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Intracranial hematomas (IHs) occur commonly after severe traumatic brain injury, but their effects on outcomes in patients with prolonged disorders of consciousness (DoC) following coma (i.e., unresponsive wakefulness syndrome and minimally conscious state) are unknown.In this multicenter longitudinal study, we compared clinical outcomes and serum neurofilament light chain (NFL) levels of 52 patients with traumatic DoC with (n = 35) and without (n = 17) IH in the acute phase. Patients were evaluated with the Coma Recovery Scale-Revised (CRS-R) at enrollment (1-3 months post-injury) and with the CRS-R, extended Glasgow Outcome Scale (GOSE), and Functional Independence Measure (FIM) at 6 months post-injury. At the same timepoints, serum NFL levels were compared between patients with and without IHs and with those of 52 sex- and age-matched healthy controls.Patients with and without IH did not differ in terms of DoC or CRS-R scores at admission, or clinical outcomes (death, unresponsive wakefulness syndrome, minimally conscious state, or emergence from minimally conscious state) or CRS-R, GOSE, or FIM scores 6 months post-injury. NFL levels were significantly higher in patients than in controls at admission and 6 months post-injury (both p 0.0001), but they did not differ between patients with and without IH.This study showed that IHs do not affect clinical outcomes or markers of axonal degeneration in patients with traumatic DoC.

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) (

(1) Background: Sustained axonal degeneration may play a critical role in prolonged disorder of consciousness (DOCs) pathophysiology. We evaluated levels of neurofilament light chain (NFL), an axonal injury marker, in patients with unresponsive wakefulness syndrome (UWS) and in the minimally conscious state (MCS) after traumatic brain injury (TBI) and hypoxic-ischemic brain injury (HIBI). (2) Methods: This prospective multicenter blinded study involved 70 patients with prolonged DOC and 70 sex-/age-matched healthy controls. Serum NFL levels were evaluated at 1–3 and 6 months post-injury and compared with those of controls. NFL levels were compared by DOC severity (UWS vs. MCS) and etiology (TBI vs. HIBI). (3) Results: Patients’ serum NFL levels were significantly higher than those of controls at 1–3 and 6 months post-injury (medians, 1729 and 426 vs. 90 pg/mL, both p &lt, 0.0001). NFL levels were higher in patients with UWS than in those in MCS at 1–3 months post-injury (p = 0.008) and in patients with HIBI than in those with TBI at 6 months post-injury (p = 0.037). (4) Conclusions: Patients with prolonged DOC present sustained axonal degeneration that is affected differently over time by brain injury severity and etiology.

The sinking skin flap syndrome (SSFS), or syndrome of the trephined, is a pathological condition arising from the presence of large bone defects of the skull. Originally described by Grant and Norcross in patients with a skin flap depression following craniectomy [1], SSFS has a multifaceted clinical presentation, including chronic fatigue, headache, dizziness, impaired vigilance, motor deficits, cognitive deficits, epileptic seizures, and visual symptoms [2]. SSFS pathophysiology is related to the atmospheric pressure exerted on the brain through the craniectomy, inducing brain compression, changes in the cerebrospinal fluid (CSF) dynamics, impaired venous return, and decrease in the regional blood flow, alone or in combination [2]. In this report we describe a case of SSFS complicated by paradoxical uncal herniation due to diuretic therapy.

INTRODUCTION/AIMS Neurophysiological patterns in patients with foodborne botulism are rarely described after the acute phase. We report data from a large Italian outbreak of botulism, with patients evaluated at different timepoints after poisoning. METHODS Eighteen male patients (mean age 47 ± 8.4 y) underwent 22 clinical and neurophysiological evaluations (4 patients were re-evaluated). The resting compound muscle action potential (CMAP) amplitude, postexercise CMAP amplitude, CMAP change after high-frequency (50 Hz) repetitive nerve stimulation (HFRNS), and motor unit action potentials (MUAPs) were assessed in the acute (4-8 days after poisoning; 5 patients), early post-acute (32-39 days after poisoning; 5 patients), and late post-acute (66-80 days after poisoning; 12 patients) phases. RESULTS In the acute, early post-acute, and late post-acute phases, respectively, reduced CMAP amplitudes were found in 100%, 20%, and 17% of patients; abnormal postexercise CMAP facilitation was observed in 100%, 40%, and 0% of patients; and pathological incremental responses to HFRNS were found in 80%, 50%, and 8% of patients. Baseline CMAP amplitudes, postexercise CMAP facilitation, and CMAP increases in response to HFRNS differed significantly between the acute and post-acute phases. Small MUAPs were found in 100% of patients in the acute and early post-acute phases and in 50% of patients in the late post-acute phase. DISCUSSION The neurophysiological findings of foodborne botulism vary considerably according to the evaluation time point. In the post-acute phase, different neurophysiological techniques must be applied to support a diagnosis of botulism.

Objective To prospectively investigate relationships of cortical somatosensory evoked potential (SEP) amplitudes with consciousness recovery and disability in the year following brain injury in patients with vegetative state/unresponsive wakefulness syndrome (VS/UWS). Methods SEPs of 42 patients with VS/UWS were recorded 51.7 ± 23.3 days post-injury. N20–P25 amplitudes were compared between patients with and without consciousness recovery at 6 months and 1 year post-injury. Results SEPs were present in 21 patients and bilaterally absent in 21 patients. N20–P25 amplitudes were significantly higher in patients who recovered consciousness than in those who died or did not recover consciousness at 6 months (median, 4.6 vs. 1.9 μV; P = 0.004) and 1 year (median, 4.6 vs. 2.1 μV; P = 0.02) after injury. The lowest N20–P25 amplitude in a patient who recovered consciousness was 2.15 μV. N20–P25 amplitudes correlated significantly with Coma Recovery Scale-Revised and Disability Rating Scale scores at 6 months and 1 year post-injury (both P Conclusions In patients with VS/UWS, SEP amplitudes are related to consciousness recovery and disability at 6 months and 1 year post-injury. Significance The evaluation of SEP amplitudes can help to refine prognoses for patients with VS/UWS.

Highlights • Muscle weakness after COVID-19 can be caused by critical illness myopathy. • Critical illness myopathy should be suspected in patients with long ICU stay. • Health systems must plan access to rehabilitative facilities after COVID-19., We describe a patient who developed diffuse and symmetrical muscle weakness after a long stay in the intensive care unit (ICU) due to coronavirus disease 2019 (COVID-19). The patient underwent a neurophysiological protocol, including nerve conduction studies, concentric needle electromyography (EMG) of the proximal and distal muscles, and direct muscle stimulation (DMS). Nerve conduction studies showed normal sensory conduction and low-amplitude compound muscle action potentials (CMAPs). EMG revealed signs of myopathy, which were more pronounced in the lower limbs. The post-DMS CMAP was absent in the quadriceps and of reduced amplitude in the tibialis anterior muscle. Based on these clinical and neurophysiological findings, a diagnosis of critical illness myopathy was made according to the current diagnostic criteria. Given the large number of patients with COVID-19 who require long ICU stays, many of these patients are very likely to develop ICU-acquired weakness, as did the patient described here. Health systems must plan to provide adequate access to rehabilitative facilities for both pulmonary and motor rehabilitative treatment after COVID-19.

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.

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.

The mechanisms involved in secondary brain injury after the acute phase of severe traumatic brain injury (TBI) are largely unknown. Ongoing axonal degeneration, consequent to the initial trauma, may lead to secondary brain injury. To test this hypothesis, we evaluated the cerebrospinal fluid (CSF) level of neurofilament light chain (NF-L), a proposed marker of axonal degeneration, in 10 patients who developed a severe disorder of consciousness after a TBI, including 7 in a minimally conscious state and 3 with unresponsive wakefulness syndrome (time since brain injury, 309 ± 169 days). CSF NF-L level was measured with a commercially available NF-L enzyme-linked immunosorbent assay. CSF NF-L level was very high in all 10 patients, ranging from 2.4- to 60.5-fold the upper normal limit (median value, 4458 pg/mL; range, 695-23,000). Moreover, NF-L level was significantly higher after a severe TBI than in a reference group of 9 patients with probable Alzheimer's disease, a population with elevated levels of CSF NF-L attributed to neuronal degeneration (median value, 1173 pg/mL; range, 670-3643; p 0.01). CSF NF-L level was correlated with time post-TBI (p = 0.04). These results demonstrate prolonged secondary brain injury, suggesting that patients exhibit ongoing axonal degeneration up to 19 months after a severe TBI.

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.Prospective cohort study.Unit for severe acquired brain injuries.Consecutive patients with UWS (N=28).Not applicable.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.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).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.

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.

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.

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-β (Aβ) metabolism and abnormal tau phosphorylation are reasonable candidates.Objective: To investigate Aβ and tau dynamics in the chronic phase of TBI.Methods: We evaluated Aβ1-42, 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 Aβ1-42 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 (...

Traumatic brain injury (TBI) is a major risk factor for Alzheimer's disease. Recent studies suggest that amyloid-beta (Aβ) deposit can be detected several years after TBI. However, it is unknown whether post-TBI Aβ deposits arise from short-term changes in Aβ metabolism or reflect a long-term sequela. To answer this question, we evaluated the cerebrospinal levels of Aβ 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 Aβ1-42 peptide was measured using a commercially available Aβ enzyme-linked immunoassay kit. Reduced Aβ1-42 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 Aβ metabolism after a TBI and they suggest a potential mechanism of long-term neurotoxicity.

Discrimination between patients in vegetative (VS) and minimally conscious state (MCS) is currently based upon the behavioral gold standard. Behavioral assessment remains equivocal and difficult to interpret as evidence for the presence or absence of consciousness, resulting in possible clinical misdiagnosis in such patients. Application of an operational architectonics (OA) strategy to electroencephalogram (EEG) analysis reveals that absence of consciousness in patients in VS is paralleled by significant impairment in overall EEG operational architecture compared to patients in MCS: neuronal assemblies become smaller, their life span shortened, and they became highly unstable and functionally disconnected (desynchronized). However, in a previous study, patients with different brain damage etiologies were intermixed. Therefore, the goal of the present study was to investigate whether the application of OA methodology to EEG could reliably dissociate patients in VS and MCS independent of brain damage etiology. We conclude that the observed EEG OA structure impairment in patients in VS and partial preservation in patients in MCS is a marker of consciousness/unconsciousness rather than physiological damage. Results of this study may have neuroscientific, clinical, and ethical implications.

Background. Patients in a vegetative state pose problems in diagnosis, prognosis, and treatment. Currently, no prognostic markers predict the chance of recovery, which has serious consequences, especially in end-of-life decision making. Objective. We aimed to assess an objective measurement of prognosis using advanced electroencephalography (EEG). Methods. EEG data (19 channels) were collected in 14 patients who were diagnosed to be persistently vegetative based on repeated clinical evaluations at 3 months following brain damage. EEG structure parameters (amplitude, duration, and variability within quasi-stationary segments, as well as the spatial synchrony between such segments and the strength of this synchrony) were used to predict recovery of consciousness 3 months later. Results. The number and strength of cortical functional connections between EEG segments were higher in patients who recovered consciousness ( P < .05 to P < .001) compared with those who did not recover. Linear regression analysis confirms that EEG structure parameters are capable of predicting ( P = .0025) recovery of consciousness 6 months postinjury, whereas the same analysis failed to significantly predict patient outcome based on aspects of their clinical history alone ( P = .629) or conventional EEG spectrum power ( P = .473). Conclusions. The result of this preliminary study demonstrates that structural strategy of EEG analysis is better suited for providing prognosis of consciousness recovery than existing methods of clinical assessment and of conventional EEG. Our results may be a starting point for developing reliable prognosticators in patients who are in a vegetative state, with the potential to improve their day-to-day management, quality of life, and access to early interventions.

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.

The default mode network (DMN) has been consistently activated across a wide variety of self-related tasks, leading to a proposal of the DMN’s role in self-related processing. Indeed, there is limited fMRI evidence that the functional connectivity within the DMN may underlie a phenomenon referred to as self-awareness. At the same time, none of the known studies have explicitly investigated neuronal functional interactions among brain areas that comprise the DMN as a function of self-consciousness loss. To fill this gap, EEG operational synchrony analysis [1, 2] was performed in patients with severe brain injuries in vegetative and minimally conscious states to study the strength of DMN operational synchrony as a function of self-consciousness expression. We demonstrated that the strength of DMN EEG operational synchrony was smallest or even absent in patients in vegetative state, intermediate in patients in minimally conscious state and highest in healthy fully self-conscious subjects. At the same time the process of ecoupling of operations performed by neuronal assemblies that comprise the DMN was highest in patients in vegetative state, intermediate in patients in minimally conscious state and minimal in healthy fully self-conscious subjects. The DMN’s frontal EEG operational module had the strongest decrease in operational synchrony strength as a function of selfconsciousness loss, when compared with the DMN’s posterior modules. Based on these results it is suggested that the strength of DMN functional connectivity could mediate the strength of self-consciousness expression. The observed alterations similarly occurred across EEG alpha, beta1 and beta2 frequency oscillations. Presented results suggest that the EEG operational synchrony within DMN may provide an objective and accurate measure for the assessment of signs of self-(un)consciousness in these challenging patient populations. This method therefore, may complement the current diagnostic procedures for patients with severe brain injuries and, hence, the planning of a rational rehabilitation intervention.

The value of resting electroencephalogram (EEG) in revealing neural constitutes of consciousness (NCC) was examined. We quantified the dynamic repertoire, duration and oscillatory type of EEG microstates in eyes-closed rest in relation to the degree of expression of clinical self-consciousness. For NCC a model was suggested that contrasted normal, severely disturbed state of consciousness and state without consciousness. Patients with disorders of consciousness were used. Results suggested that the repertoire, duration and oscillatory type of EEG microstates in resting condition quantitatively related to the level of consciousness expression in brain-damaged patients and healthy-conscious subjects. Specifically, results demonstrated that (a) decreased number of EEG microstate types was associated with altered states of consciousness, (b) unawareness was associated with the lack of diversity in EEG alpha-rhythmic microstates, and (c) the probability for the occurrence and duration of delta-, theta- and slow-alpha-rhythmic microstates were associated with unawareness, whereas the probability for the occurrence and duration of fast-alpha-rhythmic microstates were associated with consciousness. In conclusion, resting EEG has a potential value in revealing NCC. This work may have implications for clinical care and medical-legal decisions in patients with disorders of consciousness.

The aim of this study was to evaluate the presence of neuromuscular involvement in patients in vegetative and minimally conscious states (VS, MCS) following acute brain injury. Twenty-two patients (11 in VS, 11 in MCS) admitted to a rehabilitation department underwent nerve conduction, electromyography (EMG) for spontaneous activity and direct muscle stimulation (DMS). Twenty (90.9%) showed abnormal nerve conduction studies, 19 (86.4%) had spontaneous EMG activity, and 7 (31.8%) had abnormal DMS. The time spent in the intensive care unit correlated significantly with the amplitude of the compound muscle action potential of the ulnar nerve and with the amplitude of the sensory nerve action potential of the sural nerve (p < 0.05). No significant differences were found between patients in VS and MCS. Neurophysiological data indicative of neuromuscular involvement are common in patients in VS and MCS. This study underlines the need to implement strategies to prevent and to treat neuromuscular complications in patients in VS and MCS.

Traumatic brain injury (TBI) is a major risk factor for Alzheimer disease (AD). Although the mechanisms that lead to AD after a TBI are largely unknown, changes in amyloid- β (A β ) metabolism and abnormal tau phosphorylation are probably involved. In this study, we evaluated A β 1 - 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; range 92–578 days). Reduced A β 1 - 42 levels (cohort median value 258 pg/ml, range 90–833.6 pg/ml) were observed in 14/15 patients (93.3%) with severe post-TBI disorders of consciousness. Normal t-tau levels (median 95.2 pg/ml, range 52–256.9 pg/ml) were found in all patients. Normal p-tau levels (median 22.2 pg/ml, range 14–72 pg/ml) were observed in 14/15 patients, while 1 patient had a p-tau level slightly increased. In conclusion, the present findings show that reduced CSF A β levels are not paralleled by significant changes in t-tau and p-tau levels; these results suggest that treatments aimed to prevent chronic neurodegeneration and AD risk after a severe TBI may be better targeted on A β than tau.

To evaluate kinematic features in cervical dystonia (CD) patients by means of a motion analysis system (Fastrack-Polhemus, Colchester VT, USA). Small study sample. Ambulatory care. 15 CD patients and 10 healthy subjects. Not applicable. Posture at rest and voluntary movements in both groups. Posture at rest in CD patients was impaired in all planes; only 20% of the patients exhibited complex dystonic patterns at clinical evaluation, whereas more than 90% of them had complex ones at kinematic evaluation. The analysis of voluntary motion revealed a reduced range of voluntary excursion and increased execution time; the impairment was higher when the patients moved their heads towards the anti-dystonic side. Fastrack system is a sensitive tool in kinematic evaluation of CD, as it provides useful quantitative information on rest position and on motion in CD patients and may consequently improve the management of this disease.

Seizures affect about a quarter of patients with disorders of consciousness (DOC) after a coma.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.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.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%, p0.001) 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.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.

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.

We explored the action of chronic valproic acid (VPA) on the human epileptic cortex by means of transcranial magnetic stimulation (TMS). TMS is an emerging biomarker for neurotropic drugs. We had 15 drug-naive patients with different epileptic syndromes. Interictally, we measured several TMS indexes of cortical excitability before commencing VPA and 3 months later. At that time, all patients were clinical responders to the drug, whose plasma levels were in the "therapeutic range". We then compared the two conditions, while 18 healthy subjects, of whom 12 were retested at a similar delay, acted as controls. In the pooled patients, the baseline resting motor threshold to TMS was similar to that of controls, but it increased significantly (P < 0.05) after VPA. Intracortical facilitation, another index of cortical excitability, was abnormally enhanced at baseline but decreased significantly after VPA (P < 0.05). On splitting patients according to their diagnosis, the threshold increase was significant (P < 0.05) among partial, but not generalized epilepsies. The reverse was true for changes in intracortical facilitation. TMS phenomena had no linear relation to VPA serum levels. Based on the known pharmacology of TMS effects, VPA reduced the intrinsic membrane excitability of motor cortical neurons, possibly through changes in Na+ channel activity. Then, VPA corrected a transmitter-mediated interneuronal hyper-excitability of the primary motor cortex. The former effect was best seen in partial, and the latter in generalized epilepsy patients.

The ability to recognize one’s own face, or “self-face”, is a hallmark of self-awareness. In healthy subjects, the sympathetic skin response (SSR) evoked by self-face recognition has a greater area than responses evoked by other visual stimuli. We evaluated the SSRs 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 SSR was smaller in patients with unresponsive wakefulness syndrome (UWS), intermediate in patients in a minimally conscious state (MCS), and greater in healthy subjects. In patients with UWS, no differences were found between the SSR area evoked by self-face images and those evoked by other conditions. In patients in an MCS, the area of the SSR evoked by self-face presentation was greater than those evoked by other conditions, but 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. These results probably reflect a varying level of self-awareness and suggest some diagnostic implications in patients with severe disorders of consciousness.

Adequate assessment of (un)consciousness is not only of theoretical interest but also has a practical and ethical importance, especially when it comes to disorders of consciousness (DOC). Accurately determining the presence or absence of consciousness in patients with DOC allows informed decisions to be made about long-term care support, referral for rehabilitation, pain management and withdrawal of life support. In spite of significant progress in neuroimaging and the introduction of clear-cut clinical diagnostic criteria, determining the (un)consciousness still presents an important clinical problem: errors are common and have been shown to be as high as 37–43% (Tresch et al., 1991; Childs et al., 1993; Andrews et al., 1996; Schnakers et al., 2006). Assessment errors arise because the evaluation of patients with DOC is based mostly on clinical observation of subjectively interpreted behavioral responses, while conscious experience often occurs without any behavioral signs. Additionally behavioral responses of such patients are usually limited by their cognitive dysfunctions and/or by their frequent motor impairment. Therefore, determining if a non-communicative or minimally communicative patient is phenomenally conscious poses a major clinical and ethical challenge. For this reason, there is a need for paraclinical diagnostic markers for the presence or absence of consciousness. We believe that a theoretical account of what conscious experience is and how it emerges within the brain will advance the search for appropriate neuromarkers of the presence or absence of consciousness in non-communicative brain-damaged patients. In our view, several important considerations need to be kept in mind

Recent findings suggest that EEG amplitude, frequency, and reactivity are related to clinical outcomes in patients with severe disorders of consciousness. Moreover, their prognostic value increases if they are combined with a new Amplitude–Frequency–Reactivity (AFR) score (Bagnato et al., Clin Neurophysiol, 2015). This study evaluated if changes in standard EEG descriptors parallel changes in the level of consciousness in patients in a vegetative state (VS). EEGs were scored in 25 patients in a VS at admission to a rehabilitation department and six months later. Amplitude was scored as 1 if reduced or 2 if normal. Dominant frequency was scored as 1, 2, or 3 for delta, theta, or alpha, respectively. Reactivity to stimuli was scored as 1 if absent or 2 if present. Therefore, the AFR score ranged from 3 to 7. Changes in these scores after six months were compared between patients who improved ( n =14) or not ( n =11) their level of consciousness. Patients who improved their level of consciousness showed significant changes in EEG frequency ( p =0.02) and reactivity ( p =0.001). Moreover, 85.7% of them showed an increase of the AFR score ( p

back-ground EEG refers mainly to frequency (and spatial distribu-tion thereof); amplitude and reactivity were not assessed. In arecent study involving 106 patients, we found that each of theclassical descriptors of standard EEG recordings (ie, amplitude,frequency, and reactivity) was related to the level of conscious-ness or 3-month outcomes.

The value of spontaneous electroencephalography (EEG) oscillations in distinguishing patients in vegetative state (VS) and minimally conscious states (MCS) was studied.We quantified dynamic repertoire of EEG oscillations in resting condition with closed eyes in patients in VS and MCS. The exact composition of EEG oscillations was assessed by the probability-classification analysis of short-term EEG spectral patterns.The probability of delta, theta, and slow-alpha oscillations occurrence was smaller for patients in MCS than for VS. Additionally, only patients in MCS demonstrated fast-alpha oscillation occurrence. Depending on the type and composition of EEG oscillations, the probability of their occurrence was either etiology dependent or independent. The probability of EEG oscillations occurrence differentiated brain injuries with different etiologies.Spontaneous EEG oscillations have a potential value in distinguishing patients in VS and MCS.This work may have implications for clinical care, rehabilitative programs, and medical-legal decisions in patients with impaired consciousness states following coma due to acute brain injuries.The probability of delta, theta, and slow-alpha oscillations occurrence was smaller and the probability of fast-alpha oscillations occurrence was higher for patients in MCS than for patients in VS. The probability of EEG oscillations occurrence differentiated brain injuries with different etiologies. Spontaneous EEG has a potential value in distinguishing patients in VS and MCS.

Unresponsive wakefulness syndrome (UWS, previously known as vegetative state) occurs after patients survive a severe brain injury. Patients suffering from UWS have lost awareness of themselves and of the external environment and do not retain any trace of their subjective experience. Current data demonstrate that neuronal functions subtending consciousness are not completely reset in UWS; however, they are reduced below the threshold required to experience consciousness. The critical factor that determines whether patients will recover consciousness is the distance of their neuronal functions from this threshold level. Recovery of consciousness occurs through functional and/or structural changes in the brain, i.e., through neuronal plasticity. Although some of these changes may occur spontaneously, a growing body of evidence indicates that rehabilitative interventions can improve functional outcome by promoting adaptive functional and structural plasticity in the brain, especially if a comprehensive neurophysiological theory of consciousness is followed. In this review we will focus on the pathophysiological mechanisms involved in UWS and on the plastic changes operating on the recovery of consciousness.

Since most antiepileptic drugs (AEDs) have cognitive effects, the aim of this study was to evaluate the influence of AED therapy on the recovery of consciousness in 103 consecutive patients in a vegetative or minimally conscious state (VS, MCS). The levels of cognitive functioning (LCF) score was retrospectively compared after a three-month period of rehabilitation between patients who were medicated (n=54) and patients who were not medicated (n=49) with AEDs. Mean LCF scores in AED-medicated and nonmedicated patients were 2.2±0.7 and 2.3±0.8 at admission and 3.8±2.2 and 3.7±2.1 after three months, respectively (p values>0.05). These results did not change when we compared patients with the same etiology separately, with the same disorder of consciousness only, or patients treated with only one or more than one AED. In conclusion, AEDs did not affect the recovery of consciousness in a large cohort of patients in a VS or MCS following an acute brain injury.

Objective: The value of spontaneous electroencephalography (EEG) oscillations in distinguishing patients in vegetative state (VS) and minimally conscious states (MCS) was studied. Methods: We quantified dynamic repertoire of EEG oscillations in resting condition with closed eyes in patients in VS and MCS. The exact composition of EEG oscillations was assessed by the probability-classification analysis of short-term EEG spectral patterns. Results: The probability of delta, theta, and slow-alpha oscillations occurrence was smaller for patients in MCS than for VS. Additionally, only patients in MCS demonstrated fast-alpha oscillation occurrence. Depending on the type and composition of EEG oscillations, the probability of their occurrence was either etiology dependent or independent. The probability of EEG oscillations occurrence differentiated brain injuries with different etiologies. Conclusions: Spontaneous EEG oscillations have a potential value in distinguishing patients in VS and MCS. Significance: This work may have implications for clinical care, rehabilitative programs, and medical–legal decisions in patients with impaired consciousness states following coma due to acute brain injuries. Highlights: • The probability of delta, theta, and slow-alpha oscillations occurrence was smaller and the probability of fast-alpha oscillations occurrence was higher for patients in MCS than for patients in VS. • The probability of EEG oscillations occurrence differentiated brain injuries with different etiologies. • Spontaneous EEG has a potential value in distinguishing patients in VS and MCS.

Although epileptiform abnormalities are a common electroencephalographic finding after a brain injury, not much is known about their prevalence and prognostic value in patients with severe disorders of consciousness. In this study, we evaluated the occurrence of epileptiform abnormalities in the electroencephalograms recorded at admission in 106 consecutive patients with unresponsive wakefulness syndrome (UWS, 59 patients), or in a minimally conscious state (MCS, 47 patients). Using the Coma Recovery Scale Revised (CRS-R), we compared the three-month outcome of patients with and without epileptiform abnormalities. Epileptiform abnormalities were found in 34 patients (32.1%), with a similar occurrence in patients with UWS (33.9%) or in a MCS (29.8%). The CRS-R score at admission was 7.5 ± 4.6 in patients with epileptiform abnormalities, and 7.4 ± 4.3 in patients without epileptiform abnormalities. After three months, the CRS-R score was 13.6 ± 8 in patients with epileptiform abnormalities, and 15.1 ± 7.7 3 in patients without epileptiform abnormalities. ANOVA showed no significant differences between groups in the three-months changes of the CRS-R score ( F 1,104 = 1.59; p = 0.2). In conclusion, epileptiform abnormalities are common in patients with UWS or MCS after a severe brain injury; yet, their occurrence does not seem to correlate with short term outcome.

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 BDNFMet)—impairs cognitive function in healthy subjects. The aim of this study was to determine whether the BDNFMet 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 BDNFMet 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 BDNFMet polymorphism. The BDNFMet 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 BDNFMet 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.