Clinical and advanced neurophysiology in the prognostic and diagnostic evaluation of disorders of consciousness: review of an IFCN-endorsed expert group.

The analysis of spontaneous EEG activity and evoked potentialsis a cornerstone of the instrumental evaluation of patients with disorders of consciousness (DoC). Thepast few years have witnessed an unprecedented surge in EEG-related research applied to the prediction and detection of recovery of consciousness after severe brain injury,opening up the prospect that new concepts and tools may be available at the bedside. This paper provides a comprehensive, critical overview of bothconsolidated and investigational electrophysiological techniquesfor the prognostic and diagnostic assessment of DoC.We describe conventional clinical EEG approaches, then focus on evoked and event-related potentials, and finally we analyze the potential of novel research findings. In doing so, we (i) draw a distinction between acute, prolonged and chronic phases of DoC, (ii) attempt to relate both clinical and research findings to the underlying neuronal processes and (iii) discuss technical and conceptual caveats.The primary aim of this narrative review is to bridge the gap between standard and emerging electrophysiological measures for the detection and prediction of recovery of consciousness. The ultimate scope is to provide a reference and common ground for academic researchers active in the field of neurophysiology and clinicians engaged in intensive care unit and rehabilitation.

The Clinical Diagnostic Utility of Electrophysiological Techniques in Assessment of Patients With Disorders of Consciousness Following Acquired Brain Injury: A Systematic Review.

OBJECTIVE: To investigate the diagnostic utility of electrophysiological recordings during active cognitive tasks in detecting residual cognitive capacities in patients with disorders of consciousness (DoC) after severe acquired brain injury. DESIGN: Systematic review of empirical research in MEDLINE, Embase, PsycINFO, and Cochrane from January 2002 to March 2016. MAIN MEASURES: Data extracted included sample size, type of electrophysiological technique and task design, rate of cognitive responders, false negatives and positives, and excluded subjects from the study analysis. The Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) was used for quality appraisal of the retrieved literature. RESULTS: Twenty-four studies examining electrophysiological signs of command-following in patients with DoC were identified. Sensitivity rates in healthy controls demonstrated variable accuracy across the studies, ranging from 71% to 100%. In patients with DoC, specificity and sensitivity rates varied in the included studies, ranging from 0% to 100%. Pronounced heterogeneity was found between studies regarding methodological approaches, task design, and procedures of analysis, rendering comparison between studies challenging. CONCLUSION: We are still far from establishing precise recommendations for standardized electrophysiological diagnostic procedures in DoC, but electrophysiological methods may add supplemental diagnostic information of covert cognition in some patients with DoC.

Spasticity in disorders of consciousness: a behavioral study.

BACKGROUND: Spasticity is a frequent complication after severe brain injury, which may impede the rehabilitation process and diminish the patients' quality of life. AIM: We here investigate the presence of spasticity in a population of non-communicative patients with disorders of consciousness. We also evaluate the correlation between spasticity and potential factors of co-morbidity, frequency of physical therapy, time since insult, presence of pain, presence of tendon retraction, etiology and diagnosis. DESIGN: Cross-sectional study. SETTING: University Hospital of Liège, Belgium. POPULATION: Sixty-five patients with chronic (>3 months post insult) disorders of consciousness were included (22 women; mean age: 44±14 y; 40 with traumatic etiology; 40 in a minimally conscious state; time since insult: 39±37 months). METHODS: Spasticity was measured with the Modified Ashworth Scale (MAS) and pain was assessed using the Nociception Coma Scale-Revised (NCS-R). RESULTS: Out of 65 patients, 58 demonstrated signs of spasticity (89%; MAS≥1), including 40 who showed severe spasticity (61.5%; MAS≥3). Patients with spasticity receiving anti-spastic medication were more spastic than unmedicated patients. A negative correlation was observed between the severity of spasticity and the frequency of physical therapy. MAS scores correlated positively with time since injury and NCS-R scores. We did not observe a difference of spasticity between the diagnoses. CONCLUSION: A large proportion of patients with disorders of consciousness develop severe spasticity, possibly affecting their functional recovery and their quality of life. The observed correlation between degrees of spasticity and pain scores highlights the importance of pain management in these patients with altered states of consciousness. Finally, the relationship between spasticity and treatment (i.e., pharmacological and physical therapy) should be further investigated in order to improve clinical care. CLINICAL REHABILITATION IMPACT: Managing spasticity at first signs could improve rehabilitation of patients with disorders of consciousness and maximize their chances of recovery. In addition, decreasing this trouble could allow a better quality of life for these non-communicative patients.

A study of the reliability of the Nociception Coma Scale.

OBJECTIVE: In this study, we investigated the reliability of the Nociception Coma Scale which has recently been developed to assess nociception in non-communicative, severely brain-injured patients. DESIGN: Prospective cross-sequential study. SETTING: Semi-intensive care unit and long-term brain injury care. SUBJECTS: Forty-four patients diagnosed as being in a vegetative state (n=26) or in a minimally conscious state (n=18). INTERVENTIONS: Patients were assessed by two experts (rater A and rater B) on two consecutive weeks to measure inter-rater agreement and test-retest reliability. MAIN MEASURES: Total scores and subscores of the Nociception Coma Scale. RESULTS: We performed a total of 176 assessments. The inter-rater agreement was moderate for the total scores (k = 0.57) and fair to substantial for the subscores (0.33 ≤ k ≤ 0.62) on week 2. The test-retest reliability was substantial for the total scores (k = 0.66) and moderate to almost perfect for the subscores (0.53 ≤ k ≤ 0.96) for rater A. The inter-rater agreement was weaker on week 1, whereas the test-retest reliability was lower for the least experienced rater (rater B). CONCLUSIONS: This study provides further evidence of the psychometric qualities of the Nociception Coma Scale. Future studies should assess the impact of practical experience and background on administration and scoring of the scale.

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.

Burnout in healthcare workers managing chronic patients with disorders of consciousness.

OBJECTIVES: The aim of this study was to assess the presence of burnout among professional caregivers managing patients with severe brain injury recovering from coma and working in neurorehabilitation centres or nursing homes. METHODS: The Maslach Burnout Inventory was sent to 40 centres involved in the Belgian federal network for the care of vegetative and minimally conscious patients. The following demographic data were also collected: age, gender, profession, expertise in the field, amount of time spent with patients and working place. RESULTS: Out of 1068 questionnaires sent, 568 were collected (53% response rate). Forty-five were excluded due to missing data. From the 523 healthcare workers, 18% (n = 93) presented a burnout, 33% (n = 171) showed emotional exhaustion and 36% (n = 186) had a depersonalization. Profession (i.e. nurse/nursing assistants), working place (i.e. nursing home) and the amount of time spent with patients were associated with burnout. The logistic regression showed that profession was nevertheless the strongest variable linked to burnout. CONCLUSIONS: According to this study, a significant percentage of professional caregivers and particularly nurses taking care of patients in a vegetative state and in a minimally conscious state suffered from burnout. Prevention of burnout symptoms among caregivers is crucial and is expected to promote more efficient medical care of these challenging patients.

What about pain in disorders of consciousness?

The management and treatment of acute pain is very difficult in non-communicative patients with disorders of consciousness (i.e., vegetative state/unresponsive wakefulness syndrome (VS/UWS) and minimally conscious state), creating an ethical dilemma for caregivers and an emotional burden among both relatives and caregivers. In this review, we summarize recent findings about the neural substrates of nociception and pain in VS/UWS patients as well as recent behavioral assessment methods of nociception specifically designed for patients in altered states of consciousness. We will finally discuss implications for pain treatment in these patients.

Cognitive processes in disorders of consciousness as revealed by EEG time-frequency analyses.

OBJECTIVE: Although behavioral evaluation of awareness in disorders of consciousness is difficult it remains the clinical standard. We believe that the refinement of EEG and analyses techniques would improve our characterization of those patients. METHODS: We focused on cognitive processing in a sample of 12 control subjects, eight vegetative-state patients, and 13 patients in the minimally consciousness state using EEG. We used an 'active paradigm' which asks subjects to follow instructions, specifically to actively count own or other names as compared to passively listening to them. EEG data was then analyzed using an advanced EEG analysis technique. RESULTS: Results revealed that all groups exhibit a stronger theta-synchronization to their own names when forced to count them. We also observed a delay in theta power in response to targets relative to non-targets when participants were instructed to count their own name. CONCLUSION: Active paradigms are able to induce a different oscillatory activity compared to passive paradigms. Differences between controls and the pathologic groups are prominent in the theta- and alpha-band. SIGNIFICANCE: Time-frequency analyses allow to focus on distinct cognitive processes in patients with disorders of consciousness and thereby contribute to a refined understanding of severely brain-injured patients.

Attitudes towards end-of-life issues in disorders of consciousness: a European survey.

Previous European surveys showed the support of healthcare professionals for treatment withdrawal [i.e., artificial nutrition and hydration (ANH) in chronic vegetative state (VS) patients]. The recent definition of minimally conscious state (MCS), and possibly research advances (e.g., functional neuroimaging), may have lead to uncertainty regarding potential residual perception and may have influenced opinions of healthcare professionals. The aim of the study was to update the end-of-life attitudes towards VS and to determine the end-of-life attitudes towards MCS. A 16-item questionnaire related to consciousness, pain and end-of-life issues in chronic (i.e., >1 year) VS and MCS and locked-in syndrome was distributed among attendants of medical and scientific conferences around Europe (n = 59). During a lecture, the items were explained orally to the attendants who needed to provide written yes/no responses. Chi-square tests and logistic regression analyses identified differences and associations for age, European region, religiosity, profession, and gender. We here report data on items concerning end-of-life issues on chronic VS and MCS. Responses were collected from 2,475 participants. For chronic VS (>1 year), 66% of healthcare professionals agreed to withdraw treatment and 82% wished not to be kept alive (P < 0.001). For chronic MCS (>1 year), less attendants agreed to withdraw treatment (28%, P < 0.001) and wished not to be kept alive (67%, P < 0.001). MCS was considered worse than VS for the patients in 54% and for their families in 42% of the sample. Respondents' opinions were associated with geographic region and religiosity. Our data show that end-of-life opinions differ for VS as compared to MCS. The introduction of the diagnostic criteria for MCS has not substantially changed the opinions on end-of-life issues on permanent VS. Additionally, the existing legal ambiguity around MCS may have influenced the audience to draw a line between expressing preferences for self versus others, by implicitly recognizing that the latter could be a step on the slippery slope to legalize euthanasia. Given the observed individual variability, we stress the importance of advance directives and identification of proxies when discussing end-of-life issues in patients with disorders of consciousness.

[The Sensory Modality Assessment and Rehabilitation Technique (SMART): a behavioral assessment scale for disorders of consciousness]. / La Sensory Modality Assessment and Rehabilitation Technique (SMART) : une échelle comportementale d'évaluation et de revalidation pour des états altérés de conscience.

INTRODUCTION: Difficulties in detecting bedside signs of consciousness in non-communicative patients still lead to a high rate of misdiagnosis illustrating the need to employ standardized behavioral assessment scales. STATE OF ART: The Sensory Modality Assessment and Rehabilitation Technique (SMART) is a behavioral assessment scale of consciousness that assesses responses to multimodal sensory stimulation in disorders of consciousness. These stimulations can also be considered to have therapeutic value. PERSPECTIVES: We here review the different components and use of the SMART assessment and discuss its validity, reliability, and robustness in clinical practice. The scale has a high intra- and inter-observer reliability thanks to a detailed procedure description. However, in the absence of objective gold standards in the assessment of consciousness, it is currently difficult to make strong claims about its validity. A comparison between SMART and other standardized and validated coma-scales is proposed. CONCLUSION: In our view, SMART is an interesting tool for monitoring patients with altered states of consciousness subsequent to coma. Currently, we await studies on its concurrent validity as compared to other validated behavioral assessment scales and on the effect of SMART stimulations on patient outcome.

Disorders of consciousness: Moving from passive to resting state and active paradigms.

Following coma, some patients will recover wakefulness without signs of consciousness (i.e., vegetative state) or may show nonreflexive movements but with no ability for functional communication (i.e., minimally conscious state). Currently, there remains a high rate of misdiagnosis of the vegetative state. The increasing use of fMRI and EEG tools permits the clinical characterization of these patients to be improved. We first discuss "resting metabolism" and "passive activation" paradigms, used in neuroimaging and evoked potential studies, which merely identify neural activation reflecting "automatic" processing-that is, occurring without the patient's willful intervention. Secondly, we present an alternative approach consisting of instructing subjects to imagine well-defined sensory-motor or cognitive-mental actions. This strategy reflects volitional neural activation and, hence, witnesses awareness. Finally, we present results on blood-oxgen-level-dependent "default mode network"/resting state studies that might be a promising tool in the diagnosis of these challenging patients.

Different beliefs about pain perception in the vegetative and minimally conscious states: a European survey of medical and paramedical professionals.

Pain management in severely brain-damaged patients constitutes a clinical and ethical stake. At the bedside, assessing the presence of pain and suffering is challenging due to both patients' physical condition and inherent limitations of clinical assessment. Neuroimaging studies support the existence of distinct cerebral responses to noxious stimulation in brain death, vegetative state, and minimally conscious state. We here provide results from a European survey on 2059 medical and paramedical professionals' beliefs on possible pain perception in patients with disorders of consciousness. To the question "Do you think that patients in a vegetative state can feel pain?," 68% of the interviewed paramedical caregivers (n=538) and 56% of medical doctors (n=1166) answered "yes" (no data on exact profession in 17% of total sample). Logistic regression analysis showed that paramedical professionals, religious caregivers, and older caregivers reported more often that vegetative patients may experience pain. Following professional background, religion was the highest predictor of caregivers' opinion: 64% of religious (n=1009; 850 Christians) versus 52% of nonreligious respondents (n=830) answered positively (missing data on religion in 11% of total sample). To the question "Do you think that patients in a minimally conscious state can feel pain?" nearly all interviewed caregivers answered "yes" (96% of the medical doctors and 97% of the paramedical caregivers). Women and religious caregivers reported more often that minimally conscious patients may experience pain. These results are discussed in terms of existing definitions of pain and suffering, the remaining uncertainty on the clinical assessment of pain as a subjective first-person experience and recent functional neuroimaging findings on nociceptive processing in disorders of consciousness. In our view, more research is needed to increase our understanding of residual sensation in vegetative and minimally conscious patients and to propose evidence-based medical guidelines for the management of possible pain perception and suffering in these vulnerable patient populations.

Pain and non-pain processing during hypnosis: a thulium-YAG event-related fMRI study.

The neural mechanisms underlying the antinociceptive effects of hypnosis still remain unclear. Using a parametric single-trial thulium-YAG laser fMRI paradigm, we assessed changes in brain activation and connectivity related to the hypnotic state as compared to normal wakefulness in 13 healthy volunteers. Behaviorally, a difference in subjective ratings was found between normal wakefulness and hypnotic state for both non-painful and painful intensity-matched stimuli applied to the left hand. In normal wakefulness, non-painful range stimuli activated brainstem, contralateral primary somatosensory (S1) and bilateral insular cortices. Painful stimuli activated additional areas encompassing thalamus, bilateral striatum, anterior cingulate (ACC), premotor and dorsolateral prefrontal cortices. In hypnosis, intensity-matched stimuli in both the non-painful and painful range failed to elicit any cerebral activation. The interaction analysis identified that contralateral thalamus, bilateral striatum and ACC activated more in normal wakefulness compared to hypnosis during painful versus non-painful stimulation. Finally, we demonstrated hypnosis-related increases in functional connectivity between S1 and distant anterior insular and prefrontal cortices, possibly reflecting top-down modulation.

Functional connectivity in the default network during resting state is preserved in a vegetative but not in a brain dead patient.

Recent studies on spontaneous fluctuations in the functional MRI blood oxygen level-dependent (BOLD) signal in awake healthy subjects showed the presence of coherent fluctuations among functionally defined neuroanatomical networks. However, the functional significance of these spontaneous BOLD fluctuations remains poorly understood. By means of 3 T functional MRI, we demonstrate absent cortico-thalamic BOLD functional connectivity (i.e. between posterior cingulate/precuneal cortex and medial thalamus), but preserved cortico-cortical connectivity within the default network in a case of vegetative state (VS) studied 2.5 years following cardio-respiratory arrest, as documented by extensive behavioral and paraclinical assessments. In the VS patient, as in age-matched controls, anticorrelations could also be observed between posterior cingulate/precuneus and a previously identified task-positive cortical network. Both correlations and anticorrelations were significantly reduced in VS as compared to controls. A similar approach in a brain dead patient did not show any such long-distance functional connectivity. We conclude that some slow coherent BOLD fluctuations previously identified in healthy awake human brain can be found in alive but unaware patients, and are thus unlikely to be uniquely due to ongoing modifications of conscious thoughts. Future studies are needed to give a full characterization of default network connectivity in the VS patients population.

Diagnostic and prognostic use of bispectral index in coma, vegetative state and related disorders.

PRIMARY OBJECTIVE: This study investigates (1) the utility of the bispectral index (BIS) to distinguish levels of consciousness in severely brain damaged patients and, particularly, disentangle vegetative state (VS) from minimally conscious state (MCS), as compared to other EEG parameters; (2) the prognostic value of BIS with regards to recovery after 1 year. RESEARCH DESIGN: Multi-centric prospective study. METHOD AND PROCEDURES: Unsedated patients recovering from coma were followed until death or transferal. Automated electrophysiological and standardized behavioural assessments were carried out twice a week. EEG recordings were categorized according to level of consciousness (coma, VS, MCS and Exit MCS). Outcome was assessed at 1 year post-insult. MAIN OUTCOMES AND RESULTS: One hundred and fifty-six EEG epochs obtained in 43 patients were included in the analyses. BIS showed a higher correlation with behavioural scales as compared to other EEG parameters. Moreover, BIS values differentiated levels of consciousness and distinguished VS from MCS while other EEG parameters did not. Finally, higher BIS values were found in patients who recovered at 1 year post-insult as compared to patients who did not recover. CONCLUSION: EEG-BIS recording is an interesting additional method to help in the diagnosis as well as in the prognosis of severely brain injured patients recovering from coma.

Voluntary brain processing in disorders of consciousness.

BACKGROUND: Disentangling the vegetative state from the minimally conscious state is often difficult when relying only on behavioral observation. In this study, we explored a new active evoked-related potentials paradigm as an alternative method for the detection of voluntary brain activity. METHODS: The participants were 22 right-handed patients (10 traumatic) diagnosed as being in a vegetative state (VS) (n = 8) or in a minimally conscious state (MCS) (n = 14). They were presented sequences of names containing the patient's own name or other names, in both passive and active conditions. In the active condition, the patients were instructed to count her or his own name or to count another target name. RESULTS: Like controls, MCS patients presented a larger P3 to the patient's own name, in the passive and in the active conditions. Moreover, the P3 to target stimuli was higher in the active than in the passive condition, suggesting voluntary compliance to task instructions like controls. These responses were even observed in patients with low behavioral responses (e.g., visual fixation and pursuit). In contrast, no P3 differences between passive and active conditions were observed for VS patients. CONCLUSIONS: The present results suggest that active evoked-related potentials paradigms may permit detection of voluntary brain function in patients with severe brain damage who present with a disorder of consciousness, even when the patient may present with very limited to questionably any signs of awareness.

[Hypnosis and pain perception]. / Hypnose et perception de la douleur.

Improvement in functional neuroimaging allows researchers to disentangle the brain mechanisms involved in the pain modulation encountered during hypnosis. It has been shown that the anterior cingulate and prefrontal cortices are important in the modulation of incoming sensory and noxious input. Moreover, clinical studies in certain types of surgery (eg thyroidectomy, mastectomy and plastic surgery) have demonstrated that hypnosis may avoid general anesthesia.

[Pain assessment in non-communicative patients]. / Mesurer la douleur chez le patient non communicant.

Pain is a subjective experience. Its assessment is based on the subject's direct verbal report. This method of assessment is, however, impossible in patients who cannot communicate their feelings. In this context, indirect measurements such as behavioral observations or physiological measurements are needed. To facilitate the assessment of pain in non-communicative patients, numerous standardized behavioral scales have been developed. The aim of this review is to discuss the main validated pain scales employed in end-stage dementia, newborn and preverbal children, and severely brain damaged patients with a disorder of consciousness such as coma, the vegetative state or the minimally conscious state.

[Near-death experiences: fact and fancy]. / Expériences de mort imminente: phénomènes paranormaux ou neurologiques?

Seeing a bright light at the end of a tunnel or having a sense of being out of the physical body are phenomena that some patients report after having been close to death. Some spiritual and psychological theories have been developed in order to explain these near-death-experiences. Clinical studies have aimed to determine their frequency and to assess their precipitating factors. Recent neuroimaging studies, however, have shown the involvement of the temporo-parietal cortex in the generation of out-of-body experiences and are offering a physiological, neurological account for the phenomenon, rebuffing dualistic, non-physical explanations.