Serum BDNF Levels Are Reduced in Patients with Disorders of Consciousness and Are Not Modified by Verticalization with Robot-Assisted Lower-Limb Training.

Little is known about plastic changes occurring in the brains of patients with severe disorders of consciousness (DOCs) caused by acute brain injuries at rest and during rehabilitative treatment. Brain-derived neurotrophic factor (BDNF) is a neurotrophin involved in neurogenesis and synaptic plasticity whose production is powerfully modulated by physical exercise. In this study, we compared serum BDNF levels in 18 patients with unresponsive wakefulness syndrome (UWS) and in a minimally conscious state (MCS) with those in 16 sex- and age-matched healthy controls. In 12 patients, serum BDNF levels before and after verticalization with ErigoPro robot-assisted lower-limb training were compared. Serum BDNF levels were significantly lower in patients (median, 1141 pg/ml; 25th and 75th percentiles, 1016 and 1704 pg/ml) than in controls (median, 2450 pg/ml; 25th and 75th percentiles, 2100 and 2875 pg/ml; p < 0.001). BDNF levels measured before and after verticalization with robot-assisted lower-limb training did not change (p = 0.5). Moreover, BDNF levels did not differ between patients with UWS and MCS (p = 0.2), or between patients with traumatic and nontraumatic brain injuries (p = 0.6). BDNF level correlated positively with the time since brain injury (p = 0.025). In conclusion, serum BDNF levels are reduced in patients with UWS and MCS and cannot be improved by verticalization associated with passive lower-limb training. Additional studies are needed to better understand the mechanisms underlying BDNF reduction in patients with DOCs and to determine the best rehabilitative strategies to promote restorative plastic changes in these patients.

Reduced Neuron-Specific Enolase Levels in Chronic Severe Traumatic Brain Injury.

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.

Choline-PET/CT in the Differential Diagnosis Between Cystic Glioblastoma and Intraparenchymal Hemorrhage.

OBJECTIVE: Glioblastoma multiforme (GBM) represents the most common and malignant glioma, accounting for 45%-50% of all gliomas. The median survival time for patients with glioblastoma is only 12-15 months after surgical, chemioterapic and radiotherapic treatment; a correct diagnosis is naturally fundamental to establish a rapid and correct therapy. Non-invasive imaging plays a pivotal role in each phase of the diagnostic workup of patients with suspected for diagnosis. The aim of this case report was to describe the potential clinical impact of 18F-fluorocholine (FCH) PET/CT in the assessment of a cystic GBM mimicking a spontaneous hemorrhage. METHODS: a 57 years-old male with intraparenchymal hemorrhage at CT imaging initially in reduction ad serial imaging and suspected right fronto-temporo-parietal lesion at MRI underwent dynamic and static (60' after tracer injection) FCH PET/CT of the brain. RESULTS: FCH PET/CT showed rapid tracer uptake after few second from injection at dynamic acquisition and consequent incremental mild uptake at static imaging after 60 minutes at the level of oval formation in the right cerebral hemisphere characterized by annular and peripheral high metabolic activity. The central region of the lesion was characterized by the absence 18F-FCH uptake most likely due to blood component. The patient underwent surgery for tumor removal; the histopathological examination confirmed the suspect of GBM. Chemo-radiotherapic adjuvant protocol according to Stupp protocol was therefore administrated; to date the patient is alive without any progression disease at 5 months from treatment. CONCLUSION: In this case report FCH PET/CT represented the final diagnostic technique to confirm the suspicious of a cystic GBM. Our case demonstrated the potential role of 18F-FCH PET/CT for discrimination of higher proliferation area over intraparenchymal hemorrhage, supporting the potential use of this imaging biomarker in surgical or radiosurgical approach. Obviously, further prospective studies are needed to confirm this role and to exactly define possible routinely applications.

Dissociation of cerebrospinal fluid amyloid-ß and tau levels in patients with prolonged posttraumatic disorders of consciousness.

BACKGROUND: Traumatic brain injury (TBI) is a major risk factor for Alzheimer's disease (AD). Although the mechanisms that lead to AD after a TBI are unclear, we hypothesize that changes in amyloid-ß (Aß) metabolism and abnormal tau phosphorylation are reasonable candidates. OBJECTIVE: To investigate Aß and tau dynamics in the chronic phase of TBI. METHODS: We evaluated Aß1-42, total tau (t-tau), and phosphorylated tau (p-tau) levels in the cerebrospinal fluid (CSF) of 15 patients who developed a prolonged disorder of consciousness after a severe TBI (mean time from TBI 271.6 ± 176.5 days). RESULTS: Reduced Aß1-42 levels (median 258 pg/ml, range 90-833.6) were observed in 14/15 patients (93.3%) with severe post-TBI disorders of consciousness. These CSF analysis data did not correlate with time since TBI or with the patients' level of consciousness as determined by the Coma Recovery Scale Revised. Normal t-tau levels (median 95.2 pg/ml, range 52-256.9) were found in all patients. Normal p-tau levels (median 22.2 pg/ml, range 14-72) were observed in 14/15 patients, with just a single patient having a slightly increased p-tau level. CONCLUSION: The present findings show that Aß and tau are differently affected in the chronic phase of severe TBI.

Risk Factors Associated With Peripheral Neuropathy in Heart Failure Patients Candidates for Transplantation.

INTRODUCTION: Peripheral neuropathy can affect patients with heart failure, though its prevalence is unknown. After heart transplantation, it can influence the postoperative course and quality of life, but screening for neuromuscular disease is not routinely performed. OBJECTIVE: The aim of this study was to identify the factors associated with neuropathy in a population of patients with heart failure who are candidates for heart transplantation. STUDY DESIGN: Data regarding patients' clinical history, including recent hospitalizations, were collected. All patients underwent a complete neurological examination and a neurophysiological protocol including nerve conduction studies and concentric needle electromyography. RESULTS: Thirty-two patients were included in the study, and neuropathy was diagnosed in 10 (31.3%). Neuropathy was associated with the number of admissions ( P = .023; odds ratio [OR]: 1.96) and the total number of days of hospitalization in the year prior to inclusion in the study ( P = .010; OR: 1.03). The majority of hospitalizations occurred in the step-down unit (85%), with acute heart failure the leading cause of admission (42%). CONCLUSIONS: This study shows that neuropathy is frequent in patients with advanced heart failure and that hospitalization for cardiac care, also in the absence of intensive care, is a marker of high risk of neurologic damage. These data can help physicians in selecting and managing candidates for transplantation and can guide decisions on the best immunosuppressive regimen or rehabilitation strategy.

Pain assessment with the revised nociception coma scale and outcomes of patients with unresponsive wakefulness syndrome: results from a pilot study.

The aim of this study was to evaluate whether standardized responses to nociceptive pain, assessed with the revised Nociception Coma Scale (NCS-R), were correlated with the outcomes of patients with unresponsive wakefulness syndrome (UWS) 6 months after admission to a rehabilitation department. We recruited 24 consecutive patients with UWS. Patients' consciousness levels were assessed with the revised Coma Recovery Scale (CRS-R) at admission and 6 months later, and their CRS-R scores were correlated with the NCS-R scores at admission. Ten of the 24 patients with UWS recovered consciousness after 6 months. The NCS-R score at admission was correlated with the CRS-R score at admission (P = 0.02), but not after 6 months (P = 0.6). Patients with and without consciousness improvement after 6 months showed no significant difference in the NCS-R total score and sub-scores at admission (P values > 0.05). In conclusion, the correlation between NCS-R and CRS-R scores at admission suggests that the standardized assessment of pain parallels patients' levels of consciousness, and may be helpful in the clinical evaluation of patients with UWS. Pain response assessed with the NCS-R was not related to the 6-month outcomes of patients with UWS.

Infection of recurrent calcaneal ulcer caused by a biofilm-producer Myroides odoratimimus strain.

We report a case of recurrent post-traumatic ulcer infection due to Myroides odoratimimus in an immunocompromised male. We have also reviewed the medical literature on isolated M. odoratimimus infections. The strain, isolated from ulcer discharge, was multidrug-resistant and treatment with meropenem, based on susceptibility testing, led to resolution of infection. The strain was also able to form a relevant amount of biofilm over time, thus suggesting a possible role of sessile communities in the chronicization of infection. To our knowledge, this is the first description of recurrent ulcer infection caused by a biofilm-producer M. odoratimimus strain. This case reminds us of the need to consider uncommon pathogens as etiology of skin and soft tissue infections, especially in immunocompromised patients. Further, since the treatment of infections due to M. odoratimimus is often difficult both due to multidrug resistance and scarce clinical experience, antibiotic therapy should be adapted to in vitro susceptibility testing.

A New Standardization of the Bells Test: An Italian Multi-Center Normative Study.

Objective: The Bells Test is a cancelation task that is widely used for the diagnosis of unilateral spatial neglect (USN). With the aim of fostering more reliable use of this instrument, we set out to develop new norms adjusted for the possible influence of age, gender and education. We worked on the original version of the test. Methods: Normative data were collected from 401 healthy participants aged between 20 and 80 years. Individual factors that could affect performance (i.e., gender, age, and years of education) were considered. We computed several indices on the Bells Test including an asymmetry score, an accuracy score and execution time. Multiple regression analyses (for time measures) and generalized linear models (for accuracy measures) were used to check for the influence of individual predictors of performance on the Bells Test. Results: Data indicated a significant influence of age on the accuracy score and execution time variables and a marginally significant effect of education on the accuracy score variable. Wherever appropriate, cut-offs are provided for the three dependent scores on the Bells Test corrected for age and education. Conclusion: Based on a large normative sample, the present study provides new normative data on the Bells Test, which could lead to its reliable use in the diagnosis of USN.

Prolonged changes in amyloid-ß metabolism after a severe traumatic brain injury.

Traumatic brain injury (TBI) is a major risk factor for Alzheimer's disease. Recent studies suggest that amyloid-beta (Aß) deposit can be detected several years after TBI. However, it is unknown whether post-TBI Aß deposits arise from short-term changes in Aß metabolism or reflect a long-term sequela. To answer this question, we evaluated the cerebrospinal levels of Aß several months after a severe TBI. The participants of this study were eight consecutive patients who developed a disorder of consciousness after a TBI, including seven in a minimally conscious state and one with unresponsive wakefulness syndrome (mean age: 35.4±14.2 years, mean time since brain injury 297.9±189.8 days). Cerebrospinal Aß1-42 peptide was measured using a commercially available Aß enzyme-linked immunoassay kit. Reduced Aß1-42 levels were observed in seven of eight (87.5%) patients with severe post-TBI disorders of consciousness, with the magnitude of reduction among these seven patients ranging from 27 to 75.1% of the lower normal limit. These results point to prolonged changes in Aß metabolism after a TBI and they suggest a potential mechanism of long-term neurotoxicity.

Myroides odoratimimus Forms Structurally Complex and Inherently Antibiotic-Resistant Biofilm in a Wound-Like in vitro Model.

Myroides odoratimimus is an aerobic, non-fermenting Gram-negative multidrug-resistant bacterium widely distributed in nature that rarely causes infections in immunocompromised patients. We recently described in a diabetic patient a case of recurrent calcaneal ulcer infection caused by a M. odoratimimus strain showing potential for biofilm formation. For the first time, we therefore evaluated the ability of M. odoratimimus to form biofilm under different pH values and glucose concentrations using an in vitro "skin-like" model, and its susceptibility to levofloxacin, meropenem, and tigecycline. The expression of some antibiotic-resistance related genes was also monitored by RT-PCR during planktonic-to-biofilm transition. Our results indicated that M. odoratimimus can produce relevant amounts of biofilm biomass, in a time-dependent manner, especially at acidic pH and regardless of glucose concentration tested. The comparative analysis of MIC and MBC values between planktonic and sessile cells showed that resistance to antibiotics increased during the planktonic-to-biofilm transition. Viable cell count indicated that none of the tested antibiotics were able to completely eradicate preformed biofilms, although meropenem and levofloxacin were the most active causing a significant, dose-independent, reduction of biofilm's viability, as also confirmed by microscopic analysis. RT-PCR showed that antibiotic-resistance related gyrA and acrB genes are over-expressed during the transition from planktonic to sessile (biofilm) lifestyle. Overall, our findings showed that M. odoratimimus can form relevant amounts of inherently antibiotic-resistant biofilm under conditions relevant to wound site, therefore suggesting a role in the pathogenesis of chronic ulcer infections.

Changes in Standard Electroencephalograms Parallel Consciousness Improvements in Patients With Unresponsive Wakefulness Syndrome.

OBJECTIVE: To identify changes in the standard electroencephalograms (EEGs) of patients with unresponsive wakefulness syndrome (UWS) who did or did not recover consciousness 6 months after admission to a rehabilitation department. DESIGN: Prospective cohort study. SETTING: Unit for severe acquired brain injuries. PARTICIPANTS: Consecutive patients with UWS (N=28). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: EEG amplitude (reduced or normal), dominant frequency (alpha, theta, or delta), and reactivity (absent or present) were scored at admission and 6 months later. The cumulative Amplitude-Frequency-Reactivity score was evaluated. Clinical assessments were made using the Coma Recovery Scale-Revised. RESULTS: Sixteen (57.1%) of the 28 patients with UWS recovered consciousness after 6 months, while 12 patients (42.9%) did not recover consciousness. EEG improvements occurred in 14 patients with consciousness recovery (87.5%) and 2 patients without consciousness recovery (16.7%) only. Improvements in EEG dominant frequency (from the theta to the alpha band or from the delta to the theta band), reappearance of EEG reactivity, and Amplitude-Frequency-Reactivity score increase (P<.01) differentiated patients with consciousness improvement from those without consciousness improvement. Six months after admission for rehabilitation, patients with EEG improvements showed higher Coma Recovery Scale-Revised scores than did those without EEG changes (P<.01). CONCLUSIONS: Most patients who emerge from UWS demonstrate improvement in basic EEG characteristics over time. EEG changes in patients with UWS may aid in the timely recognition of patients transitioning into a minimally conscious state.

Longitudinal Assessment of Clinical Signs of Recovery in Patients with Unresponsive Wakefulness Syndrome after Traumatic or Nontraumatic Brain Injury.

Although clinical examination is the gold standard for differential diagnosis between unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS), clinical signs denoting the first occurrence of conscious behavior in patients with UWS have not been clarified. In this prospective single-center cohort study, 31 consecutive patients with UWS after traumatic brain injury (TBI) (17 patients) or non-TBI were assessed with the Coma Recovery Scale Revised (CRS-R) at admission to a rehabilitation department and after 1, 2, 3, 6, and 12 months. Of the 21 patients who recovered consciousness during the study, 90.5% recovered consciousness within the first 3 months. At the first diagnosis of emergence from UWS, 52.4% of patients showed signs of awareness in only one CRS-R subscale. In particular, 42.9% of patients showed conscious behaviors on the visual CRS-R subscale (23.8% showed visual fixation and 19.1% showed visual pursuit), and 9.5% showed conscious behaviors on the motor CRS-R subscale (half showed localization to a noxious stimulus and half showed object manipulation). Moreover, 23.8% of patients had conscious behaviors on two CRS subscales, always involving the visual and motor CRS-R subscales. The remaining patients showed conscious behaviors on more than two CRS-R subscales. In conclusion, visual fixation and visual pursuit are the commonest early clinical signs denoting MCS. When emerging from UWS, patients with TBI often showed more signs of consciousness and had higher CRS-R scores than patients with non-TBI.

The Chief Role of Frontal Operational Module of the Brain Default Mode Network in the Potential Recovery of Consciousness from the Vegetative State: A Preliminary Comparison of Three Case Reports.

It has been argued that complex subjective sense of self is linked to the brain default-mode network (DMN). Recent discovery of heterogeneity between distinct subnets (or operational modules - OMs) of the DMN leads to a reconceptualization of its role for the experiential sense of self. Considering the recent proposition that the frontal DMN OM is responsible for the first-person perspective and the sense of agency, while the posterior DMN OMs are linked to the continuity of 'I' experience (including autobiographical memories) through embodiment and localization within bodily space, we have tested in this study the hypothesis that heterogeneity in the operational synchrony strength within the frontal DMN OM among patients who are in a vegetative state (VS) could inform about a stable self-consciousness recovery later in the course of disease (up to six years post-injury). Using EEG operational synchrony analysis we have demonstrated that among the three OMs of the DMN only the frontal OM showed important heterogeneity in VS patients as a function of later stable clinical outcome. We also found that the frontal DMN OM was characterized by the process of active uncoupling (stronger in persistent VS) of operations performed by the involved neuronal assemblies.

Long-Term (Six Years) Clinical Outcome Discrimination of Patients in the Vegetative State Could be Achieved Based on the Operational Architectonics EEG Analysis: A Pilot Feasibility Study.

Electroencephalogram (EEG) recordings are increasingly used to evaluate patients with disorders of consciousness (DOC) or assess their prognosis outcome in the short-term perspective. However, there is a lack of information concerning the effectiveness of EEG in classifying long-term (many years) outcome in chronic DOC patients. Here we tested whether EEG operational architectonics parameters (geared towards consciousness phenomenon detection rather than neurophysiological processes) could be useful for distinguishing a very long-term (6 years) clinical outcome of DOC patients whose EEGs were registered within 3 months post-injury. The obtained results suggest that EEG recorded at third month after sustaining brain damage, may contain useful information on the long-term outcome of patients in vegetative state: it could discriminate patients who remain in a persistent vegetative state from patients who reach a minimally conscious state or even recover a full consciousness in a long-term perspective (6 years) post-injury. These findings, if confirmed in further studies, may be pivotal for long-term planning of clinical care, rehabilitative programs, medical-legal decisions concerning the patients, and policy makers.

EEG epileptiform abnormalities at admission to a rehabilitation department predict the risk of seizures in disorders of consciousness following a coma.

BACKGROUND: Seizures affect about a quarter of patients with disorders of consciousness (DOC) after a coma. AIMS: We investigated whether the presence of epileptiform abnormalities (EAs) in the electroencephalogram (EEG) of patients with DOC may predict the occurrence of seizures. Moreover, we evaluated whether EAs have a prognostic role in these patients. METHODS: This was a retrospective single-center cohort study of patients hospitalized between January 2005 and December 2014 in a rehabilitation department (mean time from acute brain injury: 46.1 days). We analyzed 30-minute EEGs at admittance for 112 patients with unresponsive wakefulness syndrome (UWS) or in a minimally conscious state (MCS), then compared occurrence of seizures over the following three months across patients with absent, unilateral, and bilateral EAs (generalized or bilateral independent). Outcomes at three months were assessed in the same groups using the Coma Recovery Scale Revised. RESULTS: Epileptiform abnormalities were observed in 38 patients (33.9%). Of these, 25 were unilateral, and 13 were bilateral. Seizures occurred in 84.6% of patients with bilateral EAs, which was significantly higher than in patients without EAs (10.8%, p<0.001) or with unilateral EAs (24%, p=0.001). The presence of EAs was not related to etiology or different DOC and did not significantly affect outcomes at three months. CONCLUSIONS: Patients with EAs at admission to a rehabilitation department have an increased risk of seizures. Specifically, most patients with bilateral EAs had seizures within the following 3 months. Evaluation of EAs in EEGs of patients with DOC may give valuable information in the management of antiepileptic drug treatment.

Occurrence of neuropathies in patients with severe heart failure before and after heart transplantation.

Neuropathies may affect heart reinnervation and functional outcome after heart transplantation (HT). In this study, neurological evaluations, standard nerve conduction studies, and electromyography were performed in 32 HT candidates without a previous history of neuromuscular disorder. Ten patients underwent HT and were revaluated 3 months later. We found that before HT 10 (31.3%) patients had sensorimotor polyneuropathy (18.8%) or sensory polyneuropathy (12.5%). After HT, the percentage of patients with a neuromuscular disorder increased to 70%, most of them showing new or worsening neuropathies or neuromyopathies. The most sensitive abnormality that indicated neuromuscular involvement after HT was a reduction of the compound muscle action potential (CMAP) of the deep peroneal nerve. In conclusion, neuromuscular disorders are common in HT candidates, and they further increase in occurrence after HT. A reduction of the deep peroneal nerve CMAP amplitude after HT may help to identify patients who need a more detailed neurophysiological evaluation. The diagnosis of neuromuscular disorders before and after HT may contribute to the development of more accurate therapeutic and rehabilitative strategies for these patients.

Autonomic correlates of seeing one's own face in patients with disorders of consciousness.

The ability to recognize one's own face is a hallmark of self-awareness. In healthy subjects, the sympathetic skin response evoked by self-face recognition has a greater area under the curve of the signal than responses evoked by other visual stimuli. We evaluated the sympathetic skin responses evoked by self-face images and by six other visual stimuli (conditions) in 15 patients with severe disorders of consciousness and in 15 age-matched healthy subjects. Under all conditions, the evoked area of the sympathetic skin response was smaller in patients with unresponsive wakefulness syndrome, intermediate in patients in a minimally conscious state, and greater in healthy subjects. In patients with unresponsive wakefulness syndrome, no differences were found between the sympathetic skin response area evoked by self-face images and those evoked by other conditions. In patients in a minimally conscious state, the area of the sympathetic skin response evoked by self-face presentation was greater than those evoked by other conditions, even if statistical significance was reached only in the comparison to other stimuli not involving a real face. This finding may be due to the inability of these patients to differentiate their own face from those of others. Taken together, these results probably reflect a varying level of self-awareness between patients with unresponsive wakefulness syndrome and patients in a minimally conscious state, and suggest that the autonomic correlate of self-awareness may have some diagnostic implications for these patients.

EEG predictors of outcome in patients with disorders of consciousness admitted for intensive rehabilitation.

OBJECTIVE: This study examined the prognostic value of standard EEG in patients with unresponsive wakefulness syndrome (UWS) or in a minimally conscious state (MCS). METHODS: EEGs recorded at admission in 106 patients with UWS or in a MCS were analyzed retrospectively. EEG amplitude, dominant frequency, and reactivity to stimuli were correlated to patient outcomes according to the Coma Recovery Scale Revised (CRS-R). In 101 patients, data were integrated to generate a novel Amplitude-Frequency-Reactivity (AFR) scale, with scores ranging from 3 to 7. RESULTS: Patients with reduced amplitudes showed less improvement in CRS-R scores at 3 months compared to patients with normal amplitudes. Delta, theta, and alpha frequencies were associated with the least, intermediate, and the greatest improvement in CRS-R scores, respectively. Patients with EEG reactivity showed greater improvements in CRS-R scores than patients without reactivity. The AFR scores for these patients were correlated with outcomes. CONCLUSIONS: Reduced EEG amplitudes and delta frequencies correlated with worse clinical outcomes, while alpha frequencies and reactivity correlated with better outcomes. AFR scores allowed more delineated descriptions of outcomes in patients with normal amplitude, theta frequency, and no reactivity. SIGNIFICANCE: Standard EEG descriptors are related to the 3-month outcomes in patients with disorders of consciousness.