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.

Exoskeleton-Robot Assisted Therapy in Stroke Patients: A Lesion Mapping Study.

Background: Technology-supported rehabilitation is emerging as a solution to support therapists in providing a high-intensity, repetitive and task-specific treatment, aimed at improving stroke recovery. End-effector robotic devices are known to positively affect the recovery of arm functions, however there is a lack of evidence regarding exoskeletons. This paper evaluates the impact of cerebral lesion load on the response to a validated robotic-assisted rehabilitation protocol. Methods: Fourteen hemiparetic patients were assessed in a within-subject design (age 66.9 ± 11.3 years; 10 men and 4 women). Patients, in post-acute phase, underwent 7 weeks of bilateral arm training assisted by an exoskeleton robot combined with a conventional treatment (consisting of simple physical activity together with occupational therapy). Clinical and neuroimaging evaluations were performed immediately before and after rehabilitation treatments. Fugl-Meyer (FM) and Motricity Index (MI) were selected to measure primary outcomes, i.e., motor function and strength. Functional independance measure (FIM) and Barthel Index were selected to measure secondary outcomes, i.e., daily living activities. Voxel-based lesion symptom mapping (VLSM) was used to determine the degree of cerebral lesions associated with motor recovery. Results: Robot-assisted rehabilitation was effective in improving upper limb motor function recovery, considering both primary and secondary outcomes. VLSM detected that lesion load in the superior region of the corona radiata, internal capsule and putamen were significantly associated with recovery of the upper limb as defined by the FM scores (p-level < 0.01). Conclusions: The probability of functional recovery from stroke by means of exoskeleton robotic rehabilitation relies on the integrity of specific subcortical regions involved in the primary motor pathway. This is consistent with previous evidence obtained with conventional neurorehabilitation approaches.

Care pathways models and clinical outcomes in Disorders of consciousness.

OBJECTIVE: Patients with Disorders of consciousness, are persons with extremely low functioning levels and represent a challenge for health care systems due to their high needs of facilitating environmental factors. Despite a common Italian health care pathway for these patients, no studies have analyzed information on how each region have implemented it in its welfare system correlating data with patients' clinical outcomes. MATERIALS AND METHODS: A multicenter observational pilot study was realized. Clinicians collected data on the care pathways of patients with Disorder of consciousness by asking 90 patients' caregivers to complete an ad hoc questionnaire through a structured phone interview. Questionnaire consisted of three sections: sociodemographic data, description of the care pathway done by the patient, and caregiver evaluation of health services and information received. RESULTS: Seventy-three patients were analyzed. Length of hospital stay was different across the health care models and it was associated with improvement in clinical diagnosis. In long-term care units, the diagnosis at admission and the number of caregivers available for each patient (median value = 3) showed an indirect relationship with worsening probability in clinical outcome. Caregivers reported that communication with professionals (42%) and the answer to the need of information were the most critical points in the acute phase, whereas presence of Non-Governmental Organizations (25%) and availability of psychologists for caregivers (21%) were often missing during long-term care. The 65% of caregivers reported they did not know the UN Convention on the Rights of Persons with Disabilities. CONCLUSION: This study highlights relevant differences in analyzed models, despite a recommended national pathway of care. Future public health considerations and actions are needed to guarantee equity and standardization of the care process in all European countries.

A new treatment in the rehabilitation of the paretic upper limb after stroke: the ARAMIS prototype and treatment protocol.

BACKGROUND: In recent years, as part of the rehabilitation of post stroke patients, the use of robotic technologies to improve recovery of upper limb has become more widespread. The Automatic Recovery Arm Motility Integrated System (ARAMIS) is a concept robot and prototype designed to promote the functional interaction of the arms in the neurorehabilitation of the paretic upper limb. Two computer-controlled, symmetric and interacting exoskeletons compensate for the inadequate strength and accuracy of the paretic arm and the effect of gravity during rehabilitation. Rehabilitation is possible in 3 different modalities; asynchronous, synchronous and active-assisted. OBJECTIVES: To compare the effectiveness of robotic rehabilitation by an exoskeleton prototype system with traditional rehabilitation in motor and functional recovery of the upper limb after stroke. METHODS: Case-control study, 52 patients enrolled in the study, 28 cases (women: 8, age: 65 ± 10 yrs) treated with ARAMIS and 24 controls (women: 11, age: 69 ± 7 yrs) with conventional rehabilitation. Motor impairment assessed before and after treatment with Fugl-Meyer scale and Motricity Index, level of disability assessed with the Functional Independence Measure. A questionnaire was also administered to assess the patient's tolerance to robotic therapy. RESULTS: After 28 ± 4 sessions over a 54 ± 3.6-day period, the patients treated by ARAMIS had an improvement on the Fugl-Meyer scale (global score from 43 ± 18 to 73 ± 29; p < 0.00001), Motricity Index scale (p < 0.004) and Functional Independence Measure (p < 0.001). A lesser degree of improvement was achieved using conventional rehabilitation, the Fugl-Meyer global score of the control group improved from 41 ± 13 to 58 ± 16 (p < 0.006) and the motor function item from 9.4 ± 4.1 to 14.9 ± 5.8 (p < 0.023). CONCLUSIONS: Motor improvement was greater at the wrist and hand than at shoulder and elbow level in patients treated by ARAMIS and controls, but it was significantly greater in ARAMIS-treated patients than in controls. The results indicate a greater efficacy of ARAMIS compared to conventional rehabilitation.

How Can Music Influence the Autonomic Nervous System Response in Patients with Severe Disorder of Consciousness?

Activations to pleasant and unpleasant musical stimuli were observed within an extensive neuronal network and different brain structures, as well as in the processing of the syntactic and semantic aspects of the music. Previous studies evidenced a correlation between autonomic activity and emotion evoked by music listening in patients with Disorders of Consciousness (DoC). In this study, we analyzed retrospectively the autonomic response to musical stimuli by mean of normalized units of Low Frequency (nuLF) and Sample Entropy (SampEn) of Heart Rate Variability (HRV) parameters, and their possible correlation to the different complexity of four musical samples (i.e., Mussorgsky, Tchaikovsky, Grieg, and Boccherini) in Healthy subjects and Vegetative State/Unresponsive Wakefulness Syndrome (VS/UWS) patients. The complexity of musical sample was based on Formal Complexity and General Dynamics parameters defined by Imberty's semiology studies. The results showed a significant difference between the two groups for SampEn during the listening of Mussorgsky's music and for nuLF during the listening of Boccherini and Mussorgsky's music. Moreover, the VS/UWS group showed a reduction of nuLF as well as SampEn comparing music of increasing Formal Complexity and General Dynamics. These results put in evidence how the internal structure of the music can change the autonomic response in patients with DoC. Further investigations are required to better comprehend how musical stimulation can modify the autonomic response in DoC patients, in order to administer the stimuli in a more effective way.

Nutritional parameters predicting pressure ulcers and short-term mortality in patients with minimal conscious state as a result of traumatic and non-traumatic acquired brain injury.

BACKGROUND: The association between malnutrition and worse outcomes as pressure ulcers and mortality is well established in a variety of setting. Currently none investigation was conducted in patients with long-term consequences of the acquired brain injury in which recovery from brain injury could be influenced by secondary complications. The aim of this study was to investigate the association between various nutritional status parameters (in particular albumin) and pressure ulcers formation and short-term mortality in minimal conscious state patients. METHODS: In this prospective, observational study of 5-months duration, a 30 patients sample admitted to a Neurological Institute was considered. All patients underwent a complete medical examination. Anthropometric parameters like mid-arm circumference and mid-arm muscle circumference and nutritional parameters as serum albumin and blood hemoglobin concentration were assessed. RESULTS: At univariate and logistic regression analysis, mid-arm circumference (p = 0.04; beta = -0.89), mid-arm muscle circumference (p = 0.050; beta = -1.29), hemoglobin (p = 0.04, beta -1.1) and albumin (p = 0.04, beta -7.91) were inversely associated with pressure ulcers. The area under the ROC curve for albumin to predict sores was 0.76 (p = 0.02) and mortality was 0.83 (p = 0.03). Patient with lower albumin had significantly higher short-term mortality than those with higher serum albumin (p = 0.03; χ(2) test = 6.47). CONCLUSION: Albumin, haemoglobin and mid-arm circumference are inversely associated with pressure ulcers. Albumin is a prognostic index in MCS patients. Since albumin and haemoglobin could be affected by a variety of factors, this association suggests to optimize nutrition and investigate on other mechanism leading to mortality and pressure ulcers.

Care and neurorehabilitation in the disorder of consciousness: a model in progress.

The operational model and strategies developed at the Institute S. Anna-RAN to be applied in the care and neurorehabilitation of subjects with disorders of consciousness (DOC) are described. The institute units are sequentially organized to guarantee appropriate care and provide rehabilitation programs adapted to the patients' clinical condition and individual's needs at each phase of evolution during treatment in a fast turnover rate. Patients eligible of home care are monitored remotely. Transferring advanced technology to a stage of regular operation is the main mission. Responsiveness and the time windows characterized by better residual responsiveness are identified and the spontaneous/induced changes in the autonomic system functional state and biological parameters are monitored both in dedicated sessions and by means of an ambient intelligence platform acquiring large databases from traditional and innovative sensors and interfaced with knowledge management and knowledge discovery systems. Diagnosis of vegetative state/unresponsive wakefulness syndrome or minimal conscious state and early prognosis are in accordance with the current criteria. Over one thousand patients with DOC have been admitted and treated in the years 1998-2013. The model application has progressively shortened the time of hospitalization and reduced costs at unchanged quality of services.

The Autonomic System Functional State Predicts Responsiveness in Disorder of Consciousness.

Diagnosis and early prognosis of the vegetative state/unresponsive wakefulness syndrome (VS/UWS) and its differentiation from the minimally-conscious state still rest on the clinical observation of responsiveness. The incidence of established clinical indicators of responsiveness also has proven variable in the single subject and is correlated to measures of heart rate variability (HRV) describing the sympathetic/parasympathetic balance. We tested responsiveness when the HRV descriptors nuLF and peakLF were or were not in the ranges with highest incidence of response based on findings from previous studies (10.0-70.0 and 0.05-0.11 Hz, respectively). Testing was blind by The Coma Recovery Scale-revised in the two conditions and in two experimental sessions with a one-week interval. The incidence of responses was not randomly distributed in the "response" and "no-response" conditions (McNemar test; p < 0.0001). The observed incidence in the "response" condition (visual: 55.1%; auditory: 51.5%) was higher than predicted statistically (32.1%) or described in previous clinical studies; responses were only occasional in the "no-response" condition (visual, 15.9%; auditory, 13.4%). Models validated the predictability with high accuracy. The current clinical criteria for diagnosis and prognosis based on neurological signs should be reconsidered, including variability over time and the autonomic system functional state, which could also qualify per se as an independent indicator for diagnosis and prognosis.

Advances in the neurorehabilitation of severe disorder of consciousness.

INTRODUCTION: The paper describes the evolution of knowledge concerning severe brain injury which determines the Vegetative State/Unresponsive Wakefulness Syndrome. BACKGROUND: The term Vegetative State was proposed by Jennet and Plum in 1972. Later on, the Intensive Care Units progresses increased the survival of these patients and, contemporary, decreased their characteristic conditions of cachexia and severe dystonia. In 1994, the disease was conceived as a disconnection syndrome of the hemispheres from the brainstem, mainly due to a temporary or permanent deficit of the functions of the white matter. From 2005 on, the psychophysiological parameters relative to an emotional consciousness, albeit submerged, were described. Since then, it has been recognized that the brain of these patients was not only to be considered living but also working. CONCLUSION: The latest studies that have greatly improved the knowledge of the physiopathology of this particular state of consciousness. These new insights have led to the formation of a European Union Task Force, which has proposed in 2009 to change the name from a Vegetative State to Unresponsive Wakefulness Syndrome, outlining the character of syndrome and not that of state, as forms of even late recovery in consciousness levels have been observed and described.

Paroxysmal sympathetic hyperactivity after acquired brain injury: consensus on conceptual definition, nomenclature, and diagnostic criteria.

A syndrome of paroxysmal, episodic sympathetic hyperactivity after acquired brain injury has been recognized for almost 60 years. This project sought to simplify the confused nomenclature for the condition (>31 eponyms) and simplify the nine overlapping sets of diagnostic criteria. A consensus-developed questionnaire based on a systematic review of the literature was circulated to a widely representative, international expert group utilizing a Delphi approach. Diagnostic criteria were dropped if group consensus failed to agree on their relative importance, with a goal of reaching a Cronbach α of 0.8 (suitable for research purposes). The resulting criteria were combined into an assessment measure for clinical and research settings. The consensus group recommend that the term "paroxysmal sympathetic hyperactivity" replace previous terms to describe the "syndrome, recognised in a subgroup of survivors of severe acquired brain injury, of simultaneous, paroxysmal transient increases in sympathetic [elevated heart rate, blood pressure, respiratory rate, temperature, sweating] and motor [posturing] activity." An 11 point probabilistic diagnostic scale was developed with reference to published criteria, yielding an acceptable Cronbach α of 0.8. These 11 items were proceduralized and combined with a symptom severity index to produce a diagnostic tool for use with adults (the paroxysmal sympathetic hyperactivity assessment measure [PSH-AM]). Development of a pediatric version of the scale and further research into the validity of the PSH-AM is recommended. The consensus position builds on previous literature to establish diagnostic definitions and criteria, an important move to standardize research and management of this condition.

Visual pursuit response in the severe disorder of consciousness: modulation by the central autonomic system and a predictive model.

BACKGROUND: A visual pursuit response is reportedly observed in ~20-30% of subjects in vegetative state (VS/UWS) and predicts better outcome; it is a key marker of evolution into the minimally conscious state (MCS). The probability of observing a positive response, however, has proven variable during the day, with comparable timing of the minima and maxima in VS/UWS and MCS. We verified if measures of sympathetic/parasympathetic balance are possible independent variables on which the occurrence of a pursuit response could depend and be predicted. METHODS: Fourteen subjects in VS/UWS and sixteen in MCS for more than one year were studied. A mirror was used to test the pursuit response for a total 231 useful trials. Non-invasive measures of the sympathetic/parasympathetic functional state (Heart rate variability descriptors nuLF and peakLF) used in the study of responsiveness in VS/UWS and MCS subjects were recorded and processed by descriptive statistics and advanced Support Vector Machine (SVM). RESULTS: A pursuit response was observed in 33% and 78.2% of subjects in VS or MCS, respectively. Incidence was higher at HRV nuLF values in the 20-60 range and peakLF values at 0.06-0.12 Hz (76.6%) and at nuLF values in the 10-60 range and peakLF values at 0.05-0.10 Hz (80.7%) in the VS and MCS, respectively. The SVM generated model confirmed the results in the training leave one out and 10 fold cross validation tests (81% and 81.4%). CONCLUSION: The pursuit response incidence depends to a relevant extent on the sympathetic/parasympathetic balance and autonomic functional state. Extensive monitoring appears advisable.

Heart rate variability and the central autonomic network in the severe disorder of consciousness.

OBJECTIVE: To review the applicability of heart rate variability measures in research on severe disorder of consciousness. METHODS: The available evidence on the correlation between heart rate variability measures and the outcome or residual functional state/responsiveness of severely brain-injured patients (including those in vegetative or minimally conscious states) are reviewed and discussed with reference to the central autonomic network model. RESULTS AND CONCLUSION: Heart rate variability analyses appear to be applicable to assess residual or emerging (higher level) function in brain-injured patients with disordered consciousness and to predict outcome. In this regard, the central autonomic network model is heuristic in the understanding of heart rate variability descriptors of the central nervous system/autonomic systems relationship.

Decreasing incidence of paroxysmal sympathetic hyperactivity syndrome in the vegetative state.

OBJECTIVE: To update knowledge of the incidence of paroxysmal sympathetic hyperactivity (PSH, also referred to as dysautonomia), an emergency condition tentatively attributed to sympathetic paroxysms or diencephalic-hypothalamic disarrangement associated with severe diffuse brain axonal damage or hypoxia. This condition is reportedly common in the vegetative state, threatens survival and affects outcome. METHODS: The results of a retrospective study on 333 subjects in a vegetative state admitted to a dedicated unit in 1998-2005 are compared with a survey on patients admitted to the same unit in 2006-2010. RESULTS AND COMMENT: In the 1998-2005 period, the incidence of PSH was 32% and 16% in post-traumatic and non-traumatic patients, respectively. It decreased to 18% and 7% in the 2006-2010 period. The PSH duration and the time spent in emergency units before admission and in the dedicated unit for the vegetative state after admission also decreased significantly. Incidence was greater among post-traumatic- patients; its effect on outcome does not appear to have changed.

Neurorehabilitation for severe disorder of consciousness: the S. Anna - RAN operational model.

The operational model and strategies designed for use in the S. Anna - Research in Advanced Neurorehabilitation Institute for the care and neurorehabilitation of subjects in the vegetative or minimally conscious states are described here. A total of 722 patients were admitted, cared for and discharged from the institute in the period 1998-2009. Application of the model approach has progressively shortened the time of hospitalization and rehabilitation and reduced costs.

Brain-derived neurotrophic factor (Val66Met) polymorphism does not influence recovery from a post-traumatic vegetative state: a blinded retrospective multi-centric study.

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that influences neuronal plasticity throughout life. Emergence from a vegetative state (VS) after a traumatic brain injury (TBI) implies that the brain undergoes plastic changes. A common polymorphism in the BDNF gene--BDNF Val66Met (referred to herein as BDNF(Met))--impairs cognitive function in healthy subjects. The aim of this study was to determine whether the BDNF(Met) polymorphism plays a role in the recovery of consciousness and cognitive functions in patients in a VS after a TBI. Fifty-three patients in a VS 1 month after a TBI were included in the study and genotyped for the BDNF(Met) polymorphism. Scores of levels of cognitive functioning (LCF) at 1, 3, 6, and 12 months post-TBI were retrospectively compared in patients without (Val group), and with (Met group), the BDNF(Met) polymorphism. The BDNF(Met) polymorphism was detected in 20 out of the 53 patients. The mean LCF scores in the Val and Met groups were 1.6±0.5 and 1.4±0.5 at 1 month, 2.3±0.7 and 2.5±1.2 at 3 months, 3.3±1.7 and 3.5±1.7 at 6 months, and 4±1.9 and 3.9±1.8 at 12 months, respectively (p>0.05). The percentages of patients in the Val and Met groups who emerged from the VS were 36.4% and 30% at 3 months, 66.3% and 70% at 6 months, and 70% and 87.5% at 12 months (p>0.05), respectively. These findings provide evidence that the BDNF(Met) polymorphism is not involved in cognitive improvement in patients with a VS following TBI. Future studies should focus on the role of other BDNF polymorphisms in the recovery from a VS.

Visual pursuit: within-day variability in the severe disorder of consciousness.

Visual pursuit marks substantial recuperation from a vegetative state and evolution into a minimally-conscious state, but its incidence in different studies suggests some unreliability in contrast with its established prognostic relevance. Subjects in vegetative (n=9) or minimally-conscious (n=13) states were tested for visual pursuit 6 times/day (9:30, 10:30, and 11:30 am, and 2:00, 3:00, and 4.00 pm, for a total of 132 determinations). Visual pursuit was observed at all testing times in 8 minimally-conscious patients, and never in 5 subjects in a vegetative state. Its incidence per subject ranged from 50-100% of testing times in the minimally-conscious state (83±23%), and 0-33% in a vegetative state (7%±12), with spontaneous fluctuations during the day and maximal levels at 10.30 am and 3.00 pm, and was never observed at the post-prandial time point (2:00 pm). The overall chance of observing visual tracking at least once during the day was ∼33% in the vegetative state, whereas that of not observing it in the minimally-conscious state was ∼38%. These percentages are congruent with the reported misdiagnosis rate between the two conditions, and document spontaneous variability possibly related to circadian rhythms.

Visual pursuit in the severe disorder of consciousness.

Visual pursuit is a key descriptor of the minimally conscious state (above 80% of cases). It is also observable in about 20% of subjects in vegetative state. Its reappearance after severe brain damage anticipates a favorable outcome, with recovery of consciousness in 73% of subjects (45% in the absence of it). We considered retrospectively 395 subjects in vegetative state because of traumatic (63%), massive acute vascular (30%), or diffuse anoxic-hypoxic (7%) brain damage consecutively admitted to one dedicated unit during the years 1998-2008. Visual tracking was observed in 290 subjects (73.4%) and was already detectable within 50 days from brain injury in about 60% of post-traumatic or vascular subjects and 21% of anoxic-hypoxic patients. After 230 days of follow-up or more, it was observed in 89% and 88% of post-traumatic and vascular subjects and in 67% of anoxic-hypoxic patients. Rating with the Glasgow Outcome Scale (GOS) was better in those subjects with recovered visual tracking and inversely correlated with the time of reappearance in post-traumatic and vascular subjects; also the subjects with late recovery of eye tracking (230 days or more) had better GOS outcome than those without it. The observation of visual tracking reappearing in subjects in vegetative state would reflect recuperation of the brainstem-cortical interaction and overall brain functional organization that are thought to sustain consciousness and are interfered with by the "functional disconnection," resulting in the vegetative state.