The neuroethics of disorders of consciousness: a brief history of evolving ideas.

Neuroethical questions raised by recent advances in the diagnosis and treatment of disorders of consciousness are rapidly expanding, increasingly relevant and yet underexplored. The aim of this thematic review is to provide a clinically applicable framework for understanding the current taxonomy of disorders of consciousness and to propose an approach to identifying and critically evaluating actionable neuroethical issues that are frequently encountered in research and clinical care for this vulnerable population. Increased awareness of these issues and clarity about opportunities for optimizing ethically responsible care in this domain are especially timely given recent surges in critically ill patients with prolonged disorders of consciousness associated with coronavirus disease 2019 around the world. We begin with an overview of the field of neuroethics: what it is, its history and evolution in the context of biomedical ethics at large. We then explore nomenclature used in disorders of consciousness, covering categories proposed by the American Academy of Neurology, the American Congress of Rehabilitation Medicine and the National Institute on Disability, Independent Living and Rehabilitation Research, including definitions of terms such as coma, the vegetative state, unresponsive wakefulness syndrome, minimally conscious state, covert consciousness and the confusional state. We discuss why these definitions matter, and why there has been such evolution in this nosology over the years, from Jennett and Plum in 1972 to the Multi-Society Task Force in 1994, the Aspen Working Group in 2002 and the 2018 American and 2020 European Disorders of Consciousness guidelines. We then move to a discussion of clinical aspects of disorders of consciousness, the natural history of recovery and ethical issues that arise within the context of caring for people with disorders of consciousness. We conclude with a discussion of key challenges associated with assessing residual consciousness in disorders of consciousness, potential solutions and future directions, including integration of crucial disability rights perspectives.

The Curing Coma Campaign: Framing Initial Scientific Challenges-Proceedings of the First Curing Coma Campaign Scientific Advisory Council Meeting.

Coma and disordered consciousness are common manifestations of acute neurological conditions and are among the most pervasive and challenging aspects of treatment in neurocritical care. Gaps exist in patient assessment, outcome prognostication, and treatment directed specifically at improving consciousness and cognitive recovery. In 2019, the Neurocritical Care Society (NCS) launched the Curing Coma Campaign in order to address the "grand challenge" of improving the management of patients with coma and decreased consciousness. One of the first steps was to bring together a Scientific Advisory Council including coma scientists, neurointensivists, neurorehabilitationists, and implementation experts in order to address the current scientific landscape and begin to develop a framework on how to move forward. This manuscript describes the proceedings of the first Curing Coma Campaign Scientific Advisory Council meeting which occurred in conjunction with the NCS Annual Meeting in October 2019 in Vancouver. Specifically, three major pillars were identified which should be considered: endotyping of coma and disorders of consciousness, biomarkers, and proof-of-concept clinical trials. Each is summarized with regard to current approach, benefits to the patient, family, and clinicians, and next steps. Integration of these three pillars will be essential to the success of the Curing Coma Campaign as will expanding the "curing coma community" to ensure broad participation of clinicians, scientists, and patient advocates with the goal of identifying and implementing treatments to fundamentally improve the outcome of patients.

Prognostic Value of Neurological Status on Hospital Arrival for Short-Term Outcome in Patients With Cardiovascular Shock　- Sub-analysis of the Japanese Circulation Society Cardiovascular Shock Registry.

BACKGROUND: Consciousness disturbance is one of the major clinical signs associated with shock state, but its prognostic value has not been previously evaluated in cardiovascular shock patients. We aimed to evaluate the prognostic value of neurological status for 30-day mortality in cardiovascular shock patients without out-of-hospital cardiac arrest (OHCA). Methods and Results: Patients with out-of-hospital onset cardiovascular shock were recruited from the Japanese Circulation Society Shock Registry. Neurological status upon hospital arrival was evaluated using the Japan Coma Scale (JCS). Patients were divided into 4 groups according to the JCS: alert, JCS 0; awake, JCS 1-3 (not fully alert but awake without any stimuli); arousable, JCS 10-30 (arousable with stimulation); and coma JCS 100-300 (unarousable). The primary endpoint was 30-day all-cause death. In total, 700 cardiovascular shock patients without OHCA were assessed. The coma group was associated with a higher incidence of 30-day all-cause death compared with other groups (alert, 15.3%; awake, 24.4%; arousable, 36.8%; coma, 48.5%, P<0.001). Similar trends were observed in etiologically divergent subgroups (acute coronary syndrome, non-ischemic arrhythmia, and aortic disease). On multivariate Cox regression analysis, arousable (hazard ratio [HR], 1.82; 95% CI: 1.16-2.85, P=0.009) and coma (HR, 2.72; 95% CI: 1.76-4.22, P<0.001) (reference: alert) independently predicted 30-day mortality. CONCLUSIONS: Neurological status upon hospital arrival was useful to predict 30-day mortality in cardiovascular shock patients without OHCA.

Minimally conscious state or cortically mediated state?

Durable impairments of consciousness are currently classified in three main neurological categories: comatose state, vegetative state (also recently coined unresponsive wakefulness syndrome) and minimally conscious state. While the introduction of minimally conscious state, in 2002, was a major progress to help clinicians recognize complex non-reflexive behaviours in the absence of functional communication, it raises several problems. The most important issue related to minimally conscious state lies in its criteria: while behavioural definition of minimally conscious state lacks any direct evidence of patient's conscious content or conscious state, it includes the adjective 'conscious'. I discuss this major problem in this review and propose a novel interpretation of minimally conscious state: its criteria do not inform us about the potential residual consciousness of patients, but they do inform us with certainty about the presence of a cortically mediated state. Based on this constructive criticism review, I suggest three proposals aiming at improving the way we describe the subjective and cognitive state of non-communicating patients. In particular, I present a tentative new classification of impairments of consciousness that combines behavioural evidence with functional brain imaging data, in order to probe directly and univocally residual conscious processes.

Robust EEG-based cross-site and cross-protocol classification of states of consciousness.

Determining the state of consciousness in patients with disorders of consciousness is a challenging practical and theoretical problem. Recent findings suggest that multiple markers of brain activity extracted from the EEG may index the state of consciousness in the human brain. Furthermore, machine learning has been found to optimize their capacity to discriminate different states of consciousness in clinical practice. However, it is unknown how dependable these EEG markers are in the face of signal variability because of different EEG configurations, EEG protocols and subpopulations from different centres encountered in practice. In this study we analysed 327 recordings of patients with disorders of consciousness (148 unresponsive wakefulness syndrome and 179 minimally conscious state) and 66 healthy controls obtained in two independent research centres (Paris Pitié-Salpêtrière and Liège). We first show that a non-parametric classifier based on ensembles of decision trees provides robust out-of-sample performance on unseen data with a predictive area under the curve (AUC) of ~0.77 that was only marginally affected when using alternative EEG configurations (different numbers and positions of sensors, numbers of epochs, average AUC = 0.750 ± 0.014). In a second step, we observed that classifiers based on multiple as well as single EEG features generalize to recordings obtained from different patient cohorts, EEG protocols and different centres. However, the multivariate model always performed best with a predictive AUC of 0.73 for generalization from Paris 1 to Paris 2 datasets, and an AUC of 0.78 from Paris to Liège datasets. Using simulations, we subsequently demonstrate that multivariate pattern classification has a decisive performance advantage over univariate classification as the stability of EEG features decreases, as different EEG configurations are used for feature-extraction or as noise is added. Moreover, we show that the generalization performance from Paris to Liège remains stable even if up to 20% of the diagnostic labels are randomly flipped. Finally, consistent with recent literature, analysis of the learned decision rules of our classifier suggested that markers related to dynamic fluctuations in theta and alpha frequency bands carried independent information and were most influential. Our findings demonstrate that EEG markers of consciousness can be reliably, economically and automatically identified with machine learning in various clinical and acquisition contexts.

Disorders of consciousness terminology: history, evolution and future directions.

There has been a significant evolution of nomenclature with regards to classification of persons with disorders of consciousness (DoC) over the last 100 years. This paper provides a review of the evolution of this terminology with discussion of the advantages and disadvantages of historical and current terms. Recommendations for how this evolution should continue moving forward in the best interest of patients, their families, society, clinical care, and research will also be addressed. The taxonomy we choose, hopefully by international consensus, has multifaceted implications that go well beyond just a debate on nomenclature.

An NHS Trust and others v Y and another [2018] UKSC 46: Reducing the Role of the Courts in Treatment Withdrawal.

In An NHS Trust and others v Y and another, the Supreme Court was asked to address the question of whether a court order must always be obtained before clinically assisted nutrition and hydration (CANH), which is keeping alive a person with a prolonged disorder of consciousness (PDOC). This case note explores the Court's decision to dispense with the need for such a court order and analyses that important change in approach from the perspective of the right to life protected in Article 2 European Convention on Human Rights (ECHR) as well as in the broader context of end of life decision-making.

Reforming the taxonomy in disorders of consciousness.

This article examines the serious shortcomings that characterize the current taxonomy of postcomatose disorders of consciousness (DoC), and it provides guidelines for how an improved DoC taxonomy might be developed. In particular, it is argued that behavioral criteria for the application of DoC categories should be supplemented with brain-based criteria (eg, information derived from electroencephalography and functional magnetic resonance imaging), and that the categorical framework that currently characterizes DoC should be replaced by a multidimensional framework that better captures the performance of patients across a range of cognitive and behavioural tasks. Ann Neurol 2017;82:866-872.

Value and mechanisms of EEG reactivity in the prognosis of patients with impaired consciousness: a systematic review.

BACKGROUND: Electroencephalography (EEG) is a well-established tool for assessing brain function that is available at the bedside in the intensive care unit (ICU). This review aims to discuss the relevance of electroencephalographic reactivity (EEG-R) in patients with impaired consciousness and to describe the neurophysiological mechanisms involved. METHODS: We conducted a systematic search of the term "EEG reactivity and coma" using the PubMed database. The search encompassed articles published from inception to March 2018 and produced 202 articles, of which 42 were deemed relevant, assessing the importance of EEG-R in relationship to outcomes in patients with impaired consciousness, and were therefore included in this review. RESULTS: Although definitions, characteristics and methods used to assess EEG-R are heterogeneous, several studies underline that a lack of EEG-R is associated with mortality and unfavorable outcome in patients with impaired consciousness. However, preserved EEG-R is linked to better odds of survival. Exploring EEG-R to nociceptive, auditory, and visual stimuli enables a noninvasive trimodal functional assessment of peripheral and central sensory ascending pathways that project to the brainstem, the thalamus and the cerebral cortex. A lack of EEG-R in patients with impaired consciousness may result from altered modulation of thalamocortical loop activity by afferent sensory input due to neural impairment. Assessing EEG-R is a valuable tool for the diagnosis and outcome prediction of severe brain dysfunction in critically ill patients. CONCLUSIONS: This review emphasizes that whatever the etiology, patients with impaired consciousness featuring a reactive electroencephalogram are more likely to have a favorable outcome, whereas those with a nonreactive electroencephalogram are prone to having an unfavorable outcome. EEG-R is therefore a valuable prognostic parameter and warrants a rigorous assessment. However, current assessment methods are heterogeneous, and no consensus exists. Standardization of stimulation and interpretation methods is needed.

"Look at my classifier's result": Disentangling unresponsive from (minimally) conscious patients.

Given the fact that clinical bedside examinations can have a high rate of misdiagnosis, machine learning techniques based on neuroimaging and electrophysiological measurements are increasingly being considered for comatose patients and patients with unresponsive wakefulness syndrome, a minimally conscious state or locked-in syndrome. Machine learning techniques have the potential to move from group-level statistical results to personalized predictions in a clinical setting. They have been applied for the purpose of (1) detecting changes in brain activation during functional tasks, equivalent to a behavioral command-following test and (2) estimating signs of consciousness by analyzing measurement data obtained from multiple subjects in resting state. In this review, we provide a comprehensive overview of the literature on both approaches and discuss the translation of present findings to clinical practice. We found that most studies struggle with the difficulty of establishing a reliable behavioral assessment and fluctuations in the patient's levels of arousal. Both these factors affect the training and validation of machine learning methods to a considerable degree. In studies involving more than 50 patients, small to moderate evidence was found for the presence of signs of consciousness or good outcome, where one study even showed strong evidence for good outcome.

Stratification of unresponsive patients by an independently validated index of brain complexity.

OBJECTIVE: Validating objective, brain-based indices of consciousness in behaviorally unresponsive patients represents a challenge due to the impossibility of obtaining independent evidence through subjective reports. Here we address this problem by first validating a promising metric of consciousness-the Perturbational Complexity Index (PCI)-in a benchmark population who could confirm the presence or absence of consciousness through subjective reports, and then applying the same index to patients with disorders of consciousness (DOCs). METHODS: The benchmark population encompassed 150 healthy controls and communicative brain-injured subjects in various states of conscious wakefulness, disconnected consciousness, and unconsciousness. Receiver operating characteristic curve analysis was performed to define an optimal cutoff for discriminating between the conscious and unconscious conditions. This cutoff was then applied to a cohort of noncommunicative DOC patients (38 in a minimally conscious state [MCS] and 43 in a vegetative state [VS]). RESULTS: We found an empirical cutoff that discriminated with 100% sensitivity and specificity between the conscious and the unconscious conditions in the benchmark population. This cutoff resulted in a sensitivity of 94.7% in detecting MCS and allowed the identification of a number of unresponsive VS patients (9 of 43) with high values of PCI, overlapping with the distribution of the benchmark conscious condition. INTERPRETATION: Given its high sensitivity and specificity in the benchmark and MCS population, PCI offers a reliable, independently validated stratification of unresponsive patients that has important physiopathological and therapeutic implications. In particular, the high-PCI subgroup of VS patients may retain a capacity for consciousness that is not expressed in behavior. Ann Neurol 2016;80:718-729.

[Unconsciousness and clouded awareness]. / Bewusstseinsstörung oder -trübung.

Stupor and coma are clinical states in which patients have impaired responsiveness or are unresponsive to external stimulation and are either difficult to arouse or are unarousable. The term stupor refer to states between alertness and coma. An alteration in arousal represents an acute life-threatening emergency, requiring prompt intervention for preservation of life and brain function.

Validation of the Chinese version of the FOUR score in the assessment of neurosurgical patients with different level of consciousness.

BACKGROUND: The Glasgow Coma Scale (GCS) is currently the most widely used scoring system for comatose patients. A decade ago, the Full Outline of Unresponsiveness (FOUR) score was devised to better capture four functional aspects of consciousness (eye, motor responses, brainstem reflexes, and respiration). This study aimed to validate the Chinese version of the FOUR score in patients with different levels of consciousness. METHODS: The study had two phases: (1) translation of the FOUR score, and (2) assessment of its reliability and validity. The Chinese version of the FOUR score was developed according to a standardized protocol. One hundred-twenty consecutive patients with acute brain damage, admitted to Nanfang Hospital (Southern Medical University, Guangdong, China) from November 2014 to February 2015, were enrolled. The inter-rater agreement for the FOUR score and GCS was evaluated using intraclass correlation coefficient (ICC). Receiver operating characteristic (ROC) curves were established to determine the scales' abilities to predict outcome. RESULTS: The rater agreement was excellent both for FOUR (ICC = 0.970; p < 0.001) and GCS (ICC = 0.958; p < 0.001). The FOUR score yielded an excellent test-retest reliability (ICC = 0.930; p < 0.001). Spearman's correlation coefficients between GCS and the FOUR score were high: r = 0.932, first rating; r = 0.887, second rating (all p < 0.001). Areas under the curve (AUC) for mortality were 0.834 (95 % CI, 0.740-0.928) and 0.815 (95 % CI, 0.723-0.908) for the FOUR score and GCS, respectively. CONCLUSIONS: The Chinese version of the FOUR score is a reliable scale for evaluating the level of consciousness in patients with acute brain injury.

Large scale screening of neural signatures of consciousness in patients in a vegetative or minimally conscious state.

In recent years, numerous electrophysiological signatures of consciousness have been proposed. Here, we perform a systematic analysis of these electroencephalography markers by quantifying their efficiency in differentiating patients in a vegetative state from those in a minimally conscious or conscious state. Capitalizing on a review of previous experiments and current theories, we identify a series of measures that can be organized into four dimensions: (i) event-related potentials versus ongoing electroencephalography activity; (ii) local dynamics versus inter-electrode information exchange; (iii) spectral patterns versus information complexity; and (iv) average versus fluctuations over the recording session. We analysed a large set of 181 high-density electroencephalography recordings acquired in a 30 minutes protocol. We show that low-frequency power, electroencephalography complexity, and information exchange constitute the most reliable signatures of the conscious state. When combined, these measures synergize to allow an automatic classification of patients' state of consciousness.

Multidisciplinary assessment measure for individuals with disorders of consciousness.

OBJECTIVE: This study introduces the Comprehensive Assessment Measure for the Minimally Responsive Individual (CAMMRI) and reports on its development, inter-rater reliability, construct validity and clinical value. METHODS: A multidisciplinary team of therapists developed this measure, which comprises 12 sub-tests that examine three main areas: Response to the Environment, Motor Control and Communication and Swallowing. The sub-tests are scored using a 7-point scale; sub-tests can also be administered individually. The measure was administered during a pilot project and then 1 year later to 12 adult clients with severe acquired brain injury at a long-term rehabilitation programme. The age range of the participants was 18-65 years; individuals were 1.5-10 years post-injury. RESULTS: Comparison measures included the Western Neuro Sensory Stimulation Profile (WNSSP), the Coma Recovery Scale-Revised (CRS-R) and the Chedoke McMaster Impairment Inventory (CMII). Inter-rater reliability of each sub-test ranged from 0.87-1.0, with an average of 0.90 in the first year of the assessments. CONCLUSION: Validity data supported the use of the CAMMRI for minimally conscious adults with ABI to measure behavioural changes and plan treatment for this population. Future research should focus on using this measure with other neurological populations.

Psychometric properties of the disorders of consciousness scale.

OBJECTIVE: To provide evidence for psychometric properties of the Disorders of Consciousness Scale (DOCS). DESIGN: Prospective observational cohort. SETTINGS: Seven rehabilitation facilities. PARTICIPANTS: Patients (N=174) with severe brain injury. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE DOCS RESULTS: Initial analyses suggested eliminating 6 items to maximize psychometrics, resulting in the DOCS-25. The 25 items form a unidimensional hierarchy, rating scale categories are ordered, there are no misfitting items, and differential item functioning was not found according to sex, type of brain injury, veteran status, and days from onset. Person separation reliability (.91) indicates that the DOCS-25 is appropriate for individual patient measurement. Items are well targeted to the sample, with the difference between mean person and item calibrations less than 1 logit. DOCS-25 Rasch measures result in a 62% gain in relative precision over total raw scores. Internal consistency is very good (Cronbach α=.86); interrater agreement is excellent (intracIass correlation coefficient=.90) for both the DOCS-25 and the sensory subscales. The DOCS-25 total measure, but not subscale measures, correlates with the Glasgow Coma Scale and the Coma/Near-Coma Scales and distinguishes significantly between vegetative and minimally conscious states, indicating concurrent validity. CONCLUSIONS: The DOCS-25 is psychometrically strong. It has excellent measurement precision and captures a broad range of patient function, which is critical for capturing recovery of consciousness. The sensory subscales are clinically informative but should not be reported as separate measures. The Keyform synthesizes clinical observations to visualize response patterns with potential for informing clinical decision-making. Future studies should determine sensitivity to change, examine issues of rater severity, and explore the usefulness of the Keyform in clinical practice.

Clinical assessment of patients with disorders of consciousness.

The study of pathological impairments of consciousness, as they can appear in severely brain injured patients, can be particularly useful to better clarify cognitive processes and cerebral substrates which underlie consciousness. In this review, we will introduce the disorders of consciousness that can be presented by severely brain-injured patients and the behavioural scales that can be used to assess their level of consciousness. We will also discuss the difficulty to assess and detect remnant cognitive functioning in these patients.

Validation of the Full Outline of Unresponsiveness (FOUR) Scale for conscious state in the emergency department: comparison against the Glasgow Coma Scale.

OBJECTIVES: To determine (a) the inter-rater reliability of pairs of emergency doctors' and/or nurses' ratings of the Glasgow Coma Scale (GCS) and the Full Outline of Unresponsiveness (FOUR) Scale in emergency department (ED) patients, (b) the concurrent validity of the FOUR Scale using the GCS as the reference scale and (c) doctors' and nurses' knowledge and attitudes towards the GCS and FOUR Scale. METHODS: A prospective observational study was conducted using staff participants' ratings for a convenience sample of ED patients requiring quantification of conscious state. Participating doctors and nurses attended a formal training session on the correct use of the GCS and FOUR Scale. Pairs of clinicians then independently completed the GCS and FOUR Scale on patients within 5 min of each other. RESULTS: 140 clinicians were recruited and trained in the use of the GCS and FOUR Scale. A total of 217 observations were performed on 203 patients presenting to the ED with various conditions. The inter-rater reliability for the FOUR Scale was greater than that of the GCS (FOUR: к = 0.76, p < 0.01; GCS: к = 0.59, p < 0.01). The reliability for both the GCS and the FOUR Scale was poorest within doctor-nurse pairs. CONCLUSION: The FOUR Scale showed greater reliability than the GCS in ED patients using ED clinicians as raters. A larger study of ED patients is warranted to determine the predictive validity of the FOUR Scale and to further examine the reliability of the scale in various patient populations.

Prolonged disorder of consciousness in children, an update. / Trastornos prolongados de conciencia en pediatría, una mirada actual.

The children who remain in a prolonged disorder of consciousness (PDOC) present a complex clinical, ethical, and legal challenge to health professionals and other caregivers. PDOC is defined as any disorder of consciousness that has continued for at least 4 weeks following sudden-onset brain injury. The PDOC includes the vegetative state/unresponsive wakefulness syndrome (EV/ UWS), and the minimally conscious state (MCS). Patients with PDOC lack of mental capacity to make decisions regarding their care and treatment, so these decisions have to be made for them based on their best benefits. These benefits may vary from patient to patient, between physicians, family, and the general public, creating conflict within their respective efforts to do what they belie ve is right for the patient. The diagnosis is based on clinical evaluations. These evaluations have an estimated misdiagnosis rate up to 45%, therefore they should be complemented with standardized clinical guidelines, and often with neuroimaging and neurophysiological studies. Other aspects that difficult the evaluation are variable definitions and subcategorizations of PDOC, among di fferent groups at the international level. The objective of this review is to present an update of the different types of PDOC, their definition, subcategorization, etiology, prognostic, comprehensive evaluation, and treatment in pediatrics, to contribute to the best clinical practice based on cu rrently available evidence.