Cerebrospinal fluid metabolite alterations in patients with different etiologies, diagnoses, and prognoses of disorders of consciousness.

INTRODUCTION: Medical management of disorders of consciousness (DoC) is a growing issue imposing a major burden on families and societies. Recovery rates vary widely among patients with DoC, and recovery predictions strongly influence decisions on medical care. However, the specific mechanisms underlying different etiologies, consciousness levels, and prognoses are still unclear. METHODS: We analyzed the comprehensive cerebrospinal fluid (CSF) metabolome through liquid chromatography-mass spectrometry. Metabolomic analyses were used to identify the metabolic differences between patients with different etiologies, diagnoses, and prognoses. RESULTS: We found that the CSF levels of multiple acylcarnitines were lower in patients with traumatic DoC, suggesting mitochondrial function preservation in the CNS, which might contribute to the better consciousness outcomes of these patients. Metabolites related to glutamate and GABA metabolism were altered and showed a good ability to distinguish the patients in the minimally conscious state and the vegetative state. Moreover, we identified 8 phospholipids as potential biomarkers to predict the recovery of consciousness. CONCLUSIONS: Our findings shed light on the differences in physiological activities underlying DoC with different etiologies and identified some potential biomarkers used for DoC diagnosis and prognosis.

Multidimensional assessment of heartbeat-evoked responses in disorders of consciousness.

Because consciousness does not necessarily translate into overt behaviour, detecting residual consciousness in noncommunicating patients remains a challenge. Bedside diagnostic methods based on EEG are promising and cost-effective alternatives to detect residual consciousness. Recent evidence showed that the cortical activations triggered by each heartbeat, namely, heartbeat-evoked responses (HERs), can detect through machine learning the presence of minimal consciousness and distinguish between overt and covert minimal consciousness. In this study, we explore different markers to characterize HERs to investigate whether different dimensions of the neural responses to heartbeats provide complementary information that is not typically found under standard event-related potential analyses. We evaluated HERs and EEG average non-locked to heartbeats in six types of participants: healthy state, locked-in syndrome, minimally conscious state, vegetative state/unresponsive wakefulness syndrome, comatose and brain-dead patients. We computed a series of markers from HERs that can generally separate the unconscious from the conscious. Our findings indicate that HER variance and HER frontal segregation tend to be higher in the presence of consciousness. These indices, when combined with heart rate variability, have the potential to enhance the differentiation between different levels of awareness. We propose that a multidimensional evaluation of brain-heart interactions could be included in a battery of tests to characterize disorders of consciousness. Our results may motivate further exploration of markers in brain-heart communication for the detection of consciousness at the bedside. The development of diagnostic methods based on brain-heart interactions may be translated into more feasible methods for clinical practice.

Emergent surgical evacuation of traumatic intracranial hematoma in patients with preoperative thrombocytopenia: surgical risk and early outcome.

BACKGROUND: Surgical evacuation of intracranial hematoma, including epidural, subdural, intracerebral, and intraventricular hematoma, is recommended in patients with traumatic brain injury (TBI) for prevention of cerebral herniation and possible saving of life. However, preoperative coagulopathy is a major concern for emergent surgery on patients with severe TBI. METHODS: We reviewed 65 consecutive patients with severe TBI who underwent emergency craniotomy for intracranial hematomas. RESULTS: Univariate analysis showed preoperative pupil abnormality, absence of pupil light reflex, respiratory failure, preoperative thrombocytopenia (< 100 × 109/L), increased activated partial thromboplastin time (> 36 s), low fibrinogen (< 150 mg/dL), platelet transfusion, red cell concentrate transfusion, and presence of brain contusion and traumatic subarachnoid hemorrhage (SAH) on computed tomography were correlated with poor outcome (death or vegetative state). Multivariate analysis revealed that pupil abnormality (p = 0.001; odds ratio [OR] 0.064, 95% confidence interval [CI] 0.012-0.344), preoperative thrombocytopenia (p = 0.016; OR 0.101, 95% CI 0.016-0.656), and traumatic SAH (p = 0.021; OR 0.211, 95% CI 0.057-0.791) were significant factors. Investigation of the 14 patients with preoperative thrombocytopenia found the emergency surgery was successful, with no postoperative bleeding during hospitalization. However, half of the patients died, and almost a quarter remained in the vegetative state mainly associated with severe cerebral edema. CONCLUSIONS: Emergent craniotomy for patients with severe TBI who have preoperative thrombocytopenia is often successful, but the prognosis is often poor. Emergency medical care teams and neurosurgeons should be aware of this discrepancy between successful surgery and poor prognosis in these patients. Further study may be needed on the cerebral edema regulator function of platelets.

Withdrawal of Life-Sustaining Therapies in Children With Severe Traumatic Brain Injury.

Neuroprognostication in severe traumatic brain injury (sTBI) is challenging and occurs in critical care settings to determine withdrawal of life-sustaining therapies (WLST). However, formal pediatric sTBI neuroprognostication guidelines are lacking, brain death criteria vary, and dilemmas regarding WLST persist, which lead to institutional differences. We studied WLST practice and outcome in pediatric sTBI to provide insight into WLST-associated factors and survivor recovery trajectory ≥1 year post-sTBI. This retrospective, single center observational study included patients <18 years admitted to the pediatric intensive care unit (PICU) of Erasmus MC-Sophia (a tertiary university hospital) between 2012 and 2020 with sTBI defined as a Glasgow Coma Scale (GCS) ≤8 and requiring intracranial pressure (ICP) monitoring. Clinical, neuroimaging, and electroencephalogram data were reviewed. Multi-disciplinary follow-up included the Pediatric Cerebral Performance Category (PCPC) score, educational level, and commonly cited complaints. Seventy-eight children with sTBI were included (median age 10.5 years; interquartile range [IQR] 5.0-14.1; 56% male; 67% traffic-related accidents). Median ICP monitoring was 5 days (IQR 3-8), 19 (24%) underwent decompressive craniectomy. PICU mortality was 21% (16/78): clinical brain death (5/16), WLST due to poor neurological prognosis (WLST_neuro, 11/16). Significant differences (p < 0.001) between survivors and non-survivors: first GCS score, first pupillary reaction and first lactate, Injury Severity Score, pre-hospital cardiopulmonary resuscitation, and Rotterdam CT (computed tomography) score. WLST_neuro decision timing ranged from 0 to 31 days (median 2 days, IQR 0-5). WLST_neuro decision (n = 11) was based on neurologic examination (100%), brain imaging (100%) and refractory intracranial hypertension (5/11; 45%). WLST discussions were multi-disciplinary with 100% agreement. Immediate agreement between medical team and caregivers was 81%. The majority (42/62, 68%) of survivors were poor outcome (PCPC score 3 to 5) at PICU discharge, of which 12 (19%) in a vegetative state. One year post-injury, no patients were in a vegetative state and the median PCPC score had improved to 2 (IQR 2-3). No patients died after PICU discharge. Twenty percent of survivors could not attend school 2 years post-injury. Survivors requiring an adjusted educational level increased to 45% within this timeframe. Chronic complaints were headache, behavioral problems, and sleeping problems. In conclusion, two-thirds of sTBI PICU mortality was secondary to WLST_neuro and occurred early post-injury. Median survivor PCPC score improved from 4 to 2 with no vegetative patients 1 year post-sTBI. Our findings show the WLST decision process was multi-disciplinary and guided by specific clinical features at presentation, clinical course, and (serial) neurological diagnostic modalities, of which the testing combination was determined by case-to-case variation. This stresses the need for international guidelines to provide accurate neuroprognostication within an appropriate timeframe whereby overall survivor outcome data provides valuable context and guidance in the acute phase decision process.

Severe Protracted Hypophosphatemia in a Patient with Persistent Vegetative State on Long-Term Assisted Respiratory Support.

BACKGROUND Phosphorous is an essential component of cell structure and physiology, and is required for energy conservation and expenditure. Severe hypophosphatemia can lead to profound dysfunction and injury affecting most organs and can be life-threatening. It can also compromise weaning of mechanically ventilated patients. Long-term assisted ventilatory care in ambulatory or inpatient settings is an expanding medical service for patients with various forms of persistent or progressive incapacitating diseases. Hypophosphatemia, caused by respiratory alkalosis, has been reported in critical-care settings, but its occurrence in medically stable patients requiring long-term respiratory support has not been thoroughly investigated. CASE REPORT We report the case of a ventilated patient in a chronic vegetative state displaying progressive hypophosphatemia spanning over 3 months, with plasma levels gradually declining to 0.8 mg/dL. Evaluation did not reveal conditions leading to diminished phosphate absorption or enhanced urinary phosphate excretion, but it identified respiratory alkalosis related to a recent increase in target minute-volume ventilation in the adaptive support ventilation (ASV) mode as the cause of hypophosphatemia. Despite the very low plasma phosphate level, the patient was asymptomatic, probably because this type of hypophosphatemia may not represent physiologically significant intracellular phosphate depletion. The respiratory alkalosis resolved upon decreasing the target minute-volume ventilation settings, and serum phosphate was normalized. CONCLUSIONS Since blood gases are not routinely monitored in respiratory and hemodynamically stable patients on long-term respiratory support, hypophosphatemia may herald the development of significant respiratory alkalosis. Assessment of acid-base balance is thus warranted in patients receiving long-term ventilation, especially in those developing hypophosphatemia.

Dysautonomia and Clinical Outcome in Vegetative State.

A dramatic disorder tentatively attributed to diencephalic-hypothalamic damage or dysfunction, dysautonomia, affects recovery from brain injury. Its incidence, correlation with etiology, and relevance as a predictor of outcome were retrospectively surveyed in 333 patients in vegetative state (VS) for more than 2 weeks at admission. Outcome was assessed according to the Glasgow Outcome Scale. Data were treated statistically by multi-variate analyses. Dysautonomia occurred in 26.1% of patients, with greater incidence among post-traumatic (31.9%) than non-traumatic (15.8%) patients. Outcome was worse among non-traumatic than post-traumatic patients irrespective of dysautonomia, and worst among non-traumatic patients with dysautonomia. Dysautonomia proved common among patients in VS (with incidence depending on etiology and age) and influenced the patients' outcome through mechanisms still to be defined, but conceivably mediated by diencephalic-hypothalamic unbalance.

Presynaptic dopamine deficit in minimally conscious state patients following traumatic brain injury.

Dopaminergic stimulation has been proposed as a treatment strategy for post-traumatic brain injured patients in minimally conscious state based on a clinical trial using amantadine, a weak dopamine transporter blocker. However, a specific contribution of dopaminergic neuromodulation in minimally conscious state is undemonstrated. In a phase 0 clinical trial, we evaluated 13 normal volunteers and seven post-traumatic minimally conscious state patients using 11C-raclopride PET to estimate dopamine 2-like receptors occupancy in the striatum and central thalamus before and after dopamine transporter blockade with dextroamphetamine. If a presynaptic deficit was observed, a third and a fourth 11C-raclopride PET were acquired to evaluate changes in dopamine release induced by l-DOPA and l-DOPA+dextroamphetamine. Permutation analysis showed a significant reduction of dopamine release in patients, demonstrating a presynaptic deficit in the striatum and central thalamus that could not be reversed by blocking the dopamine transporter. However, administration of the dopamine precursor l-DOPA reversed the presynaptic deficit by restoring the biosynthesis of dopamine from both ventral tegmentum and substantia nigra. The advantages of alternative pharmacodynamic approaches in post-traumatic minimally conscious state patients should be tested in clinical trials, as patients currently refractory to amantadine might benefit from them.

Provision of renal care for patients with end stage kidney disease in persistent vegetative state, in United Arab Emirates: a national survey of renal physicians.

Patients with end stage kidney disease (ESKD) with severely impaired cognitive function have no survival benefit from dialysis. We therefore undertook a survey to explore the renal physicians' practices of withholding and withdrawal of dialysis treatment in vegetative state patients in the United Arab Emirates (UAE). A cross sectional survey of 29 nephrology practices in UAE exploring physicians' practices in making decisions of withholding and withdrawal of dialysis treatment during provision end-of-life care for patients in persistent vegetative state (PVS).The majority of participants practice in governmental non-for-profit dialysis units (79%), and think they are well prepared to make decision with patients and family on issues of dialysis withdrawal and withholding (69%). If a chronic dialysis patient became permanently unconscious only few respondents (17%) indicated probability of stopping dialysis. On the other hand, more respondents (48%) reported that dialysis is likely to be withheld in PVS patients who develop kidney failure. In high risk or poor prognosis ESKD patients and given how likely they would consider each option independently, respondents reported they are likely to consider time-limited dialysis in 78% of the time followed by stopping (46%) or forgoing (27%) dialysis. Majority of the participants perceived that their decisions in providing renal care for PVS patients in UAE were influenced by the family sociocultural beliefs (76% of participants), the current hospital policies (72% of participants), and by Islamic beliefs (66% of participants). Only few perceived access to palliative care (30%) and treatment cost (17%) to have an impact on their decision making.Decisions of initiation and continuation of dialysis treatment to ESKD patients in PVS are prevalent among nephrology practices in UAE. Development of local guidelines based on the societal values along with early integration of palliative kidney failure management care would be required to improve the quality of provision of end-of-life renal care in UAE. ABBREVIATIONS: ESKD: stage kidney disease; UAE: United Arab Emirates; PVS: persistent vegetative state; RPA: Renal Physicians Association; ASN: American Society of Nephrology; EMAN: Emirates Medical Association Nephrology Society; CPR: cardiopulmonary resuscitation.

Recovery from vegetative state of patients with a severe brain injury: a 4-year real-practice prospective cohort study.

Patients who have suffered severe traumatic or nontraumatic brain injuries can show a progressive recovery, transitioning through a range of clinical conditions. They may progress from coma to a vegetative state (VS) and/or a minimally conscious state (MCS). A longer duration of the VS is known to be related to a lower probability of emergence from it; furthermore, the literature seems to lack evidence of late improvements in these patients. This real-practice prospective cohort study was conducted in inpatients in a VS following a severe brain injury, consecutively admitted to a vegetative state unit (VSU). The aim of the study was to assess their recovery in order to identify variables that might increase the probability of a VS patient transitioning to MCS. Rehabilitation treatment included passive joint mobilisation and helping/placing patients into an upright sitting position on a tilt table. All the patients underwent a specific assessment protocol every month to identify any emergence, however late, from the VS. Over a 4-year period, 194 patients suffering sequelae of a severe brain injury, consecutively seen, had an initial Glasgow Coma Scale score ≤ 8. Of these, 63 (32.5%) were in a VS, 84 (43.3%) in a MCS, and 47 (24.2%) in a coma; of the 63 patients admitted in a VS, 49 (57.1% males and 42.9% females, mean age 25.34 ± 19.12 years) were transferred to a specialist VSU and put on a slow-to-recover brain injury programme. Ten of these 49 patients were still in a VS after 36 months; of these 10, 3 recovered consciousness, transitioning to a MCS, 2 died, and 5 remained in a VS during the last 12 months of the observation. Univariate analysis identified male sex, youth, a shorter time from onset of the VS, diffuse brain injury, and the presence of status epilepticus as variables increasing the likelihood of transition to a MCS. Long-term monitoring of patients with chronic disorders of consciousness should be adequately implemented in order to optimise their access to rehabilitation services.

Judicial oversight of life-ending withdrawal of assisted nutrition and hydration in disorders of consciousness in the United Kingdom: A matter of life and death.

Mr Justice Baker delivered the Oxford Shrieval Lecture 'A Matter of Life and Death' on 11 October 2016. The lecture created public controversies about who can authorise withdrawal of assisted nutrition and hydration (ANH) in disorders of consciousness (DOC). The law requires court permission in 'best interests' decisions before ANH withdrawal only in permanent vegetative state and minimally conscious state. Some clinicians favour abandoning the need for court approval on the basis that clinicians are already empowered to withdraw ANH in other common conditions of DOC (e.g. coma, neurological disorders, etc.) based on their best interests assessment without court oversight. We set out a rationale in support of court oversight of best interests decisions in ANH withdrawal intended to end life in any person with DOC (who will lack relevant decision-making capacity). This ensures the safety of the general public and the protection of vulnerable disabled persons in society.

Evaluation of the effectiveness of transcranial direct current stimulation (tDCS) and psychosensory stimulation through DOCS scale in a minimally conscious subject.

The aim of our study was to assess the effectiveness of transcranial direct current stimulation (tDCS) on alertness improvement in a patient in a minimally conscious state (MCS) by means of disorders of consciousness scale combined with psycho-sensory stimulation. The effects of tDCS on muscle hypertonia through the Ashworth scale were also examined. tDCS was performed through a two-channel intra-cephalic stimulator. After stimulation, the patient followed a psychosensory stimulation training. Results pointed out an increase in DOCunit score, as well as an increase in alertness maintenance and an improvement in muscle hypertonia, although a MCS state persisted.

Pain perception in patients with chronic disorders of consciousness: What can limbic system tell us?

OBJECTIVE: Although it is believed that patients with Unresponsive Wakefulness Syndrome (UWS) do not feel pain, recent neuroimaging and neurophysiologic studies have demonstrated some residual traces of nociceptive processing. METHODS: To confirm this growing evidence, we evaluated 21 patients suffering from chronic disorders of consciousness (DOC) (both UWS, n=11, and Minimally Conscious State - MCS -, n=10), using an Event-Related Potential (ERP) Low-Resolution Brain Electromagnetic Tomography (LORETA) approach, based on nociceptive repeated laser stimulation (RLS). We delivered laser stimuli to the dorsum of both hands and analysed the γ-band LORETA activations and the ERP γ-power magnitude induced by laser stimulation, as well as the heart rate variability (HRV). RESULTS: We found partially preserved cortical activations and ERP γ-power magnitude in all MCS and two UWS individuals. These effects were paralleled by a purposeful behaviour, and a reduced HRV concerning nociceptive stimulation, whereas the two UWS individuals showed no more than reflex behaviours, besides a strong limbic activation. CONCLUSIONS: Some UWS patients may somehow perceive the affective components of nociceptive stimulation. SIGNIFICANCE: The diagnosis of functional locked-in syndrome should be taken into account when dealing with DOC differential diagnosis.

Retos éticos del hallazgo de consciencia encubierta con neuroimagen en estados vegetativos / Ethical challenges of the finding of covert awareness with neuroimaging in vegetative states

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Shaping thalamo-cortical plasticity: a marker of cortical pain integration in patients with post-anoxic unresponsive wakefulness syndrome?

BACKGROUND: The distinctive feature of unresponsive wakefulness syndrome (UWS) is the dissociation between arousal and awareness. Cortico-cortical and thalamo-cortical connectivity and plasticity play a key role in consciousness. UWS patients do not usually show any "cortical" behavioral sign in response to painful stimulation. Nevertheless a "focal conscious" pain perception has been hypothesized. HYPOTHESIS: Since defective plasticity and connectivity within pain matrix could be striking mechanisms of non-conscious pain perception and, consequently, of non-cortical responses in UWS subjects, aim of our study was to investigate pain-motor plasticity in such patients through a specific paired laser associative stimulation protocol (L-PAS). METHODS: We enrolled 10 post-anoxic subjects and 10 healthy controls evaluating clinical and electrophysiological parameters before and after the application of such protocol. RESULTS: Some patient showed a restored pain-motor integration with a partial motor cortex excitability modification. CONCLUSIONS: Although we studied a small cohort of post-anoxic UWS patients and the results obtained were short-lasting, L-PAS seems a feasible and suitable technique in order to induce plastic change within pain matrix in some UWS patients, allowing the production of "cortical" responses to painful stimuli, which are signs of at least partially ("focal") preserved consciousness. Cortico-thalamic plasticity could have also an important role in the emergence of pain perception as compared to other sensory modalities.

Assistive technology-based programs to promote communication and leisure activities by three children emerged from a minimal conscious state.

This study proposed the use of assistive technology (AT) to promote communication and leisure opportunities by three children with traumatic brain injury (TBI). Furthermore, it assessed the effects of such technology on the indices of positive participation and provided a social validation procedure. Three children emerged from a minimal conscious state and presenting extensive motor disabilities were involved. The intervention program allowed the participants to request and to choice preferred items independently and to perform literacy through a keyboard emulator. A multiple probe design across behaviors with post-intervention check was employed. Outcome measures were correct requests, understandable words, intervals with positive participation, and scores of social validation assessment. Request and choice behaviors and literacy improved significantly during intervention phases. During post-intervention check, all participants consolidated their performance. Moreover, indices of positive participation increased during intervention phases. Scores of social validation assessment showed that the combination of both behaviors was preferable to the same considered separately. AT program showed to be suitable for promoting constructive engagement and literacy behaviors by children with TBI. Future research is needed to generalize this data to a larger sample and to develop new technology for people with different levels of disabilities due to TBI.

Diffuse pulmonary ossification in permanent vegetative state.

Diffuse pulmonary ossification (DPO) is a rare condition characterized by diffuse metaplastic bone formation in the lungs. Two patterns have been described: dendriform, with a coral-like network of bone spiculae along the alveolar septa; and nodular, with lobulated fragments in the alveolar spaces. Dendriform DPO is frequently associated with chronic pulmonary pathologies. We present here the first case of DPO associated with a long-lasting vegetative state. Micro-computed tomography (MicroCT) was applied to analyze the distribution of pulmonary ossification in volumes of lung samples. It showed a mean volume percentage of ossification of 0.79% and 3-D reconstructions permitted to reveal the branching pattern and internal cavities of some ossifications. The occurrence of DPO in a persistent vegetative state (PVS) may be favored by recurrent pulmonary infections, due to aspiration and immunological defects, and respiratory instability, due to brain damage and the fact of being bedridden. Fibrotic reactions probably represent a preliminary step in bone formation. Further studies could examine the incidence and clinical significance of DPO in subjects in PVS or patients who are bedridden for other reasons. MicroCT may facilitate analysis of more case histories, with greater sensitivity with respect to classic microscopic analyses.

Post-coma persons with multiple disabilities use assistive technology for their leisure engagement and communication.

BACKGROUND: Interventions for post-coma persons, who have emerged from a minimally conscious state but present with extensive neuro-motor impairment and lack of or minimal verbal skills, need to promote occupation and communication through the use of assistive technology. OBJECTIVE: These two studies were aimed at assessing two technology-aided programs to promote leisure engagement and communication for three post-coma participants with multiple disabilities. METHODS: Study I assessed a program to allow a woman and a man with extensive neuro-motor impairment and lack of speech to switch on music and videos, make requests to caregivers, and send messages to (communicate with) relevant partners and receive messages from those partners. Study II assessed a program to allow a post-coma woman with extensive motor impairment and reduced verbal behavior to activate music, videos and requests, send and receive messages, and make telephone calls. RESULTS: Data showed that both programs were successful. The participants of Study I managed leisure engagement, requests, as well as text messaging. The participant of Study II showed consistent leisure engagement, text messaging, and telephone calls. CONCLUSIONS: Assistive technology can be profitably used to provide post-coma persons with multiple disabilities relevant leisure and communication opportunities.

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.