Pathophysiology of multiple sclerosis damage and repair: Linking cerebral hypoperfusion to the development of irreversible tissue loss in multiple sclerosis using magnetic resonance imaging.

BACKGROUND AND PURPOSE: Reduced cerebral perfusion has been observed in multiple sclerosis (MS) and may contribute to tissue loss both acutely and chronically. Here, we test the hypothesis that hypoperfusion occurs in MS and relates to the presence of irreversible tissue damage. METHODS: In 91 patients with relapsing MS and 26 healthy controls (HC), gray matter (GM) cerebral blood flow (CBF) was assessed using pulsed arterial spin labeling. GM volume, T1 hypointense and T2 hyperintense lesion volumes (T1LV and T2LV, respectively), and the proportion of T2-hyperintense lesion volume that appears hypointense on T1-weighted magnetic resonance imaging (T1LV/T2LV) were quantified. GM CBF and GM volume were evaluated globally, as well as regionally, using an atlas-based approach. RESULTS: Global GM CBF was lower in patients (56.9 ± 12.3 mL/100 g/min) than in HC (67.7 ± 10.0 mL/100 g/min; p < 0.001), a difference that was widespread across brain regions. Although total GM volume was comparable between groups, significant reductions were observed in a subset of subcortical structures. GM CBF negatively correlated with T1LV (r = -0.43, p = 0.0002) and T1LV/T2LV (r = -0.37, p = 0.0004), but not with T2LV. CONCLUSIONS: GM hypoperfusion occurs in MS and is associated with irreversible white matter damage, thus suggesting that cerebral hypoperfusion may actively contribute and possibly precede neurodegeneration by hampering tissue repair abilities in MS.

Immunological Profile of Vasospasm after Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) carries high mortality and disability rates, which are substantially driven by complications. Early brain injury and vasospasm can happen after SAH and are crucial events to prevent and treat to improve prognosis. In recent decades, immunological mechanisms have been implicated in SAH complications, with both innate and adaptive immunity involved in mechanisms of damage after SAH. The purpose of this review is to summarize the immunological profile of vasospasm, highlighting the potential implementation of biomarkers for its prediction and management. Overall, the kinetics of central nervous system (CNS) immune invasion and soluble factors' production critically differs between patients developing vasospasm compared to those not experiencing this complication. In particular, in people developing vasospasm, a neutrophil increase develops in the first minutes to days and pairs with a mild depletion of CD45+ lymphocytes. Cytokine production is boosted early on after SAH, and a steep increase in interleukin-6, metalloproteinase-9 and vascular endothelial growth factor (VEGF) anticipates the development of vasospasm after SAH. We also highlight the role of microglia and the potential influence of genetic polymorphism in the development of vasospasm and SAH-related complications.

Dynamic brain states in spatial neglect after stroke.

Previous studies indicated that spatial neglect is characterized by widespread alteration of resting-state functional connectivity and changes in the functional topology of large-scale brain systems. However, whether such network modulations exhibit temporal fluctuations related to spatial neglect is still largely unknown. This study investigated the association between brain states and spatial neglect after the onset of focal brain lesions. A cohort of right-hemisphere stroke patients (n = 20) underwent neuropsychological assessment of neglect as well as structural and resting-state functional MRI sessions within 2 weeks from stroke onset. Brain states were identified using dynamic functional connectivity as estimated by the sliding window approach followed by clustering of seven resting state networks. The networks included visual, dorsal attention, sensorimotor, cingulo-opercular, language, fronto-parietal, and default mode networks. The analyses on the whole cohort of patients, i.e., with and without neglect, identified two distinct brain states characterized by different degrees of brain modularity and system segregation. Compared to non-neglect patients, neglect subjects spent more time in less modular and segregated state characterized by weak intra-network coupling and sparse inter-network interactions. By contrast, patients without neglect dwelt mainly in more modular and segregated states, which displayed robust intra-network connectivity and anti-correlations among task-positive and task-negative systems. Notably, correlational analyses indicated that patients exhibiting more severe neglect spent more time and dwelt more often in the state featuring low brain modularity and system segregation and vice versa. Furthermore, separate analyses on neglect vs. non-neglect patients yielded two distinct brain states for each sub-cohort. A state featuring widespread strong connections within and between networks and low modularity and system segregation was detected only in the neglect group. Such a connectivity profile blurred the distinction among functional systems. Finally, a state exhibiting a clear separation among modules with strong positive intra-network and negative inter-network connectivity was found only in the non-neglect group. Overall, our results indicate that stroke yielding spatial attention deficits affects the time-varying properties of functional interactions among large-scale networks. These findings provide further insights into the pathophysiology of spatial neglect and its treatment.

Functional Neurologic Disorders, disorders to be managed by neurologists, or are neurologists wandering in a dangerous field with inadequate resources?

In recent years, some neurologists reconsidered their approach to Medically Unexplained Symptoms and proposed Functional Neurologic Disorders (FND) as a new entity, claiming that neurology could offer alternative treatment options to the psychotherapies provided in psychiatry settings. FNDs, for this purpose, should include only the disorders listed as Conversion from the Somatic Symptom and Related Disorders (SSRD) group. The present review analyzes the rationale of this position and challenges the arguments provided for its support. The review also discusses the systematization of these disorders as provided by public health systems. It outlines risks stemming from economic support and public funding uncertainty, given their negligible epidemiological dimensions resulting from the parcellation of SSRD. The review underlines the unresolved issue of Factitious Disorders, which are in the same SSRD category of the international classification but are, nonetheless, overlooked by the theoretical proponents of the FND entity. Comorbidity with other psychiatric disorders is also analyzed. We propose a model that supports the continuum between different SSRD conditions, including Factitious Disorders. The model is based on the emergence of feigned death reflex and deception from frontal lobe dysfunction. Finally, the paper summarizes the wealth of historical psychiatric and psychodynamic approaches and critical reviews. The study also puts in context the categorization and interpretation efforts provided by the most eminent researchers of the past century.

Thrombolysis after dabigatran reversal: A nation-wide Italian multicentre study, systematic review and meta-analysis.

Introduction: Recent anticoagulant intake represents a contraindication for thrombolysis in acute ischemic stroke. Idarucizumab reverses the anticoagulant effect of dabigatran, potentially allowing for thrombolysis. This nation-wide observational cohort study, systematic review, and meta-analysis evaluated the efficacy and safety of thrombolysis preceded by dabigatran-reversal in people with acute ischemic stroke. Patients and methods: We recruited people undergoing thrombolysis following dabigatran-reversal at 17 stroke centers in Italy (reversal-group), people on dabigatran treated with thrombolysis without reversal (no-reversal group), and age, sex, hypertension, stroke severity, and reperfusion treatment-matched controls in 1:7 ratio (control-group). We compared groups for symptomatic intracranial hemorrhage (sICH, main outcome), any brain hemorrhage, good functional outcome (mRS 0-2 at 3 months), and death. The systematic review followed a predefined protocol (CRD42017060274), and odds ratio (OR) meta-analysis was implemented to compare groups. Results: Thirty-nine patients in dabigatran-reversal group and 300 matched controls were included. Reversal was associated with a non-significant increase in sICH (10.3% vs 6%, aOR = 1.32, 95% CI = 0.39-4.52), death (17.9% vs 10%, aOR = 0.77, 95% CI = 0.12-4.93) and good functional outcome (64.1% vs 52.8%, aOR = 1.41, 95% CI = 0.63-3.19). No hemorrhagic events or deaths were registered in no-reversal group (n = 12). Pooling data from 3 studies after systematic review (n = 1879), reversal carried a non-significant trend for sICH (OR = 1.53, 95% CI = 0.67-3.50), death (OR = 1.53, 95% CI = 0.73-3.24) and good functional outcome (OR = 2.46, 95% CI = 0.85-7.16). Discussion and conclusion: People treated with reperfusion strategies after dabigatran reversal with idarucizumab seem to have a marginal increase in the risk of sICH but comparable functional recovery to matched patients with stroke. Further studies are needed to define treatment cost-effectiveness and potential thresholds in plasma dabigatran concentration for reversal.

Reduced Segregation of Brain Networks in Spatial Neglect After Stroke.

Background/Purpose: To investigate the association between the degree of spatial neglect and the changes of brain system segregation (SyS; i.e., the ratio of the extent to which brain networks interact internally and with each other) after stroke. Methods: A cohort of 20 patients with right hemisphere lesion was submitted to neuropsychological assessment as well as to resting-state functional magnetic resonance imaging session at acute stage after stroke. The severity of spatial neglect was quantified using the Center of Cancellation (CoC) scores of the Bells cancellation test. For each patient, resting-state functional connectivity (FC) matrices were assessed by implementing a brain parcellation of nine networks that included the visual network, dorsal attention network (DAN), ventral attention network (VAN), sensorimotor network (SMN), auditory network, cingulo-opercular network, language network, frontoparietal network, and default mode network (DMN). For each patient and each network, we then computed the SyS derived by subtracting the between-network FC from the within-network FC (normalized by the within-network FC). Finally, for each network, the CoC scores were correlated with the SyS. Results: The correlational analyses indicated a negative association between CoC and SyS in the DAN, VAN, SMN, and DMN (q < 0.05 false discovery rate [FDR]-corrected). Patients with more severe spatial neglect exhibited lower SyS and vice versa. Conclusion: The loss of segregation in multiple and specific networks provides a functional framework for the deficits in spatial and nonspatial attention and motor/exploratory ability observed in neglect patients.

Cerebrovascular reactivity in multiple sclerosis is restored with reduced inflammation during immunomodulation.

Cerebrovascular reactivity (CVR) reflects the capacity of the brain's vasculature to increase blood flow following a vasodilatory stimulus. Reactivity is an essential property of the brain's blood vessels that maintains nutrient supplies in the face of changing demand. In Multiple Sclerosis (MS), CVR may be diminished with brain inflammation and this may contribute to neurodegeneration. We test the hypothesis that CVR is altered with MS neuroinflammation and that it is restored when inflammation is reduced. Using a breath-hold task during functional Magnetic Resonance Imaging (MRI), we mapped grey matter and white matter CVRs (CVRGM and CVRWM, respectively) in 23 young MS patients, eligible for disease modifying therapy, before and during Interferon beta treatment. Inflammatory activity was inferred from the presence of Gadolinium enhancing lesions at MRI. Eighteen age and gender-matched healthy controls (HC) were also assessed. Enhancing lesions were observed in 12 patients at the start of the study and in 3 patients during treatment. Patients had lower pre-treatment CVRGM (p = 0.04) and CVRWM (p = 0.02) compared to HC. In patients, a lower pre-treatment CVRGM was associated with a lower GM volume (r = 0.60, p = 0.003). On-treatment, there was an increase in CVRGM (p = 0.02) and CVRWM (p = 0.03) that negatively correlated with pre-treatment CVR (GM: r = - 0.58, p = 0.005; WM: r = - 0.60, p = 0.003). CVR increased when enhancing lesions reduced in number (GM: r = - 0.48, p = 0.02, WM: r = - 0.62, p = 0.003). Resolution of inflammation may restore altered cerebrovascular function limiting neurodegeneration in MS. Imaging of cerebrovascular function may thereby inform tissue physiology and improve treatment monitoring.

EEG Abnormalities During Delirium as a Prodromal Feature of Dementia with Lewy Bodies: A Case Report.

Background: A 79-year-old woman was admitted to the Neurology Clinic of the University of Chieti-Pescara for a syncope. At admission, the occurrence of an acute stroke was ruled out. Her cognitive status was unimpaired. After three days from the hospitalization, the patient experienced an episode of mixed delirium. Objective: The present case report shows a case of delirium-onset dementia with Lewy bodies (DLB) with a specific electroencephalographic (EEG) pattern from its prodromal stage. Methods: Delirium was assessed by 4AT test. During the hospitalization, the patient underwent a quantitative EEG (QEEG) with spectral analysis. At six months from the episode of delirium, she was tested by neuropsychological evaluation, QEEG, and 18F-fluorodeoxyglucose PET/CT to assess the onset of a possible cognitive decline. Results: At baseline, the QEEG exam showed a dominant frequency (DF) in the pre-alpha band (7.5 Hz) with a dominant frequency variability (DFV) of 2 Hz. This pattern is typical of DLB at early stage. After six months, she reported attention deficits in association with cognitive fluctuation and REM sleep behavior disorder. The neurological examination revealed signs of parkinsonism. Cognitive status resulted to be impaired (MoCA = 15/30). QEEG recording confirmed the presence of a DLB-typical pattern (DF = 7.5 Hz, DFV = 2.5 Hz). The 18F-FDG-PET/CT showed a moderate bilateral posterior hypometabolism (occipital and temporal cortex), with relative sparing of the posterior cingulate cortex compared to cuneus/precuneus (Cingulate Island sign), and mild bilateral hypometabolism in frontal regions (suggestive of a DLB diagnosis). Conclusion: EEGs may represent supportive and validated biomarkers for delirium-onset prodromal DLB.

Bipolar spectrum disorders in neurologic disorders.

Psychiatric symptoms frequently predate or complicate neurological disorders, such as neurodegenerative diseases. Symptoms of bipolar spectrum disorders (BSD), like mood, behavioral, and psychotic alterations, are known to occur - individually or as a syndromic cluster - in Parkinson's disease and in the behavioral variant of frontotemporal dementia (FTD). Nonetheless, due to shared pathophysiological mechanisms, or genetic predisposition, several other neurological disorders show significant, yet neglected, clinical and biological overlaps with BSD like neuroinflammation, ion channel dysfunctions, neurotransmission imbalance, or neurodegeneration. BSD pathophysiology is still largely unclear, but large-scale network dysfunctions are known to participate in the onset of mood disorders and psychotic symptoms. Thus, functional alterations can unleash BSD symptoms years before the evidence of an organic disease of the central nervous system. The aim of our narrative review was to illustrate the numerous intersections between BSD and neurological disorders from a clinical-biological point of view and the underlying predisposing factors, to guide future diagnostic and therapeutical research in the field.

Contribution of Metabolomics to Multiple Sclerosis Diagnosis, Prognosis and Treatment.

Metabolomics-based technologies map in vivo biochemical changes that may be used as early indicators of pathological abnormalities prior to the development of clinical symptoms in neurological conditions. Metabolomics may also reveal biochemical pathways implicated in tissue dysfunction and damage and thus assist in the development of novel targeted therapeutics for neuroinflammation and neurodegeneration. Metabolomics holds promise as a non-invasive, high-throughput and cost-effective tool for early diagnosis, follow-up and monitoring of treatment response in multiple sclerosis (MS), in combination with clinical and imaging measures. In this review, we offer evidence in support of the potential of metabolomics as a biomarker and drug discovery tool in MS. We also use pathway analysis of metabolites that are described as potential biomarkers in the literature of MS biofluids to identify the most promising molecules and upstream regulators, and show novel, still unexplored metabolic pathways, whose investigation may open novel avenues of research.

The factitious/malingering continuum and its burden on public health costs: a review and experience in an Italian neurology setting.

Factitious disorder is classified as one of the five aspects of somatic symptom disorders. The fundamental element of factitious disorder is deception, i.e., pretending to have a medical or psychiatric disorder, but the enactment of deception is considered unconscious. Indeed, volition, i.e., the perception of deliberate deception, is blurred in patients presenting with factitious disorder. In the USA and the UK, factitious disorder has received constant media attention because of its forensic implications and outrageous costs for the National Health Systems. Unfortunately, a comparable level of attention is not present in Italian National Health System or the Italian mass media. The review analyzes the classifications, disorder mechanisms, costs, and medico-legal implications in the hope of raising awareness on this disturbing issue. Moreover, the review depicts 13 exemplification cases, anonymized and fictionalized by expert writers. Finally, our paper also evaluates the National Health System's expenditures for each patient, outlandish costs in the range between 50,000 and 1 million euros.

Agitation and Dementia: Prevention and Treatment Strategies in Acute and Chronic Conditions.

Agitation is a behavioral syndrome characterized by increased, often undirected, motor activity, restlessness, aggressiveness, and emotional distress. According to several observations, agitation prevalence ranges from 30 to 50% in Alzheimer's disease, 30% in dementia with Lewy bodies, 40% in frontotemporal dementia, and 40% in vascular dementia (VaD). With an overall prevalence of about 30%, agitation is the third most common neuropsychiatric symptoms (NPS) in dementia, after apathy and depression, and it is even more frequent (80%) in residents of nursing homes. The pathophysiological mechanism underlying agitation is represented by a frontal lobe dysfunction, mostly involving the anterior cingulate cortex (ACC) and the orbitofrontal cortex (OFC), respectively, meaningful in selecting the salient stimuli and subsequent decision-making and behavioral reactions. Furthermore, increased sensitivity to noradrenergic signaling has been observed, possibly due to a frontal lobe up-regulation of adrenergic receptors, as a reaction to the depletion of noradrenergic neurons within the locus coeruleus (LC). Indeed, LC neurons mainly project toward the OFC and ACC. These observations may explain the abnormal reactivity to weak stimuli and the global arousal found in many patients who have dementia. Furthermore, agitation can be precipitated by several factors, e.g., the sunset or low lighted environments as in the sundown syndrome, hospitalization, the admission to nursing residencies, or changes in pharmacological regimens. In recent days, the global pandemic has increased agitation incidence among dementia patients and generated higher distress levels in patients and caregivers. Hence, given the increasing presence of this condition and its related burden on society and the health system, the present point of view aims at providing an extensive guide to facilitate the identification, prevention, and management of acute and chronic agitation in dementia patients.

Revisiting Conventional Wisdom: What Do We Know from 30 Years of Research on Sibling Placement in Foster Care?

Background: Efforts to place sibling groups together in foster care have long been considered best practice and is required under federal law. Practice and policy guidance are based in part on the belief that sibling placement is in the best interests of children. In this article, we first review literature reviews on this topic to assess the extent to which prior efforts to characterize this body of research are thorough, objective, and based on research specific to the foster care population. We then assess the quality and volume of empirical evidence on the effects of sibling placement for the stability, permanency, and wellbeing of children in foster care to ascertain whether existing reviews accurately reflect the empirical evidence or extend beyond it without adequate empirical support. Methods: We conducted a scoping search of reviews of published research from the year 1990 to 2019 using Google Scholar, PsycInfo, EBSCO, and PubMed (Medline). From the search results, we extracted all review articles, quantitative studies, and qualitative studies on sibling placement in foster care. We identified 16 literature reviews on sibling placement in foster care. In addition, we identified 27 longitudinal quantitative studies measuring the association between sibling placement and child placement stability, permanency or wellbeing in foster care, and nine qualitative studies on the role of sibling placement or relationships for child wellbeing in foster care. Results: Many of the literature reviews relied on research evidence from non-foster care samples and studies with weak methodologies. Moreover, although the research evidence is inconclusive - with studies reporting positive, negative, and null effects -most literature reviews concluded that the practice of sibling placement was supported by research evidence. Conclusion: Although there are moral reasons to support sibling placement, the research evidence does not consistently support the practice of placing siblings together. Further research is needed to identify when sibling placement poses a risk to children and when sibling placement is likely to facilitate positive outcomes.

Low molecular weight heparin in COVID-19 patients prevents delirium and shortens hospitalization.

BACKGROUND: COVID-19 patients present with delirium during their hospitalization. AIMS: To assess the incidence of delirium in hospitalized COVID-19 patients and analyze the possible association with demographic, clinical, laboratory, and pharmacological factors. METHODS: COVID-19 patients were assessed for clinical signs of delirium and administered the assessment test for delirium and cognitive impairment (4AT) and the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) scales. RESULTS: Out of the 56 patients of our cohort, 14 (25.0%) experienced delirium. The use of low molecular weight heparin (LMWH) (enoxaparin 1 mg/kg/daily) was less frequent in patients with delirium (p = 0.004) and was accompanied by lower C reactive protein (CRP) levels (p = 0.006). DISCUSSION: The use of LMWH was associated with absence of delirium, independently of comorbidities and age. CONCLUSIONS: The use of LMWH may help preventing the occurrence of delirium in COVID-19 patients, with possible reduction of length of stay in the hospital and sequelae.

Patterns of intergenerational child protective services involvement.

BACKGROUND: Prior research on Child Protective Services (CPS) involvement among at-risk youth focuses on their roles as parents perpetrating maltreatment against biological offspring. Given family complexity and assortative partnering, measuring all CPS involvement - as perpetrators and non-offending parents of victims - provides new insight into intergenerational maltreatment patterns. OBJECTIVES: Our objective was to investigate the risk of multiple forms of parent or perpetrator CPS involvement (PP-CPS) by age 25, among those exposed to three forms of adversity in their late teens (at ages 14-17): alleged victim on a CPS investigation, out-of-home care (OHC), and poverty. PARTICIPANTS AND SETTING: We used a sample of 36,475 individuals born in 1990-1991 from the Wisconsin Data Core longitudinal administrative database, and tracked their involvement in CPS, OHC, and the food assistance program (SNAP) over time. Our sample consisted of individuals who, at ages 14-17, met one of the following criteria: were in OHC; had CPS involvement as a victim but no OHC (CPSV group), or received food assistance without CPSV or OHC (SNAP group). METHODS: Using logistic regression, we modeled four forms of PP-CPS involvement: parent-perpetrator, resident parent non-perpetrator, nonresident parent non-perpetrator, and non-biological parent-perpetrator. RESULTS: Predicted risks of any PP-CPS involvement by age 25 were 10 % (SNAP group), 17-22 % (CPSV group), and 26-33 % (OHC group); among OHC youth known to have a biological child, rates exceeded 40 %. The proportion of CPS involvement that involved parent-perpetration varied substantially by sex and adversity type. CONCLUSIONS: Focusing only on intergenerational maltreatment in which the parents are the perpetrators may substantially understate the risk of maltreatment recurring across generations.