The Prognostic Role of Candidate Serum Biomarkers in the Post-Acute and Chronic Phases of Disorder of Consciousness: A Preliminary Study.

INTRODUCTION: Serum biomarkers, such as Neurofilament Light (NF-L), Glial Fibrillary Acidic Protein (GFAP), Ubiquitin C-terminal Hydrolase (UCH-L1), and Total-tau (T-Tau) have been proposed for outcome prediction in the acute phase of severe traumatic brain injury, but they have been less investigated in patients with prolonged DoC (p-DoC). METHODS: We enrolled 25 p-DoC patients according to the Coma Recovery Scale-Revised (CRS-R). We identified different time points: injury onset (t0), first blood sampling at admission in Neurorehabilitation (t1), and second blood sampling at discharge (t2). Patients were split into improved (improved level of consciousness from t1 to t2) and not-improved (unchanged or worsened level of consciousness from t1 to t2). RESULTS: All biomarker levels decreased over time, even though each biomarker reveals typical features. Serum GFAP showed a weak correlation between t1 and t2 (p = 0.001), while no correlation was observed for serum NF-L (p = 0.955), UCH-L1 (p = 0.693), and T-Tau (p = 0.535) between t1 and t2. Improved patients showed a significant decrease in the level of NF-L (p = 0.0001), UCH-L1 (p = 0.001), and T-Tau (p = 0.002), but not for serum GFAP (p = 0.283). No significant statistical differences were observed in the not-improved group. CONCLUSIONS: A significant correlation was found between the level of consciousness improvement and decreased NF-L, UCH-L1, and T-Tau levels. Future studies on the association of serum biomarkers with neurophysiological and neuroimaging prognostic indicators are recommended.

Evaluation of the Impact of Cognitive Training on Quality of Life in Patients with Multiple Sclerosis.

OBJECTIVE: The aim of this study was to evaluate the effectiveness of cognitive rehabilitation in a group of multiple sclerosis (MS) patients. METHODS: Thirty-four patients were included in this study and randomly allocated either to treatment with multidisciplinary rehabilitation plus cognitive training or to treatment with multidisciplinary rehabilitation alone. RESULTS: After 3 months of cognitive treatment, the patients assigned to the rehabilitation plus cognitive training group displayed an improvement in the cognitive test of executive function and a marked improvement in quality of life (QoL). The patients treated with multidisciplinary rehabilitation without cognitive training improved in the physical composite score alone. Both groups of patients displayed an improvement in depression, though the improvement was confirmed at the 6-month follow-up examination (p = 0.036) only in patients treated with multidisciplinary rehabilitation plus cognitive training. CONCLUSIONS: Our results indicate that the multidisciplinary rehabilitation treatment is the best approach to treat MS. The specific effect of each treatment needs to be assessed to be able to determine its role within a multidisciplinary approach. Cognitive rehabilitation is an important aspect of this multidisciplinary approach insofar as it may improve the QoL of MS people.

Does robot-assisted gait training improve ambulation in highly disabled multiple sclerosis people? A pilot randomized control trial.

BACKGROUND: Robotic training is commonly used to assist walking training in patients affected by multiple sclerosis (MS) with non-conclusive results. OBJECTIVE: To compare the effect of robot-assisted gait training (RAGT) with that of conventional walking training (CWT) on gait competencies, global ability, fatigue and spasticity in a group of severely affected patients with MS. METHODS: A pilot, single-blind randomized controlled trial was conducted in 43 severe (Expanded Disability Status Scale (EDSS) score of 6-7.5) and non-autonomous ambulant in-patients with MS. Experimental group performed 12 sessions of RAGT, whereas control group performed the same amount of CWT. Primary outcome measures were gait ability assessed by 2 minutes walking test and Functional Ambulatory Category; secondary outcomes were global ability (modified Barthel Index), global mobility (Rivermead Mobility Index), severity of disease (EDSS) and subjectively perceived fatigue (Fatigue Severity Scale). RESULTS: The number of subjects who achieved a clinical significant improvement was significantly higher in RAGT than in CWT ( p < 0.05 for both primary outcome measures). RAGT also led to an improvement in all the other clinical parameters (global ability: p < 0.001, global mobility: p < 0.001, EDSS: p = 0.014 and fatigue: p = 0.001). CONCLUSIONS: RAGT improved the walking competencies in non-autonomous ambulant patients with MS, with benefits in terms of perceived fatigue.

The Default Mode Network Connectivity Predicts Cognitive Recovery in Severe Acquired Brain Injured Patients: A Longitudinal Study.

To study the functional connectivity in patients with severe acquired brain injury is very challenging for their high level of disability because of a prolonged period of coma, extended lesions, and several cognitive and behavioral disorders. In this article, we investigated in these patients the default mode network and somatomotor connectivity changes at rest longitudinally, in the subacute and late phase after brain injury. The aim of the study is to characterize such connectivity patterns and relate the observed changes to clinical and neuropsychological outcomes of these patients after a period of intensive neurorehabilitation. Our findings show within the default mode network a disruption of connectivity of medial pre-frontal regions and a significant change of amplitude of internal connections. Notably, strongest changes in functional connectivity significantly correlated to consistent clinical and cognitive recovery. This evidence seems to indicate that the reorganization of the Default Mode Network may represent a valid biomarker for the cognitive recovery in patients with severe acquired brain injury.

Chronic Pain in Multiple Sclerosis Patients: Utility of Sensory Quantitative Testing in Patients with Fibromyalgia Comorbidity.

BACKGROUND: Lower thermal and discomfort thresholds may predispose multiple sclerosis (MS) patients to chronic pain, but a possible effect of fibromyalgia (FM) comorbidity has never been investigated. Aims were to investigate the thermal and discomfort thresholds in the evaluation of pain intensity between MS patients with FM (PFM+) and MS patients with pain not associated to FM (PFM-). METHODS: One hundred thirty three MS patients were investigated for chronic pain. FM was assessed according to the 1990 ACR diagnostic criteria. An algometer was used to measure the thresholds in the patients and 60 matched healthy subjects. RESULTS: Chronic pain was present in 88 (66.2%) patients; 12 (13.6%) had neuropathic pain, 22 (17.3%) were PFM+ and 65 (48.9%) PFM-. PFM+ were predominantly female (p = 0.03) and had a greater EDSS (p = 0.01) than NoP; no other significant differences emerged than PFM-. The thresholds were lower in MS patients than controls (p < 0.01), mainly in the PFM+. FM severity influenced the thermal threshold (p < 0.001), while the female gender influenced the discomfort threshold (p < 0.001). CONCLUSION: Thermal and discomfort thresholds were lower in patients than controls and were the lowest in PFM+. Their more severely impaired thermal threshold supports a neurophysiological basis of such association.

Functional magnetic resonance imaging in disorders of consciousness: preliminary results of an innovative analysis of brain connectivity.

The aim of this preliminary study was to present a new approach for connectivity analysis in patients with severe acquired brain injury (ABI) that overcomes some of the difficulties created by anatomical abnormalities due to the brain injury. Using a data-driven approach, resting-state structural MRI (sMRI) and functional MRI (fMRI) data from three severe ABI patients - two with disorders of consciousness (DOC) and one who had recovered consciousness (non-DOC) - were integrated and analyzed. Parameters extracted from the distribution of the connectivity values, such as mean, standard deviation and skeweness, were considered. The distribution parameters estimated seem to provide an accurate multivariate classification of the considered cases that can be summarized as follows: connectivity in the severe ABI patients with DOC was on average lower than in the severe ABI non-DOC patient and healthy subjects. The dispersion of connectivity values of the severe ABI patients, non-DOC and DOC, was comparable, however the shape of the distribution was different in the non-DOC patient. Eventually, seed-based connectivity maps of the default mode Functional magnetic resonance imaging in disorders of consciousness: preliminary results of an innovative analysis of brain connectivity network show a pattern of increasing disruption of this network from the healthy subjects to non-DOC and DOC patients. Consistent results are obtained using an ICA-based approach..

Effect of ethylic alcohol on attentive functions involved in driving abilities.

The burden of injuries due to drunk drivers has been estimated only indirectly. Indeed, alcohol is considered one of the most important contributing cause of car crash injuries and its effect on cognitive functions needs to be better elucidated. Aims of the study were i) to examine the effect of alcohol on attentive abilities involved while driving, and ii) to investigate whether Italian law limits for safe driving are sufficiently accurate to prevent risky behaviours and car crash risk while driving. We conducted a cross-over study at IRCCS Fondazione Santa Lucia Rehabilitation Hospital in Rome. Thirty-two healthy subjects were enrolled in this experiment. Participants were submitted to an attentive test battery assessing attention before taking Ethylic Alcohol (EA-) and after taking EA (EA+). In the EA+ condition subjects drank enough wine until the blood alcohol concentration, measured by means of Breath Analyzer, was equal to or higher than 0.5 g/l. Data analysis revealed that after alcohol assumption, tonic and phasic alertness, selective, divided attention and vigilance were significantly impaired when BAC level was at least 0.5 g/l. These data reveal that alcohol has a negative effect on attentive functions which are primarily involved in driving skills and that Italian law limits are adequate to prevent risky driving behaviour.

Selective Cognitive Dysfunction Is Related to a Specific Pattern of Cerebral Damage in Persons With Severe Traumatic Brain Injury.

OBJECTIVE: Cognitive dysfunction is a common sequela of traumatic brain injury (TBI); indeed, patients show a heterogeneous pattern of cognitive deficits. This study was aimed at investigating whether patients who show selective cognitive dysfunction after TBI present a selective pattern of cerebral damage. SETTING: Post-Coma Unit, IRCCS Santa Lucia Foundation, Rome, Italy. PARTICIPANTS: We collected data from 8 TBI patients with episodic memory disorder and without executive deficits, 7 patients with executive function impairment and preserved episodic memory capacities, and 16 healthy controls. DESIGN: We used 2 complementary analyses: (1) an exploratory and qualitative approach in which we investigated the distribution of lesions in the TBI groups, and (2) a hypothesis-driven and quantitative approach in which we calculated the volume of hippocampi of individuals in the TBI and control groups. MAIN MEASURES: Neuropsychological scores and hippocampal volumes. RESULTS: We found that patients with TBI and executive functions impairment presented focal lesions involving the frontal lobes, whereas patients with TBI and episodic memory disorders showed atrophic changes of the mesial temporal structure (hippocampus). CONCLUSION: The complexity of TBI is due to several heterogeneous factors. Indeed, studying patients with TBI and selective cognitive dysfunction should lead to a better understanding of correlations with specific brain impairment and damage, better follow-up of long-term outcome scenarios, and better planning of selective and focused rehabilitation programs.

Chronic pain in multiple sclerosis: is there also fibromyalgia? An observational study.

BACKGROUND: Chronic pain is common in persons with multiple sclerosis (MS), but the co-morbidity of fibromyalgia (FM) has yet to be investigated in MS. Objectives of the study were to evaluate, among the various types of chronic pain, the frequency of FM in MS and its impact on MS patients' health-related quality of life (HRQoL). MATERIAL AND METHODS: 133 MS patients were investigated for the presence and characterization of chronic pain within 1 month of assessment. A rheumatologist assessed the presence FM according to the 1990 ACR diagnostic criteria. Depression, fatigue, and HRQoL were also assessed by means of specific scales. RESULTS: Chronic pain was present in 66.2% of patients (musculoskeletal in 86.3%; neuropathic in 13.7%; absent in 33.8% [called NoP]). Pain was diagnosed with FM (PFM+) in 17.3% of our MS patients, while 48.9% of them had chronic pain not FM type (PFM-); the prevalence of neuropathic pain in these 2 sub-groups was the same. PFM+ patients were prevalently females and had a higher EDSS than NoP. The PFM+ patients had a more pronounced depression than in the NoP group, and scored the worst in both physical and mental QoL. CONCLUSIONS: In our sample of MS patients we found a high prevalence of chronic pain, with those patients displaying a higher disability and a more severe depression. Moreover, FM frequency, significantly higher than that observed in the general population, was detected among the MS patients with chronic pain. FM occurrence was associated with a stronger impact on patients' QoL.

Supplementary motor area activation is impaired in severe traumatic brain injury parkinsonism.

A high percentage of survivors of severe traumatic brain injury present diffuse axonal injury and extrapyramidal symptoms. The association between diffuse cerebral damage and parkinsonian symptoms is probably because of the interruption of nigro-striato-frontal pathways. While functional magnetic resonance imaging (fMRI) has been widely used to investigate parkinsonism in idiopathic Parkinson disease, little is known about functional brain modifications related to post-traumatic parkinsonism (PTP). The aim of this study is to assess cerebral activity of the action-related network in patients with PTP comparing these patients to matched healthy controls. In the fMRI scanner, we proposed to 12 PTP patients and 12 healthy control participants a continuum of tasks involving action-related word production, mental simulation of action, and miming of action triggered by external stimuli such as drawings of objects. Patients with PTP showed a main effect similar to that of healthy controls in all the tasks. Direct comparison revealed hypoactivation of areas in the action-related network in patients with PTP for all the tasks. During the mime of action, which involved actual movement, the hypoactivation was localized to the motor network. Our results suggest that patients with PTP showed a cerebral reorganization for motor tasks in agreement with the cerebral reorganization observed in idiopathic Parkinson disease. For patients with PTP, supplementary motor area impairment seems to play a central role in parkinsonism, in line with the brain reorganization of action-related tasks.

Increased levels of serum MAP-2 at 6-months correlate with improved outcome in survivors of severe traumatic brain injury.

OBJECTIVE: To evaluate microtubule-associated proteins (MAP-2), a dendritic marker of both acute damage and chronic neuronal regeneration after injury, in serum of survivors after severe TBI and examine the association with long-term outcome. METHODS: Serum concentrations of MAP-2 were evaluated in 16 patients with severe TBI (Glasgow Coma Scale score [GCS] ≤ 8) 6 months post-injury and in 16 controls. Physical and cognitive outcomes were assessed, using the Glasgow Outcome Scale Extended (GOSE) and Levels of Cognitive Functioning Scale (LCFS), respectively. RESULTS: Severe TBI patients had significantly higher serum MAP-2 concentrations than normal controls with no history of TBI (p = 0.008) at 6 months post-injury. MAP-2 levels correlated with the GOSE (r = 0.58, p = 0.02) and LCFS (r = 0.65, p = 0.007) at month 6. Significantly lower serum levels of MAP-2 were observed in patients in a vegetative state (VS) compared to non-VS patients (p < 0.05). A trend tracking the level of consciousness was observed. CONCLUSIONS: Severe TBI results in a chronic release of MAP-2 into the peripheral circulation in patients with higher levels of consciousness, suggesting that remodelling of synaptic junctions and neuroplasticity processes occur several months after injury. The data indicate MAP-2 as a potential marker for emergence to higher levels of cognitive function.

Vegetative state, minimally conscious state, akinetic mutism and Parkinsonism as a continuum of recovery from disorders of consciousness: an exploratory and preliminary study.

The aim of this study was to review the usefulness of clinical and instrumental evaluation in individuals with disorders of consciousness (DOC). Thirteen subjects with severe acquired brain injury (ABI) and a diagnosis of DOC were evaluated using the Coma Recovery Scale in its revised version (CRS-R) and a new global disability index, the Post-Coma Scale (PCS). These instruments were administered both by a neutral examiner (professional) and by a professional in the presence of a caregiver. All patients were also scored using the International Classification of Functioning, Disability and Health (ICF). A statistically significant correlation between CRS-R and PCS was demonstrated. However, there also emerged significant differences in responsiveness between professional versus caregiver+professional assessment using the two scales. The emotional stimulation provided by significant others (caregivers) during administration of DOC evaluation scales may improve the assessment of responsiveness.

Post-traumatic headache: facts and doubts.

The International Classification of Headache Disorders does not separate the moderate from severe/very severe traumatic brain injury (TBI), since they are all defined by Glasgow coma scale (GCS) < 13. The distinction between the severe and very severe TBI (GCS < 8) should be made upon coma duration that in the latter may be longer than 15 days up to months in the case of vegetative state. Post-traumatic amnesia duration may double the coma duration itself. Therefore, the 3-month parameter proposed to define the occurrence or resolution of post-traumatic headache (PTH) appears inadequate. Following TBI, neuropathic pain, central pain, thalamic pain, combined pain are all possible and they call for proper pharmacological approaches. One more reason for having difficulties in obtaining information about headache in the early phase after regaining consciousness is the presence of concomitant medications that may affect pain perception. Post-traumatic stress disorder (PTSD) develops days or weeks after stress and tends to improve or disappear within 3 months after exposure; interestingly, this spontaneous timing resembles that of PTH. In our experience the number of TBI patients with PTH at 1-year follow-up is lower in those with longer coma duration and more severe TBI. Cognitive functioning evaluated after at least 12 months from TBI, showed mild or no impairment in these patients with severe TBI and PTH, whereas they have psychopathological changes, namely anxiety and depression. The majority of patients with PTH after severe/very severe TBI had skull fractures or dural lacerations and paroxystic EEG abnormalities. The combination of psychological changes (depression and anxiety) and organic features (skull fractures, dural lacerations, epileptic EEG abnormalities) in PTH may be inversely correlated with the severity of TBI, with prevalence of psychological disturbances in mild TBI and of organic lesions in severe TBI. On the other hand, only in severe TBI patients with good cognitive recovery the influence of the psychopathological disorders may play a role. In fact, the affective pain perception is probably related to the integrity of cognitive functions as in mild TBI and in severe TBI with good cognitive outcome.

Markers of lacunar stroke in patients with moderate internal carotid artery stenosis.

The benefits of surgical correction of moderate internal carotid artery stenosis have been demonstrated only in symptomatic subjects. It is debatable whether patients with lacunar infarct ipsilateral to a moderate carotid stenosis may be considered symptomatic like those with large-artery stroke. The aim of the study was to seek markers capable of differentiating patients with lacunar or non-lacunar stroke ipsilateral to a moderate internal carotid artery stenosis. We enrolled 95 patients with a first stroke ipsilateral to a moderate (50-69 %) stenosis of the internal carotid artery and divided them into lacunar and non-lacunar stroke based on clinical presentation and neuroradiological findings; 34 subjects with asymptomatic moderate carotid stenosis and 31 normal individuals were also studied. Baseline characteristics; risk factors, cerebrovascular reactivity to hypercapnia evaluated by means of the breath-holding index (BHI), the presence and severity of carotid stenosis and intimamedia thickness (IMT) of the common carotid arteries were determined. There were 36 patients with lacunar and 59 with non-lacunar stroke. Degree of stenosis, and IMT and BHI ipsilateral to symptomatic stenosis were found to be significant independent predictors as each 10 % increase of stenosis carried a 4.3 higher probability of non-lacunar stroke (95 % CI: 1.91-9.51); each decimillimeter increment in IMT increased this probability by 1.45 (95 % CI: 1.10-1.92); and the risk odds ratio associated with each 0.1 increase in BHI was 1.88 (95 % CI: 1.33-2.66). A decrease in BHI of 0.1 thus carried a 90% greater probability of having a lacunar stroke. The results show that patients with moderate internal carotid artery stenosis and lacunar stroke can be differentiated from those with non-lacunar stroke on the basis of distinctive ultrasonographic findings. Further studies are needed to clarify whether our findings have pathogenetic implications and may be of help for the planning of different therapeutic strategies in patients with moderate internal carotid stenosis and lacunar or non-lacunar ipsilateral stroke.