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Background and purpose The unanticipated detection by magnetic resonance imaging (MRI) in the brain of asymptomatic subjects of white matter lesions suggestive of multiple sclerosis (MS) has been named radiologically isolated syndrome (RIS). As the difference between early MS [i.e. clinically isolated syndrome (CIS)] and RIS is the occurrence of a clinical event, it is logical to improve detection of the subclinical form without interfering with MRI as there are radiological diagnostic criteria for that. Our objective was to use machine-learning classification methods to identify morphometric measures that help to discriminate patients with RIS from those with CIS. Methods We used a multimodal 3-T MRI approach by combining MRI biomarkers (cortical thickness, cortical and subcortical grey matter volume, and white matter integrity) of a cohort of 17 patients with RIS and 17 patients with CIS for single-subject level classification. Results The best proposed models to predict the diagnosis of CIS and RIS were based on the Naive Bayes, Bagging and Multilayer Perceptron classifiers using only three features: the left rostral middle frontal gyrus volume and the fractional anisotropy values in the right amygdala and right lingual gyrus. The Naive Bayes obtained the highest accuracy [overall classification, 0.765; area under the receiver operating characteristic (AUROC), 0.782]. Conclusions A machine-learning approach applied to multimodal MRI data may differentiate between the earliest clinical expressions of MS (CIS and RIS) with an accuracy of 78%.

The potential influence of the timing of high-efficacy disease-modifying therapies (heDMTs) on processing speed (PS) performance is critically lacking in current literature.To assess the extent to which early commencement of heDMTs would be associated with a better PS evolution as compared to moderate efficacy disease-modifying therapies (meDMTs) and delayed commencement of heDMTs.In this ongoing prospective longitudinal study, the 695 MS patients that have received a PS evaluation at 12-month of follow-up measured by the iPad®-based Processing Speed Test (PST) were retained for the analysis. All patients who had ever been prescribed a high efficacy disease-modifying therapy (heDMT) were classified in tertiles according to the proportion of their disease duration that had been on heDMTs. Based on these tertiles and the time to the first heDMT from the disease onset, patients were divided into the early heDMT group and the delayed heDMT group. Between-group differences in mean PST standardized (Z-score) change from baseline were analyzed using a linear mixed model.In the multivariable model, each year of delay in starting a heDMT was associated with increased odds of cognitive worsening at 12-month (OR = 1.0324, 95% CI = 1.014-1.062, p0.05). MeDMT-treated patients were at a significantly higher risk for cognitive worsening than early heDMT patients (OR= 2.57, 95%CI = 1.02-6.17). Linear mixed model-based adjusted mean change in PST Z-score from baseline was significantly better in those patients with the longest proportion of their disease duration treated with heDMT (highest tertile) compared to the lowest tertile (difference 0.37 [95%CI 0.02-0.92;p=0.036) and medium tertile (difference 0.39 [95%CI 0.06-0.31;p=0.037).Early he-DMT-treated patients are at significantly lower risk for cognitive worsening. Early administration of heDMTs is associated with greater cognitive functioning improvements than delayed commencement or meDMTs.

Up to a third of patients with radiologically isolated syndrome (RIS) exhibit lower-than-expected cognitive performances in neuropsychological evaluations, but the relationship between cognitive impairment (CI) and quantitative magnetic resonance (MRI) measures has not been stablished. Furthermore, the prognostic role of CI in RIS for conversion to MS is currently unknown. We assessed 17 patients with RIS and 17 matched healthy controls (HC) with a neurophychological battery and a 3T MRI. Six patients (35,3%) fulfilled our criterion for CI (scores 2 SDs below the mean of HC in at least two cognitive tests) (ci-RIS). The ci-RIS subgroup showed lower values of normalized brain and gray matter volumes when compared to HC. After a median follow-up time of 4.5 years, the ci-RIS subgroup presented a higher conversion rate to MS, suggesting that CI might be an independent risk factor for conversion to MS.

Our understanding of radiologically isolated syndrome (RIS) is evolving, as new data emerge on the clinical characterization and the pathophysiological nature of this rare entity. This topical review aims to (1) outline state-of-the-art clinical and magnetic resonance imaging findings of RIS research; (2) raise the main obstacles to RIS research; (3) discuss the most controversial issues of current RIS findings; and (4) highlight potential strategies for upcoming research studies.

Essential tremor (ET) might be a family of diseases unified by the presence of kinetic tremor, but also showing etiological, pathological, and clinical heterogeneity. In this review, we will describe the most significant clinical evidence, which suggests that ET is linked to the cerebellum. Data for this review were identified by searching PUBMED (January 1966 to May 2015) crossing the terms "essential tremor" (ET) and "cerebellum," which yielded 201 entries, 11 of which included the term "cerebellum" in the article title. This was supplemented by articles in the author's files that pertained to this topic. The wide spectrum of clinical features of ET that suggest that it originates as a cerebellar or cerebellar outflow problem include the presence of intentional tremor, gait and balance abnormalities, subtle features of dysarthria, and oculomotor abnormalities, as well as deficits in eye-hand coordination, motor learning deficits, incoordination during spiral drawing task, abnormalities in motor timing and visual reaction time, impairment of social abilities, improvement in tremor after cerebellar stroke, efficacy of deep brain stimulation (which blocks cerebellar outflow), and cognitive dysfunction. It is unlikely, however, that cerebellar dysfunction, per se, fully explains ET-associated dementia, because the cognitive deficits that have been described in patients with cerebellar lesions are generally mild. Overall, a variety of clinical findings suggest that in at least a sizable proportion of patients with ET, there is an underlying abnormality of the cerebellum and/or its pathways.

Background An association between head trauma and essential tremor (ET) has not been formally assessed. Our purpose was to assess the association between serious head trauma and ET. Methods History of head trauma was assessed in 274 ET cases and 3201 controls in the Neurological Disorders in Central Spain (NEDICES) study, a population-based study in central Spain. Head trauma was defined as serious only if the subject reported that the trauma resulted in loss of consciousness, hospitalization, or a visit to the emergency department. Results Thirty-two (11.7%) of 274 ET cases vs. 260 (8.1%) of 3201 controls reported a history of serious head trauma (p = 0.04). In an adjusted logistic regression analysis, participants who reported serious head trauma were 52% more likely to have ET (odds ratio [OR] 1.52; 95% confidence interval [CI] 1.02–2.27, p = 0.04). The odds of ET increased with increasing age of head trauma: adjusted ORs = 1.23 (95% CI 0.43–3.46, p = 0.70) for serious head trauma that occurred before age 18 years, adjusted OR = 1.49 (95% CI 0.62–3.55, p = 0.37) for serious head trauma between ages 18 to 39 years, and adjusted OR = 1.61 (95% CI 1.00–2.57, p = 0.04) for serious head trauma at age 40 years or older. Conclusions Our study suggests that serious head trauma, especially when it occurs after 40 years, is associated with increased odds of ET. Additional studies are needed to reproduce this novel finding.

Background Essential tremor (ET), a highly-prevalent, progressive, aging-associated neurological disease, poses a significant public health challenge. Aside from its associated motor features, the disease affects cognition in some patients, mood, and morale, and has been associated with increased risk of mortality in the elderly. Studies have not investigated the relationship between self-rated health and risk of ET. We determined whether baseline poor self-rated health was associated with increased risk of incident ET. Methods In this prospective, population-based study of people ≥65 years of age, subjects were evaluated at baseline and 3 years later. At baseline, subjects were asked to rate their health using a single-item health question. Hazard ratios (HR) of ET according to baseline self-rated health (very good, good, fair, poor, and very poor) were estimated with Cox models. Results The 3853 subjects had a median follow-up duration of 3.2 years. There were 82 incident ET cases. Compared to subjects who rated their health as good or very good, the risk of ET was increased for subjects who rated their health as fair (HR = 1.69, p = 0.03), and for subjects who rated their health as poor or very poor (HR = 2.12, p = 0.02). In a fully adjusted model, the risk remained increased for subjects who rated their health as poor or very poor (HR = 2.34, p = 0.01). Conclusions Subjects rating their health as poor/very poor at baseline were at increased risk of incident ET at follow-up. Premotor and/or early motor symptoms of ET could negatively influence self-perceptions of health status.

Background Multiple sclerosis (MS) patients have high rates of complications and disability, including cognitive impairment, that often, impact on caregivers' emotional health. Clarification may help identify improved supportive strategies for both caregivers and patients. Objective We aimed to analyse whether MS domain-specific cognitive impairment can influence the severity of psychiatric symptoms of MS caregivers. Methods Patients with definite MS (n = 63) and their corresponding caregivers (n = 63) were recruited. In addition, 59 matched controls were enrolled for establishing normative cognitive data. Each patient underwent a complete neuropsychological testing for cognitive impairment and thorough clinical assessment, including data of disability status (EDSS), affective and emotional symptoms (depression, anxiety, anger) and fatigue. Psychiatric symptoms of the caregivers were assessed with the Beck Anxiety Inventory (BAI) and the Beck Depression Inventory (BDI). Results In logistic regression analyses, even after controlling for other MS-related symptoms, cognitive deficits, namely impairment on Symbol Digit Modalities Test (OR = 8.03, 95% CI = 1.27–25.33, p = 0.027) and on the Paced Auditory Serial Addition Test (OR = 6.86, 95% CI = 1.07–21.97, p = 0.042), were significant and independent predictors of more severe caregivers' depressive symptoms. Conclusions Information processing speed impairment is independently associated with more severe depressive symptoms of caregivers of MS patients, thereby reflecting a further deterioration of family setting.

Background: There is evidence of the presence of a disturbed pattern of anger in multiple sclerosis (MS). Emotion changes, including anger, are thought to influence health-related quality of life (HRQoL). However, although deleterious consequences of anger on physical health have been well reported, there are no studies that have analysed the effects of anger on the HRQoL in patients with MS. Our purpose was to assess the extent to which anger impacts on the HRQoL of a cohort of MS patients. Methods: One hundred and fifty-seven consecutive MS patients were enrolled in the study. Participants were administered affective trait measures (Beck Depression Inventory, Beck Anxiety Inventory) and anger measures (the Spanish adapted version of the State-Trait Anger Expression Inventory-2). HRQoL was quantified using the Functional Assessment of MS. Results: Linear regression analyses revealed that even after controlling for socio-demographic and clinical variables, higher levels of anger expression-in (tendency to handle anger by keeping it inside) independently predicted worse overall HRQoL of MS patients (β = −0.15, p = 0.04). We further found that this relationship was moderated by gender, showing that anger expression-in is a more influential predictor of the HRQoL in women with MS. Conclusion: The present study provides evidence that anger negatively affects the HRQoL of MS patients. Our results may have implications for those involved in treating emotional complications of MS and especially regarding psychotherapeutic interventions to improve HRQoL of MS patients.

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

Background: Little information exists about how cognitive impairment in multiple sclerosis (MS) patients impacts on their caregivers’ health-related quality of life (HRQoL). Background: The objective of this paper is to examine the extent to which cognitive impairment in MS patients contributes to caregivers’ HRQoL. Methods: A total of 63 MS patients, 63 caregivers and 59 matched controls were recruited. Patients and controls underwent a neuropsychological assessment, including tests of working memory, speed of information processing, executive function, and verbal fluency. HRQoL of the caregivers was assessed by CAREQOL-MS. In logistic regression models, we adjusted for the effects of confounding variables. In these models, the dependent variable was the CAREQOL-MS (higher median of CAREQOL-MS (worse HRQoL) vs. lower median of CAREQOL-MS (better HRQoL) (reference)), and the independent variable was the impairment on each neuropsychological test vs. its integrity (reference). Results: Cognitive impairment in MS patients was significantly associated with worse caregiver HRQoL (adjusted odds ratio (OR) = 3.10, 95% confidence interval (CI) = 1.07–11.55, p = 0.04). In secondary analyses in which each neuropsychological test was entered in the analyses separately, only Symbol Digit Modalities Test (a measurement of information processing speed) impairment (OR = 4.22, 95%, CI = 1.16–14.53, p = 0.03) was significantly associated with worse caregiver HRQoL. Conclusions: MS patients’ caregivers’ HRQoL is significantly influenced by information processing speed impairment of MS patients.

Introduction In recent years there has been a focus on health-related quality of life in multiple sclerosis (MS) and in particular the importance of non-motor problems such as fatigue, pain, depression, anxiety, and cognitive disorders. However, little attention has been focused on other negative emotions, such as anger. Our purpose was to evaluate whether trait anger (a predisposition to experience frequent and intense episodes of anger over time) is different between persons with and without MS after controlling for depression, anxiety, and other socio-demographic variables. Methods 157 consecutive MS patients were enrolled in the study and compared to eighty age, gender, and education-matched healthy controls. Participants were administered affective trait measures (Beck Depression Inventory, Beck Anxiety Inventory) and the trait anger measure (the Spanish adapted version of the State–Trait Anger Expression Inventory-2 [STAXI-2]). Results MS patients had significantly higher scores on anger intensity (state anger) and trait anger than did controls. They also had a trend to experience direct anger toward other persons or objects in the environment (higher anger expression-out score) and to hold in or suppress angry feelings (higher anger expression-in score). However, in a regression analysis that adjusted for different demographic and clinical variables, we found that diagnosis category (MS patient vs. control) was associated with none of the highest quartiles of STAXI-2 scores, except for the Trait Anger scale (odds ratios between 2.35 and 3.50). Conclusions The present study provides further evidence that MS is independently associated with high trait anger.