A Novel Approach to Screen for Somatosensory Evoked Potentials in Critical Care.

BACKGROUND: Somatosensory evoked potentials (SSEPs) help prognostication, particularly in patients with diffuse brain injury. However, use of SSEP is limited in critical care. We propose a novel, low-cost approach allowing acquisition of screening SSEP using widely available intensive care unit (ICU) equipment, specifically a peripheral "train-of-four" stimulator and standard electroencephalograph. METHODS: The median nerve was stimulated using a train-of-four stimulator, and a standard 21-channel electroencephalograph was recorded to generate the screening SSEP. Generation of the SSEP was supported by visual inspection, univariate event-related potentials statistics, and a multivariate support vector machine (SVM) decoding algorithm. This approach was validated in 15 healthy volunteers and validated against standard SSEPs in 10 ICU patients. The ability of this approach to predict poor neurological outcome, defined as death, vegetative state, or severe disability at 6 months, was tested in an additional set of 39 ICU patients. RESULTS: In each of the healthy volunteers, both the univariate and the SVM methods reliably detected SSEP responses. In patients, when compared against the standard SSEP method, the univariate event-related potentials method matched in nine of ten patients (sensitivity = 94%, specificity = 100%), and the SVM had 100% sensitivity and specificity when compared with the standard method. For the 49 ICU patients, we performed both the univariate and the SVM methods: a bilateral absence of short latency responses (n = 8) predicted poor neurological outcome with 0% FPR (sensitivity = 21%, specificity = 100%). CONCLUSIONS: Somatosensory evoked potentials can reliably be recorded using the proposed approach. Given the very good but slightly lower sensitivity of absent SSEPs in the proposed screening approach, confirmation of absent SSEP responses using standard SSEP recordings is advised.

Cognitive Motor Dissociation: Gap Analysis and Future Directions.

BACKGROUND: Patients with disorders of consciousness who are behaviorally unresponsive may demonstrate volitional brain responses to motor imagery or motor commands detectable on functional magnetic resonance imaging or electroencephalography. This state of cognitive motor dissociation (CMD) may have prognostic significance. METHODS: The Neurocritical Care Society's Curing Coma Campaign identified an international group of experts who convened in a series of monthly online meetings between September 2021 and April 2023 to examine the science of CMD and identify key knowledge gaps and unmet needs. RESULTS: The group identified major knowledge gaps in CMD research: (1) lack of information about patient experiences and caregiver accounts of CMD, (2) limited epidemiological data on CMD, (3) uncertainty about underlying mechanisms of CMD, (4) methodological variability that limits testing of CMD as a biomarker for prognostication and treatment trials, (5) educational gaps for health care personnel about the incidence and potential prognostic relevance of CMD, and (6) challenges related to identification of patients with CMD who may be able to communicate using brain-computer interfaces. CONCLUSIONS: To improve the management of patients with disorders of consciousness, research efforts should address these mechanistic, epidemiological, bioengineering, and educational gaps to enable large-scale implementation of CMD assessment in clinical practice.

Pupil dilation response elicited by violations of auditory regularities is a promising but challenging approach to probe consciousness at the bedside.

Pupil dilation response (PDR) has been proposed as a physiological marker of conscious access to a stimulus or its attributes, such as novelty. In a previous study on healthy volunteers, we adapted the auditory "local global" paradigm and showed that violations of global regularity elicited a PDR. Notably without instructions, this global effect was present only in participants who could consciously report violations of global regularities. In the present study, we used a similar approach in 24 non-communicating patients affected with a Disorder of Consciousness (DoC) and compared PDR to ERPs regarding diagnostic and prognostic performance. At the group level, global effect could not be detected in DoC patients. At the individual level, the only patient with a PDR global effect was in a MCS and recovered consciousness at 6 months. Contrasting the most regular trials to the most irregular ones improved PDR's diagnostic and prognostic power in DoC patients. Pupillometry is a promising tool but requires several methodological improvements to enhance the signal-to-noise ratio and make it more robust for probing consciousness and cognition in DoC patients.

Heuristics and biases in medical decision-making under uncertainty: The case of neuropronostication for consciousness disorders.

Neuropronostication for consciousness disorders can be very complex and prone to high uncertainty. Despite notable advancements in the development of dedicated scales and physiological markers using innovative paradigms, these technical progressions are often overshadowed by factors intrinsic to the medical environment. Beyond the scarcity of objective data guiding medical decisions, factors like time pressure, fatigue, multitasking, and emotional load can drive clinicians to rely more on heuristic-based clinical reasoning. Such an approach, albeit beneficial under certain circumstances, may lead to systematic error judgments and impair medical decisions, especially in complex and uncertain environments. After a brief review of the main theoretical frameworks, this paper explores the influence of clinicians' cognitive biases on clinical reasoning and decision-making in the challenging context of neuroprognostication for consciousness disorders. The discussion further revolves around developing and implementing various strategies designed to mitigate these biases and their impact, aiming to enhance the quality of care and the patient safety.

Common Data Elements for Disorders of Consciousness: Recommendations from the Electrophysiology Working Group.

BACKGROUND: Electroencephalography (EEG) has long been recognized as an important tool in the investigation of disorders of consciousness (DoC). From inspection of the raw EEG to the implementation of quantitative EEG, and more recently in the use of perturbed EEG, it is paramount to providing accurate diagnostic and prognostic information in the care of patients with DoC. However, a nomenclature for variables that establishes a convention for naming, defining, and structuring data for clinical research variables currently is lacking. As such, the Neurocritical Care Society's Curing Coma Campaign convened nine working groups composed of experts in the field to construct common data elements (CDEs) to provide recommendations for DoC, with the main goal of facilitating data collection and standardization of reporting. This article summarizes the recommendations of the electrophysiology DoC working group. METHODS: After assessing previously published pertinent CDEs, we developed new CDEs and categorized them into "disease core," "basic," "supplemental," and "exploratory." Key EEG design elements, defined as concepts that pertained to a methodological parameter relevant to the acquisition, processing, or analysis of data, were also included but were not classified as CDEs. RESULTS: After identifying existing pertinent CDEs and developing novel CDEs for electrophysiology in DoC, variables were organized into a framework based on the two primary categories of resting state EEG and perturbed EEG. Using this categorical framework, two case report forms were generated by the working group. CONCLUSIONS: Adherence to the recommendations outlined by the electrophysiology working group in the resting state EEG and perturbed EEG case report forms will facilitate data collection and sharing in DoC research on an international level. In turn, this will allow for more informed and reliable comparison of results across studies, facilitating further advancement in the realm of DoC research.

Illusion of knowledge in statistics among clinicians: evaluating the alignment between objective accuracy and subjective confidence, an online survey.

Healthcare professionals' statistical illiteracy can impair medical decision quality and compromise patient safety. Previous studies have documented clinicians' insufficient proficiency in statistics and a tendency in overconfidence. However, an underexplored aspect is clinicians' awareness of their lack of statistical knowledge that precludes any corrective intervention attempt. Here, we investigated physicians', residents' and medical students' alignment between subjective confidence judgments and objective accuracy in basic medical statistics. We also examined how gender, profile of experience and practice of research activity affect this alignment, and the influence of problem framing (conditional probabilities, CP vs. natural frequencies, NF). Eight hundred ninety-eight clinicians completed an online survey assessing skill and confidence on three topics: vaccine efficacy, p value and diagnostic test results interpretation. Results evidenced an overall consistent poor proficiency in statistics often combined with high confidence, even in incorrect answers. We also demonstrate that despite overconfidence bias, clinicians show a degree of metacognitive sensitivity, as their confidence judgments discriminate between their correct and incorrect answers. Finally, we confirm the positive impact of the more intuitive NF framing on accuracy. Together, our results pave the way for the development of teaching recommendations and pedagogical interventions such as promoting metacognition on basic knowledge and statistical reasoning as well as the use of NF to tackle statistical illiteracy in the medical context.

Ethics Along the Continuum of Research Involving Persons with Disorders of Consciousness.

Interest in disorders of consciousness (DoC) has grown substantially over the past decade and has illuminated the importance of improving understanding of DoC biology; care needs (use of monitoring, performance of interventions, and provision of emotional support); treatment options to promote recovery; and outcome prediction. Exploration of these topics requires awareness of numerous ethics considerations related to rights and resources. The Curing Coma Campaign Ethics Working Group used its expertise in neurocritical care, neuropalliative care, neuroethics, neuroscience, philosophy, and research to formulate an informal review of ethics considerations along the continuum of research involving persons with DoC related to the following: (1) study design; (2) comparison of risks versus benefits; (3) selection of inclusion and exclusion criteria; (4) screening, recruitment, and enrollment; (5) consent; (6) data protection; (7) disclosure of results to surrogates and/or legally authorized representatives; (8) translation of research into practice; (9) identification and management of conflicts of interest; (10) equity and resource availability; and (11) inclusion of minors with DoC in research. Awareness of these ethics considerations when planning and performing research involving persons with DoC will ensure that the participant rights are respected while maximizing the impact and meaningfulness of the research, interpretation of outcomes, and communication of results.

EEG lexicality effect predicts clinical outcome in disorders of consciousness.

This study aimed at probing covert language processing in patients with disorders of consciousness. An auditory paradigm contrasting words to pronounceable pseudowords was designed, while recording bedside electroencephalogram and computing the two main correlates of lexicality: N400 and late positive component (LPC). Healthy volunteers and 19 patients, 10 in a minimally conscious state and 9 in a vegetative state (also coined unresponsive wakefulness syndrome), were recorded. N400 was present in all groups, whereas LPC was only present in the healthy volunteers and minimally conscious state groups. At the individual level, an unprecedented detection rate of N400 and LPC was reached, and LPC predicted overt cognitive improvement at 6 months. ANN NEUROL 2023;93:762-767.

Valproic acid as adjuvant treatment for convulsive status epilepticus: a randomised clinical trial.

BACKGROUND: Generalised convulsive status epilepticus (GCSE) is a medical emergency. Guidelines recommend a stepwise strategy of benzodiazepines followed by a second-line anti-seizure medicine (ASM). However, GCSE is uncontrolled in 20-40% patients and is associated with protracted hospitalisation, disability, and mortality. The objective was to determine whether valproic acid (VPA) as complementary treatment to the stepwise strategy improves the outcomes of patients with de novo established GCSE. METHODS: This was a multicentre, double-blind, randomised controlled trial in 244 adults admitted to intensive care units for GCSE in 16 French hospitals between 2013 and 2018. Patients received standard care of benzodiazepine and a second-line ASM (except VPA). Intervention patients received a 30 mg/kg VPA loading dose, then a 1 mg/kg/h 12 h infusion, whilst the placebo group received an identical intravenous administration of 0.9% saline as a bolus and continuous infusion. Primary outcome was proportion of patients discharged from hospital by day 15. The secondary outcomes were seizure control, adverse events, and cognition at day 90. RESULTS: A total of 126 (52%) and 118 (48%) patients were included in the VPA and placebo groups. 224 (93%) and 227 (93%) received a first-line and a second-line ASM before VPA or placebo infusion. There was no between-group difference for patients hospital-discharged at day 15 [VPA, 77 (61%) versus placebo, 72 (61%), adjusted relative risk 1.04; 95% confidence interval (0.89-1.19); p = 0.58]. There were no between-group differences for secondary outcomes. CONCLUSIONS: VPA added to the recommended strategy for adult GCSE is well tolerated but did not increase the proportion of patients hospital-discharged by day 15. TRIAL REGISTRATION NO: NCT01791868 (ClinicalTrials.gov registry), registered: 15 February 2012.

Description and Outcome of Severe Hypoglycemic Encephalopathy in the Intensive Care Unit.

BACKGROUND: Disorders of consciousness due to severe hypoglycemia are rare but challenging to treat. The aim of this retrospective cohort study was to describe our multimodal neurological assessment of patients with hypoglycemic encephalopathy hospitalized in the intensive care unit and their neurological outcomes. METHODS: Consecutive patients with disorders of consciousness related to hypoglycemia admitted for neuroprognostication from 2010 to 2020 were included. Multimodal neurological assessment included electroencephalography, somatosensory and cognitive event-related potentials, and morphological and quantitative magnetic resonance imaging (MRI) with quantification of fractional anisotropy. Neurological outcomes at 28 days, 3 months, 6 months, 1 year, and 2 years after hypoglycemia were retrieved. RESULTS: Twenty patients were included. After 2 years, 75% of patients had died, 5% remained in a permanent vegetative state, 10% were in a minimally conscious state, and 10% were conscious but with severe disabilities (Glasgow Outcome Scale-Extended scores 3 and 4). All patients showed pathologic electroencephalography findings with heterogenous patterns. Morphological brain MRI revealed abnormalities in 95% of patients, with various localizations including cortical atrophy in 65% of patients. When performed, quantitative MRI showed decreased fractional anisotropy affecting widespread white matter tracts in all patients. CONCLUSIONS: The overall prognosis of patients with severe hypoglycemic encephalopathy was poor, with only a small fraction of patients who slowly improved after intensive care unit discharge. Of note, patients who did not improve during the first 6 months did not recover consciousness. This study suggests that a multimodal approach capitalizing on advanced brain imaging and bedside electrophysiology techniques could improve diagnostic and prognostic performance in severe hypoglycemic encephalopathy.

Older patients with COVID-19 and neuropsychiatric conditions: A study of risk factors for mortality.

BACKGROUND: Little is known about risk factors for mortality in older patients with COVID-19 and neuropsychiatric conditions. METHODS: We conducted a multicentric retrospective observational study at Assistance Publique-Hôpitaux de Paris. We selected inpatients aged 70 years or older, with COVID-19 and preexisting neuropsychiatric comorbidities and/or new neuropsychiatric manifestations. We examined demographics, comorbidities, functional status, and presentation including neuropsychiatric symptoms and disorders, as well as paraclinical data. Cox survival analysis was conducted to determine risk factors for mortality at 40 days after the first symptoms of COVID-19. RESULTS: Out of 191 patients included (median age 80 [interquartile range 74-87]), 135 (71%) had neuropsychiatric comorbidities including cognitive impairment (39%), cerebrovascular disease (22%), Parkinsonism (6%), and brain tumors (6%). A total of 152 (79%) patients presented new-onset neuropsychiatric manifestations including sensory symptoms (6%), motor deficit (11%), behavioral (18%) and cognitive (23%) disturbances, gait impairment (11%), and impaired consciousness (18%). The mortality rate at 40 days was 19.4%. A history of brain tumor or Parkinsonism or the occurrence of impaired consciousness were neurological factors associated with a higher risk of mortality. A lower Activities of Daily Living score (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.58-0.82), a neutrophil-to-lymphocyte ratio ≥ 9.9 (HR 5.69, 95% CI 2.69-12.0), and thrombocytopenia (HR 5.70, 95% CI 2.75-11.8) independently increased the risk of mortality (all p < .001). CONCLUSION: Understanding mortality risk factors in older inpatients with COVID-19 and neuropsychiatric conditions may be helpful to neurologists and geriatricians who manage these patients in clinical practice.

Electroencephalogram in the intensive care unit: a focused look at acute brain injury.

Over the past decades, electroencephalography (EEG) has become a widely applied and highly sophisticated brain monitoring tool in a variety of intensive care unit (ICU) settings. The most common indication for EEG monitoring currently is the management of refractory status epilepticus. In addition, a number of studies have associated frequent seizures, including nonconvulsive status epilepticus (NCSE), with worsening secondary brain injury and with worse outcomes. With the widespread utilization of EEG (spot and continuous EEG), rhythmic and periodic patterns that do not fulfill strict seizure criteria have been identified, epidemiologically quantified, and linked to pathophysiological events across a wide spectrum of critical and acute illnesses, including acute brain injury. Increasingly, EEG is not just qualitatively described, but also quantitatively analyzed together with other modalities to generate innovative measurements with possible clinical relevance. In this review, we discuss the current knowledge and emerging applications of EEG in the ICU, including seizure detection, ischemia monitoring, detection of cortical spreading depolarizations, assessment of consciousness and prognostication. We also review some technical aspects and challenges of using EEG in the ICU including the logistics of setting up ICU EEG monitoring in resource-limited settings.

Management of Refractory Status Epilepticus: An International Cohort Study (MORSE CODe) Analysis of Patients Managed in the ICU.

BACKGROUND AND OBJECTIVES: Status epilepticus that continues after the initial benzodiazepine and a second anticonvulsant medication is known as refractory status epilepticus (RSE). Management is highly variable because adequately powered clinical trials are missing. We aimed to determine whether propofol and midazolam were equally effective in controlling RSE in the intensive care unit, focusing on management in resource-limited settings. METHODS: Patients with RSE treated with midazolam or propofol between January 2015 and December 2018 were retrospectively identified among 9 centers across 4 continents from upper-middle-income economies in Latin America and high-income economies in North America, Europe, and Asia. Demographics, Status Epilepticus Severity Score, etiology, treatment details, and discharge modified Rankin Scale (mRS) were collected. The primary outcome measure was good functional outcome defined as a mRS score of 0-2 at hospital discharge. RESULTS: Three hundred eighty-seven episodes of RSE (386 patients) were included, with 162 (42%) from upper-middle-income and 225 (58%) from high-income economies. Three hundred six (79%) had acute and 79 (21%) remote etiologies. Initial RSE management included midazolam in 266 (69%) and propofol in 121 episodes (31%). Seventy episodes (26%) that were initially treated with midazolam and 42 (35%) with propofol required the addition of a second anesthetic to treat RSE. Baseline characteristics and outcomes of patients treated with midazolam or propofol were similar. Breakthrough (odds ratio [OR] 1.6, 95% CI 1.3-2.0) and withdrawal seizures (OR 2.0, 95% CI 1.7-2.5) were associated with an increased number of days requiring continuous intravenous anticonvulsant medications (cIV-ACMs). Prolonged EEG monitoring was associated with fewer days of cIV-ACMs (1-24 hours OR 0.5, 95% CI 0.2-0.9, and >24 hours OR 0.7, 95% CI 0.5-1.0; reference EEG <1 hour). This association was seen in both, high-income and upper-middle-income economies, but was particularly prominent in high-income countries. One hundred ten patients (28%) were dead, and 80 (21%) had good functional outcomes at hospital discharge. DISCUSSION: Outcomes of patients with RSE managed in the intensive care unit with propofol or midazolam infusions are comparable. Prolonged EEG monitoring may allow physicians to decrease the duration of anesthetic infusions safely, but this will depend on the implementation of RSE management protocols. Goal-directed management approaches including EEG targets may hold promise for patients with RSE. CLASSIFICATION OF EVIDENCE: This study provides Class III data that propofol and midazolam are equivalently efficacious for RSE.

Cognitive-motor dissociation and time to functional recovery in patients with acute brain injury in the USA: a prospective observational cohort study.

BACKGROUND: Recovery trajectories of clinically unresponsive patients with acute brain injury are largely uncertain. Brain activation in the absence of a behavioural response to spoken motor commands can be detected by EEG, also known as cognitive-motor dissociation. We aimed to explore the role of cognitive-motor dissociation in predicting time to recovery in patients with acute brain injury. METHODS: In this observational cohort study, we prospectively studied two independent cohorts of clinically unresponsive patients (aged ≥18 years) with acute brain injury. Machine learning was applied to EEG recordings to diagnose cognitive-motor dissociation by detecting brain activation in response to verbal commands. Survival statistics and shift analyses were applied to the data to identify an association between cognitive-motor dissociation and time to and magnitude of recovery. The prediction accuracy of the model that was built using the derivation cohort was assessed using the validation cohort. Functional outcomes of all patients were assessed with the Glasgow Outcome Scale-Extended (GOS-E) at hospital discharge and at 3, 6, and 12 months after injury. Patients who underwent withdrawal of life-sustaining therapies were censored, and death was treated as a competing risk. FINDINGS: Between July 1, 2014, and Sept 30, 2021, we screened 598 patients with acute brain injury and included 193 (32%) patients, of whom 100 were in the derivation cohort and 93 were in the validation cohort. At 12 months, 28 (15%) of 193 unresponsive patients had a GOS-E score of 4 or above. Cognitive-motor dissociation was seen in 27 (14%) patients and was an independent predictor of shorter time to good recovery (hazard ratio 5·6 [95% CI 2·5-12·5]), as was underlying traumatic brain injury or subdural haematoma (4·4 [1·4-14·0]), a Glasgow Coma Scale score on admission of greater than or equal to 8 (2·2 [1·0-4·7]), and younger age (1·0 [1·0-1·1]). Among patients discharged home or to a rehabilitation setting, those diagnosed with cognitive-motor dissociation consistently had higher scores on GOS-E indicating better functional recovery compared with those without cognitive-motor dissociation, which was seen as early as 3 months after the injury (odds ratio 4·5 [95% CI 2·0-33·6]). INTERPRETATION: Recovery trajectories of clinically unresponsive patients diagnosed with cognitive-motor dissociation early after brain injury are distinctly different from those without cognitive-motor dissociation. A diagnosis of cognitive-motor dissociation could inform the counselling of families of clinically unresponsive patients, and it could help clinicians to identify patients who will benefit from rehabilitation. FUNDING: US National Institutes of Health.

Clinico-biological markers for the prognosis of status epilepticus in adults.

Prediction of mortality, functional outcome and recovery after status epilepticus (SE) is a challenge. Biological and clinical markers have been proposed to reflect the brain injury or to monitor critical ill patients' severity. The aim of this study was to characterize short-term and long-term prognostic factors for SE patients hospitalized in intensive care unit. Patient's outcome was assessed using the modified Rankin Scale at discharge and after 6-12 months. We first assessed the univariate prognosis significance of 51 clinical, demographic or biochemical markers. Next, we built multivariate clinico-biological models by combining most important factors. Statistical models' performances were compared to those of two previous published scales STESS and mSTESS. Eighty-one patients were enrolled. Thirty-five patients showed a steady state while 46 patients clinically worsened at discharge: 14 died, 14 had persistent disability at 6-12 months and 18 recovered. Logistic regression analysis revealed that clinical markers (SE refractoriness, SE duration, de novo SE) were significant independent predictors of worsening while lipids markers and progranulin better predicted mortality. The association of clinico-biological variables allowed to accurately predict worsening at discharge (AUC > 0.72), mortality at discharge (AUC 0.83) and recovery at long-term (AUC 0.89). Previous scales provided lower prediction for worsening (AUC 0.63, STESS; 0.53, mSTESS) and mortality (AUC 0.56, STESS; 0.62, mSTESS) (p < 0.001). We proposed new clinico-biological models with a strong discrimination power for prediction of short- and long-term outcome of hospitalized status epilepticus patients. Their implementation in electronic devices may enhance their clinical liability.

Proceedings of the Second Curing Coma Campaign NIH Symposium: Challenging the Future of Research for Coma and Disorders of Consciousness.

This proceedings article presents actionable research targets on the basis of the presentations and discussions at the 2nd Curing Coma National Institutes of Health (NIH) symposium held from May 3 to May 5, 2021. Here, we summarize the background, research priorities, panel discussions, and deliverables discussed during the symposium across six major domains related to disorders of consciousness. The six domains include (1) Biology of Coma, (2) Coma Database, (3) Neuroprognostication, (4) Care of Comatose Patients, (5) Early Clinical Trials, and (6) Long-term Recovery. Following the 1st Curing Coma NIH virtual symposium held on September 9 to September 10, 2020, six workgroups, each consisting of field experts in respective domains, were formed and tasked with identifying gaps and developing key priorities and deliverables to advance the mission of the Curing Coma Campaign. The highly interactive and inspiring presentations and panel discussions during the 3-day virtual NIH symposium identified several action items for the Curing Coma Campaign mission, which we summarize in this article.