Challenges and Pitfalls Associated with Diagnostic and Prognostic Applications of Functional Neuroimaging in Disorders of Consciousness

The diagnostic assessment of patients with disorder of consciousness is currently based on clinical testing at the bedside and prone to a high error rate in the assessment of the degree of conscious awareness. Investigation of more objective assessment strategies, such as the use of functional magnetic resonance imaging (fMRI) to detect conscious awareness, are becoming increasingly popular in the research community. However, inherent challenges to the use of fMRI threaten its validity as a diagnostic tool and will need to be resolved prior to its integration into the clinical setting. These challenges, which range from the heterogeneity of the patient sample to factors influencing data acquisition and biases in interpretation strategies, are discussed below. Recommendations aimed at mitigating some of the limitations are provided

Which behaviours are first to emerge during recovery of consciousness after severe brain injury?

Background. Early detection of consciousness after severe brain injury is critical for establishing an accurate prognosis and planning appropriate treatment. Objectives. To determine which behavioral signs of consciousness emerge first and to estimate the time course to recovery of consciousness in patients with severe acquired brain injury. Methods. Retrospective observational study using the Coma Recovery Scale-Revised and days to recovery of consciousness in 79 patients (51 males; 34 with traumatic brain injury; median [IQR] age 48 [26–61] years; median time since injury 26 [20–36] days) who transitioned from coma or unresponsive wakefulness syndrome (UWS)/vegetative state (VS) to the minimally conscious state (MCS) or emerged from MCS during inpatient rehabilitation. Results. Visual pursuit was the most common initial sign of MCS (41% of patients; 95% CI [30–52]), followed by reproducible command-following (25% [16–35]) and automatic movements (24% [15–33]). Ten other behaviors emerged first in less than 16% of cases. Median [IQR] time to recovery of consciousness was 44 [33–59] days. Etiology did not significantly affect time to recovered consciousness. Conclusion. Recovery of consciousness after severe brain injury is most often signaled by reemergence of visual pursuit reproducible command-following and automatic movements. Clinicians should use assessment measures that are sensitive to these behaviors because early detection of consciousness is critical for accurate prognostication and treatment planning

Predictive utility of an adapted Marshall head CT classification scheme after traumatic brain injury

Objective: To study the predictive relationship among persons with traumatic brain injury (TBI) between an objective indicator of injury severity (the adapted Marshall computed tomography [CT] classification scheme) and clinical indicators of injury severity in the acute phase, functional outcomes at inpatient rehabilitation discharge, and functional and participation outcomes at 1 year after injury, including death.Participants: The sample involved 4895 individuals who received inpatient rehabilitation following acute hospitalization for TBI and were enrolled in the Traumatic Brain Injury Model Systems National Database between 1989 and 2014.Design: Head CT variables for each person were fit into adapted Marshall CT classification categories I through IV.Main Measures: Prediction models were developed to determine the amount of variability explained by the CT classification categories compared with commonly used predictors, including a clinical indicator of injury severity.Results: The adapted Marshall classification categories aided only in the prediction of craniotomy or craniectomy during acute hospitalization, otherwise making no meaningful contribution to variance in the multivariable models predicting outcomes at any time point after injury.Conclusion: Results suggest that head CT findings classified in this manner do not inform clinical discussions related to functional prognosis or rehabilitation planning after TBI

Diagnosing Level of Consciousness: Limits of the Glasgow Coma Scale Total Score

In nearly all clinical and research contexts, the initial severity of a traumatic brain injury (TBI) is measured using the Glasgow Coma Scale (GCS) total score. The GCS total score however, may not accurately reflect level of consciousness, a critical indicator of injury severity. We investigated the relationship between GCS total scores and level of consciousness in a consecutive sample of 2455 adult subjects assessed with the GCS 69,487 times as part of the multi-center Transforming Research and Clinical Knowledge in TBI (TRACKTBI) study. We assigned each GCS subscale score combination a level of consciousness rating based on published criteria for the following disorders of consciousness (DoC) diagnoses: coma, vegetative state/ unresponsive wakefulness syndrome, minimally conscious state, and post-traumatic confusional state, and present our findings using summary statistics and four illustrative cases. Participants had the following characteristics: mean (standard deviation) age 41.9 (17.6) years, 69% male, initial GCS 3–8 = 13%; 9–12 = 5%; 13–15 = 82%. All GCS total scores between 4–14 were associated with more than one DoC diagnosis; the greatest variability was observed for scores of 7–11. Further, a wide range of total scores was associated with identical DoC diagnoses. Importantly, a diagnosis of coma was only possible with GCS total scores of 3–6. The GCS total score does not accurately reflect level of consciousness based on published DoC diagnostic criteria. To improve the classification of patients with TBI and to inform the design of future clinical trials, clinicians and investigators should consider individual subscale behaviors and more comprehensive assessments when evaluating TBI severityTRACK-TB

Central curation of Glasgow Outcome Scale-Extended data: lessons learned from TRACK-TBI

The Glasgow Outcome Scale (GOS) in its original or extended (GOSE) form is the most widely used assessment of global disability in traumatic brain injury (TBI) research. Several publications have reported concerns about assessor scoring inconsistencies, but without documentation of contributing factors. We reviewed 6801 GOSE assessments collected longitudinally, across 18 sites in the 5-year, observational Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. We recorded error rates (i.e., corrections to a section or an overall rating) based on site assessor documentation and categorized scoring issues, which then informed further training. In Cohort 1 (n=1261; 2/2014-5/2016), 24% of GOSEs had errors identified by central review. In Cohort 2 (n=1130; 6/2016-7/2018), acquired following curation of Cohort 1 data, feedback, and further training of site assessors, the error rate was reduced to 10%. GOSE sections associated with the most frequent interpretation and scoring difficulties included whether current functioning represented a change from pre-injury (466 corrected ratings in Cohort 1; 62 in Cohort 2), defining dependency in the home and community (163 corrections in Cohort 1; 3 in Cohort 2); and return to work/school (72 corrections in Cohort 1; 35 in Cohort 2). These results highlight the importance of central review in improving consistency across sites and over time. Establishing clear scoring criteria, coupled with ongoing guidance and feedback to data collectors, is essential to avoid scoring errors and resultant misclassification, which carry potential to result in “failure” of clinical trials that rely on the GOSE as their primary outcome measure

The Post-traumatic Confusional State: A Case Definition and Diagnostic Criteria

In response to the need to better define the natural history of emerging consciousness after traumatic brain injury (TBI) and to better describe the characteristics of the condition commonly labeled Post-traumatic Amnesia, a case definition and diagnostic criteria for the Post- traumatic Confusional State (PTCS) were developed. This project was completed by the Confusion Workgroup of the American Congress of Rehabilitation Medicine Brain Injury Interdisciplinary Special Interest group. The case definition was informed by an exhaustive literature review and expert opinion of workgroup members from multiple disciplines. The workgroup reviewed 2,466 abstracts and extracted evidence from 44 articles. Consensus was reached through teleconferences, face-to-face meetings, and three rounds of modified Delphi voting. The case definition provides detailed description of PTCS (1) core neurobehavioral features, (2) associated neurobehavioral features, (3) functional implications, (4) exclusion criteria, (5) lower boundary, and (6) criteria for emergence. Core neurobehavioral features include disturbances of attention, orientation, and memory as well as excessive fluctuation. Associated neurobehavioral features include emotional and behavioral disturbances, sleep-wake cycle disturbance, delusions, perceptual disturbances and confabulation. The lower boundary distinguishes PTCS from the minimally conscious state while upper boundary is marked by significant improvement in the four core and five associated features. Key research goals are establishment of cut-offs on assessment instruments and determination of levels of behavioral function that distinguish persons in PTCS from those who have emerged to the period of continued recovery

Functional Networks in Disorders of Consciousness

AbstractSevere brain injury may cause disruption of neural networks that sustain arousal and awareness, the two essential components of consciousness. Despite the potentially devastating immediate and long-term consequences, disorders of consciousness (DoC) are poorly understood in terms of their underlying neurobiology, the relationship between pathophysiology and recovery, and the predictors of treatment efficacy. Recent advances in neuroimaging techniques have enabled the study of network connectivity, providing great potential to improve the clinical care of patients with DoC. Initial discoveries in this field were made using positron emission tomography (PET). More recently, functional magnetic resonance (fMRI) techniques have added to our understanding of functional network dynamics in this population. Both methods have shown that whether at rest or performing a goal-oriented task, functional networks essential for processing intrinsic thoughts and extrinsic stimuli are disrupted in patients with DoC compared with healthy subjects. Atypical connectivity has been well established in the default mode network as well as in other cortical and subcortical networks that may be required for consciousness. Moreover, the degree of altered connectivity may be related to the severity of impaired consciousness, and recovery of consciousness has been shown to be associated with restoration of connectivity. In this review, we discuss PET and fMRI studies of functional and effective connectivity in patients with DoC and suggest how this field can move toward clinical application of functional network mapping in the future.</jats:p

Behavioral markers of recovery of consciousness after severe brain injury

Patients with an altered state of consciousness (i.e., coma, unresponsive wakefulness syndrome/vegetative state [UWS/VS], minimally conscious state [MCS] and emergence from the MCS [eMCS]) following severe brain injury are highly exposed to the risk of misdiagnosis. Detecting the transition from an unconscious to conscious state is critically important to clinical management, disposition planning and family counseling. This retrospective observational study aimed at determining which behaviors signal recovery of consciousness after severe traumatic and non-traumatic brain injury and the time course to recovery of consciousness using the Coma Recovery Scale-Revised (CRS-R) in an inpatient rehabilitation hospital with a specialized disorders of consciousness (DoC) program. Seventy-nine patients who transitioned from coma or UWS/VS to MCS or eMCS during inpatient rehabilitation were included (51 males; median age [IQR]= 48 [25.5 – 61]; TBI = 34; median time since injury at admission [IQR]: 26 [20 – 36] days). Visual pursuit was the most frequently observed behavioral sign marking recovery of consciousness (present in 37% of patients), followed by reproducible movement to command (23%) and automatic movements (22%). Ten other behaviors signaled return of conscious awareness, but these signs were first to emerge in less than 15% of cases. In 72% of the sample, the transition to conscious awareness was marked by a single behavior: visual pursuit. When two behavioral markers of consciousness emerged concurrently at time of transition (17%), visual and motor signs were most prevalent. The median time to recovery of consciousness was 44 [33 – 59] days post injury. The transition from an unconscious to conscious state is usually marked by the emergence of a single behavioral sign of consciousness. Visual pursuit, reproducible command-following and automatic movements are the most common markers of recovery of consciousness. Clinicians should utilize assessment methods that are particularly sensitive to these behaviors to avoid early misdiagnosis and inappropriate treatment recommendations