Aurore Thibaut

From unresponsive wakefulness to minimally conscious PLUS and functional locked-in syndromes: recent advances in our understanding of disorders of consciousness.

Functional neuroimaging and electrophysiology studies are changing our understanding of patients with coma and related states. Some severely brain damaged patients may show residual cortical processing in the absence of behavioural signs of consciousness. Given these new findings, the diagnostic errors and their potential effects on treatment as well as concerns regarding the negative associations intrinsic to the term vegetative state, the European Task Force on Disorders of Consciousness has recently proposed the more neutral and descriptive term unresponsive wakefulness syndrome. When vegetative/unresponsive patients show minimal signs of consciousness but are unable to reliably communicate the term minimally responsive or minimally conscious state (MCS) is used. MCS was recently subcategorized based on the complexity of patients’ behaviours: MCS+ describes high-level behavioural responses (i.e., command following, intelligible verbalizations or non-functional communication) and MCS− describes low-level behavioural responses (i.e., visual pursuit, localization of noxious stimulation or contingent behaviour such as appropriate smiling or crying to emotional stimuli). Finally, patients who show non-behavioural evidence of consciousness or communication only measurable via para-clinical testing (i.e., functional MRI, positron emission tomography, EEG or evoked potentials) can be considered to be in a functional locked-in syndrome. An improved assessment of brain function in coma and related states is not only changing nosology and medical care but also offers a better-documented diagnosis and prognosis and helps to further identify the neural correlates of human consciousness.

Diagnostic precision of PET imaging and functional MRI in disorders of consciousness: a clinical validation study

BACKGROUND Bedside clinical examinations can have high rates of misdiagnosis of unresponsive wakefulness syndrome (vegetative state) or minimally conscious state. The diagnostic and prognostic usefulness of neuroimaging-based approaches has not been established in a clinical setting. We did a validation study of two neuroimaging-based diagnostic methods: PET imaging and functional MRI (fMRI). METHODS For this clinical validation study, we included patients referred to the University Hospital of Liège, Belgium, between January, 2008, and June, 2012, who were diagnosed by our unit with unresponsive wakefulness syndrome, locked-in syndrome, or minimally conscious state with traumatic or non-traumatic causes. We did repeated standardised clinical assessments with the Coma Recovery Scale-Revised (CRS-R), cerebral (18)F-fluorodeoxyglucose (FDG) PET, and fMRI during mental activation tasks. We calculated the diagnostic accuracy of both imaging methods with CRS-R diagnosis as reference. We assessed outcome after 12 months with the Glasgow Outcome Scale-Extended. FINDINGS We included 41 patients with unresponsive wakefulness syndrome, four with locked-in syndrome, and 81 in a minimally conscious state (48=traumatic, 78=non-traumatic; 110=chronic, 16=subacute). (18)F-FDG PET had high sensitivity for identification of patients in a minimally conscious state (93%, 95% CI 85-98) and high congruence (85%, 77-90) with behavioural CRS-R scores. The active fMRI method was less sensitive at diagnosis of a minimally conscious state (45%, 30-61) and had lower overall congruence with behavioural scores (63%, 51-73) than PET imaging. (18)F-FDG PET correctly predicted outcome in 75 of 102 patients (74%, 64-81), and fMRI in 36 of 65 patients (56%, 43-67). 13 of 41 (32%) of the behaviourally unresponsive patients (ie, diagnosed as unresponsive with CRS-R) showed brain activity compatible with (minimal) consciousness (ie, activity associated with consciousness, but diminished compared with fully conscious individuals) on at least one neuroimaging test; 69% of these (9 of 13) patients subsequently recovered consciousness. INTERPRETATION Cerebral (18)F-FDG PET could be used to complement bedside examinations and predict long-term recovery of patients with unresponsive wakefulness syndrome. Active fMRI might also be useful for differential diagnosis, but seems to be less accurate. FUNDING The Belgian National Funds for Scientific Research (FNRS), Fonds Léon Fredericq, the European Commission, the James McDonnell Foundation, the Mind Science Foundation, the French Speaking Community Concerted Research Action, the University of Copenhagen, and the University of Liège.

Spasticity after stroke: physiology, assessment and treatment.

Abstract Background: Spasticity following a stroke occurs in about 30% of patients. The mechanisms underlying this disorder, however, are not well understood. Method: This review aims to define spasticity, describe hypotheses explaining its development after a stroke, give an overview of related neuroimaging studies as well as a description of the most common scales used to quantify the degree of spasticity and finally explore which treatments are currently being used to treat this disorder. Results: The lack of consensus is highlighted on the basis of spasticity and the associated absence of guidelines for treatment, use of drugs and rehabilitation programmes. Conclusions: Future studies require controlled protocols to determine the efficiency of pharmacological and non-pharmacological treatments for spasticity. Neuroimaging may help predict the occurrence of spasticity and could provide insight into its neurological basis.

tDCS in patients with disorders of consciousness Sham-controlled randomized double-blind study

Objective: We assessed the effects of left dorsolateral prefrontal cortex transcranial direct current stimulation (DLPF-tDCS) on Coma Recovery Scale–Revised (CRS-R) scores in severely brain-damaged patients with disorders of consciousness. Methods: In a double-blind sham-controlled crossover design, anodal and sham tDCS were delivered in randomized order over the left DLPF cortex for 20 minutes in patients in a vegetative state/unresponsive wakefulness syndrome (VS/UWS) or in a minimally conscious state (MCS) assessed at least 1 week after acute traumatic or nontraumatic insult. Clinical assessments were performed using the CRS-R directly before and after anodal and sham tDCS stimulation. Follow-up outcome data were acquired 12 months after inclusion using the Glasgow Outcome Scale–Extended. Results: Patients in MCS (n = 30; interval 43 ± 63 mo; 19 traumatic, 11 nontraumatic) showed a significant treatment effect (p = 0.003) as measured by CRS-R total scores. In patients with VS/UWS (n = 25; interval 24 ± 48 mo; 6 traumatic, 19 nontraumatic), no treatment effect was observed (p = 0.952). Thirteen (43%) patients in MCS and 2 (8%) patients in VS/UWS further showed postanodal tDCS-related signs of consciousness, which were observed neither during the pre-tDCS evaluation nor during the pre- or post-sham evaluation (i.e., tDCS responders). Outcome did not differ between tDCS responders and nonresponders. Conclusion: tDCS over left DLPF cortex may transiently improve signs of consciousness in MCS following severe brain damage as measured by changes in CRS-R total scores. Classification of evidence: This study provides Class II evidence that short-duration tDCS of the left DLPF cortex transiently improves consciousness as measured by CRS-R assessment in patients with MCS.

METABOLIC ACTIVITY IN EXTERNAL AND INTERNAL AWARENESS NETWORKS IN SEVERELY BRAIN-DAMAGED PATIENTS

OBJECTIVE An extrinsic cerebral network (encompassing lateral frontoparietal cortices) related to external/sensory awareness and an intrinsic midline network related to internal/self-awareness have been identified recently. This study measured brain metabolism in both networks in patients with severe brain damage. DESIGN Prospective [18F]-fluorodeoxyglucose-positron emission tomography and Coma Recovery Scale-Revised assessments in a university hospital setting. SUBJECTS Healthy volunteers and patients in vegetative state/unresponsive wakefulness syndrome (VS/UWS), minimally conscious state (MCS), emergence from MCS (EMCS), and locked-in syndrome (LIS). RESULTS A total of 70 patients were included in the study: 24 VS/UWS, 28 MCS, 10 EMCS, 8 LIS and 39 age-matched controls. VS/UWS showed metabolic dysfunction in extrinsic and intrinsic networks and thalami. MCS showed dysfunction mostly in intrinsic network and thalami. EMCS showed impairment in posterior cingulate/retrosplenial cortices. LIS showed dysfunction only in infratentorial regions. Coma Recovery Scale-Revised total scores correlated with metabolic activity in both extrinsic and part of the intrinsic network and thalami. CONCLUSION Progressive recovery of extrinsic and intrinsic awareness network activity was observed in severely brain-damaged patients, ranging from VS/UWS, MCS, EMCS to LIS. The predominance of intrinsic network impairment in MCS could reflect altered internal/self-awareness in these patients, which is difficult to quantify at the bedside.

Neural correlates of consciousness in patients who have emerged from a minimally conscious state: a cross-sectional multimodal imaging study

BACKGROUND Between pathologically impaired consciousness and normal consciousness exists a scarcely researched transition zone, referred to as emergence from minimally conscious state, in which patients regain the capacity for functional communication, object use, or both. We investigated neural correlates of consciousness in these patients compared with patients with disorders of consciousness and healthy controls, by multimodal imaging. METHODS In this cross-sectional, multimodal imaging study, patients with unresponsive wakefulness syndrome, patients in a minimally conscious state, and patients who had emerged from a minimally conscious state, diagnosed with the Coma Recovery Scale-Revised, were recruited from the neurology department of the Centre Hospitalier Universitaire de Liège, Belgium. Key exclusion criteria were neuroimaging examination in an acute state, sedation or anaesthesia during scanning, large focal brain damage, motion parameters of more than 3 mm in translation and 3° in rotation, and suboptimal segmentation and normalisation. We acquired resting state functional and structural MRI data and (18)F-fluorodeoxyglucose (FDG) PET data; we used seed-based functional MRI (fMRI) analysis to investigate positive default mode network connectivity (within-network correlations) and negative default mode network connectivity (between-network anticorrelations). We correlated FDG-PET brain metabolism with fMRI connectivity. We used voxel-based morphometry to test the effect of anatomical deformations on functional connectivity. FINDINGS We recruited a convenience sample of 58 patients (21 [36%] with unresponsive wakefulness syndrome, 24 [41%] in a minimally conscious state, and 13 [22%] who had emerged from a minimally conscious state) and 35 healthy controls between Oct 1, 2009, and Oct 31, 2014. We detected consciousness-level-dependent increases (from unresponsive wakefulness syndrome, minimally conscious state, emergence from minimally conscious state, to healthy controls) for positive and negative default mode network connectivity, brain metabolism, and grey matter volume (p<0·05 false discovery rate corrected for multiple comparisons). Positive default mode network connectivity differed between patients and controls but not among patient groups (F test p<0·0001). Negative default mode network connectivity was only detected in healthy controls and in those who had emerged from a minimally conscious state; patients with unresponsive wakefulness syndrome or in a minimally conscious state showed pathological between-network positive connectivity (hyperconnectivity; F test p<0·0001). Brain metabolism correlated with positive default mode network connectivity (Spearmans r=0·50 [95% CI 0·26 to 0·61]; p<0·0001) and negative default mode network connectivity (Spearmans r=-0·52 [-0·35 to -0·67); p<0·0001). Grey matter volume did not differ between the studied groups (F test p=0·06). INTERPRETATION Partial preservation of between-network anticorrelations, which are seemingly of neuronal origin and cannot be solely explained by morphological deformations, characterise patients who have emerged from a minimally conscious state. Conversely, patients with disorders of consciousness show pathological between-network correlations. Apart from a deeper understanding of the neural correlates of consciousness, these findings have clinical implications and might be particularly relevant for outcome prediction and could inspire new therapeutic options. FUNDING Belgian National Funds for Scientific Research (FNRS), European Commission, Natural Sciences and Engineering Research Council of Canada, James McDonnell Foundation, European Space Agency, Mind Science Foundation, French Speaking Community Concerted Research Action, Fondazione Europea di Ricerca Biomedica, University and University Hospital of Liège (Liège, Belgium), and University of Western Ontario (London, ON, Canada).

Quantitative rates of brain glucose metabolism distinguish minimally conscious from vegetative state patients

The differentiation of the vegetative or unresponsive wakefulness syndrome (VS/UWS) from the minimally conscious state (MCS) is an important clinical issue. The cerebral metabolic rate of glucose (CMRglc) declines when consciousness is lost, and may reveal the residual cognitive function of these patients. However, no quantitative comparisons of cerebral glucose metabolism in VS/UWS and MCS have yet been reported. We calculated the regional and whole-brain CMRglc of 41 patients in the states of VS/UWS (n=14), MCS (n=21) or emergence from MCS (EMCS, n=6), and healthy volunteers (n=29). Global cortical CMRglc in VS/UWS and MCS averaged 42% and 55% of normal, respectively. Differences between VS/UWS and MCS were most pronounced in the frontoparietal cortex, at 42% and 60% of normal. In brainstem and thalamus, metabolism declined equally in the two conditions. In EMCS, metabolic rates were indistinguishable from those of MCS. Ordinal logistic regression predicted that patients are likely to emerge into MCS at CMRglc above 45% of normal. Receiver-operating characteristics showed that patients in MCS and VS/UWS can be differentiated with 82% accuracy, based on cortical metabolism. Together these results reveal a significant correlation between whole-brain energy metabolism and level of consciousness, suggesting that quantitative values of CMRglc reveal consciousness in severely brain-injured patients.

The Minimal Energetic Requirement of Sustained Awareness after Brain Injury

Differentiation of the minimally conscious state (MCS) and the unresponsive wakefulness syndrome (UWS) is a persistent clinical challenge [1]. Based on positron emission tomography (PET) studies with [(18)F]-fluorodeoxyglucose (FDG) during sleep and anesthesia, the global cerebral metabolic rate of glucose has been proposed as an indicator of consciousness [2, 3]. Likewise, FDG-PET may contribute to the clinical diagnosis of disorders of consciousness (DOCs) [4, 5]. However, current methods are non-quantitative and have important drawbacks deriving from visually guided assessment of relative changes in brain metabolism [4]. We here used FDG-PET to measure resting state brain glucose metabolism in 131 DOC patients to identify objective quantitative metabolic indicators and predictors of awareness. Quantitation of images was performed by normalizing to extracerebral tissue. We show that 42% of normal cortical activity represents the minimal energetic requirement for the presence of conscious awareness. Overall, the cerebral metabolic rate accounted for the current level, or imminent return, of awareness in 94% of the patient population, suggesting a global energetic threshold effect, associated with the reemergence of consciousness after brain injury. Our data further revealed that regional variations relative to the global resting metabolic level reflect preservation of specific cognitive or sensory modules, such as vision and language comprehension. These findings provide a simple and objective metabolic marker of consciousness, which can readily be implemented clinically. The direct correlation between brain metabolism and behavior further suggests that DOCs can fundamentally be understood as pathological neuroenergetic conditions and provide a unifying physiological basis for these syndromes.

Pain issues in disorders of consciousness

Abstract Background: The assessment of pain and nociception in non-communicative patients with disorders of consciousness (DOC) is a real challenge for clinicians. It is, therefore, important to develop sensitive standardized tools usable at the bedside. Objectives: This review aims to provide an overview of the current knowledge about pain processing and assessment in patients with DOC. Methods: A search was performed on PubMed using MeSH terms including vegetative state, unresponsive wakefulness syndrome, minimally conscious state, consciousness disorders, pain, nociception, neuroimaging and pain assessment. Results: Neuroimaging studies investigating pain processing in patients with DOC and their implication for clinicians are reviewed. Current works on the development of standardized and sensitive tools for assessing nociception are described. Conclusion: The suggested pain perception capacity highlighted by neuroimaging studies in patients in a MCS and in some patients in a VS/UWS supports the idea that these patients need analgesic treatment and monitoring. The first tool which has been developed to assess nociception and pain in patients with DOC is the NCS. Its revised version represents a rapid, standardized and sensitive scale which can be easily implemented in a clinical setting. Complementary pain assessments are also under validation in order to offer more options to clinicians.

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.