Long-term clinical evolution of patients with prolonged disorders of consciousness due to severe anoxic brain injury: A meta-analytic study.

BACKGROUND AND PURPOSE: The prognosis of prolonged (28 days to 3 months post-onset) disorders of consciousness (pDoC) due to anoxic brain injury is uncertain. The present study aimed to evaluate the long-term outcome of post-anoxic pDoC and identify the possible predictive value of demographic and clinical information. METHOD: This is a systematic review and meta-analysis. The rates of mortality, any improvement in clinical diagnosis, and recovery of full consciousness at least 6 months after severe anoxic brain injury were evaluated. A cross-sectional approach searched for differences in baseline demographic and clinical characteristics between survivors and non-survivors, patients improved versus not improved, and patients who recovered full consciousness versus not recovered. RESULTS: Twenty-seven studies were identified. The pooled rates of mortality, any clinical improvement and recovery of full consciousness were 26%, 26% and 17%, respectively. Younger age, baseline diagnosis of minimally conscious state versus vegetative state/unresponsive wakefulness syndrome, higher Coma Recovery Scale Revised total score, and earlier admission to intensive rehabilitation units were associated with a significantly higher likelihood of survival and clinical improvement. These same variables, except time of admission to rehabilitation, were also associated with recovery of full consciousness. CONCLUSIONS: Patients with anoxic pDoC might improve over time up to full recovery of consciousness and some clinical characteristics can help predict clinical improvement. These new insights could support clinicians and caregivers in the decision-making on patient management.

Sham-controlled randomized multicentre trial of transcranial direct current stimulation for prolonged disorders of consciousness.

BACKGROUND AND PURPOSE: Transcranial direct current stimulation (tDCS) has been shown to improve signs of consciousness in a subset of patients with disorders of consciousness (DoC). However, no multicentre study confirmed its efficacy when applied during rehabilitation. In this randomized controlled double-blind study, the effects of tDCS whilst patients were in rehabilitation were tested at the group level and according to their diagnosis and aetiology to better target DoC patients who might repond to tDCS. METHODS: Patients received 2 mA tDCS or sham applied over the left prefrontal cortex for 4 weeks. Behavioural assessments were performed weekly and up to 3 months' follow-up. Analyses were conducted at the group and subgroup levels based on the diagnosis (minimally conscious state [MCS] and unresponsive wakefulness syndrome) and the aetiology (traumatic or non-traumatic). Interim analyses were planned to continue or stop the trial. RESULTS: The trial was stopped for futility when 62 patients from 10 centres were enrolled (44 ± 14 years, 37 ± 24.5 weeks post-injury, 18 women, 32 MCS, 39 non-traumatic). Whilst, at the group level, no treatment effect was found, the subgroup analyses at 3 months' follow-up revealed a significant improvement for patients in MCS and with traumatic aetiology. CONCLUSIONS: Transcranial direct current stimulation during rehabilitation does not seem to enhance patients' recovery. However, diagnosis and aetiology appear to be important factors leading to a response to the treatment. These findings bring novel insights into possible cortical plasticity changes in DoC patients given these differential results according to the subgroups of patients.

Risk factors for 2-year mortality in patients with prolonged disorders of consciousness: An international multicentre study.

BACKGROUND AND PURPOSE: Patients with prolonged disorders of consciousness (pDoC) have a high mortality rate due to medical complications. Because an accurate prognosis is essential for decision-making on patients' management, we analysed data from an international multicentre prospective cohort study to evaluate 2-year mortality rate and bedside predictors of mortality. METHODS: We enrolled adult patients in prolonged vegetative state/unresponsive wakefulness syndrome (VS/UWS) or minimally conscious state (MCS) after traumatic and nontraumatic brain injury within 3 months postinjury. At enrolment, we collected demographic (age, sex), anamnestic (aetiology, time postinjury), clinical (Coma Recovery Scale-Revised [CRS-R], Disability Rating Scale, Nociception Coma Scale-Revised), and neurophysiologic (electroencephalogram [EEG], somatosensory evoked and event-related potentials) data. Patients were followed up to gather data on mortality up to 24 months postinjury. RESULTS: Among 143 traumatic (n = 55) and nontraumatic (n = 88) patients (VS/UWS, n = 68, 19 females; MCS, n = 75, 22 females), 41 (28.7%) died within 24 months postinjury. Mortality rate was higher in VS/UWS (42.6%) than in MCS (16%; p < 0.001). Multivariate regression in VS/UWS showed that significant predictors of mortality were older age and lower CRS-R total score, whereas in MCS female sex and absence of alpha rhythm on EEG at study entry were significant predictors. CONCLUSIONS: This study demonstrated that a feasible multimodal assessment in the postacute phase can help clinicians to identify patients with pDoC at higher risk of mortality within 24 months after brain injury. This evidence can help clinicians and patients' families to navigate the complex clinical decision-making process and promote an international standardization of prognostic procedures for patients with pDoC.

Development of an Italian version of the functional communication measures and preliminary observations in patients with severe acquired brain injury and emerging from a prolonged disorder of consciousness.

A proper assessment tool targeting communicative abilities in patients with severe acquired brain injury (sABI), and particularly for patients recovering from prolonged disorders of consciousness (pDoC), is lacking. The Functional Communication Measures (FCM) consists of a series of rating scales, ranging from 1 (least functional) to 7 (most functional), assessing cognitive requirements for communication and communicative abilities in patients with brain injury. Here we presented exploratory data concerning an Italian adaptation of FCM administered to patients with sABI. After the translation into Italian language, the FCM was blindly administered by 2 independent speech therapists to 19 patients (10 males; median age = 58; IQR = 25) admitted to neurorehabilitation unit after sABI with a level of cognitive functioning between 4 and 8. Two further patients who presented a pDoC after sABI and emerged from the minimally conscious state (a 64-year-old female and a 74-year-old female) were also evaluated by means of the FCM, the Coma Recovery Scale-Revised, and the Disability Rating Scale. Inter-rater agreement was almost perfect for attention, memory, and swallowing items, and substantial for communicative-augmentative communication, motor speech, spoken language expression, and spoken language comprehension. Importantly, in the two pDoC patients, the FCM identified two different functioning profiles in the attention, swallowing, motor speech, and spoken language expression scales, notwithstanding the two patients achieved the same scores on scales for functional disability and consciousness level. The FCM might be a promising and easy-to-administer tool to assess communicative functions in patients with sABI, independently from evaluation of functional disability.

Epilepsy in prolonged disorders of consciousness: a systematic review.

To date, no guideline exists for the management of epilepsy in patients with prolonged Disorders of Consciousness (DoC). This review aimed to assess the occurrence of epilepsy and epileptic abnormalities (EA) in these patients, to determine their impact on recovery; and to review the effect of antiepileptic drugs (AED) and therapeutic interventions on seizure occurrence and consciousness recovery. A structured search for studies on prolonged DoC and epilepsy was undertaken following PRISMA guidelines. From an initial search resulting in 5,775 titles, twelve studies met inclusion criteria. The occurrence of epilepsy and EA in DoC was poorly and inconsistently reported across studies. The results estimated a seizure prevalence of 27% in DoC. No conclusive data were found for the effects of AED on recovery nor on the influence of any therapeutic interventions on seizure occurrence. Given the scarcity of data, it is premature to make evidence-based recommendations on epilepsy in prolonged DoC. Based on this review and current clinical practices the following are recommended: (1) repeated standard EEG for detecting seizures and EA; (2) treating epilepsy while avoiding AEDs with sedating or cognitive side-effects. Future research should use standardized classification systems for seizures and EA.

'Less is more': validation with Rasch analysis of five short-forms for the Brain Injury Rehabilitation Trust Personality Questionnaires (BIRT-PQs).

BACKGROUND: Previous analyses demonstrated a lack of unidimensionality, item redundancy, and substantial administrative burden for the Brain Injury Rehabilitation Trust Personality Questionnaires (BIRT-PQs). OBJECTIVE: To use Rasch Analysis to calibrate five short-forms of the BIRT-PQs, satisfying the Rasch model requirements. METHODS: BIRT-PQs data from 154 patients with severe Acquired Brain Injury (s-ABI) and their caregivers (total sample = 308) underwent Rasch analysis to examine their internal construct validity and reliability according to the Rasch model. RESULTS: The base Rasch analyses did not show sufficient internal construct validity according to the Rasch model for all five BIRT-PQs. After rescoring 18 items, and deleting 75 of 150 items, adequate internal construct validity was achieved for all five BIRT-PQs short forms (model chi-square p-values ranging from 0.0053 to 0.6675), with reliability values compatible with individual measurements. CONCLUSIONS: After extensive modifications, including a 48% reduction of the item load, we obtained five short forms of the BIRT-PQs satisfying the strict measurement requirements of the Rasch model. The ordinal-to-interval measurement conversion tables allow measuring on the same metric the perception of the neurobehavioral disability for both patients with s-ABI and their caregivers.

The unidimensionality of the five Brain Injury Rehabilitation Trust Personality Questionnaires (BIRT-PQs) may be improved: preliminary evidence from classical psychometrics.

Objective: To assess the internal construct validity (ICV) of the five Brain Injury Rehabilitation Trust Personality Questionnaires (BIRT-PQ) with Classical Test Theory methods.Methods: Multicenter cross-sectional study involving 11 Italian rehabilitation centers. BIRT-PQs were administered to patients with severe Acquired Brain Injury and their respective caregivers. ICV was assessed by the mean of an internal consistency analysis (ICA) and a Confirmatory Factor Analysis (CFA).Results: Data from 154 patients and their respective caregivers were pooled, giving a total sample of 308 subjects. Despite good overall values (alphas ranging from 0.811 to 0.937), the ICA revealed that several items within each scale did not contribute as expected to the total score. This result was confirmed by the CFA, which showed the misfit of the data to a unidimensional model (RMSEA ranging from 0.077 to 0.097). However, after accounting for local dependency found within the data, fitness to a unidimensional model improved significantly (RMSEA ranging from 0.050 to 0.062).Conclusion: Despite some limitations, our analyses demonstrated the lack of ICV for the BIRT-PQ total scores. It is envisaged that a more comprehensive ICV analysis will be performed with Rasch analysis, aiming to improve both the measurement properties and the administrative burden of each BIRT-PQ.

Can Salient Stimuli Enhance Responses in Disorders of Consciousness? A Systematic Review.

PURPOSE OF REVIEW: Diagnostic classification of patients with disorders of consciousness (DoC) is based on clinician's observation of volitional behaviours. However, patients' caregivers often report higher levels of responsiveness with respect to those observed during the clinical assessment. Thus, increasing efforts have been aimed at comprehending the effects of self-referential and emotional stimuli on patients' responsiveness. Here we systematically reviewed the original experimental studies that compared behavioural and electrophysiological responses with salient vs. neutral material in patients in vegetative state/unresponsive wakefulness syndrome or in minimally conscious state. RECENT FINDINGS: Most of the reviewed studies showed that salient stimuli (i.e. patient's own or familiar faces, patient's own name, and familiar voices) seem to elicit a higher amount of behavioural or electrophysiological responses with respect to neutral pictures or sounds. Importantly, a quite high percentage of patients seem to respond to salient stimuli only. The present review could foster use of personally salient stimuli in assessing DoC. However, the low overall quality of evidence and some limitations in the general reviewing process might induce caution in transferring these suggestions into clinical practice.

International survey on diagnostic and prognostic procedures in pediatric disorders of consciousness.

AIMS: 1. to investigate diagnostic and prognostic procedures routinely used by international professionals to assess children with disorders of consciousness (DoC); 2. to explore use and availability of internal and national guidelines for pediatric DoC; 3. to identify international differences in diagnostic/prognostic protocols. METHODS: The International Brain Injury Association DoC Special Interest Group emailed a survey link to 43,469 professionals. The survey included questions on diagnostic/prognostic procedures and guidelines for children with DoC. RESULTS: Data on 82 respondents [(50% physicians) primarily from Europe (43.9%)and North America (37.8%)] were analyzed. Common diagnostic tools included the Glasgow Coma Scale for clinical assessment (94%), the Coma Recovery Scale-Revised for outcome measurement (57%), and cerebral MRI (94%). Clinical features used most frequently to inform prognosis varied with patient age. Few respondents used national (28%) admission protocols for children with DoC, and most were unaware of published national guidelines for diagnostic (72%) and prognostic (85%) procedures. Compared to North American respondents, more European respondents were physicians and used neurophysiological data for prognosis. CONCLUSIONS: This international survey provides useful information about diagnostic and prognostic procedures currently used for children with DoC and highlights the need for guidelines to promote best practices for diagnosis/prognosis in pediatric DoC.

An International survey on diagnostic and prognostic protocols in patients with disorder of consciousness.

To date, no international guidelines or recommendations for diagnosis or prognosis of patients with disorders of consciousness (DoC) have been established. The International Brain Injury Association's (IBIA) Special Interest Group on Disorders of Consciousness (DoC-SIG) launched an international multicenter survey to compare diagnostic and prognostic procedures across countries and clinical settings. Objectives: To explore which specific diagnostic protocols and prognostic indices were utilized in the care for persons with DoC in different countries and to determine the usage, if any, of national guidelines in the care of such patients. Methods: The questionnaire included 17 questions in two distinct sections (I - clinical and instrumental tools and involvement of caregivers and II - clinical, anamnestic and instrumental markers). Results: Physicians composed 50% of the survey respondents (120) and were all involved in post-acute rehabilitation care. In the majority of countries, respondents reported that there were no national guidelines or recommendations for DoC care. The Glasgow Coma Scale (GCS) and the Coma Recovery Scale-Revised (CRS-R) were the most frequently used clinical scales for diagnostic purposes. The majority of respondents reported the involvement of caregivers in the evaluation of behavioral responsiveness of patient with DoC. The survey indicated that only a few centers performed neurophysiological investigations routinely as diagnostic instrumental procedures. Our results suggest that international guidelines and recommendations for the care of persons with DoC still need to be formulated and ideally agreed to by consensus.

Selegiline in Patients With Disorder of Consciousness: An Open Pilot Study.

This open study investigated the clinical effects of 10-week selegiline administration in six patients in vegetative state and in four patients in a minimally conscious state, at least 6 months after onset. Clinical outcome was assessed by Coma Recovery Scale-Revised once a week during selegiline administration and 1 month later. Three patients stopped treatment because of possible side effects. After treatment and at 1 month of follow-up, four patients showed improvements in clinical diagnosis, and three patients showed an increase in arousal level only. Selegiline might represent a relatively safe option to enhance arousal and promote recovery in brain-injured patients with disorders of consciousness.

Do Medical Complications Impact Long-Term Outcomes in Prolonged Disorders of Consciousness?

OBJECTIVE: To investigate medical complications (MCs) occurring within 6 months postinjury in brain-injured patients with prolonged disorders of consciousness (DoC) and to evaluate impact of MC on mortality and long-term clinical outcomes. DESIGN: Prospective observational cohort study. SETTING: Rehabilitation unit for acquired DoC. PARTICIPANTS: Patients (N=194) with DoC (142 in vegetative state [VS], 52 in minimally conscious state; traumatic etiology 43, anoxic 69, vascular 82) consecutively admitted to a neurorehabilitation unit within 1-3 months postonset. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Mortality and improvements in clinical diagnosis and functional disability level (assessed by Coma Recovery Scale-Revised [CRS-R] and Disability Rating Scale) at 12, 24, and 36 months postonset. RESULTS: Within 6 months postinjury, 188 of 194 patients (>95%) developed at least 1 MC and 142 of them (73%) showed at least 1 severe MC. Respiratory and musculoskeletal-cutaneous MCs were the most frequent, followed by endocrino-metabolic abnormalities. Follow-up, complete in 189 of 194 patients, showed that male sex and endocrine-metabolic MCs were associated with higher risk of mortality at all timepoints. Old age, anoxic etiology, lower CRS-R total scores, and diagnosis of VS at study entry predicted no clinical and functional improvements at most timepoints; however, epilepsy predicted no improvement in diagnosis at 24 months postonset only. CONCLUSIONS: MCs are very frequent in patients with DoC within at least 6 months after brain injury, regardless of clinical diagnosis, etiology, and age. Endocrino-metabolic MCs are independent predictors of mortality at all timepoints; however,epilepsy predicted poor long-term outcome. Occurrence and severity of MCs in patients with DoC call for long-term appropriate levels of care after the postacute phase.

Occurrence and predictive factors of heterotopic ossification in severe acquired brain injured patients during rehabilitation stay: cross-sectional survey.

OBJECTIVES: To report occurrence and identify patient's features and risk factors of heterotopic ossifications in patients with severe acquired brain injury in intensive rehabilitation centres. DESIGN: Multicentre cross-sectional survey. SETTING: A total of 48 severe acquired brain injury rehabilitation institutes. PARTICIPANTS: Traumatic and non-traumatic severe brain-injured patients ( N = 689) in rehabilitation centres on 28 May 2016. MAIN OUTCOME MEASURE: Occurrence of heterotopic ossifications diagnosed by standard radiological and/or sonographic evaluation on the basis of clinical suspicion. RESULTS: Heterotopic ossification occurred around one or more joints in 94/689 patients (13.6%) with a significantly higher prevalence in young males. Occurrence did not significantly differ in relation to aetiology (16.3% traumatic, 19.2% anoxic, 11.7% vascular and 11.5% other). Prevalence was significantly higher in patients with diffuse (23.3%) rather than focal brain lesions (12.4%) or unspecified lesions (11.2%; chi-square = 7.81, df = 2, P = 0.020); longer duration of coma ( P = 0.0016) and ventilation support ( P = 0.0145); paroxysmal sympathetic hyperactivity (22.6% versus 11.6%; chi-square = 10.81, df = 1, P = 0.001); and spasticity (22.7% versus 10.1%; chi-square = 18.63, df = 1, P < 0.0001). A longer interval between acute brain injury and admission to rehabilitation centre was significantly associated with higher frequency of heterotopic ossifications. CONCLUSION: Occurrence of heterotopic ossifications is frequent in patients with severe traumatic and non-traumatic brain-injury in rehabilitation centres. Our study confirms male gender, young age, paroxysmal sympathetic hyperactivity, spasticity, longer duration of coma and ventilation and longer interval between brain injury onset and admission to rehabilitation centre as possible risk factors. Further studies are necessary to investigate the role of early appropriate rehabilitation pathways to reduce occurrence of heterotopic ossifications.

Visual pursuit of one's own face in disorders of consciousness: a quantitative analysis.

BACKGROUND: Eye behaviour is important to distinguish minimally conscious state (MCS) from vegetative state (VS). OBJECTIVE: To search for conditions most suitable to characterize patients in MCS and in VS on quantitative assessment of visual tracking. DESIGN: This is a cross-sectional study. PARTICIPANTS: In total, 20 patients in VS, 13 in MCS plus and 11 in MCS minus participated in this study. SETTING: Neurorehabilitation Unit. METHODS: Evaluation of eye behaviour was performed by infrared system; stimuli were represented by a red circle, a picture of a patient's own face and a picture of an unfamiliar face, slowly moving on a personal computer (PC) monitor. Visual tracking on the horizontal and vertical axes was compared. MAIN OUTCOME MEASURES: The main outcome measures were proportion of on-target fixations and mean fixation duration. RESULTS: The proportion of on-target fixations differed as a function of the stimulus in patients in MCS plus but not in other groups. Own face and unfamiliar face elicited a similar proportion of on-target fixations. Tracking along the horizontal axis was more accurate than that along the vertical axis in patients in both MCS plus and MCS minus. Fixation duration did not differ among the three groups. CONCLUSIONS: Horizontal visual tracking of salient stimuli seems particularly suitable for eliciting on-target fixations. Quantitative assessment of visual tracking can complement clinical evaluation for reducing diagnostic uncertainty between patients in MCS or VS.

A multicentre study of intentional behavioural responses measured using the Coma Recovery Scale-Revised in patients with minimally conscious state.

OBJECTIVE: To investigate which conscious behaviour is most frequently detected using the Coma Recovery Scale-Revised in patients with minimally conscious state. DESIGN: Multicentre, cross-sectional study. SETTING: One intensive care unit, 8 post-acute rehabilitation centres and 2 long-term facilities. SUBJECTS: Fifty-two patients with established diagnosis of minimally conscious state of different aetiology. MAIN MEASURES: All patients were assessed by the Coma Recovery Scale-Revised. RESULTS: In most patients (34/52) non-reflexive responses were identified by two or more subscales of the Coma Recovery Scale-Revised, whereas in 14 patients only the visual subscale could identify cortically-mediated behaviours, and in the remaining 4 patients only the motor subscale did so.The clinical signs of intentional behaviour were most often detected by the visual subscale (43/52 patients) and by the motor subscale (31/52), and least frequently by the oromotor/verbal subscale (3/52) of the Coma Recovery Scale-Revised. This clinical pattern was observed independently from time post-onset and aetiology. CONCLUSIONS: Non-reflexive visual behaviour, identified by the visual subscale of Coma Recovery Scale-Revised, is the most frequently detected intentional sign consistent with the diagnosis of minimally conscious state, independently from aetiology and time post-onset.

Clinical and neuropsychological long-term outcomes after late recovery of responsiveness: a case series.

OBJECTIVE: To report clinical conditions and neuropsychological functioning of patients with late recovery of responsiveness at least 5 years after injury. DESIGN: Patient series. SETTING: Patients discharged from an inpatient rehabilitation unit. PARTICIPANTS: Patients (N=13) who recovered from a vegetative state 1 year after severe traumatic brain injury or 6 months after nontraumatic brain injury. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Coma Recovery Scale-Revised, Disability Rating Scale, and FIM. For patients who recovered full consciousness, neuropsychological tests specifically adapted for patients with very severe disabilities were used. RESULTS: After regaining responsiveness, 2 patients died because of severe clinical complications. Among the remaining 11 patients, 5 were still in a minimally conscious state at their last assessment, but 4 of them had recovered some complex behavioral responses to the environment (eg, they could follow simple commands, albeit inconsistently). Six patients had emerged from a minimally conscious state at the last evaluation. Severe functional disability was present in both patients who were conscious and patients who were minimally conscious. No patient was autonomous in common daily life activities or in transfers. All patients who were conscious showed variable cognitive impairments, and some of them also developed behavioral and psychological symptoms. However, such disturbances did not impede the patients' interaction with relatives and caregivers. CONCLUSIONS: This study provides systematic data about the course of the disease in a cohort of patients that was previously considered as exceptional. Patients with late recovery show a variable degree of functional recovery, although they experience marked residual motor and cognitive disabilities. The present findings contribute to enhance the understanding of the course of the disease in patients with late recovery and might help clinicians optimize the levels of care and provide the patients' families with correct information.

A study of the psychological distress in family caregivers of patients with prolonged disorders of consciousness during in-hospital rehabilitation.

OBJECTIVES: To study psychological distress in a sample of caregivers of patients affected by prolonged disorders of consciousness during hospital stay in the Neurorehabilitation Unit. MATERIALS AND METHODS: Twenty-four caregivers of 22 patients affected by prolonged disorders of consciousness admitted to postacute rehabilitation center, completed self-reported questionnaires for assessment of depressive symptoms, state and trait anxiety, psychophysiological disturbances, prolonged grief disorder, psychological coping strategies, quality of perceived needs, perceived social support, and caregiver burden; at admission, and after four and eight months. RESULTS: At admission depressive symptoms were found in 20/24 caregivers, high levels of anxiety in 16, and relevant psychophysiological disturbances in 10 participants; eight caregivers (32%) met criteria for prolonged grief disorder. The scores on questionnaires did not differ as a function of relatives' diagnosis (vegetative state vs. minimally conscious state). The longitudinal study (n = 18) showed a progressive and statistically significant increase of "emotional burden" during the hospital stay, whereas the remaining variables did not change significantly. CONCLUSIONS: Data confirmed the presence of severe psychological problems in caregivers of patients with prolonged disorders of consciousness. The levels of psychological distress tend to be constant over time, while the emotional burden increases.