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In this multi-center study, we provide a systematic evaluation of the clinical variability associated with paroxysmal sympathetic hyperactivity (PSH) in patients with acquired brain injury (ABI) to determine how these signs can impact outcomes. A total of 156 ABI patients with a disorder of consciousness (DoC) were admitted to neurorehabilitation subacute units (intensive rehabilitation unit; IRU) and evaluated at baseline (T0), after 4 months from event (T1), and at discharge (T2). The outcome measure was the Glasgow Outcome Scale-Extended, whereas age, sex, etiology, Coma Recovery Scale-Revised (CRS-r), Rancho Los Amigos Scale (RLAS), Early Rehabilitation Barthel Index (ERBI), PSH-Assessment Measure (PSH-AM) scores and other clinical features were considered as predictive factors. A machine learning (ML) approach was used to identify the best predictive model of clinical outcomes. The etiology was predominantly vascular (50.8%), followed by traumatic (36.2%). At admission, prevalence of PSH was 31.3%, which decreased to 16.6% and 4.4% at T1 and T2, respectively. At T2, 2.8% were dead and 61.1% had a full recovery of consciousness, whereas 36.1% remained in VS or MCS. A support vector machine (SVM)-based ML approach provides the best model with 82% accuracy in predicting outcomes. Analysis of variable importance shows that the most important clinical factors influencing the outcome are the PSH-AM scores measured at T0 and T1, together with neurological diagnosis, CRS-r, and RLAS scores measured at T0. This joint multi-center effort provides a comprehensive picture of the clinical impact of PSH signs in ABI patients, demonstrating its predictive value in comparison with other well-known clinical measurements.

Growing evidence suggests that pathophysiological mechanisms leading to neurodegeneration and neuronal loss take place during the chronic phase of a severe traumatic brain injury (TBI). In this study we evaluated a well-established marker of brain injury, the neuron-specific enolase (NSE), in the serum of 51 patients with severe TBI (86% males, mean age 33.8 ± 11.1 years). All patients' samples were available from a previous study and the mean time between TBI and blood sample collection was 23.2 ± 31.5 months (28 patients were evaluated within 12 months of TBI and 23 patients were evaluated ≥12 months after TBI). Patients' NSE levels were compared with those obtained from 30 age and sex-matched healthy controls (87% males, 33.7 ± 11.3 years). We found that NSE levels were significantly lower in patients (median 3.2 ng/mL; 25th, 75th percentile 2.5, 5.1) than in healthy controls (median 4.1 ng/mL; 25th, 75th percentile 3.1, 7.5) ( p  = 0.026). This finding was mainly driven by data from the chronic patients, that is, those who experienced their TBI at least 12 months before the evaluation. Indeed, these patients had significantly lower NSE levels (median 2.6 ng/mL; 25th, 75th percentile 1.9, 4) than healthy controls ( p  < 0.01). On the other hand, NSE levels evaluated in patients <12 months from TBI (median 3.9 ng/mL; 25th, 75th percentile 2.8, 5.7) did not significantly differ from controls ( p  = 0.3). These findings possibly reflect a progressive brain atrophy with reduced baseline NSE release in the chronic phase of a severe TBI.

The rate of paroxysmal sympathetic hyperactivity (PSH) was retrospectively assessed using the Paroxysmal Sympathetic Hyperactivity-Assessment Measure (PSH-AM) scale in patients with disorders of consciousness attributed to traumatic and non-traumatic acquired brain injury during the rehabilitation phase. These results were compared with previous studies carried out in the same clinical scenario, in order to verify the prevalence of PSH signs from 1998 to 2014. The entire sample consisted of 140 patients in vegetative state/unresponsive wakefulness syndrome or minimally conscious state admitted to a neurorehabilitation subacute unit from June 2010 to December 2014. PSH-AM revealed the presence of PSH in 16% of traumatic and 12% of non-traumatic younger patients. In the non-traumatic group, the rate was higher in patients with anoxia-hypoxia (37.5%) etiology than those with vascular brain injury (6.7%). A comparison with previous studies revealed a reduction in the number of PSH cases in traumatic patients. This study provides evidence that PSH-AM can be used prospectively to detect the rate of PSH and stratify severity of signs. Further longitudinal analysis is warranted to confirm the prevalence of PSH signs in non-traumatic brain injured patients.

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.

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 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.