European Academy of Neurology guideline on the diagnosis of coma and other disorders of consciousness.

BACKGROUND AND PURPOSE: Patients with acquired brain injury and acute or prolonged disorders of consciousness (DoC) are challenging. Evidence to support diagnostic decisions on coma and other DoC is limited but accumulating. This guideline provides the state-of-the-art evidence regarding the diagnosis of DoC, summarizing data from bedside examination techniques, functional neuroimaging and electroencephalography (EEG). METHODS: Sixteen members of the European Academy of Neurology (EAN) Scientific Panel on Coma and Chronic Disorders of Consciousness, representing 10 European countries, reviewed the scientific evidence for the evaluation of coma and other DoC using standard bibliographic measures. Recommendations followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The guideline was endorsed by the EAN. RESULTS: Besides a comprehensive neurological examination, the following suggestions are made: probe for voluntary eye movements using a mirror; repeat clinical assessments in the subacute and chronic setting, using the Coma Recovery Scale - Revised; use the Full Outline of Unresponsiveness score instead of the Glasgow Coma Scale in the acute setting; obtain clinical standard EEG; search for sleep patterns on EEG, particularly rapid eye movement sleep and slow-wave sleep; and, whenever feasible, consider positron emission tomography, resting state functional magnetic resonance imaging (fMRI), active fMRI or EEG paradigms and quantitative analysis of high-density EEG to complement behavioral assessment in patients without command following at the bedside. CONCLUSIONS: Standardized clinical evaluation, EEG-based techniques and functional neuroimaging should be integrated for multimodal evaluation of patients with DoC. The state of consciousness should be classified according to the highest level revealed by any of these three approaches.

Physical therapy in patients with disorders of consciousness: Impact on spasticity and muscle contracture.

BACKGROUND: Spasticity is a frequent complication after severe brain injury, which may prevent the rehabilitation process and worsen the patients' quality of life. OBJECTIVES: In this study, we investigated the correlation between spasticity, muscle contracture, and the frequency of physical therapy (PT) in subacute and chronic patients with disorders of consciousness (DOC). METHODS: 109 patients with subacute and chronic disorders of consciousness (Vegetative state/Unresponsive wakefulness syndrome - VS/UWS; minimally conscious state - MCS and patients who emerged from MCS - EMCS) were included in the study (39 female; mean age: 40±13.5y; 60 with traumatic etiology; 35 VS/UWS, 68 MCS, 6 EMCS; time since insult: 38±42months). The number of PT sessions (i.e., 20 to 30 minutes of conventional stretching of the four limbs) was collected based on patients' medical record and varied between 0 to 6 times per week (low PT = 0-3 and high PT = 4-6 sessions per week). Spasticity was measured with the Modified Ashworth Scale (MAS) on every segment for both upper (UL) and lower limbs (LL). The presence of muscle contracture was assessed in every joint. We tested the relationship between spasticity and muscle contracture with the frequency of PT as well as other potential confounders such as time since injury or anti-spastic medication intake. RESULTS: We identified a negative correlation between the frequency of PT and MAS scores as well as the presence of muscle contracture. We also identified that patients who received less than four sessions per week were more likely to be spastic and suffer from muscle contracture than patients receiving 4 sessions or more. When separating subacute (3 to 12 months post-insult) and chronic (>12months post-insult) patients, these negative correlations were only observed in chronic patients. A logit regression model showed that frequency of PT influenced spasticity, whereas neither time since insult nor medication had a significant impact on the presence of spasticity. On the other hand, PT, time since injury and medication seemed to be associated with the presence of muscle contracture. CONCLUSION: Our results suggest that, in subacute and chronic patients with DOC, PT could have an impact on patients' spasticity and muscles contractures. Beside PT, other factors such as time since onset and medication seem to influence the development of muscle contractures. These findings support the need for frequent PT sessions and regular re-evaluation of the overall spastic treatment for patients with DOC.

Clinical on-site monitoring of ß-lactam antibiotics for a personalized antibiotherapy.

An appropriate antibiotherapy is crucial for the safety and recovery of patients. Depending on the clinical conditions of patients, the required dose to effectively eradicate an infection may vary. An inadequate dosing not only reduces the efficacy of the antibiotic, but also promotes the emergence of antimicrobial resistances. Therefore, a personalized therapy is of great interest for improved patients' outcome and will reduce in long-term the prevalence of multidrug-resistances. In this context, on-site monitoring of the antibiotic blood concentration is fundamental to facilitate an individual adjustment of the antibiotherapy. Herein, we present a bioinspired approach for the bedside monitoring of free accessible ß-lactam antibiotics, including penicillins (piperacillin) and cephalosporins (cefuroxime and cefazolin) in untreated plasma samples. The introduced system combines a disposable microfluidic chip with a naturally occurring penicillin-binding protein, resulting in a high-performance platform, capable of gauging very low antibiotic concentrations (less than 6 ng ml-1) from only 1 µl of serum. The system's applicability to a personalized antibiotherapy was successfully demonstrated by monitoring the pharmacokinetics of patients, treated with ß-lactam antibiotics, undergoing surgery.

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

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

Designed miniaturization of microfluidic biosensor platforms using the stop-flow technique.

Here, we present a novel approach to increase the degree of miniaturization as well as the sensitivity of biosensor platforms by the optimization of microfluidic stop-flow techniques independent of the applied detection technique (e.g. electrochemical or optical). The readout of the labeled bioassays, immobilized in a microfluidic channel, under stop-flow conditions leads to a rectangular shaped peak signal. Data evaluation using the peak height allows for a high level miniaturization of the channel geometries. To study the main advantages and limitations of this method by numerical simulations, a universally applicable model system is introduced for the first time. Consequently, proof-of-principle experiments were successfully performed with standard and miniaturized versions of an electrochemical biosensor platform utilizing a repressor protein-based assay for tetracycline antibiotics. Herein, the measured current peak heights are the same despite the sextuple reduction of the channel dimensions. Thus, this results in a 22-fold signal amplification compared to the constant flow measurements in the case of the miniaturized version.

Spasticity in disorders of consciousness: a behavioral study.

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

[Transcranial direct current stimulation: a new tool for neurostimulation]. / La stimulation transcrânienne à courant continu: un nouvel outil de neurostimulation.

Transcranial direct current stimulation (tDCS) is a safe method to modulate cortical excitability. Anodal stimulation can improve the stimulated area's functions whereas cathodal stimulation reduces them. Currently, a lot of clinical trials have been conducted to study the effect of tDCS on post-stroke motor and language deficits, in depression, chronic pain, memory impairment and tinnitus in order to decrease symptoms. Results showed that, if an effect is observed with tDCS, it does not persist over time. Current studies suggest that direct current stimulation is a promising technique that helps to improve rehabilitation after stroke, to enhance cognitive deficiencies, to reduce depression and to relieve chronic pain. Moreover, it is a safe, simple and cheap device that could be easily integrated in a rehabilitation program.

Electrophysiological investigations of brain function in coma, vegetative and minimally conscious patients.

Electroencephalographic activity in the context of disorders of consciousness is a swiss knife like tool that can evaluate different aspects of cognitive residual function, detect consciousness and provide a mean to communicate with the outside world without using muscular channels. Standard recordings in the neurological department offer a first global view of the electrogenesis of a patient and can spot abnormal epileptiform activity and therefore guide treatment. Although visual patterns have a prognosis value, they are not sufficient to provide a diagnosis between vegetative state/unresponsive wakefulness syndrome (VS/UWS) and minimally conscious state (MCS) patients. Quantitative electroencephalography (qEEG) processes the data and retrieves features, not visible on the raw traces, which can then be classified. Current results using qEEG show that MCS can be differentiated from VS/UWS patients at the group level. Event Related Potentials (ERP) are triggered by varying stimuli and reflect the time course of information processing related to the stimuli from low-level peripheral receptive structures to high-order associative cortices. It is hence possible to assess auditory, visual, or emotive pathways. Different stimuli elicit positive or negative components with different time signatures. The presence of these components when observed in passive paradigms is usually a sign of good prognosis but it cannot differentiate VS/UWS and MCS patients. Recently, researchers have developed active paradigms showing that the amplitude of the component is modulated when the subject's attention is focused on a task during stimulus presentation. Hence significant differences between ERPs of a patient in a passive compared to an active paradigm can be a proof of consciousness. An EEG-based brain-computer interface (BCI) can then be tested to provide the patient with a communication tool. BCIs have considerably improved the past two decades. However they are not easily adaptable to comatose patients as they can have visual or auditory impairments or different lesions affecting their EEG signal. Future progress will require large databases of resting state-EEG and ERPs experiment of patients of different etiologies. This will allow the identification of specific patterns related to the diagnostic of consciousness. Standardized procedures in the use of BCIs will also be needed to find the most suited technique for each individual patient.

What about pain in disorders of consciousness?

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

Relationship between etiology and covert cognition in the minimally conscious state.

OBJECTIVES: Functional neuroimaging has shown that the absence of externally observable signs of consciousness and cognition in severely brain-injured patients does not necessarily indicate the true absence of such abilities. However, relative to traumatic brain injury, nontraumatic injury is known to be associated with a reduced likelihood of regaining overtly measurable levels of consciousness. We investigated the relationships between etiology and both overt and covert cognitive abilities in a group of patients in the minimally conscious state (MCS). METHODS: Twenty-three MCS patients (15 traumatic and 8 nontraumatic) completed a motor imagery EEG task in which they were required to imagine movements of their right-hand and toes to command. When successfully performed, these imagined movements appear as distinct sensorimotor modulations, which can be used to determine the presence of reliable command-following. The utility of this task has been demonstrated previously in a group of vegetative state patients. RESULTS: Consistent and robust responses to command were observed in the EEG of 22% of the MCS patients (5 of 23). Etiology had a significant impact on the ability to successfully complete this task, with 33% of traumatic patients (5 of 15) returning positive EEG outcomes compared with none of the nontraumatic patients (0 of 8). CONCLUSIONS: The overt behavioral signs of awareness (measured with the Coma Recovery Scale-Revised) exhibited by nontraumatic MCS patients appear to be an accurate reflection of their covert cognitive abilities. In contrast, one-third of a group of traumatically injured patients in the MCS possess a range of high-level cognitive faculties that are not evident from their overt behavior.

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

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

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

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

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

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

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

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