Vitamin D deficiency and effect of treatment on seizure frequency and quality of life parameters in patients with drug-resistant epilepsy: A randomized clinical trial.

OBJECTIVE: This study was undertaken to assess the effect of treatment of vitamin D deficiency in drug-resistant epilepsy. METHODS: We conducted a multicenter, double-blind, placebo-controlled, randomized clinical trial, including patients aged ≥15 years with drug-resistant focal or generalized epilepsy. Patients with 25-hydroxyvitamin D (25[OH]D) < 30 ng/mL were randomized to an experimental group (EG) receiving vitamin D3 (cholecalciferol, 100 000 IU, five doses in 3 months) or a control group (CG) receiving matched placebo. During the open-label study, EG patients received 100 000 IU/month for 6 months, whereas CG patients received five doses in 3 months then 1/month for 3 months. Monitoring included seizure frequency (SF), 25(OH)D, calcium, albumin, creatinine assays, and standardized scales for fatigue, anxiety-depression, and quality of life (Modified Fatigue Impact Scale [M-FIS], Hospital Anxiety and Depression Scale, Quality of Life in Epilepsy [QOLIE-31]) at 3, 6, and 12 months. The primary efficacy outcome was the percentage of SF reduction compared to the reference period and CG at 3 months. Secondary outcomes were SF and bilateral tonic-clonic seizure (BTCS) reduction, scale score changes, and correlations with 25(OH)D during the follow-up. RESULTS: Eighty-eight patients were enrolled in the study (56 females, aged 17-74 years), with median baseline SF per 3 months = 16.5 and ≥2 antiseizure medications in 88.6%. In 75 patients (85%), 25(OH)D was <30 ng/mL; 40 of them were randomly assigned to EG and 34 to CG. After the 3-month blinded period, SF reduction did not significantly differ between groups. However, during the open-label period, SF significantly decreased (30% median SF reduction, 33% responder rate at 12 months). BTCSs were reduced by 52%. M-FIS and QOLIE-31 scores were significantly improved at the whole group level. SF reduction correlated with 25(OH)D > 30 ng/mL for >6 months. SIGNIFICANCE: Despite no proven effect after the 3-month blinded period, the open-label study suggests that long-term vitamin D3 supplementation with optimal 25(OH)D may reduce SF and BTCSs, with a positive effect on fatigue and quality of life. These findings need to be confirmed by further long-term studies. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03475225 (03-22-2018).

Heart rate variability for neuro-prognostication after CA: Insight from the Parisian registry.

BACKGROUND: Hypoxic ischemic brain injury (HIBI) induced by cardiac arrest (CA) seems to predominate in cortical areas and to a lesser extent in the brainstem. These regions play key roles in modulating the activity of the autonomic nervous system (ANS), that can be assessed through analyses of heart rate variability (HRV). The objective was to evaluate the prognostic value of various HRV parameters to predict neurological outcome after CA. METHODS: Retrospective monocentric study assessing the prognostic value of HRV markers and their association with HIBI severity. Patients admitted for CA who underwent EEG for persistent coma after CA were included. HRV markers were computed from 5 min signal of the ECG lead of the EEG recording. HRV indices were calculated in the time-, frequency-, and non-linear domains. Frequency-domain analyses differentiated very low frequency (VLF 0.003-0.04 Hz), low frequency (LF 0.04-0.15 Hz), high frequency (HF 0.15-0.4 Hz), and LF/HF ratio. HRV indices were compared to other prognostic markers: pupillary light reflex, EEG, N20 on somatosensory evoked potentials (SSEP) and biomarkers (neuron specific enolase-NSE). Neurological outcome at 3 months was defined as unfavorable in case of best CPC 3-4-5. RESULTS: Between 2007 and 2021, 199 patients were included. Patients were predominantly male (64%), with a median age of 60 [48.9-71.7] years. 76% were out-of-hospital CA, and 30% had an initial shockable rhythm. Neurological outcome was unfavorable in 73%. Compared to poor outcome, patients with a good outcome had higher VLF (0.21 vs 0.09 ms2/Hz, p < 0.01), LF (0.07 vs 0.04 ms2/Hz, p = 0.003), and higher LF/HF ratio (2.01 vs 1.01, p = 0.008). Several non-linear domain indices were also higher in the good outcome group, such as SD2 (15.1 vs 10.2, p = 0.016) and DFA α1 (1.03 vs 0.78, p = 0.002). These indices also differed depending on the severity of EEG pattern and abolition of pupillary light reflex. These time-frequency and non-linear domains HRV parameters were predictive of poor neurological outcome, with high specificity despite a low sensitivity. CONCLUSION: In comatose patients after CA, some HRV markers appear to be associated with unfavorable outcome, EEG severity and PLR abolition, although the sensitivity of these HRV markers remains limited.

Cortical responses to looming sources are explained away by the auditory periphery.

A wealth of behavioral evidence indicate that sounds with increasing intensity (i.e. appear to be looming towards the listener) are processed with increased attentional and physiological resources compared to receding sounds. However, the neurophysiological mechanism responsible for such cognitive amplification remains elusive. Here, we show that the large differences seen between cortical responses to looming and receding sounds are in fact almost entirely explained away by nonlinear encoding at the level of the auditory periphery. We collected electroencephalography (EEG) data during an oddball paradigm to elicit mismatch negativity (MMN) and others Event Related Potentials (EPRs), in response to deviant stimuli with both dynamic (looming and receding) and constant level (flat) differences to the standard in the same participants. We then combined a computational model of the auditory periphery with generative EEG methods (temporal response functions, TRFs) to model the single-participant ERPs responses to flat deviants, and used them to predict the effect of the same mechanism on looming and receding stimuli. The flat model explained 45% variance of the looming response, and 33% of the receding response. This provide striking evidence that difference wave responses to looming and receding sounds result from the same cortical mechanism that generate responses to constant-level deviants: all such differences are the sole consequence of their particular physical morphology getting amplified and integrated by peripheral auditory mechanisms. Thus, not all effects seen cortically proceed from top-down modulations by high-level decision variables, but can rather be performed early and efficiently by feed-forward peripheral mechanisms that evolved precisely to sparing subsequent networks with the necessity to implement such mechanisms.

Cortical activations associated with spatial remapping of finger touch using EEG.

The spatial coding of tactile information is functionally essential for touch-based shape perception and motor control. However, the spatiotemporal dynamics of how tactile information is remapped from the somatotopic reference frame in the primary somatosensory cortex to the spatiotopic reference frame remains unclear. This study investigated how hand position in space or posture influences cortical somatosensory processing. Twenty-two healthy subjects received electrical stimulation to the right thumb (D1) or little finger (D5) in three position conditions: palm down on right side of the body (baseline), hand crossing the body midline (effect of position), and palm up (effect of posture). Somatosensory-evoked potentials (SEPs) were recorded using electroencephalography. One early-, two mid-, and two late-latency neurophysiological components were identified for both fingers: P50, P1, N125, P200, and N250. D1 and D5 showed different cortical activation patterns: compared with baseline, the crossing condition showed significant clustering at P1 for D1, and at P50 and N125 for D5; the change in posture showed a significant cluster at N125 for D5. Clusters predominated at centro-parietal electrodes. These results suggest that tactile remapping of fingers after electrical stimulation occurs around 100-125 ms in the parietal cortex.

Right-sided vagus nerve stimulation for drug-resistant epilepsy: A systematic review of the literature and perspectives.

BACKGROUND: Right-sided vagus nerve stimulation (RS-VNS) is indicated when the procedure was deemed not technically feasible or too risky on the indicated left side. OBJECTIVE: The present study aims to systematically review the literature on RS-VNS, assessing its effectiveness and safety. METHODS: A systematic review following PRISMA guidelines was conducted: Pubmed/MEDLINE, The Cochrane Library, Scopus, Embase and Web of science databases were searched from inception to August 13th,2023. Gray literature was searched in two libraries. Eligible studies included all studies reporting, at least, one single case of RS-VNS in patients for the treatment of drug-resistant epilepsy. RESULTS: Out of 2333 initial results, 415 studies were screened by abstract. Only four were included in the final analysis comprising seven patients with RS-VNS for a drug-resistant epilepsy. One patient experienced nocturnal asymptomatic bradycardia whereas the other six patients did not display any cardiac symptom. RS-VNS was discontinued in one case due to exercise-induced airway disease exacerbation. Decrease of epileptic seizure frequency after RS-VNS ranged from 25 % to 100 % in six cases. In the remaining case, VNS effectiveness was unclear. In one case, RS-VNS was more efficient than left-sided VNS (69 % vs 50 %, respectively) whereas in another case, RS-VNS was less efficient (50 % vs 95 %, respectively). CONCLUSION: Literature on the present topic is limited. In six out of seven patients, RS-VNS for drug-resistant epilepsy displayed reasonable effectiveness with a low complication rate. Further research, including prospective studies, is necessary to assess safety and effectiveness of RS-VNS for drug-resistant epilepsy patients.

Characteristics and Prognosis of Tumor-Related Epilepsy During Tumor Evolution in Patients With IDH Wild-Type Glioblastoma.

BACKGROUND AND OBJECTIVES: Tumor-related epilepsy is a well-known symptom of glioblastoma. However, the particular characteristics of epileptic seizures related to glioblastoma, isocitrate dehydrogenase (IDH)-wild-type is almost unexplored longitudinally during the whole course of the disease. We assessed tumor-related epilepsy and seizure control during tumor evolution and the prognostic significance of tumor-related epilepsy. METHODS: We performed an observational, retrospective single-center study at one tertiary referral neuro-oncology surgical center (2000-2020). We included adult patients treated for a newly diagnosed supratentorial glioblastoma, IDH-wild-type with available preoperative and postoperative MRI and with available epileptic seizure status at diagnosis. To determine factors associated with tumor-related epilepsy or seizure control, univariate analyses were performed using the χ2 or Fisher exact tests for categorical variables and the unpaired t test or Mann-Whitney rank-sum test for continuous variables. Predictors associated with tumor-related epilepsy and seizure control in unadjusted analysis were entered into backward stepwise logistic regression models. RESULTS: One thousand six patients were enrolled. The cumulative incidence of tumor-related epilepsy increased during tumor evolution (33.1% at diagnosis, 44.7% after oncologic treatment, 52.4% at progression, and 51.8% at the end-of-life phase) and is related to tumor features (cortex involvement, no necrosis, and small volume). Uncontrolled epileptic seizures increased during tumor evolution (20.1% at diagnosis, 32.0% after oncologic treatment, 46.7% at progression, and 41.1% at the end-of-life phase). Epileptic seizure control after oncologic treatment was related to seizure features (uncontrolled before oncologic treatment and focal-to-bilateral tonic-clonic seizures) and to the extent of resection. Epileptic seizure control at tumor progression was related to seizure features (presence at diagnosis and uncontrolled after oncologic treatment) and to the time to progression. Tumor-related epilepsy at diagnosis was a predictor of a longer overall survival (adjusted hazard ratio, 0.78; 95% CI 0.67-0.90; p < 0.001) independent of age, Karnofsky Performance Status score, tumor location and volume, extent of resection, standard combined chemoradiotherapy, levetiracetam use, and MGMT promoter methylation. DISCUSSION: The progression of tumor-related epilepsy with the evolution of glioblastoma, IDH-wild-type and the effects of surgery on seizure control argue for proper antiseizure medication and maximal safe resection. Tumor-related epilepsy is an independent predictor of a longer survival.

Aberrant brain-heart coupling is associated with the severity of post cardiac arrest brain injury.

OBJECTIVE: To investigate autonomic nervous system activity measured by brain-heart interactions in comatose patients after cardiac arrest in relation to the severity and prognosis of hypoxic-ischemic brain injury. METHODS: Strength and complexity of bidirectional interactions between EEG frequency bands (delta, theta, and alpha) and ECG heart rate variability frequency bands (low frequency, LF and high frequency, HF) were computed using a synthetic data generation model. Primary outcome was the severity of brain injury, assessed by (i) standardized qualitative EEG classification, (ii) somatosensory evoked potentials (N20), and (iii) neuron-specific enolase levels. Secondary outcome was the 3-month neurological status, assessed by the Cerebral Performance Category score [good (1-2) vs. poor outcome (3-4-5)]. RESULTS: Between January 2007 and July 2021, 181 patients were admitted to ICU for a resuscitated cardiac arrest. Poor neurological outcome was observed in 134 patients (74%). Qualitative EEG patterns suggesting high severity were associated with decreased LF/HF. Severity of EEG changes were proportional to higher absolute values of brain-to-heart coupling strength (p < 0.02 for all brain-to-heart frequencies) and lower values of alpha-to-HF complexity (p = 0.049). Brain-to-heart coupling strength was significantly higher in patients with bilateral absent N20 and correlated with neuron-specific enolase levels at Day 3. This aberrant brain-to-heart coupling (increased strength and decreased complexity) was also associated with 3-month poor neurological outcome. INTERPRETATION: Our results suggest that autonomic dysfunctions may well represent hypoxic-ischemic brain injury post cardiac arrest pathophysiology. These results open avenues for integrative monitoring of autonomic functioning in critical care patients.

Neurophysiological explorations across the spectrum of psychosis, autism, and depression, during wakefulness and sleep: protocol of a prospective case-control transdiagnostic multimodal study (DEMETER).

BACKGROUND: Quantitative electroencephalography (EEG) analysis offers the opportunity to study high-level cognitive processes across psychiatric disorders. In particular, EEG microstates translate the temporal dynamics of neuronal networks throughout the brain. Their alteration may reflect transdiagnostic anomalies in neurophysiological functions that are impaired in mood, psychosis, and autism spectrum disorders, such as sensorimotor integration, speech, sleep, and sense of self. The main questions this study aims to answer are as follows: 1) Are EEG microstate anomalies associated with clinical and functional prognosis, both in resting conditions and during sleep, across psychiatric disorders? 2) Are EEG microstate anomalies associated with differences in sensorimotor integration, speech, sense of self, and sleep? 3) Can the dynamic of EEG microstates be modulated by a non-drug intervention such as light hypnosis? METHODS: This prospective cohort will include a population of adolescents and young adults, aged 15 to 30 years old, with ultra-high-risk of psychosis (UHR), first-episode psychosis (FEP), schizophrenia (SCZ), autism spectrum disorder (ASD), and major depressive disorder (MDD), as well as healthy controls (CTRL) (N = 21 × 6), who will be assessed at baseline and after one year of follow-up. Participants will undergo deep phenotyping based on psychopathology, neuropsychological assessments, 64-channel EEG recordings, and biological sampling at the two timepoints. At baseline, the EEG recording will also be coupled to a sensorimotor task and a recording of the characteristics of their speech (prosody and turn-taking), a one-night polysomnography, a self-reference effect task in virtual reality (only in UHR, FEP, and CTRL). An interventional ancillary study will involve only healthy controls, in order to assess whether light hypnosis can modify the EEG microstate architecture in a direction opposite to what is seen in disease. DISCUSSION: This transdiagnostic longitudinal case-control study will provide a multimodal neurophysiological assessment of clinical dimensions (sensorimotor integration, speech, sleep, and sense of self) that are disrupted across mood, psychosis, and autism spectrum disorders. It will further test the relevance of EEG microstates as dimensional functional biomarkers. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT06045897.

Electroencephalography microstates imbalance across the spectrum of early psychosis, autism, and mood disorders.

BACKGROUND: Electroencephalography (EEG) microstates translate resting-state temporal dynamics of neuronal networks throughout the brain and could constitute possible markers of psychiatric disorders. We tested the hypothesis of an increased imbalance between a predominant self-referential mode (microstate C) and a decreased attentional mode (microstate D) in psychosis, mood, and autism spectrum disorders. METHODS: We retrospectively included 135 subjects from an early psychosis outpatient unit, with available eyes-closed resting-state 19 electrodes EEG. Individual-level then group-level modified K-means clustering in controls provided four microstate maps that were then backfitted to all groups. Differences between microstate parameters (occurrence, coverage, and mean duration) were computed between controls and each group, and between disease groups. RESULTS: Microstate class D parameters were systematically decreased in disease groups compared with controls, with an effect size increasing along the psychosis spectrum, but also in autism. There was no difference in class C. C/D ratios of mean duration were increased only in SCZ compared with controls. CONCLUSIONS: The decrease in microstate class D may be a marker of stage of psychosis, but it is not specific to it and may rather reflect a shared dimension along the schizophrenia-autism spectrum. C/D microstate imbalance may be more specific to schizophrenia.

Discrepancies in the late auditory potentials of post-anoxic patients: Watch out for focal brain lesions, a pilot retrospective study.

AIMS: Late auditory evoked potentials, and notably mismatch negativity (MMN) and P3 responses, can be used as part of the multimodal prognostic evaluation in post-anoxic disorders of consciousness (DOC). MMN response preferentially stems from the temporal cortex and the arcuate fasciculus. Situations with discrepant evaluations, for example MMN absent but P3 present, are frequent and difficult to interpret. We hypothesize that discrepant MMN-/P3+ results could reflect a higher prevalence of lesions in MMN generating regions. This study presents correlations between neurophysiological and neuroradiological results. METHODS: This retrospective study was conducted on 38 post-anoxic DOC patients. Brain lesions were analyzed on 3T MRI both anatomically and through computation of the local arcuate fasciculus fractional anisotropy values on Diffusion Tensor Imaging sequences. Neurophysiological data and outcome were also analyzed. RESULTS: Our cohort included 8 MMN-/P3+, 7 MMN+/P3+, 21 MMN-/P3- and 2 MMN-/P3+ patients, assessed at a median delay of 20.5 days since cardiac arrest. Our results show that MMN-/P3+ patients tended to have fewer temporal and basal ganglia lesions than MMN-/P3- patients, and more than MMN+/P3+ patients (p-values for trend: p = 0.02 for temporal and p = 0.02 for basal ganglia lesions). There was a statistical difference across groups for mean fractional anisotropy values in the arcuate fasciculus (p = 0.008). The percentage of patients regaining consciousness at three months in MMN-/P3+ patients was higher than in MMN-/P3- patients and lower than in MMN+/P3+ patients. CONCLUSION: This study suggests that discrepancies in late auditory evoked potentials may be linked to focal post-anoxic brain lesions, visible on brain MRI.

Early identification of seizure freedom with medical treatment in patients with mesial temporal lobe epilepsy and hippocampal sclerosis.

BACKGROUND: Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is usually associated with a poor response to antiseizure medications. We focused on MTLE-HS patients who were seizure free on medication to: (1) determine the clinical factors associated with seizure freedom and (2) develop a machine-learning classifier to better earlier identify those patients. METHODS: We performed a retrospective, multicentric study comparing 64 medically treated seizure-free MTLE-HS patients with 200 surgically treated drug-resistant MTLE-HS patients. First, we collected medical history and seizure semiology data. Then, we developed a machine-learning classifier based on clinical data. RESULTS: Medically treated seizure-free MTLE-HS patients were seizure-free for at least 2 years, and for a median time of 7 years at last follow-up. Compared to drug-resistant MTLE-HS patients, they exhibited: an older age at epilepsy onset (22.5 vs 8.0 years, p < 0.001), a lesser rate of: febrile seizures (39.0% vs 57.5%, p = 0.035), focal aware seizures (previously referred to as aura)(56.7% vs 90.0%, p < 0.001), autonomic focal aware seizures in presence of focal aware seizure (17.6% vs 59.4%, p < 0.001), dystonic posturing of the limbs (9.8% vs 47.0%, p < 0.001), gestural (27.4% vs 94.0%, p < 0.001), oro-alimentary (32.3% vs 75.5%, p < 0.001) or verbal automatisms (12.9% vs 36.0%, p = 0.001). The classifier had a positive predictive value of 0.889, a sensitivity of 0.727, a specificity of 0.962, a negative predictive value of 0.893. CONCLUSIONS: Medically treated seizure-free MTLE-HS patients exhibit a distinct clinical profile. A classifier built with readily available clinical data can identify them accurately with excellent positive predictive value. This may help to individualize the management of MTLE-HS patients according to their expected pharmacosensitivity.

Quantitative analysis of early-stage EEG reactivity predicts awakening and recovery of consciousness in patients with severe brain injury.

BACKGROUND: Decisions of withdrawal of life-sustaining therapy for patients with severe brain injury are often based on prognostic evaluations such as analysis of electroencephalography (EEG) reactivity (EEG-R). However, EEG-R usually relies on visual assessment, which requires neurophysiological expertise and is prone to inter-rater variability. We hypothesised that quantitative analysis of EEG-R obtained 3 days after patient admission can identify new markers of subsequent awakening and consciousness recovery. METHODS: In this prospective observational study of patients with severe brain injury requiring mechanical ventilation, quantitative EEG-R was assessed using standard 11-lead EEG with frequency-based (power spectral density) and functional connectivity-based (phase-lag index) analyses. Associations between awakening in the intensive care unit (ICU) and reactivity to auditory and nociceptive stimulations were assessed with logistic regression. Secondary outcomes included in-ICU mortality and 3-month Coma Recovery Scale-Revised (CRS-R) score. RESULTS: Of 116 patients, 86 (74%) awoke in the ICU. Among quantitative EEG-R markers, variation in phase-lag index connectivity in the delta frequency band after noise stimulation was associated with awakening (adjusted odds ratio=0.89, 95% confidence interval: 0.81-0.97, P=0.02 corrected for multiple tests), independently of age, baseline severity, and sedation. This new marker was independently associated with improved 3-month CRS-R (adjusted ß=-0.16, standard error 0.075, P=0.048), but not with mortality (adjusted odds ratio=1.08, 95% CI: 0.99-1.18, P=0.10). CONCLUSIONS: An early-stage quantitative EEG-R marker was independently associated with awakening and 3-month level of consciousness in patients with severe brain injury. This promising marker based on functional connectivity will need external validation before potential integration into a multimodal prognostic model.

Prognostication after cardiac arrest: how EEG and evoked potentials may improve the challenge.

About 80% of patients resuscitated from CA are comatose at ICU admission and nearly 50% of survivors are still unawake at 72 h. Predicting neurological outcome of these patients is important to provide correct information to patient's relatives, avoid disproportionate care in patients with irreversible hypoxic-ischemic brain injury (HIBI) and inappropriate withdrawal of care in patients with a possible favorable neurological recovery. ERC/ESICM 2021 algorithm allows a classification as "poor outcome likely" in 32%, the outcome remaining "indeterminate" in 68%. The crucial question is to know how we could improve the assessment of both unfavorable but also favorable outcome prediction. Neurophysiological tests, i.e., electroencephalography (EEG) and evoked-potentials (EPs) are a non-invasive bedside investigations. The EEG is the record of brain electrical fields, characterized by a high temporal resolution but a low spatial resolution. EEG is largely available, and represented the most widely tool use in recent survey examining current neuro-prognostication practices. The severity of HIBI is correlated with the predominant frequency and background continuity of EEG leading to "highly malignant" patterns as suppression or burst suppression in the most severe HIBI. EPs differ from EEG signals as they are stimulus induced and represent the summated activities of large populations of neurons firing in synchrony, requiring the average of numerous stimulations. Different EPs (i.e., somato sensory EPs (SSEPs), brainstem auditory EPs (BAEPs), middle latency auditory EPs (MLAEPs) and long latency event-related potentials (ERPs) with mismatch negativity (MMN) and P300 responses) can be assessed in ICU, with different brain generators and prognostic values. In the present review, we summarize EEG and EPs signal generators, recording modalities, interpretation and prognostic values of these different neurophysiological tools. Finally, we assess the perspective for futures neurophysiological investigations, aiming to reduce prognostic uncertainty in comatose and disorders of consciousness (DoC) patients after CA.

SSEP N20 and P25 amplitudes predict poor and good neurologic outcomes after cardiac arrest.

BACKGROUND: To assess in comatose patients after cardiac arrest (CA) if amplitudes of two somatosensory evoked potentials (SSEP) responses, namely, N20-baseline (N20-b) and N20-P25, are predictive of neurological outcome. METHODS: Monocentric prospective study in a tertiary cardiac center between Nov 2019 and July-2021. All patients comatose at 72 h after CA with at least one SSEP recorded were included. The N20-b and N20-P25 amplitudes were automatically measured in microvolts (µV), along with other recommended prognostic markers (status myoclonus, neuron-specific enolase levels at 2 and 3 days, and EEG pattern). We assessed the predictive value of SSEP for neurologic outcome using the best Cerebral Performance Categories (CPC1 or 2 as good outcome) at 3 months (main endpoint) and 6 months (secondary endpoint). Specificity and sensitivity of different thresholds of SSEP amplitudes, alone or in combination with other prognostic markers, were calculated. RESULTS: Among 82 patients, a poor outcome (CPC 3-5) was observed in 78% of patients at 3 months. The median time to SSEP recording was 3(2-4) days after CA, with a pattern "bilaterally absent" in 19 patients, "unilaterally present" in 4, and "bilaterally present" in 59 patients. The median N20-b amplitudes were different between patients with poor and good outcomes, i.e., 0.93 [0-2.05]µV vs. 1.56 [1.24-2.75]µV, respectively (p < 0.0001), as the median N20-P25 amplitudes (0.57 [0-1.43]µV in poor outcome vs. 2.64 [1.39-3.80]µV in good outcome patients p < 0.0001). An N20-b > 2 µV predicted good outcome with a specificity of 73% and a moderate sensitivity of 39%, although an N20-P25 > 3.2 µV was 93% specific and only 30% sensitive. A low voltage N20-b < 0.88 µV and N20-P25 < 1 µV predicted poor outcome with a high specificity (sp = 94% and 93%, respectively) and a moderate sensitivity (se = 50% and 66%). Association of "bilaterally absent or low voltage SSEP" patterns increased the sensitivity significantly as compared to "bilaterally absent" SSEP alone (se = 58 vs. 30%, p = 0.002) for prediction of poor outcome. CONCLUSION: In comatose patient after CA, both N20-b and N20-P25 amplitudes could predict both good and poor outcomes with high specificity but low to moderate sensitivity. Our results suggest that caution is needed regarding SSEP amplitudes in clinical routine, and that these indicators should be used in a multimodal approach for prognostication after cardiac arrest.

Early Clinical and Electrophysiological Brain Dysfunction Is Associated With ICU Outcomes in COVID-19 Critically Ill Patients With Acute Respiratory Distress Syndrome: A Prospective Bicentric Observational Study.

OBJECTIVES: Describe the prevalence of acute cerebral dysfunction and assess the prognostic value of an early clinical and electroencephalography (EEG) assessment in ICU COVID-19 patients. DESIGN: Prospective observational study. SETTING: Two tertiary critical care units in Paris, France, between April and December 2020. PATIENTS: Adult critically ill patients with COVID-19 acute respiratory distress syndrome. INTERVENTIONS: Neurologic examination and EEG at two time points during the ICU stay, first under sedation and second 4-7 days after sedation discontinuation. MEASUREMENTS AND MAIN RESULTS: Association of EEG abnormalities (background reactivity, continuity, dominant frequency, and presence of paroxystic discharges) with day-28 mortality and neurologic outcomes (coma and delirium recovery). Fifty-two patients were included, mostly male (81%), median (interquartile range) age 68 years (56-74 yr). Delayed awakening was present in 68% of patients (median awakening time of 5 d [2-16 d]) and delirium in 74% of patients who awoke from coma (62% of mixed delirium, median duration of 5 d [3-8 d]). First, EEG background was slowed in the theta-delta range in 48 (93%) patients, discontinuous in 25 patients (48%), and nonreactive in 17 patients (33%). Bifrontal slow waves were observed in 17 patients (33%). Early nonreactive EEG was associated with lower day-28 ventilator-free days (0 vs 16; p = 0.025), coma-free days (6 vs 22; p = 0.006), delirium-free days (0 vs 17; p = 0.006), and higher mortality (41% vs 11%; p = 0.027), whereas discontinuous background was associated with lower ventilator-free days (0 vs 17; p = 0.010), coma-free days (1 vs 22; p < 0.001), delirium-free days (0 vs 17; p = 0.001), and higher mortality (40% vs 4%; p = 0.001), independently of sedation and analgesia. CONCLUSIONS: Clinical and neurophysiologic cerebral dysfunction is frequent in COVID-19 ARDS patients. Early severe EEG abnormalities with nonreactive and/or discontinuous background activity are associated with delayed awakening, delirium, and day-28 mortality.

It's not what you say, it's how you say it: A retrospective study of the impact of prosody on own-name P300 in comatose patients.

OBJECTIVE: The acoustic characteristics of stimuli influence the characteristics of the corresponding evoked potentials in healthy subjects. Own-name stimuli are used in clinical practice to assess the level of consciousness in intensive care units. The influence of the acoustic variability of these stimuli has never been evaluated. Here, we explored the influence of this variability on the characteristics of the subject's own name (SON) P300. METHODS: We retrospectively analyzed 251 disorders of consciousness patients from Lyon and Paris Hospitals who underwent an "own-name protocol". A reverse correlation analysis was performed to test for an association between acoustic properties of own-names stimuli used and the characteristics of the P300 wave observed. RESULTS: Own-names pronounced with increasing pitch prosody showed P300 responses 66 ms earlier than own-names that had a decreasing prosody [IC95% = 6.36; 125.9 ms]. CONCLUSIONS: Speech prosody of the stimuli in the "own name protocol" is associated with latencies differences of the P300 response among patients for whom these responses were observed. Further investigations are needed to confirm these results. SIGNIFICANCE: Speech prosody of the stimuli in the "own name protocol" is a non-negligible parameter, associated with P300 latency differences. Speech prosody should be standardized in SON P300 studies.

Evoked and Event-Related Potentials as Biomarkers of Consciousness State and Recovery.

SUMMARY: The definition of consciousness has been the subject of great interest for many scientists and philosophers. To better understand how evoked potentials may be identified as biomarkers of consciousness and recovery, the different theoretical models sustaining neural correlates of consciousness are reviewed. A multimodal approach can help to better predict clinical outcome in patients presenting with disorders of consciousness. Evoked potentials are inexpensive and easy-to-implement bedside examination techniques. Evoked potentials are an integral part of prognostic evaluation, particularly in cases of cognitive motor dissociation. Prognostic criteria are well established in postanoxic disorders of consciousness, especially postcardiac arrest but are less well determined in other etiologies. In the early examination, bilateral absence of N20 in disorder of consciousness patients is strongly associated with unfavorable outcome (i.e., death or unresponsive wakefulness syndrome) especially in postanoxic etiologies. This predictive value is lower in other etiologies and probably also in children. Both N20 and mismatch negativity are proven outcome predictors for acute coma. Many studies have shown that mismatch negativity and P3a are characterized by a high prognostic value for awakening, but some patients presenting unresponsive wakefulness syndrome also process a P3a. The presence of long-latency event-related potential components in response to stimuli is indicative of a better recovery. All neurophysiological data must be integrated within a multimodal approach combining repeated clinical evaluation, neuroimaging, functional imaging, biology, and neurophysiology combining passive and active paradigms.

Effect of Levetiracetam Use Duration on Overall Survival of Isocitrate Dehydrogenase Wild-Type Glioblastoma in Adults: An Observational Study.

BACKGROUND AND OBJECTIVES: The association between levetiracetam and survival with isocitrate dehydrogenase (IDH) wild-type glioblastomas is controversial. We investigated whether the duration of levetiracetam use during the standard chemoradiation protocol affects overall survival (OS) of patients with IDH wild-type glioblastoma. METHODS: In this observational single-institution cohort study (2010-2018), inclusion criteria were (1) age ≥18 years; (2) newly diagnosed supratentorial tumor; (3) histomolecular diagnosis of IDH wild-type glioblastoma; and (4) standard chemoradiation protocol. To assess the survival benefit of levetiracetam use during the standard chemoradiation protocol (whole duration, part time, and never subgroups), a Cox proportional hazard model was constructed. We performed a case-matched analysis (1:1) between patients with levetiracetam use during the whole duration of the standard chemoradiation protocol and patients with levetiracetam use part time or never according to the following criteria: sex, age, epileptic seizures at diagnosis, Radiation Therapy Oncology Group recursive partitioning analysis (RTOG-RPA) class, tumor location, preoperative volume, extent of resection, and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. Patients with unavailable O6-methylguanine-DNA methyltransferase promoter methylation status (48.5%) were excluded. RESULTS: A total of 460 patients were included. The median OS was longer in the 116 patients with levetiracetam use during the whole duration of the standard chemoradiation protocol (21.0 months; 95% confidence interval [CI] 17.2-24.0) than in the 126 patients with part-time levetiracetam use (16.8 months; 95% CI 12.4-19.0) and in the 218 patients who never received levetiracetam (16.0 months; 95% CI 15.5-19.4; p = 0.027). Levetiracetam use during the whole duration of the standard chemoradiation protocol (adjusted hazard ratio [aHR] 0.69; 95% CI 0.52-0.93; p = 0.014), MGMT promoter methylation (aHR 0.53; 95% CI 0.39-0.71; p < 0.001), and gross total tumor resection (aHR 0.57; 95% CI 0.44-0.74; p < 0.001) were independent predictors of longer OS. After case matching (n = 54 per group), a longer OS was found for levetiracetam use during the whole duration of the standard chemoradiation protocol (hazard ratio 0.63; 95% CI 0.42-0.94; p = 0.023). DISCUSSION: Levetiracetam use during the whole standard chemoradiation protocol possibly improves OS of patients with IDH wild-type glioblastoma. It should be considered in the antitumor strategy of future multicentric trials. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that in individuals with IDH wild-type glioblastoma, levetiracetam use throughout the duration of standard chemotherapy is associated with longer median OS.