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BackgroundClinical investigations have argued for long-term neurological manifestations in both hospitalised and non-hospitalised COVID-19 patients. It is unclear whether long-term neurological symptoms and features depend on COVID-19 severity.MethodsFrom a sample of 208 consecutive non-neurological patients hospitalised for COVID-19 disease, 165 survivors were re-assessed at 6 months according to a structured standardised clinical protocol. Prevalence and predictors of long-term neurological manifestations were evaluated using multivariate logistic regression analyses.ResultsAt 6-month follow-up after hospitalisation due to COVID-19 disease, patients displayed a wide array of symptoms; fatigue (34%), memory/attention (31%) and sleep disorders (30%) were the most frequent. At neurological examination, 40% of patients exhibited neurological abnormalities, such as hyposmia (18.0%), cognitive deficits (17.5%), postural tremor (13.8%) and subtle motor/sensory deficits (7.6%). Older age, premorbid comorbidities and severity of COVID-19 were independent predictors of neurological manifestations in logistic regression analyses.ConclusionsPremorbid vulnerability and severity of SARS-CoV-2 infection impact on prevalence and severity of long-term neurological manifestations.

BackgroundCognitive deficits have been increasingly reported as possible long-term manifestations after SARS-CoV-2 infection.AimsIn this study we aimed at evaluating the factors associated with cognitive deficits 6 months after hospitalization for Coronavirus Disease 2019 (COVID-19).MethodsOne hundred and six patients, discharged from a pneumology COVID-19 unit between March 1 and May 30 2020, accepted to be evaluated at 6 months according to an extensive neurological protocol, including the Montreal Cognitive Assessment (MoCA).ResultsAbnormal MoCA scores at 6 months follow-up were associated with higher pre-hospitalization National Health System (NHS) score (Duca et al. in Emerg Med Pract 22:1–2, 2020) (OR 1.27; 95% CI 1.05–1.6; p = 0.029) and more severe pulmonary disease expressed by the Brescia-COVID Respiratory Severity Scale (Duca et al. in Emerg Med Pract 22:1–2, 2020) (BCRSS > 1OR 4.73; 95% CI 1.53–14.63; p = 0.003) during the acute phase of the disease.DiscussionThis longitudinal study showed that the severity of COVID-19, indicated by BCRSS, and a complex score given by age and premorbid medical conditions, expressed by NHS, play a major role in modulating the long-term cognitive consequences of COVID-19 disease.ConclusionsThese findings indicate that the association of age and premorbid factors might identify people at risk for long-term neurological consequences of COVID-19 disease, thus deserving longer and proper follow-up.

The COVIVAX study assessed the association between COVID-19 vaccination and the risk of common neurological disorders in a multicenter case-control design. Vaccination exposure was compared between individuals with a first diagnosis of a neurological disorder (cases) and age- and sex-matched controls. A total of 624 participants were enrolled, and after random 1:1 matching 265 cases and 265 matched controls (total 530 participants) were included in the analyses. The most frequent neurological diagnosis in cases were stroke (60.4%), multiple sclerosis (11.3%) and seizures (6.4%). The proportion of vaccinated participants was 72.1% among cases and 79.6% among controls. A protective role of vaccination on the risk of developing a new neurological disorder was detected in the unadjusted analysis (OR 0.50; 95% CI 0.29–0.86; p  = 0.0114). After adjustment for confounders, the number of vaccination doses received was associated with a reduced risk of developing new neurological disorders for participants aged over 60 years ( p  = 0.0472; OR 0.14, 95% CI 0.03–0.68), with pre-existing comorbidities ( p  = 0.0122; OR 0.04, 95% CI 0.01–0.99) and for stroke ( p  = 0.0232; OR 0.04, 95% CI 0.02–0.97). The COVIVAX study provided no warning sign regarding an increase in the risk of developing new neurological disorders following COVID-19 vaccination of any type or doses. A potentially protective effect of multiple doses of COVID-19 vaccines against the risk of stroke in people aged over 60 needs to be confirmed by further studies.

Brain functional disruption and cognitive shortfalls as consequences of neurodegeneration are among the most investigated aspects in current clinical research. Traditionally, specific anatomical and behavioral traits have been associated with neurodegeneration, thus directly translatable in clinical terms. However, these qualitative traits, do not account for the extensive information flow breakdown within the functional brain network that deeply affect cognitive skills. Behavioural variant Frontotemporal Dementia (bvFTD) is a neurodegenerative disorder characterized by behavioral and executive functions disturbances. Deviations from the physiological cognitive functioning can be accurately inferred and modeled from functional connectivity alterations. Although the need for unbiased metrics is still an open issue in imaging studies, the graph-theory approach applied to neuroimaging techniques is becoming popular in the study of brain dysfunction. In this work, we assessed the global connectivity and topological alterations among brain regions in bvFTD patients using a minimum spanning tree (MST) based analysis of resting state functional MRI (rs-fMRI) data. Whilst several graph theoretical methods require arbitrary criteria (including the choice of network construction thresholds and weight normalization methods), MST is an unambiguous modeling solution, ensuring accuracy, robustness, and reproducibility. MST networks of 116 regions of interest (ROIs) were built on wavelet correlation matrices, extracted from 41 bvFTD patients and 39 healthy controls (HC). We observed a global fragmentation of the functional network backbone with severe disruption of information-flow highways. Frontotemporal areas were less compact, more isolated, and concentrated in less integrated structures, respect to healthy subjects. Our results reflected such complex breakdown of the frontal and temporal areas at both intra-regional and long-range connections. Our findings highlighted that MST, in conjunction with rs-fMRI data, was an effective method for quantifying and detecting functional brain network impairments, leading to characteristic bvFTD cognitive, social, and executive functions disorders.

Neurodegenerative process in amyotrophic lateral sclerosis (ALS) has been proven to involve several cortical and subcortical brain regions within and beyond motor areas. However, how ALS pathology spreads progressively during disease evolution is still unknown. In this cross-sectional study we investigated 54 ALS patients, divided into 3 subsets according to the clinical stage, and 18 age and sex-matched healthy controls, by using tract-based spatial statistics (TBSS) diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) analyses. We aimed to identify white (WM) and gray matter (GM) patterns of disease distinctive of each clinical stage, corresponding to specific clinical milestones. ALS cases in stage 2A (i.e., at diagnosis) were characterized by GM and WM impairment of left motor and premotor cortices and brainstem at ponto-mesenchephalic junction. ALS patients in clinical stage 2B (with impairment of two functional regions) exhibited decreased fractional anisotropy (FA) (p<0.001, uncorrected) and increased mean (MD) and radial diffusivity (RD) (p<0.001, uncorrected) in the left cerebellar hemisphere and brainstem precerebellar nuclei, as well as in motor areas, while GM atrophy (p<0.001, uncorrected) was detected only in the left inferior frontal gyrus and right cuneus. Finally, ALS patients in stage 3 (with impairment of three functional regions) exhibited decreased FA and increased MD and RD (p<0.05, corrected) within WM underneath bilateral pre and postcentral gyri, corpus callosum midbody, long associative tracts and midbrain, while no significant clusters of GM atrophy were observed. Our findings reinforce the hypothesis that the neurodegenerative process propagates along the axonal pathways and develops beyond motor areas from early stages, involving progressively several frontotemporal regions and their afferents and efferents, while the detection of GM atrophy in earlier stages and its disappearance in later stages may be the result of reactive gliosis.

Frontotemporal dementia (FTD) is characterized by behavioural and language impairment, accompanied by atrophic changes in fronto-temporo-insular cortices. In the presymptomatic phases of genetic FTD, subtle or no volumetric changes have been reported. Transcranial magnetic stimulation (TMS) represents an approach to explore cortical connectivity, and some TMS measures have been demonstrated to be impaired in Granulin (GRN) mutation carriers. We aimed at exploring cross-sectional changes in cortical thickness (CT) and surface area (SA) in the presymptomatic phases of GRN-related FTD, and their relationship with TMS parameters. Nineteen presymptomatic GRN mutation carriers and seventeen age and sex-matched non-carriers underwent 3T MRI scanning and a paired-pulse TMS protocol. The surface-based pipeline of FreeSurfer was applied in order to obtain cortical volumes (CVs), CT and SA measures. Then, between groups differences and correlation with TMS parameters were assessed. GRN carriers showed increased CT and decreased SA of the right parietal lobe, without significant volume changes. TMS parameters of intracortical inhibition and facilitation, which were significantly impaired in presymptomatic GRN mutation carriers, correlated with reduced SA and CV of the right insula. Our results suggest that splitting CV into its two main components could improve the sensitivity when exploring structural brain changes in presymptomatic or early phases of neurodegenerative conditions. TMS parameters might reflect damage within cortical regions reported to be affected early in the conversion to the symptomatic phase of the disease.

Abstract ObjectiveThe aim of this study is to evaluate the differences in clinical presentations and the impact of healthcare organization on outcomes of neurological COVID-19 patients admitted during the first and second pandemic waves.MethodsIn this single-center cohort study, we included all patients with SARS-CoV-2 infection admitted to a Neuro-COVID Unit. Demographic, clinical, and laboratory data were compared between patients admitted during the first and second waves of the COVID-19 pandemic.ResultsTwo hundred twenty-three patients were included, of whom 112 and 111 were hospitalized during the first and second pandemic waves, respectively. Patients admitted during the second wave were younger and exhibited pulmonary COVID-19 severity, resulting in less oxygen support (n = 41, 36.9% vs n = 79, 70.5%, p < 0.001) and lower mortality rates (14.4% vs 31.3%, p = 0.004). The different healthcare strategies and early steroid treatment emerged as significant predictors of mortality independently from age, pre-morbid conditions and COVID-19 severity in Cox regression analyses.ConclusionsDifferences in healthcare strategies during the second phase of the COVID-19 pandemic probably explain the differences in clinical outcomes independently of disease severity, underlying the importance of standardized early management of neurological patients with SARS-CoV-2 infection.

BackgroundSeveral people affected by COVID-19 experienced neurological manifestations, altered sleep quality, mood disorders, and disability following hospitalization for a long time.ObjectiveTo explore the impact of different neurological symptoms on sleep quality, mood, and disability in a consecutive series of patients previously hospitalized for COVID-19 disease.MethodsWe evaluated 83 patients with COVID-19 around 3 months after hospital discharge. They were divided into 3 groups according to their neurological involvement (i.e., mild, unspecific, or no neurological involvement). Socio-demographic, clinical data, disability level, emotional distress, and sleep quality were collected and compared between the three groups.ResultsWe found that higher disability, depressive symptoms, and lower sleep quality in patients with mild neurological involvement compared to patients with unspecific and no neurological involvement. Differences between groups were also found for clinical variables related to COVID-19 severity.ConclusionAfter 3 months from hospital discharge, patients with more severe COVID-19 and mild neurological involvement experienced more psychosocial alterations than patients with unspecific or no neurological involvement. Both COVID-19 and neurological manifestations’ severity should be considered in the clinical settings to plain tailored interventions for patients recovering from COVID-19.

IntroductionBrain fog has been described up to 1 year after SARS-CoV-2 infection, notwithstanding the underlying mechanisms are still poorly investigated. In this study, we aimed to evaluate the prevalence of cognitive complaints at 1-year follow-up and to identify the factors related to persistent brain fog in COVID-19 patients.MethodsOut of 246 COVID patients, hospitalized from March 1st to May 31st, a sample of 137 patients accepted to be evaluated at 1 year from discharge, through a full clinical, neurological, and psychological examination, including the Montreal Cognitive Assessment (MoCA), impact of event scale-revised (IES-R), Zung self-rating depression scale (SDS), Zung self-rating anxiety scale (SAS), and fatigue severity scale (FSS). Subjects with prior cognitive impairment and/or psychiatric disorders were excluded.ResultsPatients with cognitive disorders exhibited lower MoCA score (22.9 ± 4.3 vs. 26.3 ± 3.1, p = 0.002) and higher IES-R score (33.7 ± 18.5 vs. 26.4 ± 16.3, p = 0.050), SDS score (40.9 ± 6.5 vs. 35.5 ± 8.6, p = 0.004), and fatigue severity scale score (33.6 ± 16.1 vs. 23.7 ± 12.5, p = 0.001), compared to patients without cognitive complaints. Logistic regression showed a significant correlation between brain fog and the self-rating depression scale values (p = 0.020), adjusted for age (p = 0.445), sex (p = 0.178), premorbid Cumulative Illness Rating Scale (CIRS) (p = 0.288), COVID-19 severity (BCRSS) (p = 0.964), education level (p = 0.784) and MoCA score (p = 0.909).ConclusionsOur study showed depression as the strongest predictor of persistent brain fog, adjusting for demographic and clinical variables. Wider longitudinal studies are warranted to better explain cognitive difficulties after COVID-19.

Background Advances in encephalitis research have improved the definition and management of encephalitis during the acute phase. Still, little is known about long-term outcomes in different subtypes of encephalitis. Objectives To analyze the prevalence and predictors of long-term clinical outcomes in different subtypes of encephalitis. Methods All patients discharged from a tertiary hub for acute neurology with a confirmed diagnosis of encephalitis were included. Encephalitis were classified into autoimmune (AE), infectious (IE) and of unknown origin (UE) according to guidelines. Long-term neurological sequelae were evaluated using a 16-item questionnaire assessing severity and frequency of neurological symptoms, disability was scored using the expanded Disability status scale (EDSS). Long-term symptoms distribution and predictors were evaluated using univariate and multivariate regression models. Results Seventy out 105 survived patients were included (AE n = 30, IE n = 12, UE n = 28). Disability at discharge was worse in AE compared to UE (p = 0.018). Additionally, AE had a higher risk of relapse (n = 8 AE, n = 1 UE, p = 0.001). 36 patients (51,4%) showed significant disability according to EDSS; whereas 72,9% reported a significant neurological long-term sequela, including cognitive deficits (50,0%), depression (41,4%) and numbness (21,0%). Older age and abnormal MRI at onset were the strongest predictors of long-term severe sequelae. independently from the subtype of encephalitis. Discussions Long-term sequelae are common in encephalitis, and are associated with MRI abnormalities, premorbid disability, and older age at onset. Further longitudinal studies are needed to focus on biological and clinical predictors, to identify patients who might benefit from cognitive and behavioral training after discharge.