Publications by authors named "Sylvain Rheims"

109 Publications

Interpreting deep learning models for epileptic seizure detection on EEG signals.

Artif Intell Med 2021 Jul 1;117:102084. Epub 2021 May 1.

Embedded Systems Laboratory (ESL), EPFL, Lausanne, Switzerland.

While Deep Learning (DL) is often considered the state-of-the art for Artificial Intel-ligence-based medical decision support, it remains sparsely implemented in clinical practice and poorly trusted by clinicians due to insufficient interpretability of neural network models. We have approached this issue in the context of online detection of epileptic seizures by developing a DL model from EEG signals, and associating certain properties of the model behavior with the expert medical knowledge. This has conditioned the preparation of the input signals, the network architecture, and the post-processing of the output in line with the domain knowledge. Specifically, we focused the discussion on three main aspects: (1) how to aggregate the classification results on signal segments provided by the DL model into a larger time scale, at the seizure-level; (2) what are the relevant frequency patterns learned in the first convolutional layer of different models, and their relation with the delta, theta, alpha, beta and gamma frequency bands on which the visual interpretation of EEG is based; and (3) the identification of the signal waveforms with larger contribution towards the ictal class, according to the activation differences highlighted using the DeepLIFT method. Results show that the kernel size in the first layer determines the interpretability of the extracted features and the sensitivity of the trained models, even though the final performance is very similar after post-processing. Also, we found that amplitude is the main feature leading to an ictal prediction, suggesting that a larger patient population would be required to learn more complex frequency patterns. Still, our methodology was successfully able to generalize patient inter-variability for the majority of the studied population with a classification F1-score of 0.873 and detecting 90% of the seizures.
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http://dx.doi.org/10.1016/j.artmed.2021.102084DOI Listing
July 2021

Electroclinical markers to differentiate between focal and generalized epilepsies.

Epileptic Disord 2021 Jun 9. Epub 2021 Jun 9.

Paediatric Neurology Division, Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, Cape Town, South Africa, Neurosciences Institute, University of Cape Town, South Africa.

Generalized-onset seizures originate at a point within the brain and rapidly engage bilaterally distributed networks, whilst focal-onset seizures originate within networks limited to one hemisphere which may be discretely localized or more widely distributed. Challenges in data capturing have resulted in a lack of consistency across incidence and prevalence studies for estimates of generalized versus focal epilepsies in population groups, with a preponderance of unclassified cases. Infants and young children can further challenge delineation due to variable expression at different stages of brain maturation and impaired ability to express sensory seizure semiology. Focal seizures are divided into those in which the affected person is aware and those with impaired awareness; these events can be motor or non-motor. Generalized seizures are also categorized as motor and non-motor, but loss of awareness occurs with most events. Delineation between generalized and focal epilepsies is important for ongoing management. EEG, neuroimaging and other investigations (genetics, immune markers, etc.) can support the outcome but distinction between focal and generalized epilepsy in isolation is rarely achieved using such techniques. Certain clinical settings such as age, underlying aetiologies, and co-morbidities may be more predisposed to specific types of epilepsy. The differentiation between generalized and focal seizures remains a clinical process based on meticulous clinical history and examination, and is of relevance for the selection of antiseizure medications and identification of patients who may be viable for epilepsy surgery.
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http://dx.doi.org/10.1684/epd.2021.1291DOI Listing
June 2021

Anatomical dissociation of intracerebral signals for reward and punishment prediction errors in humans.

Nat Commun 2021 06 7;12(1):3344. Epub 2021 Jun 7.

Univ. Grenoble Alpes, Inserm, U1216, Grenoble Institut Neurosciences, GIN, Grenoble, France.

Whether maximizing rewards and minimizing punishments rely on distinct brain systems remains debated, given inconsistent results coming from human neuroimaging and animal electrophysiology studies. Bridging the gap across techniques, we recorded intracerebral activity from twenty participants while they performed an instrumental learning task. We found that both reward and punishment prediction errors (PE), estimated from computational modeling of choice behavior, correlate positively with broadband gamma activity (BGA) in several brain regions. In all cases, BGA scaled positively with the outcome (reward or punishment versus nothing) and negatively with the expectation (predictability of reward or punishment). However, reward PE were better signaled in some regions (such as the ventromedial prefrontal and lateral orbitofrontal cortex), and punishment PE in other regions (such as the anterior insula and dorsolateral prefrontal cortex). These regions might therefore belong to brain systems that differentially contribute to the repetition of rewarded choices and the avoidance of punished choices.
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http://dx.doi.org/10.1038/s41467-021-23704-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184756PMC
June 2021

Awake craniotomy for epilepsy surgery on eloquent speech areas: a single-centre experience.

Epileptic Disord 2021 Apr;23(2):347-356

Department of Functional Neurosurgery, Hospices Civils de Lyon and University of Lyon, Lyon, France, University of Lyon, Lyon, France, Lyon's Neuroscience Research Centre, (INSERM U1028, CNRS UMR5292), University of Lyon, Lyon, France.

In patients with intractable partial epilepsy who are eligible for epilepsy surgery, the best seizure control requires complete resection of the epileptogenic zone. When the epileptogenic zone is located very near to, or even with the eloquent cortex, this can be a challenge. In this study, we investigated the efficacy of awake craniotomy techniques to completely resect these epileptic zones while preserving the neural functions. We conducted a retrospective cohort study of 17 consecutive patients with intractable partial seizures of different aetiologies (non-lesional epilepsy [n=3], tuberous sclerosis [n=1], hypoxic ischaemic insult [n=1], dysembryoplastic neuroepithelial tumours [DNET] [n=2], focal cortical dysplasia type 2 [FCD] [n=4], and other malformations of cortical development [n=6]), located in eloquent language cortex (frontal [n=7], insular [n=5], and latero-temporal [n=5] regions). All patients were operated on between 2010 and 2019 for resective epilepsy surgery under awake conditions, with the aid of direct cortical stimulation. This report aimed to study the feasibility, efficacy and limitations of using the awake craniotomy technique for surgical resections of epileptogenic zones involving eloquent language cortex. Postoperative epilepsy control and neurological function were assessed and followed. The mean follow-up period was 5.7 years. In one patient, the surgery was aborted before resection. In the other patients, Engel Class I was achieved in seven patients (43.75%) and Engel Class II in four patients (25%), and worthwhile improvement (Engel Class I and II) was achieved in 11 patients (68.75%). Postoperative neurological deficits were encountered in four patients (23.5%). However, all these deficits were regressive and were absent at the last follow-up visit. Using the awake craniotomy technique, seizure freedom can be achieved in a high proportion of patients with epileptogenic zones located in language areas, who were previously considered only candidates for palliative measures.
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http://dx.doi.org/10.1684/epd.2021.1275DOI Listing
April 2021

Ictal and Interictal Cardiac Manifestations in Epilepsy. A Review of Their Relation With an Altered Central Control of Autonomic Functions and With the Risk of SUDEP.

Front Neurol 2021 12;12:642645. Epub 2021 Mar 12.

Lyon Neuroscience Research Center, INSERM U 1028, CNRS UMR, Lyon, France.

There is a complex interrelation between epilepsy and cardiac pathology, with both acute and long-term effects of seizures on the regulation of the cardiac rhythm and on the heart functioning. A specific issue is the potential relation between these cardiac manifestations and the risk of Sudden and Unexpected Death in Epilepsy (SUDEP), with unclear respective role of centrally-control ictal changes, long-term epilepsy-related dysregulation of the neurovegetative control and direct effects on the heart function. In the present review, we detailed available data about ictal cardiac changes, along with interictal cardiac manifestations associated with long-term functional and structural alterations of the heart. Pathophysiological mechanisms of these cardiac changes are discussed, with a specific focus on central mechanisms and the investigation of a possible deregulation of the central control of autonomic functions in addition to the role of catecholamine and hypoxemia on heart.
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http://dx.doi.org/10.3389/fneur.2021.642645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994524PMC
March 2021

A survey of the European Reference Network EpiCARE on clinical practice for selected rare epilepsies.

Epilepsia Open 2021 03 13;6(1):160-170. Epub 2021 Jan 13.

IRCCS Mondino Foundation Pavia Italy.

Objective: Clinical care of rare and complex epilepsies is challenging, because evidence-based treatment guidelines are scarce, the experience of many physicians is limited, and interdisciplinary treatment of comorbidities is required. The pathomechanisms of rare epilepsies are, however, increasingly understood, which potentially fosters novel targeted therapies. The objectives of our survey were to obtain an overview of the clinical practice in European tertiary epilepsy centers treating patients with 5 arbitrarily selected rare epilepsies and to get an estimate of potentially available patients for future studies.

Methods: Members of the ( were invited to participate in a web-based survey on clinical practice of patients with Dravet syndrome, tuberous sclerosis complex (TSC), autoimmune encephalitis, and progressive myoclonic epilepsies including Unverricht Lundborg and Unverricht-like diseases. A consensus-based questionnaire was generated for each disease.

Results: Twenty-six of 30 invited epilepsy centers participated. Cohorts were present in most responding centers for TSC (87%), Dravet syndrome (85%), and autoimmune encephalitis (71%). Patients with TSC and Dravet syndrome represented the largest cohorts in these centers. The antiseizure drug treatments were rather consistent across the centers especially with regard to Dravet syndrome, infantile spasms in TSC, and Unverricht Lundborg / Unverricht-like disease. Available, widely used targeted therapies included everolimus in TSC and immunosuppressive therapies in autoimmune encephalitis. Screening for comorbidities was routinely done, but specific treatment protocols were lacking in most centers.

Significance: The survey summarizes the current clinical practice for selected rare epilepsies in tertiary European epilepsy centers and demonstrates consistency as well as heterogeneity in the treatment, underscoring the need for controlled trials and recommendations. The survey also provides estimates for potential participants of clinical trials recruited via EpiCARE, emphasizing the great potential of Reference Networks for future studies to evaluate new targeted therapies and to identify novel biomarkers.
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http://dx.doi.org/10.1002/epi4.12459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918306PMC
March 2021

Developmental and epileptic encephalopathies: recognition and approaches to care.

Epileptic Disord 2021 Feb;23(1):40-52

Paediatric Neurology Division, Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, Cape Town, South Africa, Neurosciences Institute, University of Cape Town, South Africa.

The term "developmental and epileptic encephalopathy" (DEE) refers to when cognitive functions are influenced by both seizure and interictal epileptiform activity and the neurobiological process behind the epilepsy. Many DEEs are related to gene variants and the onset is typically during early childhood. In this setting, neurocognition, whilst not improved by seizure control, may benefit from some precision therapies. In patients with non-progressive diseases with cognitive impairment and co-existing epilepsy, in whom the epileptiform activity does not affect or has minimal effect on function, the term "developmental encephalopathy" (DE) can be used. In contrast, for those patients with direct impact on cognition due to epileptic or epileptiform activity, the term "epileptic encephalopathy" (EE) is preferred, as most can revert to their normal or near normal baseline cognitive state with appropriate intervention. These children need aggressive treatment. Clinicians must tailor care towards individual needs and realistic expectations for each affected person; those with DE are unlikely to gain from aggressive antiseizure medication whilst those with EE will gain. Patients with DEE might benefit from a precision medicine approach in order to reduce the overall burden of epilepsy.
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http://dx.doi.org/10.1684/epd.2021.1244DOI Listing
February 2021

Relation between coffee consumption and risk of seizure-related respiratory dysfunction in patients with drug-resistant focal epilepsy.

Epilepsia 2021 Mar 14;62(3):765-777. Epub 2021 Feb 14.

Department of Functional Neurology and Epileptology, Hospices Civils de Lyon and University of Lyon, Lyon, France.

Objective: Caffeine is an antagonist of the adenosine pathway, which is involved in regulation of breathing. Extracellular concentrations of adenosine are increased in the immediate aftermath of a seizure. Seizure-related overstimulation of adenosine receptors might promote peri-ictal apnea. However, the relation between caffeine consumption and risk of seizure-related respiratory dysfunction in patients with drug-resistant focal epilepsy remains unknown.

Methods: We performed a cross-sectional analysis of data collected in patients included in the SAVE study in Lyon's epilepsy monitoring unit at the Adult Epilepsy Department of the Lyon University Hospital between February 2016 and October 2018. The video-electroencephalographic recordings of 156 patients with drug-resistant focal epilepsy included in the study were reviewed to identify those with ≥1 focal seizure (FS), valid pulse oximetry (SpO ) measurement, and information about usual coffee consumption. This latter was collected at inclusion using a standardized self-questionnaire and further classified into four groups: none, rare (≤3 cups/week), moderate (4 cups/week to 3 cups/day), and high (≥4 cups/day). Peri-ictal hypoxemia (PIH) was defined as SpO < 90% for at least 5 s occurring during the ictal period, the post-ictal period, or both.

Results: Ninety patients fulfilled inclusion criteria, and 323 seizures were analyzed. Both the level of usual coffee consumption (p = .033) and the level of antiepileptic drug withdrawal (p = .004) were independent risk factors for occurrence of PIH. In comparison with FS in patients with no coffee consumption, risk of PIH was four times lower in FS in patients with moderate consumption (odds ratio [OR] = .25, 95% confidence interval [CI] = .07-.91, p = .036) and six times lower in FS in patients with high coffee consumption (OR = .16, 95% CI = .04-.66, p = .011). However, when PIH occurred, its duration was longer in patients with moderate or high consumption than in those with no coffee consumption (p = .042).

Significance: Coffee consumption may be a protective factor for seizure-related respiratory dysfunction, with a dose-dependent effect.
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http://dx.doi.org/10.1111/epi.16837DOI Listing
March 2021

Seizures and epilepsy after intracerebral hemorrhage: an update.

J Neurol 2021 Feb 10. Epub 2021 Feb 10.

Lyon 1 University, Lyon, France.

Seizures are common after intracerebral hemorrhage, occurring in 6-15% of the patients, mostly in the first 72 h. Their incidence reaches 30% when subclinical or non-convulsive seizures are diagnosed by continuous electroencephalogram. Several risk factors for seizures have been described including cortical location of intracerebral hemorrhage, presence of intraventricular hemorrhage, total hemorrhage volume, and history of alcohol abuse. Seizures after intracerebral hemorrhage may theoretically be harmful as they can lead to sudden blood pressure fluctuations, increased intracranial pressure, and neuronal injury due to increased metabolic demand. Some recent studies suggest that acute symptomatic seizures (occurring within 7 days of stroke) are associated with worse functional outcome and increased risk of death despite accounting for other known prognostic factors such as age and baseline hemorrhage volume. However, the impact of seizures on prognosis is still debated and it remains unclear if treating or preventing seizures might lead to improved clinical outcome. Thus, the currently available scientific evidence does not support the routine use of antiseizure medication as primary prevention among patients with intracerebral hemorrhage. Only prospective adequately powered randomized-controlled trials will be able to answer whether seizure prophylaxis in the acute or longer term settings is beneficial or not in patients with intracerebral hemorrhage.
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http://dx.doi.org/10.1007/s00415-021-10439-3DOI Listing
February 2021

Attention deficit/hyperactivity disorder and epilepsy.

Curr Opin Neurol 2021 Apr;34(2):219-225

AP-HP, Hôpital Robert Debré, Service de Neurologie Pédiatrique.

Purpose Of Review: Attention deficit/hyperactivity disorder (ADHD) is a frequent comorbidity in patients with epilepsy and is associated with important psychosocial and academic consequences. Evidence are now available to guide diagnosis and treatment of patients with both ADHD and epilepsy.

Recent Findings: The prevalence of ADHD varies from 12 to 39% in patients with newly diagnosed epilepsy to 70% in drug-resistant epilepsy. The diagnosis of ADHD requires parent-validated and teacher-validated rating scales, based on the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV and DSM-V, to confirm the information in the rating scales by interviewing parents and to exclude other causes of symptoms. Treatment with methylphenidate is associated with clinically significant improvement of ADHD symptoms in 60-75% of patients. Recent data reinforce the hypothesis that ADHD medications do not increase risk of seizures, even in patients with epilepsy. Beyond pharmacological management, experts have recommended to include multidisciplinary involvement in transition clinics for patients with both comorbid ADHD and epilepsy.

Summary: Management of ADHD in patients with epilepsy requires implementation of evidence-based data in clinical practice both for diagnosis and treatment. Currently, there is no specific treatment of ADHD associated with epilepsy and its treatment is based on the usual treatments of ADHD, with reassuring data about their safety in epilepsy.
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http://dx.doi.org/10.1097/WCO.0000000000000903DOI Listing
April 2021

Is the mechanism of action of antiseizure drugs a key element in the choice of treatment?

Fundam Clin Pharmacol 2021 Jun 28;35(3):552-563. Epub 2020 Oct 28.

Department of Functional Neurology and Epileptology, Hospices Civils de Lyon and University of Lyon, Lyon, France.

About 25 antiseizure drugs are available for the treatment of patients with epilepsy. The choice of the most suited drug for a specific patient is primarily based on the results of the pivotal randomized clinical trials and on the patient's characteristics and comorbidities. Whether or not the mechanism of action of the antiseizure drugs should be also taken into account to better predict the patient's response to the treatment remains a matter of debate. Despite the apparent complexity and diversity of antiseizure drug mechanisms of action, the reality unfortunately remains that they are very close, in particular with regard to their relationship with the pathophysiology of epilepsy. With the only exception of the association between lamotrigine and sodium valproate, there are no clinical data that formally support a synergistic association between certain antiseizure drugs in terms of efficacy. However, anticipating risk of adverse events by limiting as far as possible the combination of drugs, which share the same mechanisms of action, is undoubtedly an important driver of daily therapeutic decisions.
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http://dx.doi.org/10.1111/fcp.12614DOI Listing
June 2021

Neural mechanisms resolving exploitation-exploration dilemmas in the medial prefrontal cortex.

Science 2020 08;369(6507)

Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.

Everyday life often requires arbitrating between pursuing an ongoing action plan by possibly adjusting it versus exploring a new action plan instead. Resolving this so-called exploitation-exploration dilemma involves the medial prefrontal cortex (mPFC). Using human intracranial electrophysiological recordings, we discovered that neural activity in the ventral mPFC infers and tracks the reliability of the ongoing plan to proactively encode upcoming action outcomes as either learning signals or potential triggers to explore new plans. By contrast, the dorsal mPFC exhibits neural responses to action outcomes, which results in either improving or abandoning the ongoing plan. Thus, the mPFC resolves the exploitation-exploration dilemma through a two-stage, predictive coding process: a proactive ventromedial stage that constructs the functional signification of upcoming action outcomes and a reactive dorsomedial stage that guides behavior in response to action outcomes.
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http://dx.doi.org/10.1126/science.abb0184DOI Listing
August 2020

Stereoelectroencephalography (SEEG) and epilepsy surgery in posttraumatic epilepsy: A multicenter retrospective study.

Epilepsy Behav 2020 11 21;112:107378. Epub 2020 Aug 21.

APHM, Timone Hospital, Epileptology Department, Marseille, France; Aix Marseille Univ, APHM, INSERM, INS, Inst Neurosci Syst, Timone Hospital, Epileptology Department, Marseille, France. Electronic address:

Purpose: Posttraumatic epilepsy (PTE) is a common cause of drug-resistant epilepsy, especially in young adults. Nevertheless, such patients are not common candidates for intracranial presurgical evaluation. We investigated the role of stereoelectroencephalography (SEEG) in defining epileptogenicity and surgical strategy in patients with PTE.

Methods: We analyzed ictal SEEG recordings from 18 patients. We determined the seizure onset zone (SOZ) by quantifying the epileptogenicity of the sampled structures, using the "epileptogenicity index" (EI). We also identified seizure onset patterns (SOPs) through visual and frequency analysis. Postsurgical outcome was assessed by Engel's classification.

Results: The SOZ in PTE was most often located in temporal lobes, followed by frontal lobes. The SOZ was network-organized in the majority of the cases. Half of the SOP did not contain fast discharges. Half of the recordings showed SOZ that were less extensive than the posttraumatic lesions seen on brain magnetic resonance imaging (MRI). All but one operated patient benefited from tailored cortectomy. Only 3 patients were contraindicated for surgical resection due to bilateral epileptogenicity. The overall surgical outcome was good in majority of patients (67% Engel I).

Conclusion: Despite the potential risk of bilateral or multifocal epilepsy, patients with PTE may benefit from presurgical assessment in well-selected cases. In this context, SEEG allows guidance of tailored resections adapted to the SOZ.
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http://dx.doi.org/10.1016/j.yebeh.2020.107378DOI Listing
November 2020

EEG in fitness to drive evaluations in people with epilepsy - Considerable variations across Europe.

Seizure 2020 Jul 30;79:56-60. Epub 2020 Apr 30.

Division of Clinical Neuroscience, National Centre for Epilepsy, Oslo University Hospital, Norway.

Purpose: Epilepsy patients consider driving issues to be one of their most serious concerns. Ideally, decisions regarding fitness to drive should be based upon thorough evaluations by specialists in epilepsy care. In 2009, an EU directive was published aiming to harmonize evaluation practices within European countries, but, despite these recommendations, whether all epileptologists use the same criteria is unclear. We therefore conducted this study to investigate routine practices on how epileptologists at European epilepsy centers evaluate fitness to drive.

Methods: A questionnaire was sent to 63 contact persons identified through the European Epi-Care and the E-pilepsy network. The questionnaire addressed how fitness-to-drive evaluations were conducted, the involvement of different professionals, the use and interpretation of EEG, and opinions on existing regulations and guidelines.

Results: The questionnaire was completed by 35 participants (56 % response rate). Results showed considerable variation regarding test routines and the emphasis placed on the occurrence and extent of epileptiform discharges revealed by EEG. 82 % of the responders agreed that there was a need for more research on how to better evaluate fitness-to-drive in people with epilepsy, and 89 % agreed that regulations on fitness to drive evaluations should be internationally coordinated.

Conclusion: Our survey showed considerable variations among European epileptologists regarding use of EEG and how findings of EEG pathology should be assessed in fitness-to-drive evaluations. There is a clear need for more research on this issue and international guidelines on how such evaluations should be carried out would be of value.
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http://dx.doi.org/10.1016/j.seizure.2020.04.013DOI Listing
July 2020

Identifying task-relevant spectral signatures of perceptual categorization in the human cortex.

Sci Rep 2020 05 12;10(1):7870. Epub 2020 May 12.

Computational Neuroscience Lab, Institute of Computer Science, University of Tartu, Tartu, Estonia.

Human brain has developed mechanisms to efficiently decode sensory information according to perceptual categories of high prevalence in the environment, such as faces, symbols, objects. Neural activity produced within localized brain networks has been associated with the process that integrates both sensory bottom-up and cognitive top-down information processing. Yet, how specifically the different types and components of neural responses reflect the local networks' selectivity for categorical information processing is still unknown. In this work we train Random Forest classification models to decode eight perceptual categories from broad spectrum of human intracranial signals (4-150 Hz, 100 subjects) obtained during a visual perception task. We then analyze which of the spectral features the algorithm deemed relevant to the perceptual decoding and gain the insights into which parts of the recorded activity are actually characteristic of the visual categorization process in the human brain. We show that network selectivity for a single or multiple categories in sensory and non-sensory cortices is related to specific patterns of power increases and decreases in both low (4-50 Hz) and high (50-150 Hz) frequency bands. By focusing on task-relevant neural activity and separating it into dissociated anatomical and spectrotemporal groups we uncover spectral signatures that characterize neural mechanisms of visual category perception in human brain that have not yet been reported in the literature.
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http://dx.doi.org/10.1038/s41598-020-64243-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217881PMC
May 2020

Transient hypoxemia induced by cortical electrical stimulation: A mapping study in 75 patients.

Neurology 2020 06 5;94(22):e2323-e2336. Epub 2020 May 5.

From the Departments of Functional Neurology and Epileptology (M.L., J.J., S.R.) and Functional Neurosurgery (M.G.), Hospices Civils de Lyon and University of Lyon, France; Department of Clinical Neurosciences (P.R.), Centre Hospitalo-Universitaire Vaudois, Lausanne, Switzerland; INSERM U1028/CNRS UMR 5292 (B.C., J.J., R.B., M.G., L.M., L.B., S.R.), Lyon's Neuroscience Research Center; Neurology Department (L.M.), University Hospital, Saint-Etienne; and Epilepsy Institute (L.B., S.R.), Lyon, France.

Objective: To identify which cortical regions are associated with direct electrical stimulation (DES)-induced alteration of breathing significant enough to impair pulse oximetry (SpO).

Methods: Evolution of SpO after 1,352 DES was analyzed in 75 patients with refractory focal epilepsy who underwent stereo-EEG recordings. For each DES, we assessed the change in SpO from 30 seconds prior to DES onset to 120 seconds following the end of the DES. The primary outcome was occurrence of stimulation-induced transient hypoxemia as defined by decrease of SpO ≥5% within 60 seconds after stimulation onset as compared to pre-DES SpO or SpO nadir <90% during at least 5 seconds. Localization of the stimulated contacts was defined according to MarsAtlas brain parcellation and Freesurfer segmentation.

Results: A stimulation-induced transient hypoxemia was observed after 16 DES (1.2%) in 10 patients (13%), including 6 in whom SpO nadir was <90%. Among these 16 DES, 7 (44%) were localized within the perisylvian cortex. After correction for individual effects and the varying number of DES contributed by each person, significant decrease of SpO was significantly associated with the localization of DES ( = 0.019).

Conclusion: Though rare, a significant decrease of SpO could be elicited by cortical direct electrical stimulation outside the temporo-limbic structures, most commonly after stimulation of the perisylvian cortex.
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http://dx.doi.org/10.1212/WNL.0000000000009497DOI Listing
June 2020

Four core properties of the human brain valuation system demonstrated in intracranial signals.

Nat Neurosci 2020 05 13;23(5):664-675. Epub 2020 Apr 13.

Motivation, Brain and Behavior Team, Institut du Cerveau, Paris, France.

Estimating the value of alternative options is a key process in decision-making. Human functional magnetic resonance imaging and monkey electrophysiology studies have identified brain regions, such as the ventromedial prefrontal cortex (vmPFC) and lateral orbitofrontal cortex (lOFC), composing a value system. In the present study, in an effort to bridge across species and techniques, we investigated the neural representation of value ratings in 36 people with epilepsy, using intracranial electroencephalography. We found that subjective value was positively reflected in both vmPFC and lOFC high-frequency activity, plus several other brain regions, including the hippocampus. We then demonstrated that subjective value could be decoded (1) in pre-stimulus activity, (2) for various categories of items, (3) even during a distractive task and (4) as both linear and quadratic signals (encoding both value and confidence). Thus, our findings specify key functional properties of neural value signals (anticipation, generality, automaticity, quadraticity), which might provide insights into human irrational choice behaviors.
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http://dx.doi.org/10.1038/s41593-020-0615-9DOI Listing
May 2020

Long-term outcomes in temporal lobe epilepsy with glutamate decarboxylase antibodies.

J Neurol 2020 Jul 28;267(7):2083-2089. Epub 2020 Mar 28.

French Reference Center on Paraneoplastic Neurological Syndromes, Hospices Civils de Lyon, Hôpital Neurologique, 69677, Bron, France.

Objective: To assess the long-term outcomes of patients with temporal lobe epilepsy and CSF anti-glutamate decarboxylase antibodies (GAD65-Abs).

Methods: We retrospectively analyzed the clinical records of 35 patients with temporal lobe epilepsy and CSF GAD65-Abs, collected from January 1993 to December 2016 and assessed cognitive impairment and seizure activity at last visit. Cognitive impairment was considered significant if impacting on daily life activities. Immunohistochemistry on rat brain slices and ELISA were used for antibody detection and titration.

Results: Median age was 30 years (range 2-63), 32/35 (91%) patients were female, and median follow-up was 68 months (range 7-232). At presentation, 20 patients had isolated temporal lobe epilepsy and 15 patients had other limbic symptoms, including anterograde amnesia (n = 10) and behavioral disturbances (n = 5). Progressive clinical deterioration over follow-up was reported in 28/35 patients (80%), including gradual increase of memory impairment (n = 25), and apparition of behavioral disturbances (n = 4) or mood disorders (n = 18). At last follow-up, 24/35 (69%) patients had cognitive disturbances with an impact on patient's daily life activities, and 28/35 (80%) still had active seizures.

Conclusion: Most patients with temporal lobe epilepsy and CSF GAD65-Abs develop a chronic disease with progressive cognitive impairment and refractory epilepsy regardless of the presence of additional limbic symptoms at onset.
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http://dx.doi.org/10.1007/s00415-020-09807-2DOI Listing
July 2020

Epileptogenicity in tuberous sclerosis complex: A stereoelectroencephalographic study.

Epilepsia 2020 01 20;61(1):81-95. Epub 2019 Dec 20.

National Institute of Health and Medical Research U1028/National Center for Scientific Research, Mixed Unit of Research 5292, Lyon Neuroscience Research Center, Lyon, France.

Objective: In tuberous sclerosis complex (TSC)-associated drug-resistant epilepsy, the optimal invasive electroencephalographic (EEG) and operative approach remains unclear. We examined the role of stereo-EEG in TSC and used stereo-EEG data to investigate tuber and surrounding cortex epileptogenicity.

Methods: We analyzed 18 patients with TSC who underwent stereo-EEG (seven adults). One hundred ten seizures were analyzed with the epileptogenicity index (EI). In 13 patients with adequate tuber sampling, five anatomical regions of interest (ROIs) were defined: dominant tuber (tuber with highest median EI), perituber cortex, secondary tuber (tuber with second highest median EI), nearby cortex (normal-appearing cortex in the same lobe as dominant tuber), and distant cortex (in other lobes). At the seizure level, epileptogenicity of ROIs was examined by comparing the highest EI recorded within each anatomical region. At the patient level, epileptogenic zone (EZ) organization was separated into focal tuber (EZ confined to dominant tuber) and complex (all other patterns).

Results: The most epileptogenic ROI was the dominant tuber, with higher EI than perituber cortex, secondary tuber, nearby cortex, and distant cortex (P < .001). A focal tuber EZ organization was identified in seven patients. This group had 80% Engel IA postsurgical outcome and distinct dominant tuber characteristics: continuous interictal discharges (IEDs; 100%), fluid-attenuated inversion recovery (FLAIR) hypointense center (86%), center-to-rim EI gradient, and stimulation-induced seizures (71%). In contrast, six patients had a complex EZ organization, characterized by nearby cortex as the most epileptogenic region and 40% Engel IA outcome. At the intratuber level, the combination of FLAIR hypointense center, continuous IEDs, and stimulation-induced seizures offered 98% specificity for a focal tuber EZ organization.

Significance: Tubers with focal EZ organization have a striking similarity to type II focal cortical dysplasia. The presence of distinct EZ organizations has significant implications for EZ hypothesis generation, invasive EEG approach, and resection strategy.
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http://dx.doi.org/10.1111/epi.16410DOI Listing
January 2020

Pain behavior without pain sensation: an epileptic syndrome of "symbolism for pain"?

Pain 2020 03;161(3):502-508

Central Integration of Pain (NeuroPain) Lab-Lyon Neuroscience Research Center, INSERM U1028, CNRS, UMR5292, Université Claude Bernard, Bron, France.

"Asymbolia for pain" has shown the potentiality of diseased insular networks to dissociate sensory from affective-behavioral dimensions of pain, resulting in the lack of appropriate motor and affective responses despite preserved sensory aspect of pain. Here, we describe 4 patients with an inverse phenomenon of asymbolia for pain, namely an isolated "symbolism for pain" triggered by epileptic seizures, characterized by pain behavior without declarative pain sensation despite fully preserved contact and vigilance. Stereoelectroencephalography demonstrated in each case focal seizure discharges within the posterior insulo-opercular cortex, with little or no propagation to other cortical structures, especially those considered to drive subjective pain experiences. The pain behavior might reflect seizure propagation from the insula to brain networks serving for behavioral responses associated with pain, including the cingulate motor region and possibly also the basal ganglia. We propose that the isolated symbolism for pain is a novel epileptic syndrome of dissociation between pain perception and behaviors associated with the insular nociceptive-related networks.
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http://dx.doi.org/10.1097/j.pain.0000000000001741DOI Listing
March 2020

Social cognition, behaviour and therapy adherence in frontal lobe epilepsy: a study combining neuroeconomic and neuropsychological methods.

R Soc Open Sci 2019 Aug 28;6(8):180850. Epub 2019 Aug 28.

Translational and Integrative Group in Epilepsy Research (TIGER), INSERM U1028, CNRS UMR5292, Lyon Neuroscience Research Center, University Lyon 1, Lyon, France.

Social behaviour of healthy humans and its neural correlates have been extensively studied in social neuroscience and neuroeconomics. Whereas it is well established that several types of epilepsies, such as frontal lobe epilepsy, lead to social cognitive impairments, experimental evidence on how these translate into behavioural symptoms is scarce. Furthermore, it is unclear whether social cognitive or behavioural disturbances have an impact on therapy adherence, which is critical for effective disease management, but generally low in these patients. In order to investigate the relationship between social cognition, social behaviour, and therapy adherence in patients with frontal lobe epilepsies (FLE), we designed a study combining conventional neuropsychological with behavioural economic and functional magnetic resonance imaging (fMRI) methodology. Fifteen patients and 15 healthy controls played a prisoners' dilemma game (an established game to operationalize social behaviour) while undergoing fMRI. Additionally, social cognitive, basic neuropsychological variables, and therapy adherence were assessed. Our results implicate that social behaviour is indeed affected and can be quantified using neuroeconomic methods in patients with FLE. Impaired social behaviour in these patients might be a consequence of altered brain activation in the medial prefrontal cortex and play a role in low therapy adherence. Finally, this study serves as an example of how to integrate neuroeconomic methods in neurology.
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http://dx.doi.org/10.1098/rsos.180850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731699PMC
August 2019

BLAST: A short computerized test to measure the ability to stay on task. Normative behavioral data and detailed cortical dynamics.

Neuropsychologia 2019 11 18;134:107151. Epub 2019 Sep 18.

INSERM, U1028, CNRS, UMR5292, Lyon Neuroscience Research Center, Lyon, France, France. Electronic address:

This article provides an exhaustive description of a new short computerized test to assess on a second-to-second basis the ability of individuals to « stay on task », that is, to apply selectively and repeatedly task-relevant cognitive processes. The task (Bron/Lyon Attention Stability Test, or BLAST) lasts around 1 min, and measures repeatedly the time to find a target letter in a two-by-two letter array, with an update of all letters every new trial across thirty trials. Several innovative psychometric measures of attention stability are proposed based on the instantaneous fluctuations of reaction times throughout the task, and normative data stratified over a wide range of age are provided by a large (>6000) dataset of participants aged 8 to 70. We also detail the large-scale brain dynamics supporting the task from an in-depth study of 32 participants with direct electrophysiological cortical recordings (intracranial EEG) to prove that BLAST involves critically large-scale executive attention networks, with a marked activation of the dorsal attention network and a deactivation of the default-mode network. Accordingly, we show that BLAST performance correlates with scores established by ADHD-questionnaires.
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http://dx.doi.org/10.1016/j.neuropsychologia.2019.107151DOI Listing
November 2019

Seizure specificities in patients with antibody-mediated autoimmune encephalitis.

Epilepsia 2019 08 8;60(8):1508-1525. Epub 2019 Jul 8.

French Reference Center for Paraneoplastic Neurological Syndromes, Hospital for Neurology and Neurosurgery Pierre Wertheimer, Lyon University Hospital, Lyon, France.

Accumulating data on patients with autoimmune encephalitis have shed light on specificities concerning clinical presentation and outcomes, which are dependent on the antigen targeted by the autoantibodies found in the patients' cerebrospinal fluid or sera. Such specificities include seizure-related clinical manifestations as well as the responsiveness to antiepileptic drugs. Although increased enthusiasm accompanies the discovery of novel antibodies and their associated clinical syndromes, several issues remain unsettled. First, it appears that therapy needs to be personalized in the view of the severity of each antibody-mediated syndrome, patient-related characteristics, and timing of treatment. Second, the lack of randomized controlled trials is a major drawback in the formulation of an appropriate immunotherapeutic strategy. In this review, we discuss the novel developments and challenges for the diagnosis and treatment of epilepsy in patients with well-characterized autoimmune encephalitis, and delineate the principles for a rational approach toward precision medicine in this emerging field.
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http://dx.doi.org/10.1111/epi.16282DOI Listing
August 2019

Postictal stereo-EEG changes following bilateral tonic-clonic seizures.

Epilepsia 2019 08 2;60(8):1743-1745. Epub 2019 Jul 2.

Inserm, INS, Institut de Neurosciences des Systèmes, Aix Marseille Univ, Marseille, France.

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http://dx.doi.org/10.1111/epi.16252DOI Listing
August 2019

Predictive factors of renal involvement in cryoglobulinaemia: a retrospective study of 153 patients.

Clin Kidney J 2019 Jun 9;12(3):365-372. Epub 2018 Nov 9.

Department of Nephrology, Université Claude Bernard Lyon 1, Centre Hospitalier Lyon Sud, Pierre-Bénite, France.

Background: The course of cryoglobulinaemia varies widely, from asymptomatic patients to severe vasculitis syndrome. Renal involvement (RI) is the major prognostic factor, and frequently occurs several years after diagnosis. However, predictive factors for RI are not well known. The aim of our study was to identify RI predictive factors during cryoglobulinaemia.

Methods: We retrospectively reviewed the clinical charts of a consecutive series of 153 patients positive for cryoglobulinaemia in the University Hospital of Lyon (France). RI was defined either histologically or biologically if cryoglobulinaemia was the only possible cause of nephropathy.

Results: Among the 153 positive patients (mean age 55 years, 37% male), cryoglobulinaemia was associated with RI in 45 (29%) patients. Sixty-five percent of patients had Type II cryoglobulinaemia, 28% had Type III and 7% had Type I. Autoimmune diseases were the most common aetiology (48%), followed by infectious diseases (18%) and lymphoproliferative disorders (13%). Membranoproliferative glomerulonephritis was the main histological pattern (93% of the 14 histological analyses). A multivariable logistic regression showed that Type II cryoglobulinaemia, a high serum cryoglobulin concentration, the presence of an IgG kappa monoclonal component and diabetes were independently associated with the risk for developing RI.

Conclusion: We identified several factors predictive of RI in patients with cryoglobulinaemia, which were different from the diagnostic criteria for cryoglobulinaemic vasculitis. This could suggest a specific pathophysiology for RI. We suggest performing an extensive renal monitoring and ensure nephroprotection when a diagnosis of cryoglobulinaemia is made in patients with these predictive factors.
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http://dx.doi.org/10.1093/ckj/sfy096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543974PMC
June 2019

Eslicarbazepine acetate in epilepsy patients with psychiatric comorbidities and intellectual disability: Clinical practice findings from the Euro-Esli study.

J Neurol Sci 2019 Jul 2;402:88-99. Epub 2019 May 2.

Hospital Universitario y Politécnico La Fe, Valencia, Spain.

Psychiatric and intellectual comorbidities are common in patients with epilepsy. However, data on the use of antiepileptic drugs in these patients are still lacking. This study assessed the real-world effectiveness and safety/tolerability of eslicarbazepine acetate (ESL) in patients with intellectual disability and psychiatric comorbidities, including a separate analysis specifically in those with depression, using data from the Euro-Esli study. Effectiveness measures included responder and seizure freedom rates. Safety and tolerability were assessed by evaluating adverse events (AEs) and ESL discontinuation due to AEs, respectively. Of the 2058 patients initially included in the Euro-Esli study, 952 patients had intellectual disability data available, 1138 had psychiatric comorbidity data available and 1134 had depression data available. Of those who had intellectual or psychiatric comorbidity data available, 11.3% (108/952) suffered from intellectual disability, 24.9% (283/1138) had a psychiatric disorder, including depression, and 12.4% (141/1134) specifically had depression. Responder and seizure freedom rates were generally comparable between patients with psychiatric comorbidity and those without, and patients with depression and those without. However, responder and seizure freedom rates were significantly lower in patients with intellectual disability compared with those without. Overall, patients with psychiatric and intellectual comorbidities experienced more AEs and AEs leading to ESL discontinuation than patients without these comorbidities. The incidence of psychiatric AEs was not significantly different for patients with psychiatric comorbidities or depression than those without, and the incidence of cognitive AEs was not significantly different for patients with intellectual disability than those without. These findings suggest that ESL is effective in patients with psychiatric and intellectual comorbidities and that its use in these patients is unlikely to exacerbate existing psychiatric or cognitive disturbances.
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http://dx.doi.org/10.1016/j.jns.2019.04.040DOI Listing
July 2019

How the insula speaks to the heart: Cardiac responses to insular stimulation in humans.

Hum Brain Mapp 2019 06 28;40(9):2611-2622. Epub 2019 Feb 28.

NeuroPain Lab, Lyon Neuroscience Research Centre, CRNL - INSERM U 1028/CNRS UMR 5292, University of Lyon, Lyon, France.

Despite numerous studies suggesting the role of insular cortex in the control of autonomic activity, the exact location of cardiac motor regions remains controversial. We provide here a functional mapping of autonomic cardiac responses to intracortical stimulations of the human insula. The cardiac effects of 100 insular electrical stimulations into 47 epileptic patients were divided into tachycardia, bradycardia, and no cardiac response according to the magnitude of RR interval (RRI) reactivity. Sympathetic (low frequency, LF, and low to high frequency powers ratio, LF/HF ratio) and parasympathetic (high frequency power, HF) reactivity were studied using RRI analysis. Bradycardia was induced by 26 stimulations (26%) and tachycardia by 21 stimulations (21%). Right and left insular stimulations induced as often a bradycardia as a tachycardia. Tachycardia was accompanied by an increase in LF/HF ratio, suggesting an increase in sympathetic tone; while bradycardia seemed accompanied by an increase of parasympathetic tone reflected by an increase in HF. There was some left/right asymmetry in insular subregions where increased or decreased heart rates were produced after stimulation. However, spatial distribution of tachycardia responses predominated in the posterior insula, whereas bradycardia sites were more anterior in the median part of the insula. These findings seemed to indicate a posterior predominance of sympathetic control in the insula, whichever the side; whereas the parasympathetic control seemed more anterior. Dysfunction of these regions should be considered when modifications of cardiac activity occur during epileptic seizures and in cardiovascular diseases.
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http://dx.doi.org/10.1002/hbm.24548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865697PMC
June 2019

Letter to the Editor. Temporal lobe epilepsy: open or stereotactic surgery?

J Neurosurg 2019 02;131(3):989

1Hospital Pierre Wertheimer, Hospices Civils de Lyon, Lyon, France.

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http://dx.doi.org/10.3171/2018.11.JNS183107DOI Listing
February 2019

Surgical techniques: Stereoelectroencephalography-guided radiofrequency-thermocoagulation (SEEG-guided RF-TC).

Seizure 2020 Apr 25;77:64-68. Epub 2019 Jan 25.

Department of Neurosurgery, Neurology & Neurosurgery Hospital Pierre Wertheimer, Hospices Civils de Lyon, France; University of Lyon, Faculty of medicine Claude Bernard, Lyon, France; NEUROPAIN team, Lyon Neuroscience Research Center, INSERM U1028, CNRS, 5292, Lyon, France.

Stereoelectroencephalography-guided radiofrequency-thermocoagulation (SEEG-guided RF-TC) consists of coupling SEEG investigation with RF-TC stereotactic lesioning directly through the recording electrodes. In this systematic review the surgical technique, indications, and outcomes are described. Maximum accuracy is reached when a frame-based procedure with a robotic assistance and a per-operative vascular X-ray imaging are performed. Monitoring of the lesioning procedure based on the impedance, a sharp modification of which indicates that the thermocoagulation has reached its maximum volume, allows the optimization of the lesion size. The first indication concerns patients in whom a SEEG is required to determine whether surgery is feasible and in whom resection is indeed possible. Even if surgery is performed owing to insufficient efficacy of SEEG-guided RF-TC, the procedure remains interesting owing to its high positive predictive value for good outcome after surgery. The second indication concerns patients in whom phase I non-invasive investigations have concluded to surgical contraindication and who may still undergo SEEG in a purely therapeutic perspective (small deep zones inaccessible to surgery and network nodes of large epileptic networks). Lastly, SEEG-guided RF-TC can be considered as a first-line treatment for periventricular nodular heterotopia (PNH). Independently of indication, the overall seizure-free rate is 23% and the responder rate is 58%. The best results are obtained for PNH (38% seizure-free and 81% responders), while the worst results have been reported for temporal lobe-epilepsy in a dedicated study. The overall complication rate is 2.5%. More evidence is needed to help determine the exact place of SEEG-guided RF-TC in the surgical management algorithm.
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http://dx.doi.org/10.1016/j.seizure.2019.01.021DOI Listing
April 2020

Risks and predictive biomarkers of sudden unexpected death in epilepsy patient.

Curr Opin Neurol 2019 04;32(2):205-212

NINDS Center for SUDEP Research and Texas Comprehensive Epilepsy Center, University of Texas Houston Health Sciences Center, Houston, Texas, USA.

Purpose Of Review: The current review updates our knowledge regarding sudden unexpected death in epilepsy patient (SUDEP) risks, risk factors, and investigations of putative biomarkers based on suspected mechanisms of SUDEP.

Recent Findings: The overall incidence of SUDEP in adults with epilepsy is 1.2/1000 patient-years, with surprisingly comparable figures in children in recently published population-based studies. This risk was found to decrease over time in several cohorts at a rate of -7% per year, for unknown reasons. Well established risk factors include frequency of generalized tonic-clonic seizures, while adding antiepileptic treatment, nocturnal supervision and use of nocturnal listening device appear to be protective. In contrast, recent data failed to demonstrate the predictive value of heart rate variability, periictal cardiorespiratory dysfunction, and postictal generalized electroencephalography suppression. Preliminary findings suggest that brainstem and thalamic atrophy may be associated with a higher risk of SUDEP. Novel experimental and human data support the primary role of generalized tonic-clonic seizure-triggered respiratory dysfunction and the likely contribution of altered brainstem serotoninergic neurotransmission, in SUDEP pathophysiology.

Summary: Although significant progress has been made during the past year in the understanding of SUDEP mechanisms and investigation of numerous potential biomarkers, we are still missing reliable predictors of SUDEP beyond the well established clinical risk factors.
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http://dx.doi.org/10.1097/WCO.0000000000000668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779136PMC
April 2019