Electrophysiological characteristics of CM-pf in diagnosis and outcome of patients with disorders of consciousness.

BACKGROUND: Deep brain stimulation (DBS) in the centromedian-parafascicular complex (CM-pf) has been reported as a potential therapeutic option for disorders of consciousness (DoC). However, the lack of understanding of its electrophysiological characteristics limits the improvement of therapeutic effect. OBJECTIVE: To investigate the CM-pf electrophysiological characteristics underlying disorders of consciousness (DoC) and its recovery. METHODS: We collected the CM-pf electrophysiological signals from 23 DoC patients who underwent central thalamus DBS (CT-DBS) surgery. Five typical electrophysiological features were extracted, including neuronal firing properties, multiunit activity (MUA) properties, signal stability, spike-MUA synchronization strength (syncMUA), and the background noise level. Their correlations with the consciousness level, the outcome, and the primary clinical factors of DoC were analyzed. RESULTS: 11 out of 23 patients (0/2 chronic coma, 5/13 unresponsive wakefulness syndrome/vegetative state (UWS/VS), 6/8 minimally conscious state minus (MCS-)) exhibited an improvement in the level of consciousness after CT-DBS. In CM-pf, significantly stronger gamma band syncMUA strength and alpha band normalized MUA power were found in MCS- patients. In addition, higher firing rates, stronger high-gamma band MUA power and alpha band normalized power, and more stable theta oscillation were correlated with better outcomes. Besides, we also identified electrophysiological properties that are correlated with clinical factors, including etiologies, age, and duration of DoC. CONCLUSION: We provide comprehensive analyses of the electrophysiological characteristics of CM-pf in DoC patients. Our results support the 'mesocircuit' hypothesis, one proposed mechanism of DoC recovery, and reveal CM-pf electrophysiological features that are crucial for understanding the pathogenesis of DoC, predicting its recovery, and explaining the effect of clinical factors on DoC.

Trastornos prolongados de conciencia postinjuria cerebral aguda / Prolonged disorders of consciousness after an acute brain injury

Only a fraction of patients in coma secondary to a primary acute brain injury develop a vegetative state (VS). At least 20% of patients show late transitions to a minimally conscious states (MCS). They are particularly common in young adults with traumatic brain injury. The main problems faced by clinicians are the diagnostic accuracy of VS and MCS as well as the usefulness of sophisticated paraclinical investigations. Specific therapies are of limited effectiveness. This population is vulnerable to misdiagnosis and limited access to medical care and rehabilitation, thus generating ethical problems.

[Prolonged disorders of consciousness after an acute brain injury]. / Trastornos prolongados de conciencia postinjuria cerebral aguda.

Only a fraction of patients in coma secondary to a primary acute brain injury develop a vegetative state (VS). At least 20% of patients show late transitions to a minimally conscious states (MCS). They are particularly common in young adults with traumatic brain injury. The main problems faced by clinicians are the diagnostic accuracy of VS and MCS as well as the usefulness of sophisticated paraclinical investigations. Specific therapies are of limited effectiveness. This population is vulnerable to misdiagnosis and limited access to medical care and rehabilitation, thus generating ethical problems.

Personalized objects can optimize the diagnosis of EMCS in the assessment of functional object use in the CRS-R: a double blind, randomized clinical trial.

BACKGROUND: Behavioral assessment has been acted as the gold standard for the diagnosis of disorders of consciousness (DOC) patients. The item "Functional Object Use" in the motor function sub-scale in the Coma Recovery Scale-Revised (CRS-R) is a key item in differentiating between minimally conscious state (MCS) and emergence from MCS (EMCS). However, previous studies suggested that certain specific stimuli, especially something self-relevant can affect DOC patients' scores of behavioral assessment scale. So, we attempted to find out if personalized objects can improve the diagnosis of EMCS in the assessment of Functional Object Use by comparing the use of patients' favorite objects and other common objects in MCS patients. METHODS: Twenty-one post-comatose patients diagnosed as MCS were prospectively included. The item "Functional Object Use" was assessed by using personalized objects (e.g., cigarette, paper) and non-personalized objects, which were presented in a random order. The rest assessments were performed following the standard protocol of the CRS-R. The differences between functional uses of the two types of objects were analyzed by the McNemar test. RESULTS: The incidence of Functional Object Use was significantly higher using personalized objects than non-personalized objects in the CRS-R. Five out of the 21 MCS studied patients, who were assessed with non-personalized objects, were re-diagnosed as EMCS with personalized objects (χ2 = 5, df = 1, p < 0.05). CONCLUSIONS: Personalized objects employed here seem to be more effective to elicit patients' responses as compared to non-personalized objects during the assessment of Functional Object Use in DOC patients. TRIAL REGISTRATION: Clinical Trials.gov: NCT02988206 ; Date of registration: 2016/12/12.

Neuroethics and Disorders of Consciousness: Discerning Brain States in Clinical Practice and Research.

Decisions about end-of-life care and participation in clinical research for patients with disorders of consciousness begin with diagnostic discernment. Accurately distinguishing between brain states clarifies clinicians' ethical obligations and responsibilities. Central to this effort is the obligation to provide neuropalliative care for patients in the minimally conscious state who can perceive pain and to restore functional communication through neuroprosthetics, drugs, and rehabilitation to patients with intact but underactivated neural networks. Efforts to bring scientific advances to patients with disorders of consciousness are reviewed, including the investigational use of deep brain stimulation in patients in the minimally conscious state. These efforts help to affirm the civil rights of a population long on the margins.

Predicting long-term neurological outcomes after severe traumatic brain injury requiring decompressive craniectomy: A comparison of the CRASH and IMPACT prognostic models.

BACKGROUND: Predicting long-term neurological outcomes after severe traumatic brain (TBI) is important, but which prognostic model in the context of decompressive craniectomy has the best performance remains uncertain. METHODS: This prospective observational cohort study included all patients who had severe TBI requiring decompressive craniectomy between 2004 and 2014, in the two neurosurgical centres in Perth, Western Australia. Severe disability, vegetative state, or death were defined as unfavourable neurological outcomes. Area under the receiver-operating-characteristic curve (AUROC) and slope and intercept of the calibration curve were used to assess discrimination and calibration of the CRASH (Corticosteroid-Randomisation-After-Significant-Head injury) and IMPACT (International-Mission-For-Prognosis-And-Clinical-Trial) models, respectively. RESULTS: Of the 319 patients included in the study, 119 (37%) had unfavourable neurological outcomes at 18-month after decompressive craniectomy for severe TBI. Both CRASH (AUROC 0.86, 95% confidence interval 0.81-0.90) and IMPACT full-model (AUROC 0.85, 95% CI 0.80-0.89) were similar in discriminating between favourable and unfavourable neurological outcome at 18-month after surgery (p=0.690 for the difference in AUROC derived from the two models). Although both models tended to over-predict the risks of long-term unfavourable outcome, the IMPACT model had a slightly better calibration than the CRASH model (intercept of the calibration curve=-4.1 vs. -5.7, and log likelihoods -159 vs. -360, respectively), especially when the predicted risks of unfavourable outcome were <80%. CONCLUSIONS: Both CRASH and IMPACT prognostic models were good in discriminating between favourable and unfavourable long-term neurological outcome for patients with severe TBI requiring decompressive craniectomy, but the calibration of the IMPACT full-model was better than the CRASH model.

Efficacy of progesterone for moderate to severe traumatic brain injury: a meta-analysis of randomized clinical trials.

Progesterone has been shown to have neuroprotective effects in multiple animal models of brain injury, whereas the efficacy and safety in patients with traumatic brain injury (TBI) remains contentious. Here, a total of seven randomized controlled trials (RCTs) with 2492 participants were included to perform this meta-analysis. Compared with placebo, there was no significant decrease to be found in the rate of death or vegetative state for patients with acute TBI (RR = 0.88, 95%CI = 0.70, 1.09, p = 0.24). Furthermore, progesterone was not associated with good recovery in comparison with placebo (RR = 1.00, 95%CI = 0.88, 1.14, p = 0.95). Together, our study suggested that progesterone did not improve outcomes over placebo in the treatment of acute TBI.

Nocturnal melatonin regulation in post-traumatic vegetative state: a possible role for melatonin supplementation?

Circadian rhythms were recently proposed as a measure of physiological state and prognosis in disorders of consciousness (DOC). So far, melatonin regulation was never assessed in vegetative state (VS). Aim of our research was to investigate the nocturnal melatonin levels and light-induced melatonin suppression in a cohort of VS patients. We assessed six consecutive patients (four men, age 33.3 ± 9.3 years) with post-traumatic VS and nine age-matched healthy volunteers (five men, age 34.3 ± 8.9 years) on two consecutive nights: one baseline and one light exposure night. During baseline, night subjects were in bed in a dim (<5 lux) room from 10 pm to 8 am. Blood samples were collected hourly 00:30-3:30 am (00:30 = MLT1; 1:30 = MLT2; 2:30 = MLT3; and 3:30 = MLT4). Identical setting was used for melatonin suppression test night, except for the exposure to monochromatic (470 nm) light from 1:30 to 3:30 am. Plasma melatonin levels were evaluated by radioimmunoassay. Magnitude of melatonin suppression was assessed by melatonin suppression score (caMSS) and suppression rate. We searched for group differences in melatonin levels, differences between repeated samples melatonin concentrations during baseline night and light exposure night, and light-induced suppression of melatonin secretion. During baseline night, controls showed an increase of melatonin (MLT4 vs MLT1, p = 0.037), while no significant changes were observed in VS melatonin levels (p = 0.172). Baseline night MLT4 was significantly lower in VS vs controls (p = 0.036). During light-exposure night, controls displayed a significant suppression of melatonin (MLT3 and MLT4 vs MLT2, p = 0.016 and 0.002, respectively), while VS patients displayed no significant changes. The magnitude of light-induced suppression of melatonin levels was statistically different between groups considering control adjusted caMSS (p = 0.000), suppression rate (p = 0.002) and absolute percentage difference (p = 0.012). These results demonstrate for the first time that VS patients present an alteration in night melatonin secretion and reduced light-induced melatonin suppression. These findings confirm previous studies demonstrating a disruption of the circadian system in DOC and suggest a possible benefit from melatonin supplementation in VS.

Bedside assessment of residual functional activation in minimally conscious state using NIRS and general linear models.

Near Infrared Spectroscopy (NIRS) was employed for the detection of possible residual functional activations in two patients in minimally conscious state. An "ad hoc" protocol for somatosensory and motor stimulations was created and administered to the patients, synchronously to NIRS recordings. One healthy subject was also assessed with the same task for comparison. Results from the healthy subject globally agree with the literature. Moreover, we could obtain significant results from the patients data. Indeed, in one patient, the NIRS channels showing activation completely correspond to regions of residual cortex underneath. In the second patient, though, together with possible residual intact cortex insulae, some channels match large cystic formations, with fluid gathering.

[Collaboration of general surgeons with neurosurgeons: what does a general surgeon need to know about neurosurgery?]. / Zusammenarbeit der Neurochirurgie mit der Allgemeinchirurgie: Was muss der Allgemeinchirurg von der Neurochirurgie wissen?

BACKGROUND: The most freq+uent disorders and injuries requiring the joint attention of general surgeons and neurosurgeons are presented and analysed in this review. METHODS: The priorities and prognosis concerning diagnostic and surgical measures for patients in coma with multiple injuries, extra- and intraspinal tumours and brain metastases are analysed. RESULTS: The urgency of general surgical and neurosurgical measures is not ruled by a preformatted pattern but by the vital needs of the individual patient. CONCLUSION: The differentiation of vital from non-vital operations or with regard to prognosis necessary from inadequate general surgical and neurosurgical measures is of fundamental importance. The successive order of general surgical and neurosurgical interventions must be adjusted to the needs of each individual patient.

The vegetative state--a syndrome in search of a name.

In 2002, Bryan Jennett chose the caption "A syndrome in search of a name" for the first chapter of his book "The vegetative state--medical facts, ethical and legal dilemmas", which, in summary, can be taken as his legacy. Jennett coined the term "VegetativeState" (VS), which became the preferential name for the syndrome of wakeful unresponsiveness in the English literature, with the intention to specify the concern and dilemmas in connection with the naming "vegetative", "persistent" and "permanent". In Europe, Apallic Syndrome (AS) is still in use. The prevalence of VS/AS in hospital settings in Europe is 0.5-2/100.000 population year; one-third traumatic brain damage, 70% following intracranial haemorrhages, tumours, cerebral hypoxemia after cardiac arrest, and end stage of certain progressive neurological diseases. VS/AS reflects brain pathology of (a) consciousness, self-awareness, (b) behaviour, and (c) certain brain structures, so that patients are awake but total unresponsive. The ambiguity of the naming "vegetative" (meant to refer to the preserved vegetative (autonomous nervous system) can suggest that the patient is no more a human but "vegetable" like. And "apallic" does not mean being definitively and completely anatomically disconnected from neocortical structures. In 2009, having joined the International Task Force on the Vegetative State, we proposed the new term "Unresponsive Wakefulness Syndrome" (UWS) to enable (neuro-)scientists, the medical community, and the public to assess and define all stages accurately in a human way. The Unresponsive Wakefulness Syndrome (UWS) could replace the VS/AS nomenclature in science and public with social competence.

Prediction of minimally conscious state with somatosensory evoked potentials in long-term unconscious patients after traumatic brain injury.

BACKGROUND: To evaluate the predictive power of somatosensory evoked potentials (SEPs) for minimally conscious state (MCS) in long-term unconscious patients after traumatic brain injury (TBI). METHODS: SEPs were recorded in 58 patients with duration of unconsciousness >30 days after TBI. SEPs were classified into three grades. Predictors including age, sex, Glasgow Coma Scale (GCS), and cause of injury were also analyzed, respectively. The outcome was divided into two groups including unconscious group and MCS group. The outcome was assessed at 12 months after TBI. RESULTS: In 58 patients, 22 of 58 were minimally conscious, 3 of 58 dead, and 33 of 57 were still in vegetative state at 12 months after TBI. SEPs grade (p = 0.001) and GCS (p = 0.010) were significantly associated with the outcome. The area under the receiver operator characteristic curve of SEPs was 0.891 ± 0.048 (p < 0.001; 95% confidence interval, 0.798-0.984) for predicting outcome, and of GCS score was only 0.746 ± 0.066 (p = 0.002; 95% confidence interval, 0.616-0.876). The accuracy of the whole model for predicting unconscious and MCS was 91.7% and 86.4%, respectively. The overall correct prediction was as high as 89.7% (p < 0.001). CONCLUSIONS: SEPs are excellent in predicting the outcome of long-term unconscious patients after TBI. SEPs should be considered more often and more routinely used after TBI.

Focal increase in cerebral blood flow after treatment with near-infrared light to the forehead in a patient in a persistent vegetative state.

OBJECTIVE: This study aimed to quantify the cerebral blood flow (CBF) after bilateral, transcranial near-infrared light-emitting diode (LED) irradiation to the forehead in a patient in a persistent vegetative state following severe head injury. BACKGROUND DATA: Positive behavioral improvement has been observed following transcranial near-infrared light therapy in humans with chronic traumatic brain injury and acute stroke. METHODS: Single-photon emission computed tomography with N-isopropyl-[123I]p-iodoamphetamine (IMP-SPECT) was performed following a series of LED treatments. RESULTS: IMP-SPECT showed unilateral, left anterior frontal lobe focal increase of 20%, compared to the pre-treatment value for regional CBF (rCBF) for this area, following 146 LED treatments over 73 days from an array of 23×850 nm LEDs, 13 mW each, held 5 mm from the skin, 30 min per session, the power density 11.4 mW/cm(2); the energy density 20.5 J/cm(2) at the skin. The patient showed some improvement in his neurological condition by moving his left arm/hand to reach the tracheostomy tube, post-LED therapy. CONCLUSIONS: Transcranial LED might increase rCBF with some improvement of neurological condition in severely head-injured patients. Further study is warranted.

Predict recovery of consciousness in post-acute severe brain injury: the role of EEG reactivity.

OBJECTIVE: This study tested the hypothesis of electroencephalographic reactivity (EEG-R) as a reliable tool for the prognostic evaluation of consciousness recovery in post-acute brain injury. METHODS: EEG was recorded in 50 unconscious patients. All patients had a GCS ≤8 and LCF score ≤2. They suffered from traumatic brain injury, cerebrovascular disease or anoxia. EEG was classified according to Synek classification (1988) as benign, malignant and 'uncertain significance'. EEG-R to painful stimuli was tested. RESULTS: Twenty per cent of patients fulfilled the criteria for benign prognosis, 38% for malignant prognosis, while 42% of them were included in the 'uncertain' category, preventing them from stating a prognosis. EEG-R was detected in 48% of patients classified 'uncertain' and 92% of them recovered consciousness within 5 months from EEG recording. Multivariable analysis indicates that an unconscious patient admitted to the Rehabilitation Unit within 2 months from brain injury, with a LCF score equal to 2 and the presence of EEG-R has a probability of recovery of consciousness higher than 97%. CONCLUSION: EEG-R is a good positive factor for the prognosis of recovery of consciousness in the post-acute phase of brain injury, with a high specificity (88.9%). Nevertheless, its absence is not invariably associated with a poor prognosis.

The place of L-dopa/carbidopa in persistent vegetative state.

BACKGROUND: The prevalence of persistent vegetative state (PVS) is estimated to be 40 to 168 per million person-years in the United States. Studies in the industrialized world have shown that the quality of life of persons with PVS is severely compromised and with paucity of data on treatment of persons with PVS. This is the first time a report of treatment of PVS with a known medication is being reported from Nigeria or sub-Saharan Africa. Our objectives were to prospectively follow up some cohorts of patients diagnosed to have PVS by a reliable and valid criteria and to look out for any response to L-dopa/carbidopa administration. DESIGN: This was a prospective case series. SETTING: The study was performed from a tertiary center. METHODS: We adopted the Multisociety Task Force of the American Academy of Neurology diagnostic criteria for PVS and minimally conscious state, and the Royal College of Physicians differential diagnostic criteria were used to include patients for the study. We also carried out detailed neurological examination of the unconscious patient to include or exclude subjects for the study. RESULTS: For the outcome measure, we adopted the ASPEN working group criteria for minimally conscious state. After 2 to 5 months of administration of L-dopa/carbidopa; 4 patients (4 = 36.4%) showed significant clinical improvement. Two (2 = 18.2%) who did not improve eventually died. One case (case 5) died after a second bleed. CONCLUSION: There were some remarkable responses to L-dopa/carbidopa after about 2 to 6 months of therapy.

Care protocol for persistent vegetative states (PVS) and minimally conscious state (MSC) in Lorraine: retrospective study over an 18-year period.

OBJECTIVES: Retrospective analysis of the efficiency of a protocol for care of chronic vegetative states (CVS) and minimally conscious state (MCS) in Lorraine. MATERIAL AND METHOD: Two indicators are used: protocol activity (number of patients hospitalized between 1988 and 2006, number of admissions per year, of requests per year, origin of requests, waiting time) and the epidemiological data (age, sex ratio, etiology, length of stay, geographic origin, number of deaths, number of hospital discharges). The number of CVS and MCS and patients having progressed towards arousal is specified as well as the technical procedures (orthopedic surgery, number of tracheotomies). RESULTS: Forty-seven patients (30 males and 17 females) were hospitalized in a 12-bed unit. The number of admissions per year was 2.4, and the annual number of requests varied between five and 15. Hospitalization times ranged from six to 18 months. The average length of hospitalization was 41 months. Eighty-eight percent of the cases were residents of Lorraine. The etiology was traumatic (53%), vascular (38% including 12% anoxia), miscellaneous (9%). Fifteen percent rate of return to arousal (average time period: 28.41 months, traumatic etiology) with hospital discharge in four cases. CONCLUSION: The protocol is managed as part of a local scheme and enables an appropriate response to a specific clinical profile by providing up-to-date multidiscipline follow-up care and a rapid solution should intercurrent events occur (signs of arousal, orthopedic deterioration, change of environment). Typical limitations are geographical remoteness and difficulties with family support care.

Cardiac arrest after intragastric balloon insertion in a super-obese patient.

A super-obese patient who suffered from severe sleep apnea (SSA) and other comorbidities underwent insertion of a BioEnterics intragastric balloon (BIB) before bariatric surgery. During the night, he was victim of cardiac arrest. After cardiopulmonary resuscitation and return of spontaneous circulation, he was transferred to intensive care unit. Two hours later, he developed an unexpected symptomatic bradycardia, and BIB was removed. The patient had no further cardiac complications, but he had a poor neurological outcome. In our opinion, such a severe cardiac event was the result of several causes. The BIB induces vagal nerve activation by stretching the gastric wall. In addition, super-obese patients with sleep apnea and other comorbitities have an increased risk of potentially fatal cardiac arrhythmias especially during the night. For all these reasons, we think that these patients may benefit from further preoperative cardiac investigations and a more intensive control during the first postinsertion day.

A clinical and EEG scoring system that predicts early cortical response (N20) to somatosensory evoked potentials and outcome after cardiac arrest.

BACKGROUND: Anoxic coma following cardiac arrest is a common problem with ethical, social, and legal consequences. Except for unfavorable somatosensory-evoked potentials (SSEP) results, predictors of unfavorable outcome with a 100% specificity and a high sensitivity are lacking. The aim of the current research was to construct a clinical and EEG scoring system that predicts early cortical response (N20) to somatosensory evoked potentials and 6-months outcome in comatose patients after cardiac arrest. METHODS: We retrospectively reviewed the records of all consecutive patients who suffered cardiac arrest outside our hospital and were subsequently admitted to our facility from November 2002 to July 2006. We scored each case based on early clinical and EEG factors associated with unfavorable SSEPs, and we assessed the ability of this score to predict SSEP results and outcome. RESULTS: Sixty-six patients qualified for inclusion in the cohort. Among them, 34 (52%) had unfavorable SSEP results. At day three, factors independently associated with unfavorable SSEPs were: absence of corneal (14 points) and pupillary (21 points) reflexes, myoclonus (25 points), extensor or absent motor response to painful stimulation (28 points), and malignant EEG (11 points). A score >40 points had a sensitivity of 85%, a specificity of 84%, and a positive predictive value (PPV) of 85% to predict unfavorable SSEP results. A score >88 points had a PPV of 100%, but a sensitivity of 18%. Overall, this score had an area under ROC curves of 0.919. In addition, at day three, a score > 69 points had a PPV of 100% with a sensitivity of 32% to predict death or vegetative state. CONCLUSION: A scoring system based on a combination of clinical and EEG findings can predict the absence of early cortical response to SSEPs. In settings without access to SSEPs, this score may help decision-making in a subset of comatose survivors after a cardiac arrest.

Affirming the right to care, preserving the right to die: disorders of consciousness and neuroethics after Schiavo.

In this article, I attempt to untangle some of the cultural, philosophical, and ethical currents that informed the Schiavo case. My objective is to better apprehend what the Schiavo case means for end-of-life care in general and to assert that our discourse about the ethical issues attendant to brain injury will be impoverished if we limit our discussions about disorders of consciousness solely to the vegetative state. If we ignore emerging developments in neuroscience that are helping to elucidate the nature of these disorders and fail to broaden the conversation about brain injury, beyond the unmitigated futility of the permanent vegetative state, we will imperil others who might improve and be helped. Through such efforts we can help mitigate the tragedy of the Schiavo case and overcome the rhetoric that marked the national discourse in March 2005. Once the complexity of disorders of consciousness is appreciated, rhetorical statements about a right to die or a right to life are exposed as being incompatible with the challenge of providing care to such patients. This is especially true as neuroscience brings greater diagnostic refinement to their assessment and management, a topic addressed in this article, which specifically focuses on the clinical and ethical implications of the recently described minimally conscious state. Instead of staking out ideological positions that do not meet the needs of patients or families, we should strive to both preserve the right to die for those who are beyond hope while affirming the right to care to those who might benefit from coming advances in neuroscience. If we can achieve that delicate balance, we will be able to transcend the partisan debate that shrouded the life and death of Theresa Marie Schiavo and begin to articulate a palliative neuroethics of care for those touched by severe brain injury and disorders of consciousness.