Peripheral blood BDNF and soluble CAM proteins as possible markers of prolonged disorders of consciousness: a pilot study.

Although clinical examination still represents the gold standard for the differential diagnosis of prolonged disorders of consciousness (pDoC), the introduction of innovative markers is essential for diagnosis and prognosis, due to the problem of covert cognition. We evaluated the brain-derived neurotrophic factor protein (BDNF) and the soluble cell adhesion molecules proteins (CAMs) in a cohort of prolonged disorders of consciousness patients to identify a possible application in the clinical context. Furthermore, peripheral blood determinations were correlated with imaging parameters such as white matter hyperintensities (WMH), cranial standardized uptake value (cSUV), electroencephalography (EEG) data and clinical setting. Our results, although preliminary, identify BDNF as a possible blood marker for the diagnosis of pDoC (p value 0.001), the soluble CAMs proteins CD44, Vcam-1, E-selectin (p value < 0.01) and Icam-3 (p value < 0.05) showed a higher peripheral blood value in pDoC compared with control. Finally, soluble Ncam protein could find useful applications in the clinical evolution of the pDoC, showing high levels in the MCS and EMCS subgroups (p value < 0. 001) compared to VS/UWS.

An innovative approach for the evaluation of prolonged disorders of consciousness using NF-L and GFAP biomarkers: a pivotal study.

Behavioral assessments during the clinical evaluation in prolonged disorders of consciousness patients could be not sufficient for a correct diagnosis and prognostication. To this aim, we used an innovative approach, involving the ultra-sensitive determination of biological markers, correlating them with imaging parameters to investigate the prolonged disorders of consciousness (pDoC).We assessed the serum concentration of neurofilament light chain(NF-L) and glial fibrillary acidic protein (GFAP) in pDoC (n = 16), and healthy controls (HC, n = 6) as well as several clinical imaging parameters such as Fractional Anisotropy (FA), Whole Brain SUV, and White Matter Hyperintensities volumes (WMH) using PET-MRI acquisition. As for differential diagnosis task, only the imaging WMH volume was able to discriminate between vegetative state/unresponsive wakefulness syndrome (VS/UWS), and minimally conscious state (MCS) patients (p-value < 0.01), while all selected markers (both imaging and in vitro) were able to differentiate between pDoC patients and HC. At subject level, serum NF-L concentrations significantly differ according to clinical progression and consciousness recovery (p-value < 0.01), highlighting a potential play for the longitudinal management of these patients.

Multi-center observational study on occurrence and related clinical factors of neurogenic heterotopic ossification in patients with disorders of consciousness.

Aims: to assess occurrence and clinical correlates of neurogenic heterotopic ossifications (NHO) in patients with prolonged disorder of consciousness (DoC).Design: multi-center cross-sectional observational study.Setting: 23 intensive neurorehabilitation units.Subjects: 287 patients with prolonged disorder of consciousness (DoC; 150 in vegetative state, VS, and 128 in minimally conscious state, MCS) of different etiology (vascular = 125, traumatic = 83, anoxic = 56, others = 14).Main Measures: clinical evidence of NHO confirmed by standard radiological and/or sonographic evaluation; Coma Recovery Scale-Revised; Disability Rating Scale (DRS); Early Rehabilitation Barthel Index; presence of ventilator support, spasticity, bone fractures and paroxysmal sympathetic hyperactivity.Results: 31 patients (11.2%) presented NHO. Univariate analyses showed that NHO was associated with VS diagnosis, traumatic etiology, high DRS category and total score, and high occurrence of limb spasticity and bone fractures. A cluster-corrected binary logistic regression model (excluding spasticity available in a subset of patients) showed that only lower DRS total score and presence of bone fractures were independently associated with NHO.Conclusions: NHO are relatively frequent in patients with DoC, and are independently associated with functional disability, bone fractures and spasticity. These findings contribute to identifying patients with DoC prone to develop NHO and requiring special interventions to improve functional recovery.

Multi-center study on overall clinical complexity of patients with prolonged disorders of consciousness of different etiologies.

Aim: to assess overall clinical complexity of patients with acquired disorders of consciousness (DoC) in vegetative state/unresponsive wakefulness syndrome (VS/UWS) vs. minimally conscious state- MCS) and in different etiologies..Design: Multi-center cross-sectional observational study.Setting: 23 intensive neurorehabilitation units.Subjects: 264 patients with DoC in the post-acute phase: VS/UWS = 141, and MCS = 123 due to vascular (n = 125), traumatic (n = 83) or anoxic (n = 56) brain injury.Main Measures: Coma Recovery Scale-Revised, and Disability Rating Scale (DRS); presence of medical devices (e.g., for eating or breathing); occurrence and severity of medical complications.Results: patients in DoC, and particularly those in VS/UWS, showed severe overall clinical complexity. Anoxic patients had higher overall clinical complexity, lower level of responsiveness/consciousness, higher functional disability, and higher needs of medical devices. Vascular patients had worse premorbid clinical comorbidities. The two etiologies showed a comparable rate of MC, higher than that observed in traumatic etiology.Conclusion: overall clinical complexity is significantly higher in VS/UWS than in MCS, and in non-traumatic vs. traumatic etiology. These findings could explain the worse clinical evolution reported in anoxic and vascular etiologies and in VS/UWS patients and contribute to plan patient-tailored care and rehabilitation programmes.

Consensus statement from the international consensus meeting on post-traumatic cranioplasty.

BACKGROUND: Due to the lack of high-quality evidence which has hindered the development of evidence-based guidelines, there is a need to provide general guidance on cranioplasty (CP) following traumatic brain injury (TBI), as well as identify areas of ongoing uncertainty via a consensus-based approach. METHODS: The international consensus meeting on post-traumatic CP was held during the International Conference on Recent Advances in Neurotraumatology (ICRAN), in Naples, Italy, in June 2018. This meeting was endorsed by the Neurotrauma Committee of the World Federation of Neurosurgical Societies (WFNS), the NIHR Global Health Research Group on Neurotrauma, and several other neurotrauma organizations. Discussions and voting were organized around 5 pre-specified themes: (1) indications and technique, (2) materials, (3) timing, (4) hydrocephalus, and (5) paediatric CP. RESULTS: The participants discussed published evidence on each topic and proposed consensus statements, which were subject to ratification using anonymous real-time voting. Statements required an agreement threshold of more than 70% for inclusion in the final recommendations. CONCLUSIONS: This document is the first set of practical consensus-based clinical recommendations on post-traumatic CP, focusing on timing, materials, complications, and surgical procedures. Future research directions are also presented.

European Academy of Neurology guideline on the diagnosis of coma and other disorders of consciousness.

BACKGROUND AND PURPOSE: Patients with acquired brain injury and acute or prolonged disorders of consciousness (DoC) are challenging. Evidence to support diagnostic decisions on coma and other DoC is limited but accumulating. This guideline provides the state-of-the-art evidence regarding the diagnosis of DoC, summarizing data from bedside examination techniques, functional neuroimaging and electroencephalography (EEG). METHODS: Sixteen members of the European Academy of Neurology (EAN) Scientific Panel on Coma and Chronic Disorders of Consciousness, representing 10 European countries, reviewed the scientific evidence for the evaluation of coma and other DoC using standard bibliographic measures. Recommendations followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The guideline was endorsed by the EAN. RESULTS: Besides a comprehensive neurological examination, the following suggestions are made: probe for voluntary eye movements using a mirror; repeat clinical assessments in the subacute and chronic setting, using the Coma Recovery Scale - Revised; use the Full Outline of Unresponsiveness score instead of the Glasgow Coma Scale in the acute setting; obtain clinical standard EEG; search for sleep patterns on EEG, particularly rapid eye movement sleep and slow-wave sleep; and, whenever feasible, consider positron emission tomography, resting state functional magnetic resonance imaging (fMRI), active fMRI or EEG paradigms and quantitative analysis of high-density EEG to complement behavioral assessment in patients without command following at the bedside. CONCLUSIONS: Standardized clinical evaluation, EEG-based techniques and functional neuroimaging should be integrated for multimodal evaluation of patients with DoC. The state of consciousness should be classified according to the highest level revealed by any of these three approaches.

Demographical and clinical indices for long-term evolution of patients in vegetative or in minimally conscious state.

Objective. To evaluate the prognostic value of demographical, anamnestic, and clinical findings on long-term outcome (up to 36 months) in individuals with severe brain injury in vegetative state (VS) or in minimally conscious state (MCS).Participants. Patients (N = 216) in VS (N = 159) or in MCS (N = 57) consecutively admitted to a neurorehabilitation unit within 1-3 months after severe anoxic (n = 71), vascular (n = 96), or traumatic (n = 49) brain injury.Main outcome. Mortality and improvements in clinical diagnosis at 12, 24, and 36 months after brain injury. Multivariable logistic regression analyses were performed to verify independent relationships of variables collected at study entry with outcome measures.Results. In patients in VS, at the 12-month follow-up, higher level of responsiveness assessed by the Coma Recovery Scale-Revised (CRS-R) total scores at study entry predicted a higher likelihood of both survival and clinical improvement, whereas younger age predicted survival only. At 24 months, female sex and higher CRS-R total scores tended to be associated with clinical improvements. In patients in MCS, younger age and female predicted consciousness recovery at 12 months.Conclusions. Several patients' features easy to collect in rehabilitation setting might help clinicians in prognostication of long-term mortality and clinical evolution of VS and MCS.

Psychological distress is associated with altered cognitive functioning in family caregivers of patients with disorders of consciousness.

OBJECTIVES: To analyse the possible presence of reduced cognitive efficiency in family caregivers of patients with prolonged disorders of consciousness (DOC). SUBJECTS: The participants were 27 caregivers of 25 patients with DOC admitted to the severe brain injury units of the ICS Maugeri, Institutes of Telese Terme and Sciacca, Italy. METHODS: We examined cognitive functions such as short- and long-term memory, executive functions and attention by means of standardized tests. We also assessed features of psychological distress such as anxiety, depression, psychophysiological symptoms, prolonged grief disorder, psychological burden and quality of life. All scores on neuropsychological tests were compared with those of the 15 matched control subjects. RESULTS: Enrolled family caregivers showed high frequency of clinically relevant depressive symptoms and anxiety; half of them met the criteria for prolonged grief disorder. Caregivers achieved scores lower than the matched controls on tests for selective attention, verbal fluency and long-term spatial memory. CONCLUSIONS: Family caregivers' burden is associated with a reduced efficiency of selected executive measures and visuospatial learning. These results emphasize the need for appropriate psychological and cognitive supporting therapies for family caregivers of patients with DOC, also considering their delicate involvement in clinical decision-making and in providing care.

An Italian multicentre validation study of the coma recovery scale-revised.

BACKGROUND: Rate of misdiagnosis of disorders of consciousness (DoC) can be reduced by employing validated clinical diagnostic tools, such as the Coma Recovery Scale-Revised (CRS-R). An Italian version of the CRS-R has been recently developed, but its applicability across different clinical settings, and its concurrent validity and diagnostic sensitivity have not been estimated yet. AIM: To perform a multicentre validation study of the Italian version of the Coma Recovery Scale-Revised (CRS-R). DESIGN: Analysis of inter-rater reliability, concurrent validity and diagnostic sensitivity of the scale. SETTING: One Intensive Care Unit, 8 Post-acute rehabilitation centres and 2 Long-term facilities POPULATION: Twenty-seven professionals (physicians, N.=11; psychologists, N.=5; physiotherapists, N.=3; speech therapists, N.=6; nurses, N.=2) from 11 Italian Centres. METHODS: CRS-R and Disability Rating Scale (DRS) applied to 122 patients with clinical diagnosis of Vegetative State (VS) or Minimally Conscious State (MCS). RESULTS: CRS-R has good-to-excellent inter-rater reliability for all subscales, particularly for the communication subscale. The Italian version of the CRS-R showed a high sensitivity and specificity in detecting MCS with reference to clinical consensus diagnosis. The CRS-R showed good concurrent validity with the Disability Rating Scale, which had very low specificity with reference to clinical consensus diagnosis. CONCLUSIONS: The Italian version of the CRS-R is a valid scale for use from the sub-acute to chronic stages of DoC. It can be administered reliably by all members of the rehabilitation team with different specialties, levels of experience and settings. CLINICAL REHABILITATION IMPACT: The present study promote use of the Italian version of the CRS-R to improve diagnosis of DoC patients, and plan tailored rehabilitation treatment.

Quantitative assessment of visual behavior in disorders of consciousness.

The study of eye behavior is of paramount importance in the differential diagnosis of disorders of consciousness (DoC). In spite of this, assessment of eye movement patterns in patients with vegetative state (VS) or minimally conscious state (MCS) only relies on clinical evaluation. In this study we aimed to provide a quantitative assessment of visual tracking behavior in response to moving stimuli in DoC patients. Nine VS patients and nine MCS patients were recruited in a Neurorehabilitation Unit for patients with chronic DoC; 11 matched healthy subjects were tested as the control group. All participants under went a quantitative evaluation of eye-tracking pattern by means of a computerized infrared eye-tracker system; stimuli were represented by a red circle or a small color picture slowly moving on a PC monitor. The proportion of on- or off-target fixations differed significantly between MCS and VS. Most importantly, the distribution of fixations on or off the target in all VS patients was at or below the chance level, whereas in the MCS group seven out of nine patients showed a proportion of on-target fixations significantly higher than the chance level. Fixation length did not differ among the three groups significantly. The present quantitative assessment of visual behaviour in a tracking task demonstrated that MCS and VS patients differ in the proportion of on-target fixations. These results could have important clinical implications since the quantitative analysis of visual behavior might provide additional elements in the differential diagnosis of DoC.

Late recovery after traumatic, anoxic, or hemorrhagic long-lasting vegetative state.

OBJECTIVES: Late recovery of awareness in vegetative state (VS) is considered as an exceptional outcome, and has been reported prevalently after traumatic brain injury (TBI). The present prospective study aimed to verify frequency of late recovery (later than 1 year postonset in TBI and 3 months postonset in patients without TBI) of responsiveness and consciousness in traumatic and nontraumatic long-lasting (more than 6 months after onset) VS. METHODS: Fifty inpatients with long-lasting VS (36% TBI, 36% hemorrhagic, and 28% anoxic) were enrolled and followed up for a mean of 25.7 months from onset (5 patients for more than 4 years). Level of responsiveness and functional disability were evaluated by means of validated scales (Coma Recovery Scale-Revised and Disability Rating Scale). RESULTS: At the end of the study, 21 patients (42%) had died, 17 patients (34%) were in VS, and 2 patients with TBI (4%) had recovered responsiveness within 12 months postonset. The remaining 10 (20%) patients with TBI and patients without TBI showed late recovery of responsiveness; 6 of them (12%) further progressed to consciousness. Late recovery was significantly associated with younger age and was relatively more frequent in TBI. Functional abilities were severely impaired in all patients. CONCLUSIONS: This clinical study demonstrates that late recovery of responsiveness and consciousness is not exceptional in patients with traumatic and nontraumatic VS, although with residual severe disability.

Gelastic epilepsy: symptomatic and cryptogenic cases.

PURPOSE: To describe the etiology, characteristics, and clinical evolution of epilepsy in patients with gelastic seizures (GSs). METHODS: Nine patients whose seizures were characterized by typical laughing attacks were observed between 1986 and 1997. Patients were selected based on electroencephalogram (EEG) or video-EEG recordings of at least one GS and on magnetic resonance imaging (MRI) study. RESULTS: Five patients were affected by symptomatic localization-related epilepsy (LRE), with four of the patients' disorders related to a hypothalamic hamartoma (HH) and one to tuberous sclerosis (TS) without evident hypothalamic lesions. In four patients (the cryptogenic cases) MRI was negative also in these cases, clinical and EEG data suggested a focal origin of the seizures. The epileptic syndrome in the HH cases was usually drug-resistant, and was surgically treated in two of the patients. The patient with TS became seizure free with vigabatrin. In the cryptogenic cases, the ictal, clinical, and EEG semiology were similar to the symptomatic cases: the clinical evolution was variable, with patients having transient drug resistance or partial response to treatment. No cognitive defects were observed in the cryptogenic patients. None of the nine patients had precocious puberty. CONCLUSIONS: We confirm the frequent finding of HHs in GSs and further underline how GSs may also be observed in patients without MRI lesions and with normal neurologic status. In these patients, clinical and EEG seizure semiology is similar to symptomatic cases, but the clinical evolution is usually more benign.

Transient global amnesia of epileptic origin accompanied by fever.

The case of a previously healthy 69-year-old female patient is described who presented, in a period of 6 months, 3 long-lasting (from 2 hour- to 10 hour-duration) episodes of transient global amnesia accompanied by a temperature rise. During one of these episodes an EEG was obtained, showing a diffuse alteration, focal slowing, and bitemporal asynchronous paroxysmal activity giving rise to electrical ictal discharges. Interictal EEGs were normal. Cerebral computed tomography was normal. Carbamazepine was given with complete control of the attacks. These episodes may be interpreted as complex partial status with unusual semeiology.

Reduced fertility and neuroendocrine dysfunction in women with epilepsy.

A reduction of fertility in women with epilepsy has been reported since 1950 and is confirmed in recent epidemiological studies. This phenomenon has usually been attributed to the increase of medical and socioeconomic problems in these patients or to hyposexuality, which has been consistently observed in epileptic subjects. Recently, a higher occurrence of reproductive endocrine diseases has been reported in epileptic women and proposed as an important cause of reduced fertility. In particular, polycystic ovary syndrome and hypothalamic ovarian failure have been reported in epileptic women with increased frequency compared to the general population. Moreover, an abnormal pattern of luteinizing hormone (LH) pulsatility has been observed in normally cycling, drug-free epileptic women. We suggest that epilepsy may interfere with the functional activity of the gonadotropin releasing hormone (GnRH) pulse generator. It is possible that paroxysmal discharges spreading within the hypothalamus might affect the regularity of the GnRH pulse generator; alternatively, a neurotransmitter dysfunction might at the same time be responsible both for the lowering of the seizure threshold and for the dysfunction of GnRH secretion. The consequent alteration of LH pulsatility might in the long run, under the effect of additional factors, give rise to a clinical reproductive endocrine disorder.

The use of EEG activating procedures in epileptology.

Epileptic seizures and EEG interictal paroxysmal activity (PA) usually occur in an apparently unpredictable fashion, and a small number of patients with truly epileptic seizures may not present any PA on repeated EEGs. With the aim of increasing the possibility of recording interictal or ictal PA, several activation procedures are routinely carried out. In rarer instances, seizures seem to be more or less specifically evoked by unusual triggering procedures, or are chronologically related to biological rhythms. These different activating procedures may have different effectiveness depending on the type of epileptic syndrome. In the present paper the Authors describe the different activating procedures, both routinely employed and unusual ones. Their possible differential use with regard to the different epileptic syndromes and to the specific epileptologic history of the patient are examined. A selective use of these procedures is suggested, as an accurate choice of such techniques may increase the diagnostic usefulness of the EEG, in particular in patients whose basal recording is not contributory.