaminase (ADAR1, ADAR2) involved in the production of 5-HT2C isoforms. Interictal ventilation was assessed with whole-body plethysmography before and 2 h after administration of SB242084 (2 mg/kg), a specific antagonist of 5-HT2C. As expected, SB242084 administration induced a progressive decrease in ventilatory parameters and an alteration of breathing stability in both control and EPI rats. However, the size of the SB242084 effect was lower in EPI rats than in controls. Increased 5-HT2C gene expression in the brainstem of EPI rats could be part of a compensatory mechanism against epilepsy-related low 5-HT tone and expression of 5-HT2C isoforms for which 5-HT affinity might be lower.

Combining general and personal models for epilepsy detection with hyperdimensional computing.

Epilepsy is a highly prevalent chronic neurological disorder with great negative impact on patients' daily lives. Despite this there is still no adequate technological support to enable epilepsy detection and continuous outpatient monitoring in everyday life. Hyperdimensional (HD) computing is a promising method for epilepsy detection via wearable devices, characterized by a simpler learning process and lower memory requirements compared to other methods. In this work, we demonstrate additional avenues in which HD computing and the manner in which its models are built and stored can be used to better understand, compare and create more advanced machine learning models for epilepsy detection. These possibilities are not feasible with other state-of-the-art models, such as random forests or neural networks. We compare inter-subject model similarity of different classes (seizure and non-seizure), study the process of creating general models from personal ones, and finally posit a method of combining personal and general models to create hybrid models. This results in an improved epilepsy detection performance. We also tested knowledge transfer between models trained on two different datasets. The attained insights are highly interesting not only from an engineering perspective, to create better models for wearables, but also from a neurological perspective, to better understand individual epilepsy patterns.

Impaired post-sleep apnea autonomic arousals in patients with drug-resistant epilepsy.

OBJECTIVE: Sudden and unexpected deaths in epilepsy (SUDEP) pathophysiology may involve an interaction between respiratory dysfunction and sleep/wake state regulation. We investigated whether patients with epilepsy exhibit impaired sleep apnea-related arousals. METHODS: Patients with drug-resistant (N = 20) or drug-sensitive (N = 20) epilepsy and obstructive sleep apnea, as well as patients with sleep apnea but without epilepsy (controls, N = 20) were included. We explored (1) the respiratory arousal threshold based on nadir oxygen saturation, apnea-hypopnea index, and fraction of hypopnea among respiratory events; (2) the cardiac autonomic response to apnea/hypopnea quantified as percentages of changes from the baseline in RR intervals (RRI), high (HF) and low (LF) frequency powers, and LF/HF. RESULTS: The respiratory arousal threshold did not differ between groups. At arousal onset, RRI decreased (-9.42%) and LF power (179%) and LF/HF ratio (190%) increased. This was followed by an increase in HF power (118%), p < 0.05. The RRI decrease was lower in drug-resistant (-7.40%) than in drug-sensitive patients (-9.94%) and controls (-10.91%), p < 0.05. LF and HF power increases were higher in drug-resistant (188%/126%) than in drug-sensitive patients (172%/126%) and controls (177%/115%), p < 0.05. CONCLUSIONS: Cardiac reactivity following sleep apnea is impaired in drug-resistant epilepsy. SIGNIFICANCE: This autonomic dysfunction might contribute to SUDEP pathophysiology.

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.

Phosphatidylserine enriched with polyunsaturated n-3 fatty acid supplementation for attention-deficit hyperactivity disorder in children and adolescents with epilepsy: A randomized placebo-controlled trial.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is a frequent comorbidity in children with epilepsy, which management mostly relies on the usual treatments of ADHD, especially methylphenidate. Supplementation with polyunsaturated n-3 Fatty Acid (PUFA) has been proposed as an alternative therapeutic approach in ADHD without epilepsy but has never been evaluated in epilepsy-associated ADHD. METHODS: A multicenter double blind randomized placebo-controlled trial evaluating supplementation with PUFA, in eicosapentaenoic- and docosahexaenoic-acid form, conjugated to a phospholipid vector (PS-Omega3) in children aged >6 and <16-years old, and suffering from any type of epilepsy and ADHD (inattentive or combined type) according to DSM-V. After a 4-week baseline period, patients were allocated (1:1) either to placebo group or to PS-Omega 3 group and entered a 12 week-double-blind treatment period which was followed by a 12 week-open-label treatment period. The primary outcome was the reduction of the ADHD-rating scale IV attention-deficit subscore after 12 weeks of treatment. RESULTS: The study was stopped early because of lack of eligible participants and the expected sample size was not reached. Seventy-four patients were randomized, 44 in PS-Omega3, and 30 in the placebo group. The reduction after 12 weeks of treatment in the inattention subscore of the ADHD-IV scale was -1.57 in the PS-Omega3 group, and -2.90 in the placebo group (p = 0.33, α = 5%). Results were similar after 24 weeks of treatment and for all other ADHD-related secondary outcomes, with no difference between placebo and PS-Omega3. CONCLUSION: Our study remaining underpowered, no formal conclusion about the effect of Ps-Omega3 could be drawn. However, our data strongly suggested that the PS-Omega 3 formulation used in the current study did not improve ADHD symptoms in children with epilepsy. PLAIN LANGUAGE SUMMARY: Supplementation with polyunsaturated n-3 Fatty Acid (PUFA) has been proposed in ADHD but has never been evaluated in patients with both epilepsy and ADHD. To address this issue, we conducted a multicenter double blind randomized placebo-controlled trial evaluating supplementation with PUFA in children with epilepsy and ADHD. The study was stopped early because of lack of eligible participants, hampering formal conclusion. However, the evolution of the ADHD symptoms at 12 and 24 weeks did not differ between placebo and PUFA supplementation, strongly suggesting that PUFA did not improve ADHD symptoms in children with epilepsy.

Outcome of Epilepsy Surgery in MRI-Negative Patients Without Histopathologic Abnormalities in the Resected Tissue.

BACKGROUND AND OBJECTIVE: Patients with presumed nonlesional focal epilepsy-based on either MRI or histopathologic findings-have a lower success rate of epilepsy surgery compared with lesional patients. In this study, we aimed to characterize a large group of patients with focal epilepsy who underwent epilepsy surgery despite a normal MRI and had no lesion on histopathology. Determinants of their postoperative seizure outcomes were further studied. METHODS: We designed an observational multicenter cohort study of MRI-negative and histopathology-negative patients who were derived from the European Epilepsy Brain Bank and underwent epilepsy surgery between 2000 and 2012 in 34 epilepsy surgery centers within Europe. We collected data on clinical characteristics, presurgical assessment, including genetic testing, surgery characteristics, postoperative outcome, and treatment regimen. RESULTS: Of the 217 included patients, 40% were seizure-free (Engel I) 2 years after surgery and one-third of patients remained seizure-free after 5 years. Temporal lobe surgery (adjusted odds ratio [AOR]: 2.62; 95% CI 1.19-5.76), shorter epilepsy duration (AOR for duration: 0.94; 95% CI 0.89-0.99), and completely normal histopathologic findings-versus nonspecific reactive gliosis-(AOR: 4.69; 95% CI 1.79-11.27) were significantly associated with favorable seizure outcome at 2 years after surgery. Of patients who underwent invasive monitoring, only 35% reached seizure freedom at 2 years. Patients with parietal lobe resections had lowest seizure freedom rates (12.5%). Among temporal lobe surgery patients, there was a trend toward favorable outcome if hippocampectomy was part of the resection strategy (OR: 2.94; 95% CI 0.98-8.80). Genetic testing was only sporadically performed. DISCUSSION: This study shows that seizure freedom can be reached in 40% of nonlesional patients with both normal MRI and histopathology findings. In particular, nonlesional temporal lobe epilepsy should be regarded as a relatively favorable group, with almost half of patients achieving seizure freedom at 2 years after surgery-even more if the hippocampus is resected-compared with only 1 in 5 nonlesional patients who underwent extratemporal surgery. Patients with an electroclinically identified focus, who are nonlesional, will be a promising group for advanced molecular-genetic analysis of brain tissue specimens to identify new brain somatic epilepsy genes or epilepsy-associated molecular pathways.

Are we there yet? A critical evaluation of sudden and unexpected death in epilepsy models.

Although animal models have helped to elaborate meaningful hypotheses about the pathophysiology of sudden and unexpected death in epilepsy (SUDEP), specific prevention strategies are still lacking, potentially reflecting the limitations of these models and the intrinsic difficulties of investigating SUDEP. The interpretation of preclinical data and their translation to diagnostic and therapeutic developments in patients thus require a high level of confidence in their relevance to model the human situation. Preclinical models of SUDEP are heterogeneous and include rodent and nonrodent species. A critical aspect is whether the animals have isolated seizures exclusively induced by a specific trigger, such as models where seizures are elicited by electrical stimulation, pharmacological intervention, or DBA mouse strains, or whether they suffer from epilepsy with spontaneous seizures, with or without spontaneous SUDEP, either of nongenetic epilepsy etiology or from genetically based developmental and epileptic encephalopathies. All these models have advantages and potential disadvantages, but it is important to be aware of these limitations to interpret data appropriately in a translational perspective. The majority of models with spontaneous seizures are of a genetic basis, whereas SUDEP cases with a genetic basis represent only a small proportion of the total number. In almost all models, cardiorespiratory arrest occurs during the course of the seizure, contrary to that in patients observed at the time of death, potentially raising the issue of whether we are studying models of SUDEP or models of periseizure death. However, some of these limitations are impossible to avoid and can in part be dependent on specific features of SUDEP, which may be difficult to model. Several preclinical tools are available to address certain gaps in SUDEP pathophysiology, which can be used to further validate current preclinical models.

Developmental epileptic encephalopathy in DLG4-related synaptopathy.

OBJECTIVE: The postsynaptic density protein of excitatory neurons PSD-95 is encoded by discs large MAGUK scaffold protein 4 (DLG4), de novo pathogenic variants of which lead to DLG4-related synaptopathy. The major clinical features are developmental delay, intellectual disability (ID), hypotonia, sleep disturbances, movement disorders, and epilepsy. Even though epilepsy is present in 50% of the individuals, it has not been investigated in detail. We describe here the phenotypic spectrum of epilepsy and associated comorbidities in patients with DLG4-related synaptopathy. METHODS: We included 35 individuals with a DLG4 variant and epilepsy as part of a multicenter study. The DLG4 variants were detected by the referring laboratories. The degree of ID, hypotonia, developmental delay, and motor disturbances were evaluated by the referring clinician. Data on awake and sleep electroencephalography (EEG) and/or video-polygraphy and brain magnetic resonance imaging were collected. Antiseizure medication response was retrospectively assessed by the referring clinician. RESULTS: A large variety of seizure types was reported, although focal seizures were the most common. Encephalopathy related to status epilepticus during slow-wave sleep (ESES)/developmental epileptic encephalopathy with spike-wave activation during sleep (DEE-SWAS) was diagnosed in >25% of the individuals. All but one individual presented with neurodevelopmental delay. Regression in verbal and/or motor domains was observed in all individuals who suffered from ESES/DEE-SWAS, as well as some who did not. We could not identify a clear genotype-phenotype relationship even between individuals with the same DLG4 variants. SIGNIFICANCE: Our study shows that a subgroup of individuals with DLG4-related synaptopathy have DEE, and approximately one fourth of them have ESES/DEE-SWAS. Our study confirms DEE as part of the DLG4-related phenotypic spectrum. Occurrence of ESES/DEE-SWAS in DLG4-related synaptopathy requires proper investigation with sleep EEG.

Deep-learning predicted PET can be subtracted from the true clinical fluorodeoxyglucose PET co-registered to MRI to identify the epileptogenic zone in focal epilepsy.

OBJECTIVE: Normal interictal [18 F]FDG-PET can be predicted from the corresponding T1w MRI with Generative Adversarial Networks (GANs). A technique we call SIPCOM (Subtraction Interictal PET Co-registered to MRI) can then be used to compare epilepsy patients' predicted and clinical PET. We assessed the ability of SIPCOM to identify the Resection Zone (RZ) in patients with drug-resistant epilepsy (DRE) with reference to visual and statistical parametric mapping (SPM) analysis. METHODS: Patients with complete presurgical work-up and subsequent SEEG and cortectomy were included. RZ localisation, the reference region, was assigned to one of eighteen anatomical brain regions. SIPCOM was implemented using healthy controls to train a GAN. To compare, the clinical PET coregistered to MRI was visually assessed by two trained readers, and a standard SPM analysis was performed. RESULTS: Twenty patients aged 17-50 (32 ± 7.8) years were included, 14 (70%) with temporal lobe epilepsy (TLE). Eight (40%) were MRI-negative. After surgery, 14 patients (70%) had a good outcome (Engel I-II). RZ localisation rate was 60% with SIPCOM vs 35% using SPM (P = 0.015) and vs 85% using visual analysis (P = 0.54). Results were similar for Engel I-II patients, the RZ localisation rate was 64% with SIPCOM vs 36% with SPM. With SIPCOM localisation was correct in 67% in MRI-positive vs 50% in MRI-negative patients, and 64% in TLE vs 43% in extra-TLE. The average number of false-positive clusters was 2.2 ± 1.3 using SIPCOM vs 2.3 ± 3.1 using SPM. All RZs localized with SPM were correctly localized with SIPCOM. In one case, PET and MRI were visually reported as negative, but both SIPCOM and SPM localized the RZ. SIGNIFICANCE: SIPCOM performed better than the reference computer-assisted method (SPM) for RZ detection in a group of operated DRE patients. SIPCOM's impact on epilepsy management needs to be prospectively validated.

BDNF as potential biomarker of epilepsy severity and psychiatric comorbidity: pitfalls in the clinical population.

BACKGROUND: Several studies implicate brain-derived neurotrophic factor (BDNF) in the pathophysiology of epilepsy. In particular, preclinical data suggest that lower serum BDNF is a biomarker of epilepsy severity and psychiatric comorbidities. We tested this prediction in clinical epilepsy cohorts. METHODS: Patients with epilepsy were recruited from 4 epilepsy centers in France and serum BDNF was quantified. Clinical characteristics including epilepsy duration, classification, localization, etiology, seizure frequency and drug resistance were documented. Presence of individual anti-seizure medications (ASM) was noted. Screening for depression and anxiety symptoms was carried out in all patients using the NDDI-E and the GAD-7 scales. In patients with positive screening for anxiety and/or depression, detailed psychiatric testing was performed including the Mini International Neuropsychiatric Interview (MINI), STAI-Y, Holmes Rahe Stressful Events Scale and Beck Depression Interview. Descriptive analysis was applied. Spearman's test and Pearson's co-efficient were used to assess the association between BDNF level and continuous variables. For discrete variables, comparison of means (Student's t-test, Mann-Whitney u-test) was used to compare mean BDNF serum level between groups. Multivariate analysis was performed using a regression model. RESULTS: No significant correlation was found between serum BDNF level and clinical features of epilepsy or measures of depression. The main group-level finding was that presence of any ASM at was associated with increased BDNF; this effect was particularly significant for valproate and perampanel. CONCLUSION: Presence of ASM affects serum BDNF levels in patients with epilepsy. Future studies exploring BDNF as a possible biomarker of epilepsy severity and/or psychiatric comorbidity must control for ASM effects.

How valid are proxy assessment of mental health and sleep comorbidities of patients with epilepsy using standardized questionnaires?

BACKGROUND: The study aimed to determine the level of agreement between patients with epilepsy and their proxies when assessing psychiatric comorbidities, sleep disorders, and medication adherence using standardized questionnaires. METHODS: This agreement study is an ancillary analysis of the PRERIES study, a matched case-control study exploring SUDEP risk factors. Controls aged 15 years and older, with active epilepsy or in remission for less than 5 years were recruited between 01/01/2011 and 03/31/2019. An interview was carried out by a trained psychologist on both the patient and a proxy-respondent. During these independent interviews, the following comorbidities were explored: psychiatric comorbidities using the MINI, the STAI- Y2 and NDDI-E scales, sleep disorders with the SDQ-SA and Epworth scales and medication adherence. Level of agreement between patient and their proxy was estimated using Gwet's AC1&2. RESULTS: Among the 107 patient-proxy dyads recruited, proxy respondents were mainly family members (65.4%) or spouses (30.8%). Exploration of present major depression showed excellent agreement at 0.81 [0.65;0.97], as well as exploration of dysthymia at 0.96 [0.61;1]. Suicidal risk evaluation had a lesser agreement at 0.77 [0.60;0.94]. Agreement on anxiety was moderate 0.5 [0.38;0.62]. For sleep disorder, SDQ-SA presented a better agreement than the Epworth questionnaire with respectively 0.73 [0.51;0.95] and 0.45 [0.26;0.63]. For medication adherence, the overall agreement rate was excellent (0.90 [0.78;1]). CONCLUSION: Exploration of potential risk factors through families can give valuable and relatively robust information, especially if the respondent lives with the patient, and should be retrieved, when possible, in usual clinical setting.

Mapping Lesion-Related Epilepsy to a Human Brain Network.

Importance: It remains unclear why lesions in some locations cause epilepsy while others do not. Identifying the brain regions or networks associated with epilepsy by mapping these lesions could inform prognosis and guide interventions. Objective: To assess whether lesion locations associated with epilepsy map to specific brain regions and networks. Design, Setting, and Participants: This case-control study used lesion location and lesion network mapping to identify the brain regions and networks associated with epilepsy in a discovery data set of patients with poststroke epilepsy and control patients with stroke. Patients with stroke lesions and epilepsy (n = 76) or no epilepsy (n = 625) were included. Generalizability to other lesion types was assessed using 4 independent cohorts as validation data sets. The total numbers of patients across all datasets (both discovery and validation datasets) were 347 with epilepsy and 1126 without. Therapeutic relevance was assessed using deep brain stimulation sites that improve seizure control. Data were analyzed from September 2018 through December 2022. All shared patient data were analyzed and included; no patients were excluded. Main Outcomes and Measures: Epilepsy or no epilepsy. Results: Lesion locations from 76 patients with poststroke epilepsy (39 [51%] male; mean [SD] age, 61.0 [14.6] years; mean [SD] follow-up, 6.7 [2.0] years) and 625 control patients with stroke (366 [59%] male; mean [SD] age, 62.0 [14.1] years; follow-up range, 3-12 months) were included in the discovery data set. Lesions associated with epilepsy occurred in multiple heterogenous locations spanning different lobes and vascular territories. However, these same lesion locations were part of a specific brain network defined by functional connectivity to the basal ganglia and cerebellum. Findings were validated in 4 independent cohorts including 772 patients with brain lesions (271 [35%] with epilepsy; 515 [67%] male; median [IQR] age, 60 [50-70] years; follow-up range, 3-35 years). Lesion connectivity to this brain network was associated with increased risk of epilepsy after stroke (odds ratio [OR], 2.82; 95% CI, 2.02-4.10; P < .001) and across different lesion types (OR, 2.85; 95% CI, 2.23-3.69; P < .001). Deep brain stimulation site connectivity to this same network was associated with improved seizure control (r, 0.63; P < .001) in 30 patients with drug-resistant epilepsy (21 [70%] male; median [IQR] age, 39 [32-46] years; median [IQR] follow-up, 24 [16-30] months). Conclusions and Relevance: The findings in this study indicate that lesion-related epilepsy mapped to a human brain network, which could help identify patients at risk of epilepsy after a brain lesion and guide brain stimulation therapies.

An international survey of SEEG cortical stimulation practices.

OBJECTIVE: Cortical stimulation is an important component of stereoelectroencephalography (SEEG). Despite this, there is currently no standardized approach and significant heterogeneity in the literature regarding cortical stimulation practices. Via an international survey of SEEG clinicians, we sought to examine the spectrum of cortical stimulation practices to reveal areas of consensus and variability. METHODS: A 68-item questionnaire was developed to understand cortical stimulation practices including neurostimulation parameters, interpretation of epileptogenicity, functional and cognitive assessment and subsequent surgical decisions. Multiple recruitment pathways were pursued, with the questionnaire distributed directly to 183 clinicians. RESULTS: Responses were received from 56 clinicians across 17 countries with experience ranging from 2 to 60 years (M = 10.73, SD = 9.44). Neurostimulation parameters varied considerably, with maximum current ranging from 3 to 10 mA (M = 5.33, SD = 2.29) for 1 Hz and from 2 to 15 mA (M = 6.54, SD = 3.68) for 50 Hz stimulation. Charge density ranged from 8 to 200 µC/cm2 , with up to 43% of responders utilizing charge densities higher than recommended upper safety limits, i.e. 55 µC/cm2 . North American responders reported statistically significant higher maximum current (P < 0.001) for 1 Hz stimulation and lower pulse width for 1 and 50 Hz stimulation (P = 0.008, P < 0.001, respectively) compared to European responders. All clinicians evaluated language, speech, and motor function during cortical stimulation; in contrast, 42% assessed visuospatial or visual function, 29% memory, and 13% executive function. Striking differences were reported in approaches to assessment, classification of positive sites, and surgical decisions guided by cortical stimulation. Patterns of consistency were observed for interpretation of the localizing capacity of stimulated electroclinical seizures and auras, with habitual electroclinical seizures induced by 1 Hz stimulation considered the most localizing. SIGNIFICANCE: SEEG cortical stimulation practices differed vastly across clinicians internationally, highlighting the need for consensus-based clinical guidelines. In particular, an internationally standardized approach to assessment, classification, and functional prognostication will provide a common clinical and research framework for optimizing outcomes for people with drug-resistant epilepsy.

CB2 receptor in the CNS: From immune and neuronal modulation to behavior.

Despite low levels of cannabinoid receptor type 2 (CB2R) expression in the central nervous system in human and rodents, a growing body of evidence shows CB2R involvement in many processes at the behavioral level, through both immune and neuronal modulations. Recent in vitro and in vivo evidence have highlighted the complex role of CB2R under physiological and inflammatory conditions. Under neuroinflammatory states, its activation seems to protect the brain and its functions, making it a promising target in a wide range of neurological disorders. Here, we provide a complete and updated overview of CB2R function in the central nervous system of rodents, spanning from modulation of immune function in microglia but also in other cell types, to behavior and neuronal activity, in both physiological and neuroinflammatory contexts.

Assessing epilepsy-related autonomic manifestations: Beyond cardiac and respiratory investigations.

The Autonomic Nervous System (ANS) regulates many critical physiological functions. Its control relies on cortical input, especially limbic areas, which are often involved in epilepsy. Peri-ictal autonomic dysfunction is now well documented, but inter-ictal dysregulation is less studied. In this review, we discuss the available data on epilepsy-related autonomic dysfunction and the objective tests available. Epilepsy is associated with sympathetic-parasympathetic imbalance and a shift towards sympathetic dominance. Objective tests report alterations in heart rate, baroreflex function, cerebral autoregulation, sweat glands activity, thermoregulation, gastrointestinal and urinary function. However, some tests have found contradictory results and many tests suffer from a lack of sensitivity and reproducibility. Further study on interictal ANS function is required to further understand autonomic dysregulation and the potential association with clinically-relevant complications, including risk of Sudden Unexpected Death In Epilepsy (SUDEP).

Subject-Specific Activation of Central Respiratory Centers during Breath-Holding Functional Magnetic Resonance Imaging.

BACKGROUND: Voluntary breath-holding (BH) triggers responses from central neural control and respiratory centers in order to restore breathing. Such responses can be observed using functional MRI (fMRI). OBJECTIVES: We used this paradigm in healthy volunteers with the view to develop a biomarker that could be used to investigate disorders of the central control of breathing at the individual patient level. METHOD: In 21 healthy human subjects (mean age±SD, 32.8 ± 9.9 years old), fMRI was used to determine, at both the individual and group levels, the physiological neural response to expiratory and inspiratory voluntary apneas, within respiratory control centers in the brain and brainstem. RESULTS: Group analysis showed that expiratory BH, but not inspiratory BH, triggered activation of the pontine respiratory group and raphe nuclei at the group level, with a significant relationship between the levels of activation and drop in SpO2. Using predefined ROIs, expiratory BH, and to a lesser extent, inspiratory BH were associated with activation of most respiratory centers. The right ventrolateral nucleus of the thalamus, right pre-Bötzinger complex, right VRG, right nucleus ambiguus, and left Kölliker-Fuse-parabrachial complex were only activated during inspiratory BH. Individual analysis identified activations of cortical/subcortical and brainstem structures related to respiratory control in 19 out of 21 subjects. CONCLUSION: Our study shows that BH paradigm allows to reliably trigger fMRI response from brainstem and cortical areas involved in respiratory control at the individual level, suggesting that it might serve as a clinically relevant biomarker to investigate conditions associated with an altered central control of respiration.

Update on the controversial identity of cells expressing cnr2 gene in the nervous system.

The function of cannabinoid receptor type 2 (CB2R), mainly expressed by leukocytes, has long been limited to its peripheral immunomodulatory role. However, the use of CB2R-specific ligands and the availability of CB2R-Knock Out mice revealed that it could play a functional role in the CNS not only under physiological but also under pathological conditions. A direct effect on the nervous system emerged when CB2R mRNA was detected in neural tissues. However, accurate mapping of CB2R protein expression in the nervous system is still lacking, partly because of the lack of specificity of antibodies available. This review examines the regions and cells of the nervous system where CB2R protein is most likely present by cross-referencing mRNA and protein data published to date. Of the many antibodies developed to target CB2R, only a few have partially passed specificity tests and detected CB2R in the CNS. Efforts must be continued to support the development of more specific and better validated antibodies in each of the species in which CB2R protein is sought or needs to be quantified.

Early-Stage Contactin-Associated Protein-like 2 Limbic Encephalitis: Clues for Diagnosis.

BACKGROUND AND OBJECTIVES: Previous studies suggested that autoimmune limbic encephalitis with antibodies against contactin-associated protein-like 2 (CASPR2-encephalitis) is clinically heterogeneous and progresses slowly, preventing its early recognition. We aimed to describe the onset and progression of CASPR2-encephalitis and to assess long-term outcomes. METHODS: We retrospectively analyzed the medical records of all patients whose CSF tested positive for anti-CASPR2 antibodies in our center between 2006 and 2020. Standardized telephone interviews of all available patients and relatives were conducted, assessing long-term functional independence using the Functional Activity Questionnaire (FAQ) and quality of life using the 36-Item Short-Form Survey (SF36). RESULTS: Forty-eight patients were included (98% males; median age 64 years), and 35 participated in telephone interviews (73%). At onset, 81% had at least 1 neurologic symptom among the following: limbic (54%), peripheral nerve hyperexcitability (PNH; 21%), and/or cerebellar symptoms (17%). Most of the patients (75%) had initially symptoms of only one of these categories. Limbic symptoms at onset included mostly seizures (33%), while memory disturbances were less frequent (10%). PNH signs were mostly neuropathic pain (9/10 patients). Other symptoms seen at onset included asthenia (33%), mood disorders (25%), and insomnia (21%); 19% of patients did not show any limbic, peripheral, or cerebellar symptom at onset but only asthenia (15%), mood disorders (6%), weight loss (8%), dysautonomia (4%), and/or insomnia (2%). The peak of the disease was attained in median 16.7 months after onset. Over the study period (median follow-up, 58.8 months, range 10.6-189.1), 77% of patients developed ≥3 core CASPR2 symptoms and 42% fulfilled the diagnostic criteria for autoimmune limbic encephalitis, although all patients ultimately developed limbic symptoms. At the last visit, most interviewed patients (28/35 patients, 80%; median, 5 years after onset) had recovered functional independence (FAQ <9) while only the vitality subscore of the SF36 was lower than normative data (mean 49.9 vs 58.0, p = 0.0369). DISCUSSION: CASPR2-encephalitis has a progressive course and is highly heterogeneous at the early stage. In men older than 50 years, otherwise unexplained seizures, cerebellar ataxia, and/or neuropathic pain are suggestive of early-stage CASPR2-encephalitis, especially if they coincide with recent asthenia, mood disorders, or insomnia.

Visceral and emotional responses to direct electrical stimulations of the cortex.

OBJECTIVE: Visceral sensations are bodily symptoms which are component manifestations of emotions frequently reported during epileptic seizures. Nowadays, the underlying mechanism and location of brain areas involved in the processing of these sensations remain unclear. Our objectives were to characterize the type and frequency of visceral and emotional responses evoked by electrical stimulations, to produce a mapping of brain structures involved in their processing, and to assess the link between visceral sensations and emotional feelings. METHODS: We reviewed 12,088 bipolar stimulations performed in 203 patients during the presurgical evaluation of drug refractory epilepsy. Responses to stimulation were divided into viscero-sensitive, viscero-vegetative, and emotional sensations. Univariate analysis and conditional logistic regression were used to assess the association between visceral and emotional sensations and localization of the stimulated contacts. RESULTS: In total, 543 stimulations evoked visceral and emotional sensations. Stimulations of operculo-insulolimbic structures (amygdala, anterior and posterior insula, anterior and mid-cingulate cortex, hippocampus, parahippocampus, temporal pole, frontal and parietal operculum) were significantly more associated with visceral and emotional sensations than all other cortical regions. Preferential implication of certain brain structures, depending on the type of visceral responses was evidenced: temporo-mesial structures, insula, and frontoparietal operculum for viscero-sensitive sensations; amygdala, insula, anterior and mid-cingulate cortex, and temporal pole for viscero-vegetative sensations; temporo-mesial structures, anterior cingulate cortex, and frontal operculum for emotional sensations. INTERPRETATION: Our data can help to guide SEEG explorations when visceral or emotional symptoms are part of the ictal semiology. They also bring some insights into the mechanisms of visceroception and the functional significance of the co-localization of visceral and emotional representations in the human brain.