Diagnostic Developments in Differentiating Unresponsive Wakefulness Syndrome and the Minimally Conscious State

When treating patients with a disorder of consciousness (DOC), it is essential to obtain an accurate diagnosis as soon as possible to generate individualized treatment programs. However, accurately diagnosing patients with DOCs is challenging and prone to errors when differentiating patients in a Vegetative State/Unresponsive Wakefulness Syndrome (VS/UWS) from those in a Minimally Conscious State (MCS). Upwards of ~40% of patients with a DOC can be misdiagnosed when specifically designed behavioral scales are not employed or improperly administered. To improve diagnostic accuracy for these patients, several important neuroimaging and electrophysiological technologies have been proposed. These include Positron Emission Tomography (PET), functional Magnetic Resonance Imaging (fMRI), Electroencephalography (EEG), and Transcranial Magnetic Stimulation (TMS). Here, we review the different ways in which these techniques can improve diagnostic differentiation between VS/UWS and MCS patients. We do so by referring to studies that were conducted within the last 10 years, which were extracted from the PubMed database. In total, 55 studies met our criteria (clinical diagnoses of VS/UWS from MCS as made by PET, fMRI, EEG and TMS- EEG tools) and were included in this review. By summarizing the promising results achieved in understanding and diagnosing these conditions, we aim to emphasize the need for more such tools to be incorporated in standard clinical practice, as well as the importance of data sharing to incentivize the community to meet these goals.

Nociceptive Response Is a Possible Marker of Evolution in the Level of Consciousness in Unresponsive Wakefulness Syndrome Patients

The Nociception Coma Scale (NCS) and its revised version (NCS-R) were used to evaluate behavioral responses to pain in non-communicative patients. We hypothesized that if patients demonstrate changes to their NCS(-R) scores over time, their evolving behavioral abilities could indicate a forthcoming diagnostic improvement with the Coma Recovery Scale-Revised (CRS-R). Forty-three Vegetative State/Unresponsive Wakefulness Syndrome (VS/UWS) patients were enrolled in the study. The patients were assessed weekly using the CRS-R and NCS(-R) for four consecutive weeks. The first assessment was within 10 days after hospitalization. The assessments were performed between 09:30 and 11:30 AM in a room with constant levels of humidity, light and temperature, as well as an absence of transient noise. Noxious stimuli were administered using a Newton-meter, with pressure applied to the fingernail bed for a maximum of 5 s unless interrupted by a behavioral response from subjects. Seventeen patients demonstrated improvements in their level of consciousness, 13 of whom showed significant behavioral changes through the NCS(-R) before being diagnosed with a Minimally Conscious State (MCS) according to the CRS-R. The behavioral changes observed using the NCS(-R) corresponded to a high probability of observing an improvement from VS/UWS to MCS. To characterize the increased likelihood of this transition, our results present threshold scores of ≥5 for the NCS (accuracy 86%, sensitivity 87%, and specificity 86%) and ≥3 for the NCS-R (accuracy 77%, sensitivity 89%, and specificity 73%). In conclusion, a careful evaluation of responses to nociceptive stimuli in DOC patients could constitute an effective procedure in assessing their evolving conscious state.

Biochemical Studies on Cerebrospinal Fluid in Patients With Unresponsive Wakefulness Syndrome: Toward a Potential Search for Biomarkers

Background: This study aimed to examine and screen patients for potential biomarkers for the diagnosis of unresponsive wakefulness syndrome (UWS). Methods: Patients with UWS, patients who regained consciousness (RC; patients in a minimally conscious state), and patients who had emerged from the minimally conscious state were evaluated using the Coma Recovery Scale-Revised (CRS-R). Cerebrospinal fluid (CSF) was collected from five healthy controls and 10 patients (5 UWS; 5 RC). Two-dimensional electrophoresis and proteomic analysis were used to examine and identify differentially expressed proteins in the CSF. Results: Compared with the control group, there were at least six proteins expressed at higher levels and two proteins expressed at lower levels in the CSF of the RC group than in the CSF of the UWS group. However, expression of vitamin D-binding protein (VDP) showed a further increase of 4.52-fold, that of DNA replication licensing factor mini-chromosome maintenance 4 (MCM4) showed a reduction of -20.61-fold, and that of hemoglobin subunit beta reversed to -8.34-fold in the UWS group. Another converse expression was of protein coenzyme Q-binding protein COQ10 homolog A (COQ10A), which was -4.31-fold in the RC group and 1.51-fold in the UWS group, compared to the control group. Expression of other proteins demonstrated an ascending trend in the RC group compared to the control group. Conclusions: The three differentially expressed proteins, VDP, DNA replication licensing factor MCM4, and hemoglobin subunit beta, may be involved in consciousness maintenance. This study identified potential biomarkers for UWS and will provide new insights into the pathogenesis of UWS.

Evaluation of structural variations in the pituitary gland, hormonal status and laboratory markers of the central nervous system functioning in patients with chronic disorders of consciousness

BACKGROUND: Consciousness is the state of being awake and aware of oneself and the environment. The disorders of consciousness result from pathologies that impair awareness. The development of effective comprehensive personalized interventions contributing to the recovery of consciousness in patients with chronic disorders of consciousness is one of the most pressing and challenging tasks in modern rehabilitation. AIM: The aim of this study was to understand structural problems of the pituitary gland, blood levels of gonadotropins and melatonin as well as brain damage markers in the blood and cerebrospinal fluid in patients with chronic disorders of consciousness and to analyze the levels of the above markers among different groups of patients depending on the level of impaired consciousness. MATERIALS AND METHODS: We examined 61 chronic disorders of consciousness patients and identified three groups depending on the level of consciousness including 24 patients with unresponsive wakefulness syndrome, 24 patients with a minus minimally conscious state, and 13 patients with minimally conscious state plus. We performed magnetic resonance imaging of chiasmatic-sellar region and determined blood serum levels of follicle-stimulating and luteinizing hormones and melatonin, as well as urinary level of 6-sulfatoxymelatonin and the content of brain derived neurotrophic factor (BDNF), apoptosis antigen (APO-1), FasL, glutamate, and S100 protein in the blood serum and cerebrospinal fluid. RESULTS: The patients were examined in the age ranging from 15 to 61 years old. Patient groups were homogeneous by the level of consciousness in terms of age and duration of chronic disorders of consciousness by the time of examination. The patients did not differ in the pituitary volume regardless of the level of consciousness. No significant differences were found between the groups with different levels of consciousness when studying the levels of melatonin in the blood serum and its metabolite in the urine. A peak in melatonin secretion was detected at 3 a.m. in 54.5 % of the patients, which can be considered as a favorable prognostic marker for further recovery of consciousness. Hypogonadotropic ovarian failure was found in 34 % of the patients, with normogonadotropic ovarian failure in the remaining patients. Serum APO-1 and BDNF levels were significantly higher in patients with minimally conscious state relative to those with unresponsive wakefulness syndrome. Significantly lower levels of glutamate in the cerebrospinal fluid were detected in women with unresponsive wakefulness syndrome compared to patients with minimally conscious state. CONCLUSIONS: Further in-depth examination and accumulation of data on patients with chronic disorders of consciousness may provide an opportunity to identify highly informative markers for predicting outcomes and to develop new effective approaches to rehabilitation of consciousness in this category of patients.

Modulated Neuroprotection in Unresponsive Wakefulness Syndrome after Severe Traumatic Brain Injury

Background: We aimed to assess the effects of modulated neuroprotection with intermittent administration in patients with unresponsive wakefulness syndrome (UWS) after severe traumatic brain injury (TBI). Methods: Retrospective analysis of 60 patients divided into two groups, with and without neuroprotective treatment with Actovegin, Cerebrolysin, pyritinol, L-phosphothreonine, L-glutamine, hydroxocobalamin, alpha-lipoic acid, carotene, DL-α-tocopherol, ascorbic acid, thiamine, pyridoxine, cyanocobalamin, Q 10 coenzyme, and L-carnitine alongside standard treatment. Main outcome measures: Glasgow Coma Scale (GCS) after TBI, Extended Glasgow Coma Scale (GOS E), Disability Rankin Scale (DRS), Functional Independence Measurement (FIM), and Montreal Cognitive Assessment (MOCA), all assessed at 1, 3, 6, 12, and 24 months after TBI. Results: Patients receiving neuroprotective treatment recovered more rapidly from UWS than controls (p = 0.007) passing through a state of minimal consciousness and gradually progressing until the final evaluation (p = 0.000), towards a high cognitive level MOCA = 22 ± 6 points, upper moderate disability GOS-E = 6 ± 1, DRS = 6 ± 4, and an assisted gait, FIM =101 ± 25. The improvement in cognitive and physical functioning was strongly correlated with lower UWS duration (−0.8532) and higher GCS score (0.9803). Conclusion: Modulated long-term neuroprotection may be the therapeutic key for patients to overcome UWS after severe TBI.

Assessment of Language Functions in Patients With Disorders of Consciousness Using an Alternative Communication Tool

This study aimed to describe the percentage of tasks involving language functions that were completed by patients diagnosed with disorders of consciousness, as observed during neurorehabilitation conducted for different periods of time using an alternative communication tool. The project involved six participants, who were observed for 1 month, 6 months, and 1 year. The patients were asked to solve tasks involving language functions with the use of an eye-controlled device. The language functions were evaluated on the basis of the average number of tasks performed by the patients, which was 70.45% for the whole subject group. It is not entirely clear what determined the changes in language functions during the research. It is crucial that patients performed the presented tasks even though their state of consciousness, as confirmed through medical documentation (unresponsive wakefulness syndrome), did not suggest the possibility of establishing any contact with them.

The Timecourse of Electrophysiological Brain–Heart Interaction in DoC Patients

Disorders of Consciousness (DOC) are a spectrum of pathologies affecting one’s ability to interact with the external world. Two possible conditions of patients with DOC are Unresponsive Wakefulness Syndrome/Vegetative State (UWS/VS) and Minimally Conscious State (MCS). Analysis of spontaneous EEG activity and the Heart Rate Variability (HRV) are effective techniques in exploring and evaluating patients with DOC. This study aims to observe fluctuations in EEG and HRV parameters in the morning/afternoon resting-state recording. The study enrolled 13 voluntary Healthy Control (HC) subjects and 12 DOC patients (7 MCS, 5 UWS/VS). EEG and EKG were recorded. PSDalpha, PSDtheta powerband, alpha-blocking, alpha/theta of the EEG, Complexity Index (CI) and SDNN of EKG were analyzed. Higher values of PSDalpha, alpha-blocking, alpha/theta and CI values and lower values of PSD theta characterized HC individuals in the morning with respect to DOC patients. In the afternoon, we detected a significant difference between groups in the CI, PSDalpha, PSDtheta, alpha/theta and SDNN, with lower PSDtheta value for HC. CRS-R scores showed a strong correlation with recorded parameters mainly during evaluations in the morning. Our finding put in evidence the importance of the assessment, as the stimulation of DOC patients in research for behavioural response, in the morning.