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Background: Radiologically isolated syndrome (RIS) patients might have psychiatric and cognitive deficits, which suggests an involvement of major resting-state functional networks. Notwithstanding, very little is known about the neural networks involved in RIS., Objective: To examine functional connectivity differences between RIS and healthy controls using resting-state functional magnetic resonance imaging (fMRI)., Methods: Resting-state fMRI data in 25 RIS patients and 28 healthy controls were analyzed using an independent component analysis; in addition, seed-based correlation analysis was used to obtain more information about specific differences in the functional connectivity of resting-state networks. Participants also underwent neuropsychological testing., Results: RIS patients did not differ from the healthy controls regarding age, sex, and years of education. However, in memory (verbal and visuospatial) and executive functions, RIS patients' cognitive performance was significantly worse than the healthy controls. In addition, fluid intelligence was also affected. Twelve out of 25 (48%) RIS patients failed at least one cognitive test, and six (24.0%) had cognitive impairment. Compared to healthy controls, RIS patients showed higher functional connectivity between the default mode network and the right middle and superior frontal gyri and between the central executive network and the right thalamus ( p FDR < 0.05; corrected). In addition, the seed-based correlation analysis revealed that RIS patients presented higher functional connectivity between the posterior cingulate cortex, an important hub in neural networks, and the right precuneus., Conclusion: RIS patients had abnormal brain connectivity in major resting-state neural networks and worse performance in neurocognitive tests. This entity should be considered not an "incidental finding" but an exclusively non-motor (neurocognitive) variant of multiple sclerosis., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: To understand COVID-19 characteristics in people with multiple sclerosis (MS) and identify high-risk individuals due to their immunocompromised state resulting from the use of disease-modifying treatments., Methods: Retrospective and multicenter registry in patients with MS with suspected or confirmed COVID-19 diagnosis and available disease course (mild = ambulatory; severe = hospitalization; and critical = intensive care unit/death). Cases were analyzed for associations between MS characteristics and COVID-19 course and for identifying risk factors for a fatal outcome., Results: Of the 326 patients analyzed, 120 were cases confirmed by real-time PCR, 34 by a serologic test, and 205 were suspected. Sixty-nine patients (21.3%) developed severe infection, 10 (3%) critical, and 7 (2.1%) died. Ambulatory patients were higher in relapsing MS forms, treated with injectables and oral first-line agents, whereas more severe cases were observed in patients on pulsed immunosuppressors and critical cases among patients with no therapy. Severe and critical infections were more likely to affect older males with comorbidities, with progressive MS forms, a longer disease course, and higher disability. Fifteen of 33 patients treated with rituximab were hospitalized. Four deceased patients have progressive MS, 5 were not receiving MS therapy, and 2 were treated (natalizumab and rituximab). Multivariate analysis showed age (OR 1.09, 95% CI, 1.04-1.17) as the only independent risk factor for a fatal outcome., Conclusions: This study has not demonstrated the presumed critical role of MS therapy in the course of COVID-19 but evidenced that people with MS with advanced age and disease, in progressive course, and those who are more disabled have a higher probability of severe and even fatal disease., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Diffusion tensor imaging (DTI) studies have detected white matter microstructural changes in essential tremor (ET). However, it is still unclear whether these changes are related to cognitive deficits, which have been described in ET patients. DTI-derived fractional anisotropy, mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity measures were compared between 23 ET patients and 23 age-, gender-, and education-matched healthy individuals, using whole-brain tract-based spatial statistics. Correlations of white matter changes with scores obtained from a detailed neuropsychological assessment were subsequently examined. ET patients demonstrated increases in MD in the bilateral posterior corona radiata, bilateral superior longitudinal fasciculus, bilateral fornix (cres)/stria terminalis, genu and splenium of the corpus callosum, bilateral anterior and posterior limbs of internal capsule, bilateral retrolenticular region part of internal capsule, and left posterior thalamic radiation. Except for the genu of the corpus callosum, an increase in AD values was also found in these same tracts. Furthermore, increased MD and AD values in different white matter areas was negatively correlated with performance on language and verbal memory and positively with visuospatial ability. These correlations suggest that white matter changes might be involved in the pathogenesis of cognitive deficits in ET.

Background: Orthostatic tremor (OT) remains among the most intriguing and poorly understood of movement disorders. Compared to Parkinson's disease or even essential tremor, there are very few articles addressing more basic science issues. In this review, we will discuss the findings of main case series on OT, including data on etiology, pathophysiology, diagnostic approach, treatment strategies, and outcome., Methods: Data for this review were identified by searching PUBMED (January 1966 to August 2016) for the terms "orthostatic tremor" or "shaky leg syndrome," which yielded 219 entries. We did not exclude papers on the basis of language, country, or publication date. The electronic database searches were supplemented by articles in the authors' files that pertained to this topic., Results: Owing to its rarity, the current understanding of OT is limited and is mostly based on small case series or case reports. Despite this, a growing body of evidence indicates that OT might be a progressive condition that is clinically heterogeneous (primary vs. secondary cases) with a broader spectrum of clinical features, mainly cerebellar signs, and possible cognitive impairment and personality disturbances. Along with this, advanced neuroimaging techniques are now demonstrating distinct anatomical and functional changes, some of which are consistent with neuronal loss., Discussion: OT might be a family of diseases, unified by the presence of leg tremor, but further characterized by etiological and clinical heterogeneity. More work is needed to understand the pathogenesis of this condition., Competing Interests: Funding: Dr. Benito-León is supported by the National Institutes of Health, Bethesda, MD, USA (NINDS #R01 NS39422), the Commission of the European Union (grant ICT-2011-287739, NeuroTREMOR), and the Spanish Health Research Agency (grant FIS PI12/01602). Conflict of Interest: The authors report no conflict of interest. Ethics Statement: This study was reviewed by the authors’ institutional ethics committee and was considered exempted from further review.

To date, it remains largely unknown whether there is in radiologically isolated syndrome (RIS) brain damage beyond visible T2 white matter lesions. We used single- voxel proton magnetic resonance spectroscopy and diffusion tensor imaging (3 T MRI) to analyze normal-appearing brain tissue regions in 18 RIS patients and 18 matched healthy controls. T2-hyperintense lesion volumes and structural brain volumes were also measured. The absolute metabolite concentrations and ratios of total N-acetylaspartate+N-acetylaspartyl glutamate (NAA), choline-containing compounds, myoinositol, and glutamine-glutamate complex to creatine were calculated. Spectral analysis was performed by LCModel. Voxelwise morphometry analysis was performed to localize regions of brain tissue showing significant changes of fractional anisotropy or mean diffusivity. Compared with healthy controls, RIS patients did not show any significant differences in either the absolute concentration of NAA or NAA/Cr ratio in mid-parietal gray matter. A trend toward lower NAA concentrations (-3.35%) was observed among RIS patients with high risk for conversion to multiple sclerosis. No differences in the other metabolites or their ratios were observed. RIS patients showed lower fractional anisotropy only in clusters overlapping lesional areas, namely in the cingulate gyrus bilaterally and the frontal lobe subgyral bilaterally (P < 0.001). Normalized brain and cortical volumes were significantly lower in RIS patients than in controls (P = 0.01 and P = 0.03, respectively). Our results suggest that in RIS, global brain and cortical atrophy are not primarily driven by significant occult microstructural normal appearing brain damage. Longitudinal MRI studies are needed to better understand the pathological processes underlying this novel entity., Competing Interests: The authors have no conflicts of interest to disclose.

Very little is known about the pathogenesis of orthostatic tremor (OT). We have observed that OT patients might have deficits in specific aspects of neuropsychological function, particularly those thought to rely on the integrity of the prefrontal cortex, which suggests a possible involvement of frontocerebellar circuits. We examined whether resting-state functional magnetic resonance imaging (fMRI) might provide further insights into the pathogenesis on OT. Resting-state fMRI data in 13 OT patients (11 women and 2 men) and 13 matched healthy controls were analyzed using independent component analysis, in combination with a "dual-regression" technique, to identify group differences in several resting-state networks (RSNs). All participants also underwent neuropsychological testing during the same session. Relative to healthy controls, OT patients showed increased connectivity in RSNs involved in cognitive processes (default mode network [DMN] and frontoparietal networks), and decreased connectivity in the cerebellum and sensorimotor networks. Changes in network integrity were associated not only with duration (DMN and medial visual network), but also with cognitive function. Moreover, in at least 2 networks (DMN and medial visual network), increased connectivity was associated with worse performance on different cognitive domains (attention, executive function, visuospatial ability, visual memory, and language). In this exploratory study, we observed selective impairments of RSNs in OT patients. This and other future resting-state fMRI studies might provide a novel method to understand the pathophysiological mechanisms of motor and nonmotor features of OT., Competing Interests: The authors have no conflicts of interest to disclose.

The unanticipated magnetic resonance imaging (MRI) detection in the brain of asymptomatic subjects of white matter lesions suggestive of multiple sclerosis has recently been named as radiologically isolated syndrome (RIS). The pathophysiological processes of RIS remain largely unknown and questions as to whether gray matter alterations actually occur in this entity are yet to be investigated in more detail. By means of a 3 T multimodal MRI approach, we searched for cortical and deep gray matter changes in a cohort of RIS patients. Seventeen RIS patients, 17 clinically isolated syndrome (CIS) patients (median disease duration from symptom onset = 12 months), and 17 healthy controls underwent MRI and neuropsychological testing. Normalized deep gray matter volumes and regional cortical thickness were assessed using FreeSurfer. SIENAX was used to obtain normalized global and cortical brain volumes. Voxelwise morphometry analysis was performed by using SPM8 software to localize regions of brain tissue showing significant changes of fractional anisotropy or mean diffusivity. Although no differences were observed between CIS and healthy controls groups, RIS patients showed significantly lower normalized cortical volume (673 ± 27.07 vs 641 ± 35.88 [cm³ × 10³, Tukey P test = 0.009) and mean thalamic volume (0.0051 ± 0.4 vs 0.0046 ± 0.4 mm, P = 0.014) compared with healthy controls. RIS patients also showed significant thinning in a number of cortical areas, that were primarily distributed in frontal and temporal lobes (P < 0.05, uncorrected). Strong correlations were observed between T2-white matter lesion volume and regional cortical thickness (rho spearman ranging from 0.60 to 0.80). Our data suggest that white matter lesions on T2-weighted images are not the only hallmark of RIS. Future longitudinal studies with larger samples are warranted to better clarify the effect of RIS-related white matter lesions on gray matter tissue., Competing Interests: The authors have no funding and conflicts of interest.

Evidence regarding the relationship between performance on specific cognitive domains and cause of death is scarce. We assessed whether specific cognitive domains predicted mortality and the presence of any association with specific causes of death in a population-dwelling sample of non-demented older adults. In this population-based, prospective study (NEDICES), 2,390 non-demented subjects ≥65 years completed a brief neuropsychological battery. Cox's proportional hazards models, adjusted by sociodemographic and comorbidity factors, global cognitive performance, educational level, and premorbid intelligence were used to assess the risk of death. Participants were followed for a median of 9.2 years (range 0.01-10.7), after which the death certificates of those who died were examined. 880 (36.8%) of 2,390 participants died over a median follow-up of 5.5 years (range 0.01-10.5). Using adjusted Cox regression models, we found that hazard ratios for mortality in participants within the lowest tertiles (worse performance) were 1.31 (speed of cognitive processing, p = 0.03); 1.22 (semantic fluency, p = 0.04), 1.32 (delayed free recall, p = 0.003), and 1.23 (delayed logical memory, p = 0.03). Poor performance on delayed recall and speed of cognitive processing tests were associated with dementia and cerebrovascular disease mortality, respectively. Further, poor performance on semantic fluency was associated with decreased cancer mortality. In this study of community dwelling non-demented older adults, worse neuropsychological performance was associated with increased risk of mortality. Performance on specific cognitive domains were related to different causes of death. Of particular note there appears to be an inverse association between poor semantic fluency and cancer mortality.

Background: Eyelid nystagmus is a rare clinical phenomenon described mostly related to brainstem or cerebellum lesions. The mechanism of this phenomenon is incompletely understood., Patients and Methods: We report 2 cases of eyelid nystagmus induced by carbamazepine and oxcarbazepine intoxication., Conclusions: Carbamazepine and derivatives may induce eyelid nystagmus in the setting of acute intoxication. To the best of our knowledge, these are the first cases of drug-related eyelid nystagmus.