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See detailDiagnostic accuracy of a CRS-R modified score in patients with disorders of consciousness.
Annen, Jitka ULiege; Filippini, Maria Maddalena ULiege; Bonin, Estelle ULiege et al

in Brain Injury (2019, March 16)

Introduction The Coma Recovery Scale-Revised (CRS-R) is the gold standard diagnostic tool for assessing patients with disorders of consciousness (DOC) after severe acquired brain injury (Giacino, Kalmar ... [more ▼]

Introduction The Coma Recovery Scale-Revised (CRS-R) is the gold standard diagnostic tool for assessing patients with disorders of consciousness (DOC) after severe acquired brain injury (Giacino, Kalmar and Whyte, 2004; Seel et al., 2010). Differential diagnosis of DOC includes the unresponsive wakefulness syndrome (UWS;(Laureys et al., 2010)), characterized by the recovery of eye-opening but no behavioral evidence of self or environmental awareness, and the minimally conscious state (MCS; (Giacino et al., 2002)) defined by clearly discernible but inconsistent behavioral signs of conscious awareness. The CRS-R assesses reflexes and cognitively mediated behavior in six domains, namely auditory (4 items), visual (5 items), motor (6 items), oromotor (3 items), communication (2 items) and arousal (3 items). Items in every subscale are hierarchically ordered (i.e. reflexive to cognitively-mediated behaviors; higher level behaviors correspond to higher level of neurologic functioning and ability to demonstrate lower-level behaviors or disappearance of pathological behaviors as sign of recovery) and can be used to infer the patient’s level of consciousness (La Porta et al., 2013; Gerrard, Zafonte and Giacino, 2014). Several studies on DOC investigating markers of consciousness, recovery and treatment used the CRS-R total score (i.e. addition of the highest scores reached for each subscale) as regressor in neuroimaging analyses (Bruno et al., 2012; Thibaut et al., 2012; Margetis et al., 2014; Bagnato et al., 2015). However, ignoring the hierarchy of the subscales in the CRS-R total score reduces the sensitivity for the diagnosis of MCS patients (i.e., 100% specificity for UWS but false negative diagnostic error of 22%, with a cut-off CRS-R total score of 10 (Bodien et al., 2016)). In addition, the ordinal nature of the CRS-R total score make it limited to use with parametric statistical tests (e.g., requiring normal distribution). A solution to this problem has been proposed by Sattin and colleagues (2015) who computed a CRS-R modified score (CRS-R MS1), by considering reflexes and cognitively mediated behaviors separately, reliably distinguishing between UWS and MCS patients. These authors also argue that the interpretation of the total CRS-R scores is limited due to “the underlying assumption that if a patient is able to show higher-level behaviors, he/she is also able to show lower-level responses”. Sattin et al. (2015) propose to account for the number of presented responses in every subscale (i.e., every items in a subscale should be assessed and scored). One major drawback to this approach is that according to the CRS-R guidelines, the assessor should start assessing the highest item and move to the next subscale once an item is scored, in line with the hierarchical organization of the scale. This means that, if the CRS-R is performed according to the guidelines (for which the CRS-R has been validated), the CRS-R modified score cannot be calculated. Even if assessing all items might be valid, it is unlikely to be done in many clinical and research settings as it would increase assessment time and fatigue the patient. We here propose to adapt the CRS-R MS1 by considering only the highest score reached on every subscale, respecting the CRS-R guidelines. Methods One-hundred twenty-four patients admitted to the University Hospital of Liège were assessed multiple times with the CRS-R, at least once including the assessment of all items. Patients for whom the CRS-R assessment including all items provided the same diagnosis as the patient’s final diagnosis were selected. The study was approved by the ethics committee of the University Hospital of Liège and the legal guardians of patients gave written informed consent for participation in the study, in accordance with the Declaration of Helsinki. The CRS-R total score and two CRS-R MS were calculated for every patient. The CRS-R MS combines scores for reflexes and cognitive behaviors of every CRS-R subscale which can be used to obtain the CSR-R MS from a transposition matrix. The CRS-R MS1 was calculated as previously described (Sattin et al., 2015), and the CRS-R MS2 only used the highest score in every subscale (i.e., assuming that lower items were successful). Statistics were performed in R (R Core team, 2012). We assessed group differences in age (two sample t-test), time since injury (two sample t-test) and etiology (χ2 test). Receiver Operating Characteristic were calculated to obtain the sensitivity and specificity at several classification thresholds (package pROC (Robin et al., 2011)). We calculated the correlation between the CRSR MS1 and CRSR MS2 using Pearson correlation, and both scores with the CRS-R total score using Spearman correlation. Finally, we used a Kolmogorov-Smirnoff test to evaluate whether CRSR MS1 and CRSR MS2 come from different distributions (i.e., if one approach provides additional information over the other). Results Eighty-five MCS patients (26 females; mean age 40.4 (SD±17.4) years old; 43 traumatic; mean time since injury 2.7 (SD±4.0) years) and 39 UWS patients (14 females; mean age 50.6 (SD±16.5) years old; 29 traumatic; mean time since injury 1.2 (SD±1.8) years) were included in the study. MCS patients were older (t(77.6)-3.15, p<0.002 95%CI[-16.7, -3.7]), were in a more chronic stage (t(121.9)=2.9, p = 0.005, 95%CI[974,427]), and suffered more often from a traumatic brain injury (χ2=6.8, p = 0.01) than UWS patients. The ROC analysis for both MS showed an AUC of 1 (cut-off:8.315, 100% specificity and sensitivity). The ROC analysis for the CRS-R total score showed an AUC of 0.94 (cut-off:9, sensitivity = 100%, specificity = 67%). A correlation was found between the CRSR total score and both the CRSR MS1 (r = 0.94, p < 0.0001, figure 1A) and CRSR MS2 (r = 0.96, p < 0.0001, figure 1B). The two CRS-R MS correlated (r = 0.96, p = 0.0001, figure 1C). CRSR MS1 and CRSR MS2 were drawn from the same distribution (D(124)= 0.13, p = 0.25). Discussion CRSR MS2 correlated strongly with the CRSR MS1, and perfectly discriminated UWS from MCS patients. As for accurate diagnosis the CRS-R should be repeated (preferably five times (Wannez et al., 2018)) short assessments are preferred, and possibly also reduce effects of fatigue. Second, the CRSR MS2 can be calculated with CRS-R assessments performed according to the CRS-R guidelines, facilitating its use in clinical environments, and in research settings where CRSR MS2 can be used pro- and retrospectively for research protocols. Furthermore, the results indicate that the two modified scores share the same distribution. This suggests that assessing all CRS-R items as proposed previously does not significantly contribute to the stratification of patients. The CRSR MS2 code is available via: Github A remaining limitation of the proposed score is that it does not allow to distinguish MCS minus (i.e. showing language independent signs of awareness, like visual pursuit) from MCS plus (i.e. showing language dependent signs of awareness) patients, or emergence from MCS. However, a clear consensus about the diagnostic criteria is needed before an updated modified score can be provided. In conclusion, the current analyses show that the calculation of the CRS-R modified score using the highest item in every subscale is valid for clinical diagnosis, and provides perspective for its use for research. Figure Figure 1. Correlation between the CRS-R total score and the CRS-R MS1 (1A), CRSR MS2 (1B), and between the two modified CRS-R scores (1C). MCS plus patients are here characterized by command following, intelligible verbalization and/or intentional communication. Acknowledgements This project has received funding from the University and University Hospital of Liege, the Belgian National Funds for Scientific Research (FRS-FNRS), the European Union’s Horizon 2020 Framework Programme for Research and Innovation under the Specific Grant Agreement No. 785907 (Human Brain Project SGA2) the Luminous project (EU-H2020-fetopenga686764), the Center-TBI project (FP7-HEALTH- 602150), the Public Utility Foundation ‘Université Européenne du Travail’, “Fondazione Europea di Ricerca Biomedica”, the Bial Foundation, the Mind Science Foundation and the European Commission, the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 778234, European Space Agency (ESA) and the Belgian Federal Science Policy Office (BELSPO) for their support in the framework of the PRODEX Programme. CC is a post-doctoral Marie Sklodowska-Curie fellow (H2020-MSCA-IF-2016-ADOC-752686), and SL is research director at FRS-FNRS. We are highly grateful to the members of the Liège Coma Science Group for their assistance in clinical evaluations, and we thank all the patients and their families and the Neurology department of the University hospital of Liège. [less ▲]

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See detailIs auditory localization a sign of consciousness? Evidence from neuroimaging and electrophysiology
Carrière, Manon ULiege; Cassol, Helena ULiege; Aubinet, Charlène ULiege et al

Conference (2019, March 16)

Background Auditory localization is often part of the clinical evaluation of patients recovering from coma. There is however no clear consensus whether it should be considered as a reflex or as a ... [more ▼]

Background Auditory localization is often part of the clinical evaluation of patients recovering from coma. There is however no clear consensus whether it should be considered as a reflex or as a conscious behavior. For example, auditory localisation corresponds to the diagnosis of unresponsive wakefulness syndrome (UWS) in the Coma Recovery Scale-Revised, while it is considered a sign of consciousness in other post-coma scales. This study aims to determine if auditory localization reflects conscious processing in patients with disorders of consciousness. Methods We first evaluated the proportion of patients with and without auditory localisation in 186 patients with severe brain injury, including 64 UWS, 28 minimally conscious minus (MCS-), 71 minimally conscious plus (MCS+), i.e., language relatively preserved) and 23 who emerged from MCS (EMCS). We then measured brain metabolism using fluorine-18 fluorodeoxyglucose positron emission tomography, functional connectivity using magnetic resonance imaging (MRI) and high-density electroencephalography (EEG) in patients in UWS with and without auditory localization. Findings Auditory localization was observed in 12% of patients in UWS, 46% of patients in MCS-, 62% of patients in MCS+ and 78% of patients in EMCS. Brain metabolism of patients in UWS without auditory localization was mostly restricted to primary areas, whereas a more widespread activity, including associative areas, was observed in patients in UWS with auditory localisation. Brain functional connectivity was also higher in patients in UWS with auditory localisation in the frontoparietal fMRI resting state network, along with higher EEG connectivity in alpha frequency band, compared to patients without auditory localization. Finally, differences were also found regarding the outcome, as the survival rate at two years appeared to be significantly higher in UWS patients with auditory localization as compared to those without auditory localization. Interpretation. Both clinical data in post-comatose patients and neuroimaging examinations in UWS patients with and without auditory localization support the idea that auditory localization should be considered as a sign of consciousness. [less ▲]

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See detailNeurophysiological effects and behavioral outcomes after tPCS and tDCS in a patient in minimally conscious state
Barra, Alice ULiege; Mortaheb, Sepehr ULiege; Carrière, Manon ULiege et al

Conference (2019, March 15)

Introduction: Non-invasive brain stimulation (NIBS)(1-4) is a promising path in the search for treatments of patients with disorders of consciousness (DOC). Transcranial pulsed-current stimulation (tPCS ... [more ▼]

Introduction: Non-invasive brain stimulation (NIBS)(1-4) is a promising path in the search for treatments of patients with disorders of consciousness (DOC). Transcranial pulsed-current stimulation (tPCS) has been used to modulate cortical and subcortical neural connectivity within 6-10Hz(5). It was successfully employed to enhance motor and cognitive functions in healthy volunteers (6) and it is theoretically able to reach deeper brain structures(7) . On the other hand, transcranial direct-current stimulation (tDCS) over left dorsolateral prefrontal cortex (DLPFC) has shown to improve cognitive functions in DOC patients as measured by the Coma Recovery Scale-Revised (CRS-R) in about 50% of patients in minimally conscious state (MCS) (8,9). These are preliminary results of an ongoing study that aim to investigate the effects of tPCS and tDCS on one patient with DOC. Methods: This was a randomized double-blind sham-controlled clinical trial on a patient with DOC. The Subject received 3 sessions of stimulation: active tPCS sham tDCS, sham tPCS with active tDCS, and sham tPCS with sham tDCS. Before and after each session we evaluated the patient with the CRS-R and recorded 10 minutes of resting EEG. The stimulation target for tPCS was the bimastoid line with a random frequency of 6-10Hz (2mA peak to peak), whereas the target for tDCS was the left DLPFC with 2mA of intensity. EEG data were pre-processed and the power of signal was calculated for each frequency band: Delta (0-4 Hz), Theta (4-8 Hz), Alpha (8-12 Hz) and Beta (12-25 Hz). A non-parametric corrected cluster permutation test(10) was used to statistically compare the power maps before and after each session. Electrode clusters with p-value below 0.01 were considered as significantly different. Results and Discussion: An increase of Alpha and Beta power and decrease of Theta and Delta power was observed after anodal tDCS together with an increase of behavioural responsiveness as measured by the CRS-R score. After active tPCS, a significant increase was observed in Theta power consistently with the frequency of the stimulation (6-10Hz). However, this increase did not result in any measurable behavioural improvement maybe due to insufficient number of sessions or inadequate frequency of stimulation. Nevertheless, it could be relevant to mention that the patient’s caregivers noticed longer periods of wakefullness and higher arousal after tPCS. Therefore, it may be hypothesized that the CRS-R was not sensitive enough to capture these behavioural changes. Conclusion: In conclusion, here tDCS and tPCS induced distinct neurophysiological and clinical effects. So far, tDCS seems to be confirmed as a promising tool to improve behavioural responsiveness of patients with DOC. On the other hand, tPCS should be explored in larger cohorts to understand if this type of stimulation can reach similar results as the ones observed for tDCS. [less ▲]

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See detailInternational validation of the Phone Outcome Questionnaire for patients with Disorders Of Consciousness
Wolff, Audrey ULiege; Estraneo, Anna; Noé, Quique et al

Poster (2019, March 15)

Assessing the evolution of severely brain-injured patients with disorders of consciousness (DOC) with current tools like the Glasgow Outcome Scale-Extended (GOS-E) remains a challenge. At the bedside, the ... [more ▼]

Assessing the evolution of severely brain-injured patients with disorders of consciousness (DOC) with current tools like the Glasgow Outcome Scale-Extended (GOS-E) remains a challenge. At the bedside, the most reliable diagnostic tool is currently the Coma Recovery Scale-Revised. The CRS-R distinguishes patients with unresponsive wakefulness syndrome (UWS) from patients in minimally conscious state (MCS) and patients who have emerged from MCS (EMCS). This international multi-centric study aims to validate a phone outcome questionnaire (POQ) based on the CRS-R and compare it to the CRS-R performed at the bedside and to the GOS-E which evaluates the level of disability and assigns patient’s in outcomes categories. The POQ will allow clinicians to probe the evolution of patient’s state of consciousness based on caregivers feedback. This research project is part of the International Brain Injury Association, Disorders of Consciousness-Special Interest Group (DOCSIG) and DOCMA consortium. [less ▲]

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See detailNociception Coma Scale Revised allows to identify patients with preserved neural basis for pain experience.
Bonin, Estelle ULiege; Lejeune, Nicolas; Thibaut, Aurore ULiege et al

Poster (2019, March 14)

The Nociception Coma Scale-Revised (NCS-R) was developed to help assessing pain in non-communicative patients with disorders of consciousness (DOC). Several studies have shown its sensitivity in assessing ... [more ▼]

The Nociception Coma Scale-Revised (NCS-R) was developed to help assessing pain in non-communicative patients with disorders of consciousness (DOC). Several studies have shown its sensitivity in assessing responses to acute noxious stimuli. However, they failed to determine a reliable cut-off score that could be used to infer pain processing in these patients. This retrospective cross-sectional study aimed to determine an NCS-R cut-off score supporting preserved neural basis for pain experience, based on brain metabolism as measured by fluorodeoxyglucose positron emission tomography (FDG-PET). We included FDG-PET confirmed patient with unresponsive wakefulness syndrome (UWS) (n=13) and looked at their highest NCS-R total scores. As the highest score was 4, we determined the cut-off of 5 and compared the brain metabolism of these patients with matched DOC patients with a cut-off score ≥ 5 (i.e., potential pain) and healthy controls. We found a higher global cerebral metabolism in healthy subjects compared with both patients’ groups and also in patients with potential pain compared with FDG-PET confirmed UWS. We observed a preserved metabolism in the left insula in patients with potential pain when compared with FDG-PET confirmed UWS. We also found a preservation of the connectivity between the left insula and the medial frontal gyrus in patients with potential pain compared with FDG-PET confirmed UWS. Our data suggest that using the cut-off score of 5 can be helpful to improve pain management in DOC patients. Future studies should focus on patients showing scores below this cut-off to better characterize their profile and improve cares. [less ▲]

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See detailImproving responsiveness to non-invasive brain stimulation in minimally conscious state patients: a closed-loop approach
Martens, Géraldine ULiege; Barra, Alice ULiege; Carrière, Manon ULiege et al

Poster (2019, February)

Transcranial direct current stimulation (tDCS) applied on the left dorsolateral prefrontal cortex has already been shown to efficiently promote the recovery of conscious awareness in patients with ... [more ▼]

Transcranial direct current stimulation (tDCS) applied on the left dorsolateral prefrontal cortex has already been shown to efficiently promote the recovery of conscious awareness in patients with disorders of consciousness following severe brain injury, especially those in minimally conscious state (MCS)1. However, one potential barrier to clinically respond to tDCS is accounting for the timing of the stimulation with regard to the fluctuations of vigilance that characterize this population2. Indeed, the vigilance of MCS patients has periodic average cycles of 70 minutes (range 57-80 minutes)3, potentially preventing them to be in an optimal neural state to benefit from tDCS when applied at random moments. To tackle this issue, we propose a new protocol to optimize the application of tDCS by selectively stimulating at high vigilance and low vigilance states, as measured by real-time spectral entropy (as a marker of vigilance3) and based on pre-identified individual thresholds, in a closed-loop fashion. We will conduct a clinical trial on 36 patients in MCS who will undergo a 4-hour EEG recording beforehand to set individual vigilance thresholds. The patients will then be randomized in three groups based on the moment of tDCS application: high vigilance, low vigilance and sham. These EEG-tDCS sessions will last for 6 hours with a maximum of two tDCS sessions of 20 min at 2 mA. Behavioral effects will be assessed using the Coma Recovery Scale-Revised4 at baseline, after 3 and 6 hours. The device used will be provided by Starlab and enable real-time analysis of EEG dynamics and spectral entropy as well as control of the tDCS stimulator (a customized version of Neuroelectrics’ Startsim 8). This unique and novel approach will provide new insights for the identification of tDCS responders and provide treatment options for the challenging population of patients with disorders of consciousness. [less ▲]

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See detailRecent advance in the treatment of patients with disorders of consciousness: a review of transcranial direct current stimulation efficacy
Martens, Géraldine ULiege; Barra, Alice ULiege; Laureys, Steven ULiege et al

Poster (2019, February)

Severe brain injured patients with disorders of consciousness (DOC) represent a challenging population to treat. Non-invasive brain stimulation techniques, such as transcranial direct-current stimulation ... [more ▼]

Severe brain injured patients with disorders of consciousness (DOC) represent a challenging population to treat. Non-invasive brain stimulation techniques, such as transcranial direct-current stimulation (tDCS) can transiently improve the level of consciousness of DOC patients, as measured with the Coma Recovery Scale-Revised (CRS-R). However, it is still unclear which proportion of patients can benefit from it, how long the effects can last and which brain region represent the best area to target. We here reviewed tDCS-based clinical trials on DOC to shed light on these issues. Eight articles met our criteria: three articles evaluated the effects of a single stimulation session and 5 articles assessed the effects of repeated stimulation sessions. The areas targeted by the stimulation in the articles included the following regions: the left dorsolateral prefrontal cortex (left DLPFC – F3, 5 studies), the posterior parietal cortex / precuneus (Pz, one study), the primary motor cortex (M1 - C3 or C4, one study) and the frontoparietal network bilaterally (F3, F4, CP5 and CP6, one study). Left DLPFC was the most used target, both for single and repeated session studies and has showed to effectively increase patient’s responsiveness in the CRS-R compared to other stimulated regions. Repeated session studies generally show larger effect size of tDCS treatment and higher number of responders as compared to single session. Furthermore, we found that the number of responders of repeated session studies (39 out of 110 in total) is significantly higher (p=0.0125) than the number of responders of single session studies (22 out of 111 in total). From this retrospective exploration of tDCS clinical trials, it emerged that the left DLPFC seems to be the most powerful and promising target to improve behavioural responsiveness of DOC patients whereas the strength and duration of tDCS aftereffects seems to increase with the number of sessions. [less ▲]

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See detailClinical and electrophysiological investigation of spastic muscle overactivity in patients with disorders of consciousness following severe brain injury
Martens, Géraldine ULiege; Deltombe, Thierry; Foidart-Dessalle, Marguerite ULiege et al

in Clinical Neurophysiology (2019), 130(2),

Objective The clinical and electrophysiological profile of spastic muscle overactivity (SMO) is poorly documented in patients with disorders of consciousness (DOC) following severe cortical and ... [more ▼]

Objective The clinical and electrophysiological profile of spastic muscle overactivity (SMO) is poorly documented in patients with disorders of consciousness (DOC) following severe cortical and subcortical injury. We aim at investigating the link between the clinical observations of SMO and the electrophysiological spastic over-reactivity in patients with prolonged DOC. Methods We prospectively enrolled adult patients with DOC at least 3 months post traumatic or non-traumatic brain injury. The spastic profile was investigated using the Modified Ashworth Scale and the Hmax/Mmax ratio. T1 MRI data and impact of medication were analyzed as well. Results 21 patients were included (mean age: 41 ± 11 years; time since injury: 4 ± 5 years; 9 women; 10 traumatic etiologies). Eighteen patients presented signs of SMO and 11 had an increased ratio. Eight patients presented signs of SMO but no increased ratio. We did not find any significant correlation between the ratio and the MAS score for each limb (all ps > 0.05). The presence of medication was not significantly associated with a reduction in MAS scores or Hmax/Mmax ratios. Conclusions In this preliminary study, the Hmax/Mmax ratio does not seem to reflect the clinical MAS scores in patients with DOC. This supports the fact they do not only present spasticity but other forms of SMO and contracture. Significance Patients with DOC are still in need of optimized tools to evaluate their spastic profile and therapeutic approaches should be adapted accordingly. [less ▲]

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See detailLa spasticité est-elle un facteur de prédictif de l'état nutritionnel des patients en état de conscience altérée ?
FADEUR, Marjorie ULiege; Ippoliti, Camilla ULiege; MALHERBE, Christian ULiege et al

Poster (2018, November 28)

Introduction et objectif de l’étude La littérature scientifique concernant l’état nutritionnel des patients en état de conscience altérée (ECA) est à l’heure actuelle très pauvre. Le but de cette étude ... [more ▼]

Introduction et objectif de l’étude La littérature scientifique concernant l’état nutritionnel des patients en état de conscience altérée (ECA) est à l’heure actuelle très pauvre. Le but de cette étude prospective observationnelle transversale est d’investiguer la relation entre le profil nutritionnel de ces patients et leur état de conscience. Matériel et Méthodes Nous avons collecté et analysé les données cliniques (état de conscience, spasticité) et nutritionnelles (indice de masse corporelle (IMC), apports nutritionnels, biologie) de 80 patients en état d’éveil non répondant (ENR), en état de conscience minimale (ECM) ou en état de conscience minimale émergeant (EECM). Les patients ont été classés selon le résultat de l’analyse nutritionnelle : bien nourri, à risque de dénutrition et dénutri. Résultats De nos 80 patients (43 ± 15 ans), 19 étaient en ENR (24%), 47 en ECM (59%) et 14 en EECM (17%). Parmi eux, 7 (9%) étaient à risque de dénutrition et les 73 autres (91%) étaient bien nourris. L’IMC de ces sujets n’est pas lié à leur niveau d’ECA (p = 0,093), au délai après l’accident (p = 0,12) ou à l’étiologie de leur état neurologique (p = 0,51). Une différence entre l’apport énergétique réellement administré à ces patients et celui qu’ils devraient théoriquement recevoir sur base des recommandations nutritionnelles (30 kcal/kg de poids de calcul) est observée. Les sujets obèses (≥ 30 kg/m²) recevaient 631 ± 328 kcal en moins/jour par rapport aux recommandations et ceux en surpoids (25-29,9 kg/m²), 415 ± 390 kcal/j en moins également. En revanche, les patients avec un IMC faible (< 18,5 kg/m²) recevaient 106 kcal ± 299 kcal/j en plus. La comparaison du niveau de spasticité en fonction de l’IMC révèle une corrélation significative (r = - 0,30, p = 0,009) et montre que les patients les moins spastiques au niveau des membres inférieurs sont plus à risque d’avoir un surpoids (IMC = 27,7 ± 7,5 kg/m²). Au contraire les plus spastiques à ce niveau sont plus à risque d’avoir un IMC plus faible (22,1 ±3,8 kg/m²). Parmi les 9 sujets avec un IMC < 18,5 kg/m², 7 présentent une spasticité sévère, et les 2 autres une spasticité modérée, au niveau des membres inférieurs. L’étude de la différence d’apport énergétique par rapport à la spasticité montre que les patients non spastiques recevaient 297 ± 318 kcal/j en moins par rapport aux recommandations, contre 222 ± 430 kcal/j pour une spasticité moyenne et 41 ± 406 kcal/j pour des niveaux de spasticité plus élevés. Conclusion Nos résultats indiquent que la majorité des patients ECA ont un état nutritionnel satisfaisant. Cet état nutritionnel ne semble pas lié au niveau de conscience, ni au délai ou à la cause de leur accident. Les patients les moins spastiques présentent des critères de surpoids malgré un apport énergétique considérablement réduit par rapport aux recommandations nutritionnelles. En revanche, un niveau élevé de spasticité est associé à un niveau de sous poids (IMC < 18,5 kg/m²) en dépit d’un apport énergétique supérieur à l’objectif préconisé par ces recommandations. Des analyses complémentaires sont en cours (calorimétrie indirecte, impédancemétrie, étude de la spasticité et imagerie métabolique) afin de mieux comprendre les mécanismes sous-jacents. [less ▲]

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See detailTreating severely brain-injured patients with apomorphine: study protocol for a double blind randomized placebo-controlled trial using behavioral and neuroimaging assessments
Sanz, Leandro ULiege; Lejeune, Nicolas; Thibaut, Aurore ULiege et al

in Frontiers in Neuroscience (2018, October)

Background: Patients who survive severe brain injury may develop chronic disorders of consciousness. Treating these patients to improve recovery is extremely challenging because of the absence of ... [more ▼]

Background: Patients who survive severe brain injury may develop chronic disorders of consciousness. Treating these patients to improve recovery is extremely challenging because of the absence of international guidelines and scarce therapeutic options (Schnakers and Monti, 2017). Among pharmacological treatments, apomorphine, a potent direct non-specific dopamine agonist with a high affinity for D2 receptors, has exhibited promising behavioral effects and safety of use in small-sample pilot studies (Fridman et al., 2009, 2010). However, despite the improvement compared to historical data, the lack of a control group could not eliminate the possibility that the effect was a result of spontaneous recovery, and the true efficacy of apomorphine for the recovery of consciousness remains unclear (Gosseries et al., 2014). In addition, the underlying neural mechanisms of this treatment are still unknown. An upregulation of central thalamic activity through a modulation of the anterior forebrain mesocircuit has been proposed as a possible explanation (Schiff, 2010a, 2010b) but the absence of neuroimaging and neurophysiological data prevent definitive confirmation. This clinical trial aims to 1) verify and quantify the efficacy of apomorphine subcutaneous infusion in patients with disorders of consciousness, 2) better identify the rate and the phenotype of responders to treatment, 3) evaluate tolerance and side effects occurrence in this specific patient population and 4) investigate the neural networks underlying its modulating action on consciousness using multimodal outcome measurements. Methods/design: This study is a prospective double-blind randomized placebo-controlled trial. Forty-eight patients diagnosed with disorders of consciousness (i.e., unresponsive wakefulness syndrome and minimally conscious state) will be randomized to receive a 30-day regimen of either apomorphine hydrochloride or placebo via daily 12-hour subcutaneous infusions. Patients will be monitored at baseline 30 days before initiation of therapy, during treatment and for 30 days after treatment washout, followed by a two-year remote follow-up. In an initial study phase, up to six patients will be treated in an open-label fashion. Behavioral outcome measures will include weekly assessments using standardized scales such as the Coma Recovery Scale – Revised (CRS-R) (Giacino et al., 2004) and the Nociception Coma Scale – Revised (NCS-R) (Chatelle et al., 2012) during the inpatient phase. Tolerance and safety of use will be monitored using a specifically designed Adverse Events Questionnaire filled weekly by the referent physician, from treatment initiation to the end of the inpatient phase. Long-term behavioral follow-up will be performed at 6, 12 and 24 months post-treatment by telephone interview using the Glasgow Outcome Scale – Extended (GOS-E) (Levin et al., 2001) as well as phone-adapted versions of the CRS-R and the Adverse Events Questionnaire. Neurophysiological and neuroimaging measures will complement clinical evaluations and provide data on brain activity. Resting-state high-density electroencephalography (EEG) will be acquired weekly during the whole inpatient phase. In addition, participants will be assessed before and after treatment with Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET), EEG during auditory paradigms and 24-hours EEG recordings. To measure changes in circadian rhythm, body core temperature (Matsumoto et al., 2013) and body movements (Cruse et al., 2013) will be recorded with non-invasive portable devices throughout the whole duration of the inpatient phase (Figure 1). Statistical analyses will be performed blindly to detect changes in behavioral status, circadian rhythmicity, brain metabolism and functional connectivity both at the individual level (comparing before and after treatment) and at the group level (comparing the apomorphine and the placebo arms). Behavioral response will be determined by changes of diagnosis using the CRS-R, and further analyses will also look at changes between the non-responding and the responding patient subgroups. Age, gender, etiology, time since injury and diagnosis will also be included as regressors. Hypotheses: Based on the mesocircuit hypothesis, we postulate a modulation in the activity of the network’s anterior forebrain structures following administration of apomorphine (Figure 2), which will translate into the following changes: 1) A behavioral improvement such that the CRS-R diagnosis and total score will improve in responding patients, while NCS-R scores may also increase, reflecting a higher perception of pain; along with long-term functional recovery measured by sustained higher GOS-E and CRS-R scores at follow-up compared to the placebo group; 2) A relative recovery of sleep-wake cycles measured by a normalization of circadian rhythmicity as well as an increase in total body movements; 3) A metabolic improvement with significant increase of whole-brain glucose uptake, with highest increase of values found in the striatum, thalamus and frontoparietal cortical areas measured with PET; 4) A modulation of dynamic connectivity in response to apomorphine measured by resting-state fMRI analyses (seed-based and whole-brain connectivity measures) and changes of resting-state EEG connectivity metrics (notably increased mean alpha spectral connectivity, participation coefficient and delta modularity). Additionally, we can expect improvements after treatment in less specific measures of recovery such as sleep cycle architecture on 24-hours EEG hypnograms and the probability of consciousness given by a machine learning multivariate classifier derived from EEG recordings during auditory paradigms (Engemann et al., 2015). While improvements can be expected as well in the placebo arm due to spontaneous recovery and placebo effect, we hypothesize that responding patients in the apomorphine arm will exhibit significantly higher increases in these different markers of recovery. Discussion: New multimodal approaches using neurophysiology and neuroimaging allow a more accurate diagnosis of patients with disorders of consciousness but the current available treatments remain inefficient. This study aims to verify the efficacy of apomorphine for the recovery of consciousness in the first randomized placebo-controlled double-blind trial using multimodal measurement methods. The results will contribute to define the role of dopamine agonists in the treatment of this challenging population of patients and help identify the neural underpinnings underlying the modulation of consciousness networks by apomorphine. Notably, this trial is designed to bring objective neuroimaging and neurophysiological evidence to further assess the validity of the mesocircuit hypothesis and its modulation by pharmacological agents, which may open new therapeutic perspectives. [less ▲]

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See detailBrain, behavior, and cognitive interplay in disorders of consciousness: A multiple case study
Aubinet, Charlène ULiege; Murphy, Leslie; Bahri, Mohamed Ali ULiege et al

in Frontiers in Neurology (2018), 9(665), 1-10

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See detailA multiple case study investigating the sub-categorization of the minimally conscious state
Aubinet, Charlène ULiege; Panda, Rajanikant ULiege; Cassol, Helena ULiege et al

Poster (2018, June 28)

The minimally conscious state (MCS) was sub-categorized in MCS+ and MCS- based on language-related behaviors (i.e., command-following, intelligible verbalization or intentional communication). Due to ... [more ▼]

The minimally conscious state (MCS) was sub-categorized in MCS+ and MCS- based on language-related behaviors (i.e., command-following, intelligible verbalization or intentional communication). Due to pronosis implications, it is important to detect signs of MCS+ and evaluate patients’ likelihood to recover such behaviors. We here aim to describe behavioral and neuroimaging data of severe brain-injured patients who evolved from MCS- to MCS+. Four patients were thus assessed at two time points by means of repeated Coma Recovery Scale-Revised. During their first week of assessments, they were diagnosed as MCS-. They later recovered language-related behaviors (i.e., MCS+), when reassessed during their second week of evaluations. All patients underwent a positron emission tomography (PET-scan) and magnetic resonance imaging (including voxel-based morphometry – VBM) exams during both weeks of assessments. We here compared the neuroimaging differences between the two exams in these four patients. PET-scan results showed that all patients presented partial recovery of metabolism in temporal lobules, reflecting compensation either from left-sided language areas or from their contralateral regions. VBM results showed that two patients presented a significant increase of grey matter volume, particularly concerning either bilateral frontal areas or the left caudate, which was related to memory, learning and language abilities. The other two patients did not show difference in grey matter structure between MCS- and MCS+. We conclude that the clinical evolution of patients from MCS- to MCS+ suggests the reappearance of language-based behavioral signs, but also the partial recovery of metabolism and grey matter structure in cerebral regions that are involved in language processing. All patients recovered signs of MCS+ at an advance chronic stage. These neuroimaging results highlight the remaining neuroplasticity in chronic MCS. [less ▲]

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See detailTutorial "Single-case evaluation of consciousness: same patient, different modalities": fMRI-based assessment of a single patient
Demertzi, Athina ULiege; Annen, Jitka ULiege; Chatelle, Camille ULiege et al

Conference (2018, June 24)

Tutorial: Patients with disorders of consciousness are by definition unable to communicate. This makes the evaluation of their state of consciousness a major challenge. To date, there are not standardized ... [more ▼]

Tutorial: Patients with disorders of consciousness are by definition unable to communicate. This makes the evaluation of their state of consciousness a major challenge. To date, there are not standardized guidelines as to how a post-comatose patient can be evaluated by means of assisting technologies. With this tutorial, we bring together specialists from three expert centers dealing with intensive evaluation of the state of consciousness in patients sustaining severe brain injuries. Our aim is to illustrate how we can infer a clinical diagnosis by integrating different data from behavioral and brain function as measured with different technological modalities. Specifically, we will discuss the case of a patient for whom behavioral, electrophysiological and neuroimaging data have been acquired with the aim to provide a global diagnosis of the state of consciousness. We will show how each of these evaluations are performed in step-by-step manner. Each presenter will further illustrate the methodological challenges and pragmatic solutions towards the inference of valid conclusions. In order to integrate the results into a global diagnostic category, we wish to engage the audience to participate interactively towards the composition of a final diagnostic report, as we typically do at our clinical sites [less ▲]

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See detailTranscranial direct current stimulation unveils covert consciousness
Thibaut, Aurore ULiege; Chatelle, Camille ULiege; VANHAUDENHUYSE, Audrey ULiege et al

in Brain Stimulation (2018), 11(3), 642-644

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See detailRandomized controlled trial of home-based 4-week tDCS in chronic minimally conscious state
Martens, Géraldine ULiege; Lejeune, Nicolas ULiege; O'Brien, Anthony et al

in Brain Stimulation (2018)

Background Patients with chronic disorders of consciousness face a significant lack of treatment options. Objective We aimed at investigating the feasibility and the behavioral effects of home-based ... [more ▼]

Background Patients with chronic disorders of consciousness face a significant lack of treatment options. Objective We aimed at investigating the feasibility and the behavioral effects of home-based transcranial direct current stimulation (tDCS), applied by relatives or caregivers, in chronic patients in minimally conscious state (MCS). Methods Each participant received, in a randomized order, 20 sessions of active and 20 sessions of sham tDCS applied over the prefrontal cortex for 4 weeks; separated by 8 weeks of washout. Level of consciousness was assessed using the Coma Recovery Scale-Revised before the first stimulation (baseline), after the end of the 20 tDCS sessions (direct effects) and 8 weeks after the end of each stimulation period (long-term effects). Reported adverse events and data relative to the adherence (i.e., amount of sessions effectively received) were collected as well. Results Twenty-seven patients completed the study and 22 patients received at least 80% of the stimulation sessions. All patients tolerated tDCS well, no severe adverse events were noticed after real stimulation and the overall adherence (i.e., total duration of stimulation) was good. A moderate effect size (0.47 and 0.53, for modified intention to treat and per protocol analysis, respectively) was observed at the end of the 4 weeks of tDCS in favor of the active treatment. Conclusions We demonstrated that home-based tDCS can be used adequately outside a research facility or hospital by patients’ relatives or caregivers. In addition, 4 weeks of tDCS moderately improved the recovery of signs of consciousness in chronic MCS patients. [less ▲]

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See detailGlobal structural integrity and effective connectivity in patients with disorders of consciousness
BODART, Olivier ULiege; Amico, Enrico; Gomez, Francisco et al

in Brain Stimulation (2018)

Background Previous studies have separately reported impaired functional, structural, and effective connectivity in patients with disorders of consciousness (DOC). The perturbational complexity index (PCI ... [more ▼]

Background Previous studies have separately reported impaired functional, structural, and effective connectivity in patients with disorders of consciousness (DOC). The perturbational complexity index (PCI) is a transcranial magnetic stimulation (TMS) derived marker of effective connectivity. The global fractional anisotropy (FA) is a marker of structural integrity. Little is known about how these parameters are related to each other. Objective We aimed at testing the relationship between structural integrity and effective connectivity. Methods We assessed 23 patients with severe brain injury more than 4 weeks post-onset, leading to DOC or locked-in syndrome, and 14 healthy subjects. We calculated PCI using repeated single pulse TMS coupled with high-density electroencephalography, and used it as a surrogate of effective connectivity. Structural integrity was measured using the global FA, derived from diffusion weighted imaging. We used linear regression modelling to test our hypothesis, and computed the correlation between PCI and FA in different groups. Results Global FA could predict 74% of PCI variance in the whole sample and 56% in the patients' group. No other predictors (age, gender, time since onset, behavioural score) improved the models. FA and PCI were correlated in the whole population (r = 0.86, p < 0.0001), the patients, and the healthy subjects subgroups. Conclusion We here demonstrated that effective connectivity correlates with structural integrity in brain-injured patients. Increased structural damage level decreases effective connectivity, which could prevent the emergence of consciousness. [less ▲]

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