Multimodal Neuroimaging Approach to Variability of Functional Connectivity in Disorders of Consciousness: A PET/MRI Pilot Study.

Behavioral assessments could not suffice to provide accurate diagnostic information in individuals with disorders of consciousness (DoC). Multimodal neuroimaging markers have been developed to support clinical assessments of these patients. Here we present findings obtained by hybrid fludeoxyglucose (FDG-)PET/MR imaging in three severely brain-injured patients, one in an unresponsive wakefulness syndrome (UWS), one in a minimally conscious state (MCS), and one patient emerged from MCS (EMCS). Repeated behavioral assessment by means of Coma Recovery Scale-Revised and neurophysiological evaluation were performed in the two weeks before and after neuroimaging acquisition, to ascertain that clinical diagnosis was stable. The three patients underwent one imaging session, during which two resting-state fMRI (rs-fMRI) blocks were run with a temporal gap of about 30 min. rs-fMRI data were analyzed with a graph theory approach applied to nine independent networks. We also analyzed the benefits of concatenating the two acquisitions for each patient or to select for each network the graph strength map with a higher ratio of fitness. Finally, as for clinical assessment, we considered the best functional connectivity pattern for each network and correlated graph strength maps to FDG uptake. Functional connectivity analysis showed several differences between the two rs-fMRI acquisitions, affecting in a different way each network and with a different variability for the three patients, as assessed by ratio of fitness. Moreover, combined PET/fMRI analysis demonstrated a higher functional/metabolic correlation for patients in EMCS and MCS compared to UWS. In conclusion, we observed for the first time, through a test-retest approach, a variability in the appearance and temporal/spatial patterns of resting-state networks in severely brain-injured patients, proposing a new method to select the most informative connectivity pattern.

Selegiline in Patients With Disorder of Consciousness: An Open Pilot Study.

This open study investigated the clinical effects of 10-week selegiline administration in six patients in vegetative state and in four patients in a minimally conscious state, at least 6 months after onset. Clinical outcome was assessed by Coma Recovery Scale-Revised once a week during selegiline administration and 1 month later. Three patients stopped treatment because of possible side effects. After treatment and at 1 month of follow-up, four patients showed improvements in clinical diagnosis, and three patients showed an increase in arousal level only. Selegiline might represent a relatively safe option to enhance arousal and promote recovery in brain-injured patients with disorders of consciousness.

Visual pursuit of one's own face in disorders of consciousness: a quantitative analysis.

BACKGROUND: Eye behaviour is important to distinguish minimally conscious state (MCS) from vegetative state (VS). OBJECTIVE: To search for conditions most suitable to characterize patients in MCS and in VS on quantitative assessment of visual tracking. DESIGN: This is a cross-sectional study. PARTICIPANTS: In total, 20 patients in VS, 13 in MCS plus and 11 in MCS minus participated in this study. SETTING: Neurorehabilitation Unit. METHODS: Evaluation of eye behaviour was performed by infrared system; stimuli were represented by a red circle, a picture of a patient's own face and a picture of an unfamiliar face, slowly moving on a personal computer (PC) monitor. Visual tracking on the horizontal and vertical axes was compared. MAIN OUTCOME MEASURES: The main outcome measures were proportion of on-target fixations and mean fixation duration. RESULTS: The proportion of on-target fixations differed as a function of the stimulus in patients in MCS plus but not in other groups. Own face and unfamiliar face elicited a similar proportion of on-target fixations. Tracking along the horizontal axis was more accurate than that along the vertical axis in patients in both MCS plus and MCS minus. Fixation duration did not differ among the three groups. CONCLUSIONS: Horizontal visual tracking of salient stimuli seems particularly suitable for eliciting on-target fixations. Quantitative assessment of visual tracking can complement clinical evaluation for reducing diagnostic uncertainty between patients in MCS or VS.

Do Medical Complications Impact Long-Term Outcomes in Prolonged Disorders of Consciousness?

OBJECTIVE: To investigate medical complications (MCs) occurring within 6 months postinjury in brain-injured patients with prolonged disorders of consciousness (DoC) and to evaluate impact of MC on mortality and long-term clinical outcomes. DESIGN: Prospective observational cohort study. SETTING: Rehabilitation unit for acquired DoC. PARTICIPANTS: Patients (N=194) with DoC (142 in vegetative state [VS], 52 in minimally conscious state; traumatic etiology 43, anoxic 69, vascular 82) consecutively admitted to a neurorehabilitation unit within 1-3 months postonset. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Mortality and improvements in clinical diagnosis and functional disability level (assessed by Coma Recovery Scale-Revised [CRS-R] and Disability Rating Scale) at 12, 24, and 36 months postonset. RESULTS: Within 6 months postinjury, 188 of 194 patients (>95%) developed at least 1 MC and 142 of them (73%) showed at least 1 severe MC. Respiratory and musculoskeletal-cutaneous MCs were the most frequent, followed by endocrino-metabolic abnormalities. Follow-up, complete in 189 of 194 patients, showed that male sex and endocrine-metabolic MCs were associated with higher risk of mortality at all timepoints. Old age, anoxic etiology, lower CRS-R total scores, and diagnosis of VS at study entry predicted no clinical and functional improvements at most timepoints; however, epilepsy predicted no improvement in diagnosis at 24 months postonset only. CONCLUSIONS: MCs are very frequent in patients with DoC within at least 6 months after brain injury, regardless of clinical diagnosis, etiology, and age. Endocrino-metabolic MCs are independent predictors of mortality at all timepoints; however,epilepsy predicted poor long-term outcome. Occurrence and severity of MCs in patients with DoC call for long-term appropriate levels of care after the postacute phase.

Family caregivers' opinions about interaction with the environment in consciousness disorders.

OBJECTIVES: To assess family caregivers' opinions about level of interaction with the environment in their relatives with disorders of consciousness (DOCs) and to explore psychological features of caregivers whose opinions diverge from clinicians' diagnosis. METHOD: Forty-five family caregivers of 38 DOC inpatients without communication abilities answered 2 questions assessing their opinion about level of interaction with the environment in their relatives. Self-report questionnaires were used to evaluate caregivers' depression, anxiety, psychophysiological disturbances, prolonged grief disorder, coping strategies, quality of perceived needs and social support. RESULTS: Fifteen caregivers (5 relatives of patients in vegetative state and 10 of patients in minimally conscious state) considered their relatives able to communicate, in contrast with clinical diagnosis. These caregivers had significantly higher depressive symptoms, and higher worries about possible death of their relatives with respect to the remaining caregivers. CONCLUSIONS: Caregivers of DOC patients detected some interaction with the environment in their relatives more often than care professionals. This is likely related to caregivers' beliefs and expectations, but is also based on observations closer and longer than those possible for physicians. These considerations are important to build a therapeutic alliance with caregivers and to involve them in the diagnostic process and rehabilitative program. (PsycINFO Database Record

Repeated transcranial direct current stimulation in prolonged disorders of consciousness: A double-blind cross-over study.

OBJECTIVE: To evaluate effects of 5 sessions of transcranial direct current stimulation (tDCS) over the left dorsolateral prefrontal cortex in patients with prolonged disorders of consciousness (DOC). METHODS: Seven patients in vegetative state (VS) and 6 in minimally conscious state (MCS), at ≥3months after brain injury, were randomized into two groups: group 1 received one week of active tDCS and 1week of sham stimulation, separated by 1 resting week; group 2 received active and sham stimulation in reverse order. We performed clinical and EEG evaluations before and after the first stimulation session, two hours after the last weekly stimulation, twice during the resting week, and during a 3-month follow-up. RESULTS: We observed small changes of patients' conditions after the first tDCS session and immediately after the 5 active stimulations. Substantial clinical and EEG changes were observed in 5/13 patients (3 in MCS and 2 in VS) starting after entire (active and sham) stimulation protocol and further progressing during the next months. No baseline features distinguished patients who improved from patients who did not improve. CONCLUSIONS: Repeated tDCS did not exert remarkable short-term clinical and EEG effects in patients with prolonged DOC. Further studies should ascertain whether tDCS might promote clinical recovery in the long-term period.

Long-term outcome of patients with disorders of consciousness with and without epileptiform activity and seizures: a prospective single centre cohort study.

Brain-injured patients can experience epileptic seizures beyond 1 week from injury (unprovoked remote symptomatic epileptic seizures). In our longitudinal observational study, we analysed occurrence of unprovoked remote epileptic seizures and interictal epileptiform activity in 130 traumatic, vascular or anoxic inpatients with disorders of consciousness (DOC), with a clinical diagnosis of vegetative state (n = 97) or minimally conscious state (n = 33). We also investigated impact of epileptic seizures and epileptiform activity on clinical outcome (30 months post-onset). Epileptic seizures occurred in 35/130 patients (26.9 %), epileptiform activity in 61/130 (46.9 %) patients, without significant differences related to clinical diagnosis or aetiology. Among patients with epileptiform activity, only 26/61 (42.6 %) developed clinically evident seizures. Mortality at 30 months was not significantly influenced by the presence of seizures or epileptiform activity. The proportion of patients who recovered at long-term follow-up was higher in patients without than in patients with epileptic seizures, but was similar in patients with or without epileptiform activity. The presence of epileptic seizures but not of epileptiform activity, significantly affected the level of responsiveness at final outcome. In conclusion, seizures were detected in about one third of the whole sample, and in about a half of patients with epileptiform activity, regardless of clinical diagnosis or aetiology. Although epileptic seizures or epileptiform activity did not significantly affect mortality rate, we demonstrated that epileptic seizures could hamper recovery of consciousness. Epileptic seizures thus qualify as one of the factors largely undetermined at the moment which can influence prognosis in DOC patients.

Standard EEG in diagnostic process of prolonged disorders of consciousness.

OBJECTIVE: This cross-sectional study assessed the ability of standard EEG in distinguishing vegetative state (VS) from minimally conscious state plus (MCS+) or MCS minus (MCS-), and to correlate EEG features with aetiology and level of responsiveness assessed by Coma Recovery Scale-Revised (CRS-R). METHODS: We analyzed background EEG activity and EEG reactivity to eye opening and closing and to tactile, acoustic, nociceptive stimuli and Intermittent Photic Stimulation (IPS) in 73 inpatients (VS=37, MCS-=11, MCS+=25), with traumatic (n=21), vascular (n=25) or anoxic (n=27) aetiology. RESULTS: All patients, but one, showed abnormal background activity. EEG abnormalities were more severe in VS than in MCS+ or MCS-, and in anoxic than other aetiologies. MCS+ patients with normal or Mildly Abnormal background activity showed higher scores on CRS-R than patients with moderate to severe EEG abnormalities. Reactivity to IPS, and acoustic stimuli was significantly more frequent in MCS+ and MCS- than in VS patients. CONCLUSIONS: EEG features differ between VS and MCS- or MCS+ patients and can provide evidence of relative sparing of thalamocortical connections in MCS+ patients. In anoxic patients EEG organization is more severely impaired and provides less discriminative diagnostic information. SIGNIFICANCE: Conventional EEG can help clinicians to disentangle VS from MCS patients.

Does pain relief influence recovery of consciousness? A case report of a patient treated with ziconotide.

For people with cervical spinal cord injury (SCI), access to computers can be difficult, thus several devices have been developed to facilitate their Disorders of consciousness (DOC) are difficult to classify. The degree of consciousness varies from coma to vegetative state or unresponsive wakefulness syndrome (UWS) and minimally conscious state. Correct diagnosis has important ethical and legal implications, and pain may be cause of misdiagnosis. We describe here a patient with traumatic brain injury, classified as UWS. His clinical picture was dominated by spasticity, and pain. He underwent intrathecal treatment of spasticity with baclofen. Improvement was not that expected. However, there was a dramatic improvement when ziconotide was added to relieve pain; the patient began to eat by mouth, talk, and his tracheal tube could be removed and he is currently classified as having severe disability. The suspension of ziconotide caused a clear re-worsening of clinical condition, reverted by his reintroduction. Pain is an important factor in patients with DOC. Anecdotal reports of improved consciousness with intrathecal baclofen therapy may be due to pain relief. Reduction of pain in DOC is important and drugs should not interfere with cognition, and must be effective and manageable. Ziconotide may be one of the possible candidate due to its synergistic antispastic action in combination with baclofen when an intratecal pump has been implanted.

A study of the psychological distress in family caregivers of patients with prolonged disorders of consciousness during in-hospital rehabilitation.

OBJECTIVES: To study psychological distress in a sample of caregivers of patients affected by prolonged disorders of consciousness during hospital stay in the Neurorehabilitation Unit. MATERIALS AND METHODS: Twenty-four caregivers of 22 patients affected by prolonged disorders of consciousness admitted to postacute rehabilitation center, completed self-reported questionnaires for assessment of depressive symptoms, state and trait anxiety, psychophysiological disturbances, prolonged grief disorder, psychological coping strategies, quality of perceived needs, perceived social support, and caregiver burden; at admission, and after four and eight months. RESULTS: At admission depressive symptoms were found in 20/24 caregivers, high levels of anxiety in 16, and relevant psychophysiological disturbances in 10 participants; eight caregivers (32%) met criteria for prolonged grief disorder. The scores on questionnaires did not differ as a function of relatives' diagnosis (vegetative state vs. minimally conscious state). The longitudinal study (n = 18) showed a progressive and statistically significant increase of "emotional burden" during the hospital stay, whereas the remaining variables did not change significantly. CONCLUSIONS: Data confirmed the presence of severe psychological problems in caregivers of patients with prolonged disorders of consciousness. The levels of psychological distress tend to be constant over time, while the emotional burden increases.

Clinical and neuropsychological long-term outcomes after late recovery of responsiveness: a case series.

OBJECTIVE: To report clinical conditions and neuropsychological functioning of patients with late recovery of responsiveness at least 5 years after injury. DESIGN: Patient series. SETTING: Patients discharged from an inpatient rehabilitation unit. PARTICIPANTS: Patients (N=13) who recovered from a vegetative state 1 year after severe traumatic brain injury or 6 months after nontraumatic brain injury. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Coma Recovery Scale-Revised, Disability Rating Scale, and FIM. For patients who recovered full consciousness, neuropsychological tests specifically adapted for patients with very severe disabilities were used. RESULTS: After regaining responsiveness, 2 patients died because of severe clinical complications. Among the remaining 11 patients, 5 were still in a minimally conscious state at their last assessment, but 4 of them had recovered some complex behavioral responses to the environment (eg, they could follow simple commands, albeit inconsistently). Six patients had emerged from a minimally conscious state at the last evaluation. Severe functional disability was present in both patients who were conscious and patients who were minimally conscious. No patient was autonomous in common daily life activities or in transfers. All patients who were conscious showed variable cognitive impairments, and some of them also developed behavioral and psychological symptoms. However, such disturbances did not impede the patients' interaction with relatives and caregivers. CONCLUSIONS: This study provides systematic data about the course of the disease in a cohort of patients that was previously considered as exceptional. Patients with late recovery show a variable degree of functional recovery, although they experience marked residual motor and cognitive disabilities. The present findings contribute to enhance the understanding of the course of the disease in patients with late recovery and might help clinicians optimize the levels of care and provide the patients' families with correct information.

Predictors of recovery of responsiveness in prolonged anoxic vegetative state.

OBJECTIVE: The number of patients in prolonged postanoxic vegetative state (VS) is increasing. However, little information is available about prognostic markers of long-term outcome in patients who remain in VS more than 1 month postonset. The present 2-year prospective clinical study aimed to identify prognostic markers, recorded in the chronic phase, that might be useful for predicting recovery of responsiveness in a cohort of postanoxic VS patients. METHODS: We enrolled 43 inpatients with prolonged anoxic VS (23 female; age range 12-83 years). We collected data about medical history, clinical findings, and neurophysiological assessments at study entry (1-6 months postonset), and assessed their relationships with outcome at 24 months postonset; for defining outcome, patients were classified as responsive or unresponsive on the basis of clinical criteria and on Coma Recovery Scale-Revised (CRS-R). RESULTS: Nine patients had recovered responsiveness (but 2 of them died after awakening), whereas 12 patients remained in VS and 22 had died in VS. Functional abilities were severely affected in all responsive survivors. Responsive patients were significantly younger and showed higher CRS-R total score and lower Disability Rating Scale score at study entry than patients who did not recover. All responsive survivors had spared pupillary light reflex and nociceptive response, and paroxysmal sympathetic hyperactivity. Logistic regression analysis showed that the presence of median nerve somatosensory evoked potentials and CRS-R total score ≥ 6 were significant predictors of recovery of responsiveness. CONCLUSIONS: Clinical features and evoked potentials are useful predictors of long-term recovery of responsiveness in patients with prolonged postanoxic VS.