Clinical and molecular characterization of patients with YWHAG-related epilepsy.

OBJECTIVE: YWHAG variant alleles have been associated with a rare disease trait whose clinical synopsis includes an early onset epileptic encephalopathy with predominantly myoclonic seizures, developmental delay/intellectual disability, and facial dysmorphisms. Through description of a large cohort, which doubles the number of reported patients, we further delineate the spectrum of YWHAG-related epilepsy. METHODS: We included in this study 24 patients, 21 new and three previously described, with pathogenic/likely pathogenic variants in YWHAG. We extended the analysis of clinical, electroencephalographic, brain magnetic resonance imaging, and molecular genetic information to 24 previously published patients. RESULTS: The phenotypic spectrum of YWHAG-related disorders ranges from mild developmental delay to developmental and epileptic encephalopathy (DEE). Epilepsy onset is in the first 2 years of life. Seizure freedom can be achieved in half of the patients (13/24, 54%). Intellectual disability (23/24, 96%), behavioral disorders (18/24, 75%), neurological signs (13/24, 54%), and dysmorphisms (6/24, 25%) are common. A genotype-phenotype correlation emerged, as DEE is more represented in patients with missense variants located in the ligand-binding domain than in those with truncating or missense variants in other domains (90% vs. 19%, p < .001). SIGNIFICANCE: This study suggests that pathogenic YWHAG variants cause a wide range of clinical presentations with variable severity, ranging from mild developmental delay to DEE. In this allelic series, a genotype-phenotype correlation begins to emerge, potentially providing prognostic information for clinical management and genetic counseling.

Locked-in syndrome after central pontine myelinolysis, an outstanding outcome of two patients.

OBJECTIVE: Central pontine myelinolysis (CPM) is a rare demyelinating disease that affects the pons and which can cause extreme disabilities such as locked-in syndrome (LIS) in the initial phase. The aim of the study was to describe the evolution over a 12-month period of two patients with CPM causing an initial LIS. METHOD: We retrospectively report the unexpected clinical outcome of these two patients in relation with the anatomical damages documented by brain MRI, associated with diffusion tensor imaging and reconstruction of corticospinal tracts in tractography. The following clinical parameters systematically assessed at 3, 6, 9, and 12 months: muscle testing on 12 key muscles (Medical Research Council), prehension metrics (box and block test and purdue pegboard), and independence for acts of daily living (functional independence measure). RESULTS: Both patients showed a progressive recovery beginning between 2 and 3 months after the onset of symptoms, leading to almost complete autonomy at 12 months (FIM > 110), with motor strength greater than 4/5 in all joint segments (MRC > 50/60). On brain MRI with tractography, CST appeared partially preserved at pons level. INTERPRETATION: The possibility of a near-complete functional recovery at 12 months is important to consider given the ethical issues at stake and the discussions about limiting care that may take place initially. It seems to be the consequence of reversible myelin damage combined with partially preserved neurons. Development of collateral pathways or resolution of conduction block may explain this recovery. MRI comprising DTI and tractography could play a key role in the prognosis of motor recovery.

GABAergic inhibition shapes behavior and neural dynamics in human visual working memory.

Neuronal inhibition, primarily mediated by GABAergic neurotransmission, is crucial for brain development and healthy cognition. Gamma-aminobutyric acid concentration levels in sensory areas have been shown to correlate with hemodynamic and oscillatory neuronal responses. How these measures relate to one another during working memory, a higher-order cognitive process, is still poorly understood. We address this gap by collecting magnetoencephalography, functional magnetic resonance imaging, and Flumazenil positron emission tomography data within the same subject cohort using an n-back working-memory paradigm. By probing the relationship between GABAA receptor distribution, neural oscillations, and Blood Oxygen Level Dependent (BOLD) modulations, we found that GABAA receptor density in higher-order cortical areas predicted the reaction times on the working-memory task and correlated positively with the peak frequency of gamma power modulations and negatively with BOLD amplitude. These findings support and extend theories linking gamma oscillations and hemodynamic responses to gamma-aminobutyric acid neurotransmission and to the excitation-inhibition balance and cognitive performance in humans. Considering the small sample size of the study, future studies should test whether these findings also hold for other, larger cohorts as well as to examine in detail how the GABAergic system and neural fluctuations jointly support working-memory task performance.

Interrater reliability in neurology objective structured clinical examination across specialties.

PURPOSE: To assess interrater reliability and examiners' characteristics, especially specialty, associated with scoring of neurology objective structured clinical examination (OSCE). MATERIAL AND METHODS: During a neurology mock OSCE, five randomly chosen students volunteers were filmed while performing 1 of the 5 stations. Video recordings were scored by physicians from the Lyon and Clermont-Ferrand university teaching hospitals to assess students performance using both a checklist scoring and a global rating scale. Interrater reliability between examiners were assessed using intraclass coefficient correlation. Multivariable linear regression models including video recording as random effect dependent variable were performed to detect factors associated with scoring. RESULTS: Thirty examiners including 15 (50%) neurologists participated. The intraclass correlation coefficient of checklist scores and global ratings between examiners were 0.71 (CI95% [0.45-0.95]) and 0.54 (CI95% [0.28-0.91]), respectively. In multivariable analyses, no factor was associated with checklist scores, while male gender of examiner was associated with lower global rating (ß coefficient = -0.37; CI 95% [-0.62-0.11]). CONCLUSIONS: Our study demonstrated through a video-based scoring method that agreement among examiners was good using checklist scoring while moderate using global rating scale in neurology OSCE. Examiner's specialty did not affect scoring whereas gender was associated with global rating scale.

Helium Optically Pumped Magnetometers Can Detect Epileptic Abnormalities as Well as SQUIDs as Shown by Intracerebral Recordings.

Magnetoencephalography based on superconducting quantum interference devices (SQUIDs) has been shown to improve the diagnosis and surgical treatment decision for presurgical evaluation of drug-resistant epilepsy. Still, its use remains limited because of several constraints such as cost, fixed helmet size, and the obligation of immobility. A new generation of sensors, optically pumped magnetometers (OPMs), could overcome these limitations. In this study, we validate the ability of helium-based OPM (4He-OPM) sensors to record epileptic brain activity thanks to simultaneous recordings with intracerebral EEG [stereotactic EEG (SEEG)]. We recorded simultaneous SQUIDs-SEEG and 4He-OPM-SEEG signals in one patient during two sessions. We show that epileptic activities on intracerebral EEG can be recorded by OPMs with a better signal-to noise ratio than classical SQUIDs. The OPM sensors open new venues for the widespread application of magnetoencephalography in the management of epilepsy and other neurologic diseases and fundamental neuroscience.

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.

A New Generation of OPM for High Dynamic and Large Bandwidth MEG: The 4He OPMs-First Applications in Healthy Volunteers.

MagnetoEncephaloGraphy (MEG) provides a measure of electrical activity in the brain at a millisecond time scale. From these signals, one can non-invasively derive the dynamics of brain activity. Conventional MEG systems (SQUID-MEG) use very low temperatures to achieve the necessary sensitivity. This leads to severe experimental and economical limitations. A new generation of MEG sensors is emerging: the optically pumped magnetometers (OPM). In OPM, an atomic gas enclosed in a glass cell is traversed by a laser beam whose modulation depends on the local magnetic field. MAG4Health is developing OPMs using Helium gas (4He-OPM). They operate at room temperature with a large dynamic range and a large frequency bandwidth and output natively a 3D vectorial measure of the magnetic field. In this study, five 4He-OPMs were compared to a classical SQUID-MEG system in a group of 18 volunteers to evaluate their experimental performances. Considering that the 4He-OPMs operate at real room temperature and can be placed directly on the head, our assumption was that 4He-OPMs would provide a reliable recording of physiological magnetic brain activity. Indeed, the results showed that the 4He-OPMs showed very similar results to the classical SQUID-MEG system by taking advantage of a shorter distance to the brain, despite having a lower sensitivity.

Etiology matters for neuroprognostication: A multimodal electrophysiological investigation in a case of Bickerstaff's brainstem encephalitis.

We report the case of a 19-year-old patient with an acute-onset non-traumatic coma. Brain MRI scan was normal, CSF showed mild pleocytosis and moderately elevated protein, and continuous EEG-monitoring was compatible with spindle-coma. Cortical somatosensory evoked potentials (SSEPs) and middle-latency auditory evoked potentials (MLAEPs) were bilaterally absent, and brainstem auditory evoked potentials suggested a brainstem dysfunction. Serum anti-GQ1b and anti-GT1a IgG antibodies positivity suggested Bickerstaff's brainstem encephalitis (BBE). The clinical and functional outcomes were favorable and normal cortical SSEPs/MLAEPs reappeared in a few weeks. Based on this report, in cases of unexplained MRI-negative coma with neurophysiological evidence of brainstem dysfunction, BBE should be eliminated before considering withdrawal of life-sustaining therapy (WLST).

Epileptic spasms are associated with increased stereo-electroencephalography derived functional connectivity in tuberous sclerosis complex.

OBJECTIVE: Epileptic spasms (ES) are common in tuberous sclerosis complex (TSC). However, the underlying network alterations and relationship with epileptogenic tubers are poorly understood. We examined interictal functional connectivity (FC) using stereo-electroencephalography (SEEG) in patients with TSC to investigate the relationship between tubers, epileptogenicity, and ES. METHODS: We analyzed 18 patients with TSC who underwent SEEG (mean age = 11.5 years). The dominant tuber (DT) was defined as the most epileptogenic tuber using the epileptogenicity index. Epileptogenic zone (EZ) organization was quantitatively separated into focal (isolated DT) and complex (all other patterns). Using a 20-min interictal recording, FC was estimated with nonlinear regression, h2 . We calculated (1) intrazone FC within all sampled tubers and normal-appearing cortical zones, respectively; and (2) interzone FC involving connections between DT, other tubers, and normal cortex. The relationship between FC and (1) presence of ES as a current seizure type at the time of SEEG, (2) EZ organization, and (3) epileptogenicity was analyzed using a mixed generalized linear model. Spike rate and distance between zones were considered in the model as covariates. RESULTS: Six patients had ES as a current seizure type at time of SEEG. ES patients had a greater number of tubers with a fluid-attenuated inversion recovery hypointense center (p < .001), and none had TSC1 mutations. The presence of ES was independently associated with increased FC within both intrazone (p = .033) and interzone (p = .011) networks. Post hoc analyses identified that increased FC was associated with ES across tuber and nontuber networks. EZ organization and epileptogenicity biomarkers were not associated with FC. SIGNIFICANCE: Increased cortical synchrony among both tuber and nontuber networks is characteristic of patients with ES and independent of both EZ organization and tuber epileptogenicity. This further supports the prospect of FC biomarkers aiding treatment paradigms in TSC.

Peri-ictal hypoxemia during temporal lobe seizures: A SEEG study.

Focal seizures originating from the temporal lobe are commonly associated with peri-ictal hypoxemia (PIH). During the course of temporal lobe seizures, epileptic discharges often not only spread within various parts of the temporal lobe but also possibly insula and frontal lobe. The link between spatial propagation of the seizure discharges and PIH is still unclear. The present study investigates the involvement of several brain structures including medial temporal structures, temporal pole, anterior insula, and frontal cortex in the occurrence of PIH. Using quantitative indices obtained during SEEG (stereoencephalography) recordings in 38 patients, we evaluated the epileptogenicity, the spatial propagation, and functional connectivity between those structures during seizures leading to PIH. Multivariate statistical analyses of SEEG quantitative indices showed that temporal lobe seizures leading to PIH are characterized by a strong involvement of amygdala and anterior insula during seizure propagation and a more widespread involvement of medial temporal lobe structures, lateral temporal lobe, temporal pole, and anterior cingulate at the end of the seizures. On the contrary, seizure-onset zone was not associated with PIH occurrence. During seizure propagation, anterior insula, temporal pole, and temporal lateral neocortex activities were correlated with intensity of PIH. Lastly, PIH occurrence was also related to a widespread increase of synchrony between those structures. Those results suggest that PIH occurrence during temporal lobe seizures may be related to the activation of a widespread network of cortical structures, among which amygdala and anterior insula are key nodes.

Predictors of functional outcome after spinal cord surgery: Relevance of intraoperative neurophysiological monitoring combined with preoperative neurophysiological and MRI assessments.

OBJECTIVES: To assess the accuracy of intraoperative neurophysiological monitoring (IONM) in predicting immediate and 3-month postoperative neurological new deficit (or deterioration) in patients benefiting from spinal cord (SC) surgery; and to identify factors associated with a higher risk of postoperative clinical worsening. METHODS: Consecutive patients who underwent SC surgery with IONM were included. Pre and postoperative clinical (modified McCormick scale), radiological (lesion-occupying area ratio), and electrophysiological features were collected. RESULTS: A total of 99 patients were included: 14 (14.1%) underwent extradural surgery, 50 (50.5%) intradural extramedullary surgery, and 35 (35.4%) intramedullary surgery. Cumulatively, multimodal IONM (motor and somatosensory evoked potentials, D-wave whenever possible) significantly predicted postoperative deficits (p<0.001), with a sensitivity, specificity, positive predictive value, and negative predictive value of 0.81, 0.93, 0.83, and 0.92, respectively. Sixty (60.6%) patients displayed no IONM change, whereas 39 (39.4%) displayed IONM worsening. In multivariate analysis, predictors for postoperative clinical worsening were: abnormal preoperative electrophysiological assessment (p=0.03), intramedullary tumor (p<0.001), lesion-occupying area ratio ≥0.7 (p<0.001), and IONM alterations (p<0.001). Three months after the surgical procedure, in patients presenting at least one of the risk factors described above, 45/81 (55.6%) and 19/81 (23.5%) were clinically and electrophysiologically improved, respectively; while 13/81 (16.0%) and 10/81 (12.3%) were clinically and electrophysiologically worsened. CONCLUSION: Multimodal IONM is an essential tool to guide SC surgery, and enables the accurate prediction of postoperative neurological outcome. Specific attention should be given to patients presenting with preoperative electrophysiological abnormalities, large tumor volume, and intramedullary tumor location.

CERMEP-IDB-MRXFDG: a database of 37 normal adult human brain [18F]FDG PET, T1 and FLAIR MRI, and CT images available for research.

We present a database of cerebral PET FDG and anatomical MRI for 37 normal adult human subjects (CERMEP-IDB-MRXFDG). Thirty-nine participants underwent static [18F]FDG PET/CT and MRI, resulting in [18F]FDG PET, T1 MPRAGE MRI, FLAIR MRI, and CT images. Two participants were excluded after visual quality control. We describe the acquisition parameters, the image processing pipeline and provide participants' individual demographics (mean age 38 ± 11.5 years, range 23-65, 20 women). Volumetric analysis of the 37 T1 MRIs showed results in line with the literature. A leave-one-out assessment of the 37 FDG images using Statistical Parametric Mapping (SPM) yielded a low number of false positives after exclusion of artefacts. The database is stored in three different formats, following the BIDS common specification: (1) DICOM (data not processed), (2) NIFTI (multimodal images coregistered to PET subject space), (3) NIFTI normalized (images normalized to MNI space). Bona fide researchers can request access to the database via a short form.

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

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 (SpO2 ) 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 SpO2 < 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.

Semi-automatic Extraction of Functional Dynamic Networks Describing Patient's Epileptic Seizures.

Intracranial electroencephalography (EEG) studies using stereotactic EEG (SEEG) have shown that during seizures, epileptic activity spreads across several anatomical regions from the seizure onset zone toward remote brain areas. A full and objective characterization of this patient-specific time-varying network is crucial for optimal surgical treatment. Functional connectivity (FC) analysis of SEEG signals recorded during seizures enables to describe the statistical relations between all pairs of recorded signals. However, extracting meaningful information from those large datasets is time consuming and requires high expertise. In the present study, we first propose a novel method named Brain-wide Time-varying Network Decomposition (BTND) to characterize the dynamic epileptogenic networks activated during seizures in individual patients recorded with SEEG electrodes. The method provides a number of pathological FC subgraphs with their temporal course of activation. The method can be applied to several seizures of the patient to extract reproducible subgraphs. Second, we compare the activated subgraphs obtained by the BTND method with visual interpretation of SEEG signals recorded in 27 seizures from nine different patients. As a whole, we found that activated subgraphs corresponded to brain regions involved during the course of the seizures and their time course was highly consistent with classical visual interpretation. We believe that the proposed method can complement the visual analysis of SEEG signals recorded during seizures by highlighting and characterizing the most significant parts of epileptic networks with their activation dynamics.

Defining the phenotype of FHF1 developmental and epileptic encephalopathy.

Fibroblast growth-factor homologous factor (FHF1) gene variants have recently been associated with developmental and epileptic encephalopathy (DEE). FHF1 encodes a cytosolic protein that modulates neuronal sodium channel gating. We aim to refine the electroclinical phenotypic spectrum of patients with pathogenic FHF1 variants. We retrospectively collected clinical, genetic, neurophysiologic, and neuroimaging data of 17 patients with FHF1-DEE. Sixteen patients had recurrent heterozygous FHF1 missense variants: 14 had the recurrent p.Arg114His variant and two had a novel likely pathogenic variant p.Gly112Ser. The p.Arg114His variant is associated with an earlier onset and more severe phenotype. One patient carried a chromosomal microduplication involving FHF1. Twelve patients carried a de novo variant, five (29.5%) inherited from parents with gonadic or somatic mosaicism. Seizure onset was between 1 day and 41 months; in 76.5% it was within 30 days. Tonic seizures were the most frequent seizure type. Twelve patients (70.6%) had drug-resistant epilepsy, 14 (82.3%) intellectual disability, and 11 (64.7%) behavioral disturbances. Brain magnetic resonance imaging (MRI) showed mild cerebral and/or cerebellar atrophy in nine patients (52.9%). Overall, our findings expand and refine the clinical, EEG, and imaging phenotype of patients with FHF1-DEE, which is characterized by early onset epilepsy with tonic seizures, associated with moderate to severe ID and psychiatric features.

Recognition of musical emotions and their perceived intensity after unilateral brain damage.

For the hemispheric laterality of emotion processing in the brain, two competing hypotheses are currently still debated. The first hypothesis suggests a greater involvement of the right hemisphere in emotion perception whereas the second hypothesis suggests different involvements of each hemisphere as a function of the valence of the emotion. These hypotheses are based on findings for facial and prosodic emotion perception. Investigating emotion perception for other stimuli, such as music, should provide further insight and potentially help to disentangle between these two hypotheses. The present study investigated musical emotion perception in patients with unilateral right brain damage (RBD, n = 16) or left brain damage (LBD, n = 16), as well as in matched healthy comparison participants (n = 28). The experimental task required explicit recognition of musical emotions as well as ratings on the perceived intensity of the emotion. Compared to matched comparison participants, musical emotion recognition was impaired only in LBD participants, suggesting a potential specificity of the left hemisphere for explicit emotion recognition in musical material. In contrast, intensity ratings of musical emotions revealed that RBD patients underestimated the intensity of negative emotions compared to positive emotions, while LBD patients and comparisons did not show this pattern. To control for a potential generalized emotion deficit for other types of stimuli, we also tested facial emotion recognition in the same patients and their matched healthy comparisons. This revealed that emotion recognition after brain damage might depend on the stimulus category or modality used. These results are in line with the hypothesis of a deficit of emotion perception depending on lesion laterality and valence in brain-damaged participants. The present findings provide critical information to disentangle the currently debated competing hypotheses and thus allow for a better characterization of the involvement of each hemisphere for explicit emotion recognition and their perceived intensity.

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

OBJECTIVE: To identify which cortical regions are associated with direct electrical stimulation (DES)-induced alteration of breathing significant enough to impair pulse oximetry (SpO2). METHODS: Evolution of SpO2 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 SpO2 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 SpO2 ≥5% within 60 seconds after stimulation onset as compared to pre-DES SpO2 or SpO2 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 SpO2 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 SpO2 was significantly associated with the localization of DES (p = 0.019). CONCLUSION: Though rare, a significant decrease of SpO2 could be elicited by cortical direct electrical stimulation outside the temporo-limbic structures, most commonly after stimulation of the perisylvian cortex.

Epileptogenicity in tuberous sclerosis complex: A stereoelectroencephalographic study.

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.

Regularized siamese neural network for unsupervised outlier detection on brain multiparametric magnetic resonance imaging: Application to epilepsy lesion screening.

In this study, we propose a novel anomaly detection model targeting subtle brain lesions in multiparametric MRI. To compensate for the lack of annotated data adequately sampling the heterogeneity of such pathologies, we cast this problem as an outlier detection problem and introduce a novel configuration of unsupervised deep siamese networks to learn normal brain representations using a series of non-pathological brain scans. The proposed siamese network, composed of stacked convolutional autoencoders as subnetworks is designed to map patches extracted from healthy control scans only and centered at the same spatial localization to 'close' representations with respect to the chosen metric in a latent space. It is based on a novel loss function combining a similarity term and a regularization term compensating for the lack of dissimilar pairs. These latent representations are then fed into oc-SVM models at voxel-level to produce anomaly score maps. We evaluate the performance of our brain anomaly detection model to detect subtle epilepsy lesions in multiparametric (T1-weighted, FLAIR) MRI exams considered as normal (MRI-negative). Our detection model trained on 75 healthy subjects and validated on 21 epilepsy patients (with 18 MRI-negatives) achieves a maximum sensitivity of 61% on the MRI-negative lesions, identified among the 5 most suspicious detections on average. It is shown to outperform detection models based on the same architecture but with stacked convolutional or Wasserstein autoencoders as unsupervised feature extraction mechanisms.

BLAST paradigm: A new test to assess brief attentional fluctuations in children with epilepsy, ADHD, and normally developing children.

BACKGROUND: Pure attentional deficits are still underdiagnosed in children with epilepsy. While attention-deficit hyperactivity disorder (ADHD) is historically the most studied cause of attentional disorders, an important number of children with epilepsy and attentional complaints do not fully meet the DSM-V (Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition) criteria for ADHD and may be excluded from specific care. Clinical tools currently available are insufficient to detect more subtle but clinically relevant attentional fluctuations. OBJECTIVE/METHODS: The recently developed Bron-Lyon Attention Stability Test (BLAST) was used to evaluate brief attentional fluctuations with a high temporal precision. Drawing on two new attentional indices, we evaluated spontaneous fluctuations of response accuracy and timing, underlying attentional stability. The main objective was to assess attentional stability in children with i) epilepsy with comorbid ADHD, ii) epilepsy without comorbid ADHD, iii) ADHD not medicated and without epilepsy, and iv) normal development. Further objectives were to assess the main determinants of attentional stability in those groups, including the effect of factors related to the epileptic condition. RESULTS: In 122 children with epilepsy (67 with comorbid ADHD), 52 children with ADHD, and 53 healthy controls, we demonstrated lower attentional stability in both the groups with epilepsy and ADHD compared with healthy children. In children with epilepsy, BLAST scores were negatively associated with earlier seizure onset and AED (antiepileptic drug) polytherapy, while the seizure frequency, epilepsy duration, or type did not influence BLAST scores. CONCLUSIONS: This study demonstrates that attentional stability is impaired in children with epilepsy and/or ADHD. Bron-Lyon Attention Stability Test seems to be a sensitive test to detect attentional stability deficit in children with epilepsy and with attentional complaints who did not meet all criteria of ADHD. We propose that BLAST could be a useful clinical neuropsychological tool to assess attentional disorders in children.