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See detailClinical and neuroimaging improvements after apomorphine treatment in a patient with chronic disorders of consciousness following brain hemorrhage
Sanz, Leandro ULiege; Lejeune, Nicolas; Blandiaux, Séverine ULiege et al

in Brain Injury (in press)

Background: There are few available therapeutic options to promote recovery among patients with disorders of consciousness (DOC). Among pharmacological treatments, apomorphine, a dopamine agonist, has ... [more ▼]

Background: There are few available therapeutic options to promote recovery among patients with disorders of consciousness (DOC). Among pharmacological treatments, apomorphine, a dopamine agonist, has exhibited promising behavioral effects in traumatic brain injury. Its efficacy among patients with non-traumatic brain injury has never been documented and its action on brain activity remains unknown. We report the case of a patient with DOC following intracranial hemorrhage, who was treated with apomorphine in a prospective open-label study. Methods/design: A 47-year-old woman with chronic DOC (minimally conscious state; MCS) following spontaneous rupture of a left carotidal aneurysm (132 days since onset), was treated with apomorphine for 30 days. The drug was administered via subcutaneous infusions 12 hours per day, with escalating doses up to 6 mg/h. The patient was monitored 30 days before initiation of therapy, during treatment and 30 days after withdrawal, using the Coma Recovery Scale – Revised (CRS-R). High-density electroencephalography (hdEEG) and fluorodeoxyglucose positron emission tomography (FDG-PET) were acquired before and after treatment. Outcome measures included CRS-R diagnosis, FDG-PET standardized uptake values, a multivariate classifier integrating 68 individual hdEEG markers and hdEEG functional connectivity using debiased weighted phase lag index. Results: Before treatment, CRS-R scores were compatible with a diagnosis of unresponsive wakefulness syndrome (UWS) in 8/9 evaluations, and with a MCS- only once. During treatment, the patient was diagnosed as UWS in 2/8 evaluations, MCS- in 5/8 evaluations and MCS+ once, characterized by the presence of reproducible response to command. After treatment withdrawal, she was diagnosed UWS once and MCS- in 4/5 evaluations. Compared to 54 healthy controls, FDG-PET whole brain metabolism revealed a 59% metabolic drop before treatment and 51% after treatment, with increases in right temporal, parietal and frontal cortical areas. The multivariate classifier using resting-state hdEEG data was in favor of a UWS before treatment, while it indicated a MCS after treatment. Most of the individual markers increased after treatment, including alpha and beta spectral power, spectral entropy, Kolmogorov complexity and permutation entropy. Functional connectivity analyses also indicated an increase in network centrality predominant in the alpha frequency band after treatment compared to before treatment. Discussion: After treatment with apomorphine, this patient showed improvements both at the clinical and neuroimaging levels. While signs of consciousness were only observed once at baseline, most of the assessments performed during and after treatment led to a diagnosis of MCS. Notably, a reproducible response to command was observed once during treatment, leading to a change of diagnosis. Brain activity measures all increased after treatment compared to before treatment. These multimodal improvements suggest that apomorphine may be efficient to promote the recovery of non-traumatic DOC patients, and that its action can be measured through different changes in brain imaging markers. Clinical trial identifiers: EudraCT 2018-003144-23; Clinicaltrials.gov NCT03623828 [less ▲]

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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 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 detailPupil diameter and Behavioral Responsiveness in Disorders of Consciousness
Mortaheb, Sepehr ULiege; Bonin, Estelle ULiege; Laureys, Steven ULiege et al

Poster (2019, March 15)

The clinical diagnosis of consciousness is mainly based on bedside observation of the patient's responses using standardized neurobehavioral scales. By definition, it is common to observe vigilance ... [more ▼]

The clinical diagnosis of consciousness is mainly based on bedside observation of the patient's responses using standardized neurobehavioral scales. By definition, it is common to observe vigilance fluctuation in patients in minimally conscious state (MCS) who would show reproducible but fluctuating signs of consciousness [1]. As the probability to detect voluntary responses depends on the patient's level of vigilance at the time of assessment, multiple assessments are needed in order to detect signs of consciousness and avoid misdiagnosis [2]. If this fluctuation is known in disorders of consciousness (DOC), it remains poorly understood and characterized. In this study, we investigated the relationship between pupil diameter (suggested as an objective physiological measure of alertness level in healthy subjects [3-6]) and behavioral responsiveness in DOC patients. To this end, five patients with chronic DOC (1 unresponsive wakefulness syndrome [UWS; ie, reflexive responses], 2 MCS- [ie, signs of consciousness but no signs of language preservation, 2 MCS+ [ie, signs of language preservation]; 3 males; age=47±15.16 (median ± SD), median TSI=284 days) were enrolled. For each patient, four behavioral assessments were performed in a single day using the Coma Recovery Scale-Revised. Before each assessment, pupil response was recorded for 10 minuttients (MCS-) was excluded from the analysis due to eye closure during whole recording period. Pupil diameter was recorded using Phasya Drowsimeter R100 glasses (eye images acquired at 120 Hz with a high-speed camera integrated into the glasses). Eye closure periods were marked manually. Several parameters were investigated: eye opening percentage (EOP), as well as median, variance, entropy, and Lempel-Ziv complexity of the pupil diameter. We here provide preliminary descriptive results for this small sample. We observed lower EOP and median pupil diameter when the patients were unresponsive (i.e., diagnosis of UWS) vs. when they were responsive at bedside (i.e., MCS; median EOP=74.78% vs 99.6%, median pupil diameter=21 vs 28). Variance did not show any specific pattern; however, complexity measures of entropy and Lempel-Ziv were also lower in the UWS (median entropy=9.83 vs 10.58 and median Lempel-Ziv complexity=121 vs 328). Median pupil diameter also seemed to be more sensitive to behavioural changes across different assessments. These preliminary data suggest that higher responsiveness is related to higher median and complexity of the pupillometry signal and eye opening percentage at rest, supporting that pupillometry markers could be used as potential predictor of behavioral responsiveness in DOC patients. [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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