Effect of Sociodemographic Factors, Concomitant Disease States, and Measures Performed in the Emergency Department on Patient Disability in Ischemic Stroke: Retrospective Study from Lebanon.

BACKGROUND: Stroke is a leading cause of death and disability in developed countries. The major factor affecting long-term survival other than age is the disability severity caused by stroke. The modified Rankin Scale (mRS) is a global functional endpoint measurement used in acute stroke to evaluate the degree of disability or dependence in daily life activities. The objective of this study was to assess the effects of sociodemographic factors, concomitant disease states, and some measures performed in the emergency department (ED) on patients' disability. METHODS: We conducted a retrospective study on ischemic stroke patients admitted to Intensive Care Unit of three Lebanese university hospitals between June and December 2016. Patients were excluded if they had been discharged from ED without hospital admission or if mRS was not performed. The mRS was further subdivided into two categories considered as "good prognosis" (0-2 or 0-3) and "poor prognosis" (>2 or > 3). RESULTS: 204 patients were included in the study with mean age of 65.4 ± 11.9 years, hypertension was the most previous concomitant past medical disease (77.1%), and 27.1% of these patients had previous history of stroke. No significant differences were found in both mRS categories for all sociodemographic factors, and past medical history except that arrhythmia was significantly more common in the higher mRS categories > 2 and > 3. Based on multivariable analysis, there was a trend for previous intake of calcium channel blocker to be associated with lower mRS at admission (beta -0.586). However, intracranial arterial stenosis, ED blood glucose > 180 mg/dL, and performing brain imaging above 20 minutes after patient presentation to ED were significantly associated with higher mRS scores at discharge with an ORa and (confidence interval) of 2.986 (0.814, 10.962), 3.301 (1.072, 1.261), and 1.138 (1.071, 9.080), respectively. CONCLUSION: mRS is affected by previous disease states, prescribed medications, and acute measures performed in ED. It is also influenced by intracranial arterial stenosis etiology, which is associated with worse outcome.

Mild encephalopathy with reversible splenial lesion: Description of nine cases and review of the literature.

Mild encephalopathy/encephalitis with reversible splenial lesion (MERS) is a transient clinico-radiological syndrome characterized by non-specific encephalopathy and specific magnetic resonance imaging (MRI) pattern. MRI shows an ovoid lesion in the mid-splenium of the corpus callosum (SCC), with signal-intensity anomaly similar to stroke but vanishing within few weeks. Although there are a lot of child MERS cases descriptions, there are just a few adult-onset reported. Our goal is to provide a better clinical and radiological description of this entity. We reported nine adult-onset cases of MERS managed in our stroke unit between 2017 and 2019. The study of our adult series suggests that epilepsy and the context of an infection are very common in MERS. Adult cases show frequent focal neurological deficits and few encephalopathies compared to children. The measurement of very low ADC values in SCC lesion is a new radiological feature of MERS that should be systematically assessed in suspected cases to differentiate this complex syndrome from SCC strokes.

Importance, limits and caveats of the use of "disorders of consciousness" to theorize consciousness.

The clinical and fundamental exploration of patients suffering from disorders of consciousness (DoC) is commonly used by researchers both to test some of their key theoretical predictions and to serve as a unique source of empirical knowledge about possible dissociations between consciousness and cognitive and/or neural processes. For instance, the existence of states of vigilance free of any self-reportable subjective experience [e.g. "vegetative state (VS)" and "complex partial epileptic seizure"] originated from DoC and acted as a cornerstone for all theories by dissociating two concepts that were commonly equated and confused: vigilance and conscious state. In the present article, we first expose briefly the major achievements in the exploration and understanding of DoC. We then propose a synthetic taxonomy of DoC, and we finally highlight some current limits, caveats and questions that have to be addressed when using DoC to theorize consciousness. In particular, we show (i) that a purely behavioral approach of DoC is insufficient to characterize the conscious state of patients; (ii) that the comparison between patients in a minimally conscious state (MCS) and patients in a VS [also coined as unresponsive wakefulness syndrome (UWS)] does not correspond to a pure and minimal contrast between unconscious and conscious states and (iii) we emphasize, in the light of original resting-state positron emission tomography data, that behavioral MCS captures an important but misnamed clinical condition that rather corresponds to a cortically mediated state and that MCS does not necessarily imply the preservation of a conscious state.

Combined behavioral and electrophysiological evidence for a direct cortical effect of prefrontal tDCS on disorders of consciousness.

Severe brain injuries can lead to long-lasting disorders of consciousness (DoC) such as vegetative state/unresponsive wakefulness syndrome (VS/UWS) or minimally conscious state (MCS). While behavioral assessment remains the gold standard to determine conscious state, EEG has proven to be a promising complementary tool to monitor the effect of new therapeutics. Encouraging results have been obtained with invasive electrical stimulation of the brain, and recent studies identified transcranial direct current stimulation (tDCS) as an effective approach in randomized controlled trials. This non-invasive and inexpensive tool may turn out to be the preferred treatment option. However, its mechanisms of action and physiological effects on brain activity remain unclear and debated. Here, we stimulated 60 DoC patients with the anode placed over left-dorsolateral prefrontal cortex in a prospective open-label study. Clinical behavioral assessment improved in twelve patients (20%) and none deteriorated. This behavioral response after tDCS coincided with an enhancement of putative EEG markers of consciousness: in comparison with non-responders, responders showed increases of power and long-range cortico-cortical functional connectivity in the theta-alpha band, and a larger and more sustained P300 suggesting improved conscious access to auditory novelty. The EEG changes correlated with electric fields strengths in prefrontal cortices, and no correlation was found on the scalp. Taken together, this prospective intervention in a large cohort of DoC patients strengthens the validity of the proposed EEG signatures of consciousness, and is suggestive of a direct causal effect of tDCS on consciousness.

Auditory Event-Related "Global Effect" Predicts Recovery of Overt Consciousness.

Objective: To explore whether the presence of an event-related potential (ERP) "global effect" (GE+)-that corresponds to a correlate of conscious processing in the local-global auditory task-predicts behaviorally overt consciousness recovery in a large cohort of patients suffering from disorders of consciousness (DOC). Methods: We conducted a prospective study on all DOC patients evaluated during the 2009-2018 period. Behavioral examination included Coma Recovery Scale-Revised (CRS-R) scores and bedside high-density EEG recordings. Consciousness recovery was evaluated at 6 months by a structured phone interview. The predictive value of a GE+ was calculated both on survivors and on all patients. Results: A total of 236 patients with a documented outcome and technically valid EEG recordings could be included. Among them, 66 patients had a GE+ status (28%). Presence of GE+ predicted behaviorally overt consciousness recovery in survivors with high specificity (Sp = 84%) and high positive predictive value (PPV = 80%) but with low sensitivity (Se = 35%) and low negative predictive value (NPV = 42%). Positive likelihood ratio (LR+) of GE+ was superior to LR+ of initial clinical status and of ERP effect indexing unconscious auditory processing [local effect (LE)]. Interpretation: Our results demonstrate that the presence of a bedside ERP GE+ is highly predictive of behaviorally overt consciousness recovery in DOC patients, regardless of the delay, of behavioral status, and of the etiology of brain dysfunction. However, the absence of this effect is not a reliable predictor of negative outcome. This study provides Class III evidence that the presence of an ERP "global effect" predicts consciousness recovery in DOC patients.

Wisdom of the caregivers: pooling individual subjective reports to diagnose states of consciousness in brain-injured patients, a monocentric prospective study.

OBJECTIVES: The clinical distinction between vegetative state/unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS) is a key step to elaborate a prognosis and formulate an appropriate medical plan for any patient suffering from disorders of consciousness (DoC). However, this assessment is often challenging and may require specialised expertise. In this study, we hypothesised that pooling subjective reports of the level of consciousness of a given patient across several nursing staff members can be used to clinically detect MCS. SETTING AND PARTICIPANTS: Patients referred to consciousness assessment were prospectively screened. MCS (target condition) was defined according to the best Coma Recovery Scale-Revised score (CRS-R) obtained from expert physicians (reference standard). 'DoC-feeling' score was defined as the median of individual subjective reports pooled from multiple staff members during a week of hospitalisation (index test). Individual ratings were collected at the end of each shift using a 100 mm Visual Analogue Scale, blinded from the reference standard. Diagnostic accuracy was evaluated using area under the receiver operating characteristic curve (AUC), sensitivity and specificity metrics. RESULTS: 692 ratings performed by 83 nursing staff members were collected from 47 patients. Twenty patients were diagnosed with UWS and 27 with MCS. DoC-feeling scores obtained by pooling all individual ratings obtained for a given patient were significantly greater in patients with MCS than with UWS (59.2 mm (IQR: 27.3-77.3) vs 7.2 mm (IQR: 2.4-11.4); p<0.001) yielding an AUC of 0.92 (95% CI 0.84 to 0.99). CONCLUSIONS: DoC-feeling capitalises on the expertise of nursing staff to evaluate patients' consciousness. Together with the CRS-R as well as with brain imaging, DoC-feeling might improve diagnostic and prognostic accuracy of patients with DoC.

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

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

Survival and consciousness recovery are better in the minimally conscious state than in the vegetative state.

BACKGROUND: The prognosis value of early clinical diagnosis of consciousness impairment is documented by an extremely limited number of studies, whereas it may convey important information to guide medical decisions. OBJECTIVE: We aimed at determining if patients diagnosed at an early stage (<90 days after brain injury) as being in the minimally conscious state (MCS) have a better prognosis than patients in the vegetative state/Unresponsive Wakefulness syndrome (VS/UWS), independent of care limitations or withdrawal decisions. METHODS: Patients hospitalized in ICUs of the Pitié-Salpêtrière Hospital (Paris, France) from November 2008 to January 2011 were included and evaluated behaviourally with standardized assessment and with the Coma Recovery Scale-Revised as being either in the VS/UWS or in the MCS. They were then prospectively followed until 1July 2011 to evaluate their outcome with the GOSE. We compared survival function and outcomes of these two groups. RESULTS: Both survival function and outcomes, including consciousness recovery, were significantly better in the MCS group. This difference of outcome still holds when considering only patients still alive at the end of the study. CONCLUSIONS: Early accurate clinical diagnosis of VS/UWS or MCS conveys a strong prognostic value of survival and of consciousness recovery.

Multidimensional cognitive evaluation of patients with disorders of consciousness using EEG: A proof of concept study.

The use of cognitive evoked potentials in EEG is now part of the routine evaluation of non-communicating patients with disorders of consciousness in several specialized medical centers around the world. They typically focus on one or two cognitive markers, such as the mismatch negativity or the P3 to global auditory regularity. However it has become clear that none of these markers in isolation is at the same time sufficiently specific and sufficiently sensitive to be taken as the unique gold standard for diagnosing consciousness. A good way forward would be to combine several cognitive markers within the same test to improve evaluation. Furthermore, given the diversity of lesions leading to disorders of consciousness, it is important not only to probe whether a patient is conscious or not, but also to establish a more general and nuanced profile of the residual cognitive capacities of each patient using a combination of markers. In the present study we built a unique EEG protocol that probed 8 dimensions of cognitive processing in a single 1.5 h session. This protocol probed variants of classical markers together with new markers of spatial attention, which has not yet been studied in these patients. The eight dimensions were: (1) own name recognition, (2) temporal attention, (3) spatial attention, (4) detection of spatial incongruence (5) motor planning, and (6,7,8) modulations of these effects by the global context, reflecting higher-level functions. This protocol was tested in 15 healthy control subjects and in 17 patients with various etiologies, among which 13 could be included in the analysis. The results in the control group allowed a validation and a specific description of the cognitive levels probed by each marker. At the single-subject level, this combined protocol allowed assessing the presence of both classical and newly introduced markers for each patient and control, and revealed that the combination of several markers increased diagnostic sensitivity. The presence of a high-level effect in any of the three tested domains distinguished between minimally conscious and vegetative patients, while the presence of low-level effects was similar in both groups. In summary, this study constitutes a validated proof of concept in favor of probing multiple cognitive dimensions to improve the evaluation of non-communicating patients. At a more conceptual level, this EEG tool can help achieve a better understanding of disorders of consciousness by exploring consciousness in its multiple cognitive facets.

Multidrug-resistant bacteria transmitted through high-density EEG in ICU.

PURPOSE: Prevention of multidrug resistant (MDR) bacterial contamination remains a major challenge in ICUs. Many hospital outbreaks involving MDR transmitted through environmental contamination have been reported. Bedside high-density EEG allow for dynamic cognitive evaluation in brain-injured patients and is used more and more frequently in clinical practice to evaluate brain function and predict outcome in severely neurologically impaired patients. Unfortunately, the material used for this procedure is not entirely disposable. METHOD: We performed a systematic analysis of MDR bacterial contamination in patients contaminated in our ICU using specific bacteriological methods. RESULTS: We report a proven case of cross-contamination of an extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae strain, and a possible case of cross-contamination of a carbapenem-resistant Acinetobacter baumannii strain. CONCLUSION: Cross-contamination of MDR bacteria is possible through high-density EEG material. However, appropriate procedures can decrease this risk.

Dissociating temporal attention from spatial attention and motor response preparation: A high-density EEG study.

Engagement of various forms of attention and response preparation determines behavioral performance during stimulus-response tasks. Many studies explored the respective properties and neural signatures of each of these processes. However, very few experiments were conceived to explore their interaction. In the present work we used an auditory target detection task during which both temporal attention on the one side, and spatial attention and motor response preparation on the other side could be explicitly cued. Both cueing effects speeded response times, and showed strictly additive effects. Target ERP analysis revealed modulations of N1 and P3 responses by these two forms of cueing. Cue-target interval analysis revealed two main effects paralleling behavior. First, a typical contingent negative variation (CNV), induced by the cue and resolved immediately after target onset, was found larger for temporal attention cueing than for spatial and motor response cueing. Second, a posterior and late cue-P3 complex showed the reverse profile. Analyses of lateralized readiness potentials (LRP) revealed both patterns of motor response inhibition and activation. Taken together these results help to clarify and disentangle the respective effects of temporal attention on the one hand, and of the combination of spatial attention and motor response preparation on the other hand on brain activity and behavior.

Probing ERP correlates of verbal semantic processing in patients with impaired consciousness.

Our ability to identify covert cognitive abilities in non-communicating patients is of prime importance to improve diagnosis, to guide therapeutic decisions and to better predict their cognitive outcome. In the present study, we used a basic and rigorous paradigm contrasting pairs of words orthogonally. This paradigm enables the probing of semantic processing by comparing neural activity elicited by similar words delivered in various combinations. We describe the respective timing, topography and estimated cortical sources of two successive event-related potentials (ERP) components (N400 and late positive component (LPC)) using high-density EEG in conscious controls (N=20) and in minimally conscious (MCS; N=15) and vegetative states (VS; N=15) patients recorded at bedside. Whereas N400-like ERP components could be observed in the VS, MCS and conscious groups, only MCS and conscious groups showed a LPC response, suggesting that this late effect could be a potential specific marker of conscious semantic processing. This result is coherent with recent findings disentangling early and local non-conscious responses (e.g.: MMN in odd-ball paradigms, N400 in semantic violation paradigms) from late, distributed and conscious responses (e.g.: P3b to auditory rule violation) in controls and in patients with disorders of consciousness. However, N400 and LPC responses were not easily observed at the individual level, - even in conscious controls - , with standard ERP analyses, which is a limiting factor for its clinical use. Of potential interest, the only 3 patients presenting both significant N400 and LPC effects were MCS, and 2 of them regained consciousness and functional language abilities.

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

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

Information sharing in the brain indexes consciousness in noncommunicative patients.

Neuronal theories of conscious access tentatively relate conscious perception to the integration and global broadcasting of information across distant cortical and thalamic areas. Experiments contrasting visible and invisible stimuli support this view and suggest that global neuronal communication may be detectable using scalp electroencephalography (EEG). However, whether global information sharing across brain areas also provides a specific signature of conscious state in awake but noncommunicating patients remains an active topic of research. We designed a novel measure termed "weighted symbolic mutual information" (wSMI) and applied it to 181 high-density EEG recordings of awake patients recovering from coma and diagnosed in various states of consciousness. The results demonstrate that this measure of information sharing systematically increases with consciousness state, particularly across distant sites. This effect sharply distinguishes patients in vegetative state (VS), minimally conscious state (MCS), and conscious state (CS) and is observed regardless of etiology and delay since insult. The present findings support distributed theories of conscious processing and open up the possibility of an automatic detection of conscious states, which may be particularly important for the diagnosis of awake but noncommunicating patients.

Event related potentials elicited by violations of auditory regularities in patients with impaired consciousness.

Improving our ability to detect conscious processing in non communicating patients remains a major goal of clinical cognitive neurosciences. In this perspective, several functional brain imaging tools are currently under development. Bedside cognitive event-related potentials (ERPs) derived from the EEG signal are a good candidate to explore consciousness in these patients because: (1) they have an optimal time resolution within the millisecond range able to monitor the stream of consciousness, (2) they are fully non-invasive and relatively cheap, (3) they can be recorded continuously on dedicated individual systems to monitor consciousness and to communicate with patients, (4) and they can be used to enrich patients' autonomy through brain-computer interfaces. We recently designed an original auditory rule extraction ERP test that evaluates cerebral responses to violations of temporal regularities that are either local in time or global across several seconds. Local violations led to an early response in auditory cortex, independent of attention or the presence of a concurrent visual task, while global violations led to a late and spatially distributed response that was only present when subjects were attentive and aware of the violations. In the present work, we report the results of this test in 65 successive recordings obtained at bedside from 49 non-communicating patients affected with various acute or chronic neurological disorders. At the individual level, we confirm the high specificity of the 'global effect': only conscious patients presented this proposed neural signature of conscious processing. Here, we also describe in details the respective neural responses elicited by violations of local and global auditory regularities, and we report two additional ERP effects related to stimuli expectancy and to task learning, and we discuss their relations to consciousness.

Can fast-component of nystagmus on caloric vestibulo-ocular responses predict emergence from vegetative state in ICU?

The aim of the study was to determine if bedside caloric vestibulo-ocular responses (VOR) are able to predict consciousness recovery from clinically determined vegetative state (VS) in the ICU. Twenty-six severely brain injured patients that were clinically in VS were included. Horizontal VOR were tested at bedside by cold-water irrigation of the external auditory canal. Visual inspection evaluated the presence of a slow drift toward the side of stimulation (slow-component of nystagmus or tonic deviation) as well as the presence of a rapid compensatory movement/jerk back to the midline (fast-component of nystagmus). Patients were then divided into two groups according to whether they eventually regained consciousness or not. Patients were 59 ± 21 years old. Thirteen out of 26 patients ultimately recovered consciousness and 13 remained unconscious. Thirteen patients (100%) presented a slow-component of nystagmus during VOR testing in the group that recovered consciousness and 11 (85%) in the group that remained unconscious. All the patients that recovered consciousness (13, 100%) presented a fast-component of nystagmus during VOR testing compared to only one of 11 patients (8%) in the group that remained unconscious. Sensitivity of fast-component of nystagmus during VOR testing to predict recovering of consciousness was 1.00, specificity was 0.92, positive predictive value was 0.93 and negative predictive value was 1.00. Bedside VOR testing in clinically VS patients seems able to predict consciousness recovery from vegetative state and could help to preclude active medical treatment withdrawal and to indicate the need for further complementary explorations, i.e. event-related potentials, functional MRI or PET-scan.

[Familial amyloidotic polyneuropathies]. / Neuropathies amyloïdes héréditaires: aspects cliniques et neuropathologiques.

Transthyretin familial amyloid polyneuropathy (TTRFAP) is an autosomal dominant neuropathy that is fatal within about 10 years after symptom onset. TTRFAP is observed worldwide, albeit with a higher frequency of the most common variant, Val30met, in Portugal, Sweden and Japan. Various phenotypic differences are observed. TTRFAP should be considered in patients with a progressive axonal polyneuropathy of unknown origin, especially when associated with autonomic nervous system dysfunction. A positive family history is found in most cases when onset begins around 30 years of age, while late-onset FAP is often sporadic and may be confused with chronic inflammatory demyelinating polyneuropathy. Nerve biopsy is often used to confirm the presence of extracellular amyloid deposits in interstitial tissue of the endoneurial space, although amyloid can also befound in muscle, salivary gland and abdominal fat. It is important to stress that biopsy negativity does not rule out amyloidosis. Genetic testing for TTR gene mutations should be performed in case of progressive length-dependent axonal polyneuropathy predominantly involving small nerve fibers.