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Introduction: Multiple Sclerosis (MS) can affect the ability to perform complex tasks such as driving. The Expanded Disability Status Scale (EDSS) overlooks cognitive deficits crucial for driving. We investigated the relationship between the Multiple Sclerosis Functional Composite (MSFC), which includes cognitive assessment, and EDSS in relation to driving performance., Methods:  This exploratory study involved 30 MS patients (mean EDSS 2.4 ± 2.0) and 15 healthy controls. We correlated the results of the EDSS, MSFC, and driving performance tests, namely the Two-Hand Coordination Test (2HAND) and the Speed Anticipation Reaction Test (SART)., Results: Patients did not differ from the healthy controls regarding age, sex, and driving experience. However, they exhibited lower mean Z-scores in MSFC, particularly in motor domains, but not in cognitive function. The mean Z-score for the 25-foot Walk test was -0.42 in patients compared to -0.04 in controls. For the 9-hole Peg Test, it was 0.17 in patients versus 1.47 in controls. Patients had a mean total error time of 19.7 seconds for both hands in the 2HAND test, compared to 7.7 seconds in controls. In MS patients, the MSFC and EDSS significantly correlated with SART and 2HAND components. While upper limb function (9-HPT) did not correlate with 2HAND, cognitive function (PASAT) did correlate with the number of 2HAND errors, indicating that cognitive dysfunction impacts driving performance more than physical dysfunction., Conclusion: The MSFC may provide valuable insights into the driving abilities of MS patients, potentially offering advantages over the EDSS in predicting driving performance. Further research with larger, more diverse populations across various driving environments is necessary to validate these findings., Competing Interests: Declaration of Competing Interest There are no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: A wide variety of associated movement disorders has been described in multiple sclerosis., Phenomenology Shown: A 57-year-old woman with primary progressive multiple sclerosis developed spinal segmental myoclonus associated with focal myelitis., Educational Value: Movement disorders in multiple sclerosis are phenomenologically diverse and have varied pathophysiological mechanisms, making it essential to identify them to initiate appropriate treatment., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2024 The Author(s).)

Introduction: Fatigue is one of the most disabling symptoms of multiple sclerosis (MS), and effective treatments are lacking. Amantadine is one of the most used treatments, although its efficacy is under debate. Transcranial magnetic stimulation (TMS) is a promising intervention that has shown positive effects in some preliminary investigations. We aim to investigate the effect of 6 weeks of amantadine and/or TMS in fatigue due to MS., Methods and Analysis: The study is a national, multicentre, phase 3, randomised, double-blind, cross-over, placebo-controlled and sham-controlled clinical trial. Adult patients with relapsing-remitting MS, Expanded Disability Status Scale score of 1.5-4.5 and Fatigue Severity Score>4 are eligible for the trial. Participants will be randomised to one of the sequences of the study. Each sequence consists of four periods of 6 weeks of treatment and three washout periods of 12-18 weeks. All patients will receive all the combinations of therapies. The primary outcome is the Modified Fatigue Impact Scale. The secondary outcomes are the Symbol Digit Modalities Test (cognition), Beck Depression Inventory-II (depressive symptoms) and Short-Survey 12 (quality of life). Safety and cost-effectiveness will also be evaluated. An exploratory substudy including MRI and blood biomarkers will be conducted., Ethics and Dissemination: The study is approved by the Ethics Committee of the Hospital Clinico San Carlos and the Spanish Agency of Medications and Medical Devices. All study findings will be published in scientific peer-reviewed journals and presented at relevant scientific conferences., Trial Registration Number: EudraCT 2021-004868-95; NCT05809414., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: As their disease evolves, most patients with progressive forms of multiple sclerosis (MS) develop particular healthcare needs that are not always addressed with usual follow-up. To adapt neurological care to these patients, we created a specific consultation for patients with progressive MS in our centre in 2019., Objectives: To explore the main unmet care needs of patients with progressive MS in our setting, and to establish the usefulness of the specific consultation to address them., Methods: Literature review and interviews with patients and healthcare professionals were conducted to identify the main unmet needs in routine follow-up. Two questionnaires were developed, assessing the importance of the unmet needs identified and the usefulness of the consultation to meet them, for patients under follow-up in the specific consultation and their informal caregivers., Results: Forty-one patients and nineteen informal caregivers participated. The most important unmet needs were the information about the disease, access to social services and coordination between specialists. A positive correlation was found between the importance of these unmet needs and the responsiveness to each of them in the specific consultation., Conclusions: The creation of a specific consultation may improve attention to the healthcare needs of patients with progressive MS., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Several recent works have raised the possibility of the contribution of the lymphocyte activation gene 3 (LAG3) protein in the inflammatory processes of multiple sclerosis (MS). Results of studies on the possible association between LAG3 gene variants and the risk of MS have been inconclusive. In this study, we tried to show the possible association between the most common single nucleotide variants (SNVs) in the CD4 and LAG3 genes (these two genes are closely related) and the risk of MS in the Caucasian Spanish population. We studied the genotypes and allelic variants CD4 rs1922452 , CD4 rs951818 , and LAG3 rs870849 in 300 patients diagnosed with MS and 400 healthy patients using specific TaqMan -based qPCR assays. We analyzed the possible influence of the genotype frequency on age at the onset of MS, the severity of MS, clinical evolutive subtypes of MS, and the HLADRB1*1501 genotype. The frequencies of the CD4 rs1922452 , CD4 rs951818 , and LAG3 rs870849 genotypes and allelic variants were not associated with the risk of MS and were unrelated to gender, age at onset and severity of MS, the clinical subtype of MS, and HLADRB1*1501 genotype. The results of the current study showed a lack of association between the CD4 rs1922452 , CD4 rs951818 , and LAG3 rs870849 SNVs and the risk of developing MS in the Caucasian Spanish population.

Despite the importance of cognitive function in multiple sclerosis, it is poorly represented in the Expanded Disability Status Scale (EDSS), the commonly used clinical measure to assess disability, suggesting that an analysis of eye movement, which is generated by an extensive and well-coordinated functional network that is engaged in cognitive function, could have the potential to extend and complement this more conventional measure. We aimed to measure the eye movement of a case series of MS patients with relapsing−remitting MS to assess their cognitive status using a conventional gaze tracker. A total of 41 relapsing−remitting MS patients and 43 age-matched healthy controls were recruited for this study. Overall, we could not find a clear common pattern in the eye motor abnormalities. Vertical eye movement was more impaired in MS patients than horizontal movement. Increased latencies were found in the prosaccades and reflexive saccades of antisaccade tests. The smooth pursuit was impaired with more corrections (backup and catchup movements, p<0.01). No correlation was found between eye movement variables and EDSS or disease duration. Despite significant alterations in the behavior of the eye movements in MS patients, which are compatible with altered cognitive status, there is no common pattern of these alterations. We interpret this as a consequence of the patchy, heterogeneous distribution of white matter involvement in MS that provokes multiple combinations of impairment at different points in the different networks involved in eye motor control. Further studies are therefore required.

Background: Multiple sclerosis (MS), a subset of chronic primary inflammatory demyelinating disorders of the central nervous system, is closely associated with various movement disorders. These disorders may be due to MS pathophysiology or be coincidental. This review describes the full spectrum of movement disorders in MS with their possible mechanistic pathways and therapeutic modalities., Methods: The authors conducted a narrative literature review by searching for 'multiple sclerosis' and the specific movement disorder on PubMed until October 2021. Relevant articles were screened, selected, and included in the review according to groups of movement disorders., Results: The most prevalent movement disorders described in MS include restless leg syndrome, tremor, ataxia, parkinsonism, paroxysmal dyskinesias, chorea and ballism, facial myokymia, including hemifacial spasm and spastic paretic hemifacial contracture, tics, and tourettism. The anatomical basis of some of these disorders is poorly understood; however, the link between them and MS is supported by clinical and neuroimaging evidence. Treatment options are disorder-specific and often multidisciplinary, including pharmacological, surgical, and physical therapies., Discussion: Movements disorders in MS involve multiple pathophysiological processes and anatomical pathways. Since these disorders can be the presenting symptoms, they may aid in early diagnosis and managing the patient, including monitoring disease progression. Treatment of these disorders is a challenge. Further work needs to be done to understand the prevalence and the pathophysiological mechanisms responsible for movement disorders in MS., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2022 The Author(s).)

Introduction: A growing number of studies have evaluated the effects of transcranial magnetic stimulation (TMS) for the symptomatic treatment of multiple sclerosis (MS)., Methods: We performed a PubMed search for articles, recent books, and recommendations from the most relevant clinical practice guidelines and scientific societies regarding the use of TMS as symptomatic treatment in MS., Conclusions: Excitatory electromagnetic pulses applied to the affected cerebral hemisphere allow us to optimise functional brain activity, including the transmission of nerve impulses through the demyelinated corticospinal pathway. Various studies into TMS have safely shown statistically significant improvements in spasticity, fatigue, lower urinary tract dysfunction, manual dexterity, gait, and cognitive deficits related to working memory in patients with MS; however, the exact level of evidence has not been defined as the results have not been replicated in a sufficient number of controlled studies. Further well-designed, randomised, controlled clinical trials involving a greater number of patients are warranted to attain a higher level of evidence in order to recommend the appropriate use of TMS in MS patients across the board. TMS acts as an adjuvant with other symptomatic and immunomodulatory treatments. Additional studies should specifically investigate the effect of conventional repetitive TMS on fatigue in these patients, something that has yet to see the light of day., (Copyright © 2018 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.)

The possible role of oxidative stress and nitric oxide (NO) in the pathogenesis of multiple sclerosis (MS) has been suggested by several neuropathological, biochemical, and experimental data. Because the single-nucleotide polymorphism (SNP) rs2070744 in the endothelial nitric oxide synthase (eNOS or NOS3) gene (chromosome 7q36.1) showed association with the risk for MS in Iranians, we attempted to replicate the possible association between this SNP and the risk for MS in the Caucasian Spanish population. The frequencies of NOS3rs2070744 genotypes and allelic variants in 300 patients diagnosed with MS and 380 healthy controls were assessed with a TaqMan-based qPCR assay. The possible influence of the genotype frequency on age at onset of MS, the severity of MS, clinical evolutive subtypes of MS, and HLA-DRB1*1501 genotype were also analyzed. The frequencies of rs2070744 genotypes and allelic variants were not associated with the risk of developing MS and were not influenced by gender, age at onset and severity of MS, the clinical subtype of MS or the HLA-DRB1*1501 genotype. This study found a lack of association between NOS3 rs2070744 SNP and the risk for MS in Caucasian Spanish people.

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%., (© 2019 EAN.)

Substantial epidemiological evidence supports the involvement of the Epstein-Barr virus (EBV) in multiple sclerosis (MS). Mechanisms through which EBV may increase MS risk are reviewed here. Most individuals contract EBV in early childhood yet only develop MS in early adulthood, by which time EBV has been latent for decades. When latent, EBV is confined to a minute subset of memory B cells: about 1000 cells in peripheral blood and 500,000 cells in the lymphoid system, mainly in the mouth. Reactivation of EBV in the central nervous system (CNS) has been proposed as a cause of MS. Alternatively, EBV may enable the recognition of "forbidden" antigens by memory B cells through its presence in this leukocyte type, as first proposed by Pender. Though the requirement for B cells in MS supports both hypotheses, EBV has not been consistently found in MS lesions, as would be expected. EBV episome replication during B cell division is now known to be inefficient, resulting in some descendant B cells becoming EBV-free after a few dozen divisions. EBV-free memory B cells in the CNS may thus have descended from a memory B cell which matured while containing EBV episomes, enabling its B cell receptor to recognize "forbidden" MS-causing antigens in the CNS, even if EBV is absent from this site., (Copyright © 2017 Elsevier B.V. All rights reserved.)

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., (© The Author(s), 2016.)

Several neurochemical, neuropathological, and experimental data suggest a possible role of oxidative stress in the ethiopathogenesis of multiple sclerosis(MS). Heme-oxygenases(HMOX) are an important defensive mechanism against oxidative stress, and HMOX1 is overexpressed in the brain and spinal cord of MS patients and in experimental autoimmune encephalomyelitis(EAE). We analyzed whether common polymorphisms affecting the HMOX1 and HMOX2 genes are related with the risk to develop MS. We analyzed the distribution of genotypes and allelic frequencies of the HMOX1 rs2071746, HMOX1 rs2071747, HMOX2 rs2270363, and HMOX2 rs1051308 SNPs, as well as the presence of Copy number variations(CNVs) of these genes in 292 subjects MS and 533 healthy controls, using TaqMan assays. The frequencies of HMOX2 rs1051308AA genotype and HMOX2 rs1051308A and HMOX1 rs2071746A alleles were higher in MS patients than in controls, although only that of the SNP HMOX2 rs1051308 in men remained as significant after correction for multiple comparisons. None of the studied polymorphisms was related to the age at disease onset or with the MS phenotype. The present study suggests a weak association between HMOX2 rs1051308 polymorphism and the risk to develop MS in Spanish Caucasian men and a trend towards association between the HMOX1 rs2071746A and MS risk.

Introduction: Multiple sclerosis (MS) is the second most important cause of disability of a neurological origin in young adults. Both the physical and the psychiatric (affective and psychotic disorders) clinical signs and symptoms have a negative impact on the patients' health-related quality of life., Aim: To shed light on the prevalence and pathogenesis of the affective and psychotic symptoms present in MS., Development: This review includes an update of the most significant studies published in the literature that have analysed the prevalence and pathogenesis of affective and psychotic signs and symptoms in patients with MS. The evidence available to date was reviewed in order to explore the association between the affective and psychotic symptoms of MS., Conclusions: Depression is the most frequent psychiatric disorder in MS. Further research is needed to clarify the underlying mechanisms that can trigger affective and psychotic symptoms in MS. Controlling those symptoms in patients with MS could improve their health-related quality of life.

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., (© The Author(s), 2014.)

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., (Copyright © 2015 Elsevier B.V. All rights reserved.)

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., (© The Author(s), 2014.)

Introduction: The type of diet has been related with the inflammatory process that forms part of multiple sclerosis. In recent years, different lines of research have generated a large body of knowledge about the role played by diet in the pathogenesis of multiple sclerosis., Aim: To conduct a critical examination of the evidence suggesting the existence of a relationship between different types of diets and foods and multiple sclerosis., Development: The work includes an update of the most significant studies that have analysed the role played by diet in the pathogenesis and treatment of multiple sclerosis. In order to explore the association between diet and the risk of multiple sclerosis, the authors examined the currently available evidence, which ranged from observation-based studies to intervention studies., Conclusions: Further research on nutrition as a risk factor is needed, as it could be related with the disease and controlling it could lead to a significant reduction in the incidence or progression of the disease.

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., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: A possible role of oxidative stress in the pathogenesis of multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis has been suggested. The detoxification enzyme NAD(P)H dehydrogenase, quinone 1 (NQO1) has been found up-regulated in MS lesions. A previous report described an association between the SNP rs1800566 in the NQO1 gene and the risk for MS in the Greek population. The aim of this study was to replicate a possible influence of the. SNP rs1800566 in the NQO1 gene in the risk for MS in the Spanish Caucasian population., Methods: We analyzed allelic and genotypic frequency of NQO1 rs1800566 in 290 patients with MS and 310 healthy controls, using TaqMan Assays., Results: NQO1 rs1800566 allelic and genotypic frequencies did not differ significantly between MS patients and controls, and were unrelated with age of onset of MS, gender, and clinical type of MS., Conclusions: Our results indicate that NQO1 rs1800566 does not have an effect on MS disease risk.

Background/objectives: Some experimental data suggest a possible role of tau protein in the pathogenesis of multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis. The aim of this study was to investigate a possible influence of the SNP rs1052553 in the MAPT gene in the risk for relapsing bout onset (relapsing-remitting and secondary progressive) MS., Methods: We analyzed the allelic and genotype frequency of MAPT rs1052553, which has been associated with some neurodegenerative diseases, in 259 patients with relapsing bout onset MS and 291 healthy controls, using TaqMan Assays., Results: MAPT rs1052553 allelic and genotype frequencies did not differ significantly between relapsing bout onset MS patients and controls, and were unrelated with the age of onset of MS or gender., Conclusions: These results suggest that MAPT rs1052553 polymorphism is not related with the risk for relapsing bout onset MS., (Copyright © 2013 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Background: Some epidemiological, genetic, and experimental data suggest a possible role of vitamin D in the pathogenesis of multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis. Data on the possible contribution of several single nucleotide polymorphisms (SNP) in the vitamin D receptor (VDR) gene to the risk for MS are controversial. Several studies suggested an interaction between some SNPs in the VDR gene and HLADRB1*1501 in the risk for MS., Objectives: The aim of this study was to investigate a possible influence of the SNPs rs2228570 and rs731236 in the VDR gene in the risk for MS. A secondary objective was to address the possible interactions between VDR genes and HLADRB1*1501., Methods: We analyzed the allelic and genotype frequency of VDR rs2228570, rs731236, and HLADRB1*1501 (rs3135388) in 303 patients with MS and 310 healthy controls, using TaqMan Assays. We also conducted a meta-analysis, that was carried out by using the software Meta-Disc 1.1.1 (http://www.hrc.es/investigacion/metadisc.html; Unit of Clinical Statistics, Hospital Ramón y Cajal, Madrid, Spain). Heterogeneity between studies in terms of degree of association was tested using the Q-statistic., Results: VDR rs2228570 and rs731236 allelic and genotype frequencies did not differ significantly between MS patients and controls, and were unrelated with the age of onset of MS, gender, and course of MS. HLADRB1*1501 showed a high association with the risk of developing MS 4.76(95% C.I.  = 3.14-7.27; p<0.0001). The meta-analysis, after excluding data of one study that was responsible of heterogeneity for rs731236 polymorphism, showed lack of relation of both SNPs with the risk for MS. HLADRB1*1501 showed lack of interaction with VDR rs2228570 and rs731236 in increasing MS risk., Conclusions: These results suggest that VDR rs2228570 and rs731236 polymorphisms are not related with the risk for MS, and did not confirm interaction between these VDR SNPs and HLADRB1 in the risk for MS.

Background: Some recent experimental data suggest a possible role of LINGO-1 in the pathogenesis of multiple sclerosis (MS). In an attempt to identify genetic biomarkers related to MS susceptibility, we genotyped two common SNPs in the LINGO1 gene which have been associated to other neurological conditions, in patients with MS and in healthy subjects. These SNPs are linked to several SNPs within the LINGO1 gene, especially in individuals of Oriental or Caucasian descent., Methods: We analyzed the allelic and genotype frequency of two LINGO1 variants (rs9652490 and rs11856808) in 293 patients with MS and 318 healthy controls, using KASPar assays., Results: LINGO1 rs9652490 and rs11856808 allelic and genotype frequencies did not differ significantly between MS patients and controls. The minor allele frequencies for rs9652490 were 0.171 (95% CI = 0.140-0.201) and 0.167 (95% CI = 0.138-0.196 for cases and controls respectively (p = 0.853). For rs11856808 the minor allele frequencies were 0.317 (95% CI = 0.280-0.355) and 0.310 (95% CI = 0.274-0.346) for cases and controls, respectively (p = 0.773). Allele and genotype frequencies were unrelated with the age of onset of MS, gender, and clinical course of MS. In addition, haplotype analyses did not reveal any putative risk related to haplotypes., Conclusions: These results suggest that LINGO1 rs9652490 and rs11856808 polymorphisms are not related with risk for MS. This study adds to other published evidence indicating that, to date, the LINGO1 SNPs studied here could be useful risk biomarkers of developing essential tremor, but not other movement disorders.

Introduction: The main effects of vitamin D have to do with the homeostasis of calcium and phosphorous, and also with the regulation of bone remodelling. Yet, in recent years, different lines of research have given rise to a large body of knowledge about its role in the pathogenesis and the treatment of multiple sclerosis (MS). AIM. To carry out a critical review of the evidence that relates vitamin D with MS from an epidemiological, genetic, immunological and therapeutic point of view., Development: The work includes an update of the most significant studies that have analysed the role played by vitamin D in the pathogenesis and the treatment of MS. In order to explore the association between concentrations of vitamin D and the risk of MS, the authors examined the available evidence, which included both observation-based studies and intervention studies., Conclusions: Observation-based studies have shown a consistent inverse relationship between concentrations of vitamin D and the risk of MS. The intervention studies (basically randomised double-blind placebo-controlled trials), however, offer data that are not conclusive. The current context opens up the possibility of conducting prospective and intervention-based studies in the future that will settle the nature of this association in a more convincing manner.

Background and Purpose: To determine the value of health-related quality of life (HRQOL) in predicting progression of disability in patients with multiple sclerosis (MS) over a period of 2 years., Methods: Patients with MS were recruited in 13 outpatient clinics in Madrid, Spain. Baseline HRQOL was quantified using the Functional Assessment of MS (FAMS) and disability with Kurtzke Expanded Disability Status (EDSS). A clinical meaningful deterioration of disability was defined as an increased of ≥1 point in baseline EDSS scores of ≤5.5 and an increase of ≥0.5 point in baseline EDSS scores of ≥6.0. We dichotomized the change in disability according to clinical meaningful deterioration (dependent variable) and performed a logistic regression analysis with the tertiles of the FAMS scores (the upper tertile [high HRQOL] was the reference) as independent variable, adjusting by socio-demographic and clinical variables., Results: Out of 371 enrolled patients, 61 patients with MS dropped out during the 2-year follow-up. Of the remaining 310, 94 (30.3%) had clinical meaningful deterioration of disability. The odds of clinical meaningful deterioration of disability were higher as HRQOL decreased with a significant dose-dependent effect. Adjusted odds ratios were 2.61 [95% confidence interval (CI) 95% = 1.12-6.09], [middle tertile vs. upper tertile (reference)]; and 3.27 (95% CI = 1.31-8.18), (lower tertile vs. upper tertile)., Conclusions: The identification of those patients with MS with poor HRQOL may be important in assessing the risk of future disability progression. Clearly, impaired HRQOL should be one of the primary concerns amongst clinicians who provide treatment to patients affected by MS., (© 2012 The Author(s) European Journal of Neurology © 2012 EFNS.)

Background: An association between multiple sclerosis (MS) prevalence as well as MS mortality and vitamin D nutrition has led to the hypothesis that high levels of vitamin D could be beneficial for MS. The purpose of this systematic review is to establish whether there is evidence for or against vitamin D in the treatment of MS., Methods: Systematic literature searches were performed to locate randomized, placebo-controlled, double-blind trials measuring the clinical effect of vitamin D on MS in human participants. Data were extracted in a standardized manner, and methodological quality was assessed by the Jadad score., Results: Five trials were located that met the selection criteria. Of the 5 trials, 4 showed no effect of vitamin D on any outcome, and 1 showed a significant effect, namely by a reduction in the number of T1 enhancing lesions on brain magnetic resonance imaging. Three studies commented on adverse effects of vitamin D, with gastrointestinal adverse effects being the most frequently reported. The literature is limited by small study sizes (ranging from 23 to 68 patients), heterogeneity of dosing, form of vitamin D tested (vitamin D3 in 4 trials and vitamin D2 in 1) and clinical outcome measures. Therefore, a meta-analysis was not performed., Conclusions: The evidence for vitamin D as a treatment for MS is inconclusive. Larger studies are warranted to assess the effect of vitamin D on clinical outcomes in patients with MS. We further encourage researchers to also test the effect of vitamin D on the health-related quality of life experienced by patients and their families., (Copyright © 2012 S. Karger AG, Basel.)

Objective: To develop and test the first specific instrument for assessing caregiver health-related quality of life (HRQOL) in multiple sclerosis (MS) (CAREQOL-MS)., Study Design and Setting: Questionnaire items were derived from a literature review and the views of patients, caregivers, and experts. Instrument was reduced after the analyses of caregivers' interviews and experts' opinions. CAREQOL-MS psychometric properties were assessed in 276 MS caregivers., Results: The final version consisted of 24 items (five subscales) and was free of floor or ceiling effects. For subscales, the Cronbach's alpha coefficient ranged from 0.75 to 0.90. The item-total correlation was 0.62-0.74 for subscale I (physical burden/global health); 0.56-0.74 for subscale II (social impact); 0.52-0.62 for subscale III (emotional impact), and 0.58-0.65 for subscale IV (need of help); subscale V (emotional reactions) had only two items. The intraclass correlation coefficient (0.96 for the total score; 0.75-0.95 for subscales) suggested satisfactory reproducibility. Association was close between CAREQOL-MS subscales and the Zarit burden interview and moderate with short form 36 mental/physical components. CAREQOL-MS subscales scores significantly increased (worse HRQOL) with increasing caregivers' age and Expanded Disability Status Scale. The standard error of the measurement ranged from 0.91 to 2.43 for subscales., Conclusions: Our results provided initial evidence of the usefulness and satisfactory psychometric properties of the CAREQOL-MS., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The TNF-related apoptosis inducing ligand (TRAIL)/TRAIL receptor system participates in crucial steps in immune cell activation or differentiation. It is able to inhibit proliferation and activation of T cells and to induce apoptosis of neurons and oligodendrocytes, and seems to be implicated in autoimmune diseases. Thus, TRAIL and TRAIL receptor genes are potential candidates for involvement in susceptibility to multiple sclerosis (MS). To test whether single-nucleotide polymorphisms (SNPs) in the human genes encoding TRAIL, TRAILR-1, TRAILR-2, TRAILR-3 and TRAILR-4 are associated with MS susceptibility, we performed a candidate gene case-control study in the Spanish population. 59 SNPs in the TRAIL and TRAIL receptor genes were analysed in 628 MS patients and 660 controls, and validated in an additional cohort of 295 MS patients and 233 controls. Despite none of the SNPs withstood the highly conservative Bonferroni correction, three SNPs showing uncorrected p values<0.05 were successfully replicated: rs4894559 in TRAIL gene, p = 9.8×10(-4), OR = 1.34; rs4872077, in TRAILR-1 gene, p = 0.005, OR = 1.72; and rs1001793 in TRAILR-2 gene, p = 0.012, OR = 0.84. The combination of the alleles G/T/A in these SNPs appears to be associated with a reduced risk of developing MS (p = 2.12×10(-5), OR = 0.59). These results suggest that genes of the TRAIL/TRAIL receptor system exerts a genetic influence on MS.

Candida infection among multiple sclerosis (MS) patients has not been studied in depth. We determined whether there is an association between serological evidence of Candida infection and MS. Blood specimens were obtained from 80 MS patients and 240 matched controls. Immunofluorescence analysis and ELISA were used to detect Candida species antibodies and slot-blot to detect antigens. Using immunofluorescence analysis, moderate to high concentrations of serum antibodies to Candida famata were present in 30 (37.5%) MS patients vs. 30 (12.5%) controls (p < 0.001). Results for Candida albicans were 47.5% (38/80) in MS patients vs. 21.3% (51/240) in controls (p < 0.001), for Candida parapsilosis 37% (28/80) vs. 17.1% (41/240) (p < 0.001) and for Candida glabrata 46.3% (37/80) vs. 17.5% (42/240) (p < 0.001), respectively. After adjusting for age and gender, the odds ratios (95% confidence intervals) for MS, according to the presence of Candida antigens were: 2.8 (0.3-23.1, p = 0.337) for Candida famata; 1.5 (0.7-3.4, p = 0.290) for Candida albicans; 7.3 (3.2-16.6, p < 0.001) for Candida parapsilosis; and 3.0 (1.5-6.1, p = 0.002) for Candida glabrata. The results were similar after excluding ten patients on immunosuppressants. The results of this single study suggest that Candida species infection may be associated with increased odds of MS.

It has been suggested a possible role of oxidative stress and lipid peroxidation in the inflammatory processes and in the pathogenesis of multiple sclerosis. Human serum paraoxonase 1 is a polymorphic enzyme encoded by the gene PON1, located in chromosome 7q21.3, that plays a major role in the metabolism of organophosporus compounds, and in the protection against oxidative stress. Paraoxonase-1 activity has been found decreased in the plasma of multiple sclerosis patients. An association between PON1 polymorphism and the risk of multiple sclerosis has been described in Italians. To investigate the possible association between the PON1 genotype and allelic variants of the polymorphisms L55M and Q192R and the risk for multiple sclerosis in the Spanish Caucasian population; we studied the frequency of the PON1 genotypes and allelic variants in 228 patients with multiple sclerosis and 220 healthy controls using a PCR-RLFP method. The frequencies of the PON1 genotypes and allelic variants did not differ significantly between patients and controls, and were unrelated with gender, age of onset, and course of the disease. The OR (95% confidence intervals) for the variant alleles PON1-55L and PON1-192R were 0.96 (0.73-1.26) and 1.01 (0.76-1.35), respectively. The results of the present study suggest that PON1 polymorphism is not related with the risk for multiple sclerosis in our population.

The MRI Barkhof-Tintoré criteria have proved to be highly specific for predicting conversion to clinically definite multiple sclerosis in patients with clinically isolated syndromes (CIS), but lacked an optimal sensitivity. In order to improve the accuracy of early multiple sclerosis diagnosis, new imaging criteria have been proposed by Swanton et al. We aimed to evaluate the accuracy of both MRI criteria for dissemination in space to predict conversion from CIS to clinically definite multiple sclerosis. We studied 79 CIS patients with baseline MRI performed within the first 3 months after onset. The sensitivity and specificity of both MRI criteria to predict conversion to clinically definite multiple sclerosis were analysed. The time to develop clinically definite multiple sclerosis from CIS onset, according to each imaging criteria, was studied by Kaplan-Meier survival curves. The overall conversion rate was 75.7% with a median follow-up of 57 months. Barkhof- Tintoré's criteria showed a sensitivity of 71.9% and a specificity of 77.2%. Swanton's criteria had a sensitivity of 91.2% and a specificity of 68.1%. Both MRI criteria identified CIS patients with higher risk and faster conversion to clinically definite multiple sclerosis. Swanton's criteria are simpler and more sensitive than Barkhof-Tintoré's criteria, with a slight decrease in specificity. These results reinforce their use in multiple sclerosis diagnosis.

Little information exists about caregivers of persons with multiple sclerosis (MS). Our aims were to describe the characteristics of a sample of caregivers of persons with MS, assess their perceived burden, health-related quality of life, and investigate factors influencing this burden. We studied 278 caregivers of persons with MS, recruited from a Spanish cross-sectional survey, measuring health-related quality of life by the 36-Item Short-Form Health Survey (SF-36) and burden by the Zarit Caregiver Burden Interview. Of the caregivers, 56.8% were female and their mean age was 50.1 +/- 12.6 years. Their main relationship with the person with MS was spouse/partner (52.9%) and son or daughter (25.9%). Caregiver General Health, Mental Health, Bodily Pain, and Role-emotional Functioning were the most affected dimensions on the SF-36. Multiple regression analysis showed that independent and significant predictors of burden were Role-emotional Functioning and Vitality dimensions SF-36 scores of caregivers, and the Expanded Disability Status Scale scores. The total adjusted variance explained by these variables (adjusted R(2)) was 0.512. Emotional factors and the disability of the person with MS were major predictors of burden. Psychological and social support should be considered to reduce caregiver burden.

Background/aims: Cognitive dysfunction is a major handicap in multiple sclerosis (MS). Its prevalence varies due to disease heterogeneity and methodological issues. A neuropsychological battery of intermediate size was designed for and explored in the screening of cognitive dysfunction in MS patients., Methods: The battery was administered to a hospital-based sample of 191 MS patients and 50 matched controls. Eleven test scores measuring verbal fluency, verbal learning, attention, calculation and visuoperceptual ability were selected on the basis of sensitivity and lack of redundancy. Two alternative approaches were compared for diagnosis of cognitive dysfunction based, firstly, on the number of failed tasks, and secondly, on a single standardized global score., Results: The approach based on the number of failed tasks discriminated better than did the global approach between patients and controls. Using a cutoff of two altered scores, a cognitive dysfunction prevalence of 34% was obtained. The score yielded after summing errors in all tests was the most frequently altered and proved particularly useful for detecting minimally impaired patients., Conclusion: The purpose-designed battery was adequate for the screening of cognitive dysfunction in MS patients. The better accuracy of the single-task approach might reflect MS heterogeneity., (2008 S. Karger AG, Basel.)

Introduction: Comparing the perceptions of multiple sclerosis (MS) patients and caregivers with regard to the same social and familial issues, as well as delving deeper into the factors that determine the quality of life of these patients and their relatives by using a qualitative methodology, can help us to complete the information on the same topic that has already been collected using scales and quantitative protocols., Aim: To analyse how a group of people with MS and their caregivers perceive the disease by examining the way they talk about their experience with it., Subjects and Methods: A qualitative methodology was used; more particularly, data were obtained by holding six discussion groups made up of patients and caregivers, who were members of MS patient associations., Results: People with MS reported the social stigma attached to suffering from the disease. Many of the caregivers thought that patients with MS did not accept the disease and felt that over-protection was of little help in coming to terms with the disease and should therefore be avoided. Remunerated work was described by caregivers as a factor that, at the same time, generated and protected the burden., Conclusions: The social stigma, the lack of work and coming to terms with MS were the greatest issues for the patient, while support from the family network, the relationship that should be established with the patient, the impact of MS on children and the role played by remunerated work were the main dimensions of the disease for the caregiver.

Objective: The Fatigue Impact Scale for Daily Use (D-FIS) is an eight-item instrument designed to measure subjective daily experience of fatigue. This study sought to determine the metric properties of the D-FIS in multiple sclerosis (MS) patients., Methods: Sixty-eight patients with operationally-defined MS and fatigue (54.8% of the sample) underwent the D-FIS. Usual clinical measures for MS, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Functional Assessment of Multiple Sclerosis (FAMS) were also applied. In addition, patients with fatigue completed the Fatigue Descriptive Scale, the Multidimensional Fatigue Inventory (MFI), a Visual Analogue Scale for Fatigue (VAS-F), and a Global Perception of Fatigue Scale (GPF)., Results: Full computable data, 95.6%; both floor and ceiling effect=1.54%; item-total correlation=0.62 (item 1) to 0.84 (item 6); Cronbach's alpha=0.91; item homogeneity =0.55; standard error of measurement=3.18; convergent validity with other fatigue measures=-0.57 (VAS-F); 0.52 (GPF); and 0.46 (MFI-general fatigue). Test-retest reliability (ICC)=0.81. There was a strong association between health-related quality of life (HRQoL) (FAMS) and D-FIS (rS=0.70)., Conclusions: In this study, D-FIS proved to be a feasible and valid instrument for measuring MSrelated fatigue, a frequent symptom associated with deterioration of patients' HRQoL.

Health-related quality of life (HRQoL) has been more intensively studied in multiple sclerosis (MS) than in any other neurological disorder. Traditional medical models of impairment and disability are an incomplete summary of disease burden. Quality of life can be thought of as the sum of all sources of satisfaction (including anticipated sources) minus all threats (including anticipated threats). Many psychosocial factors-including coping, mood, self-efficacy, and perceived support-influence the quality of life of patients with MS more than biological variables such as weakness or extent of MRI lesions. Neuropsychiatric complications such as cognitive impairment and fatigue are also important predictors, even in those patients in the early stages of the disease. We review generic and specific HRQoL measures to help clinicians choose the most appropriate therapies. Subjective (self-report) HRQoL measures may serve to alert clinicians to areas that would otherwise be overlooked. Studies of new interventions should include an assessment of HRQoL not just impairment or disability alone.

Purpose: There is increasing recognition that the global wellbeing of patients with chronic neurological disease is an important outcome in research and clinical practice alike. Many studies involving individuals with multiple sclerosis have demonstrated that the overall wellbeing is not a simple manifestation of impairment or disability. The strongest correlations with health-related quality of life appear to be patient rated emotional adjustment to illness and patient rated handicap. In recent years, health-related quality of life questionnaires that measure the physical, social, emotional, and occupational impact of illness have been developed and validated in populations with MS. Most questionnaires are now available in a range of languages. This development is likely to lead to increasing recognition of neuropsychiatric complications of MS in clinical practice and better quantification of treatment responses in clinical trials., Conclusion: Further work is required to decide which scale is most suited to which purpose. Assessment of multiple sclerosis-specific health-related quality of life should be included in future clinical trials to provide a complete picture of patients' health status.

Purpose: To describe the profile of Multiple Sclerosis (MS) patient caregivers and assess their caregiving burden., Methods: A total of 91 MS patients, recruited from a Spanish longitudinal survey, and their corresponding caregivers were studied. Caregivers were administered a questionnaire that collected social and demographic data, and a generic caregiver burden interview (the Zarit scale). Furthermore, MS patients were administered a specific health-related quality of life (HRQoL) instrument (the modified Spanish version of the Functional Assessment of Multiple Sclerosis)., Results: 24.5% of the sample required caregivers to perform activities of daily life. Caregiver profile was as follows: 67% female; mean age, 51.5 +/- 14.1 years; and mean daily time devoted to care, 11.5 +/- 8.2 h. Most caregivers had some type of support, 67% informal and 31.9% formal. The amount of time spent in caring for relatives was the main item determining the burden of MS-patient caregivers. Moreover, MS patient's HRQoL showed a moderate inverse correlation with caregiver burden., Conclusions: In contrast to previous studies, most Spanish MS-patient caregivers are female, and there is a considerable percentage of parent caregivers. A greater degree of formal support and an improvement in MS patients' HRQoL may serve to reduce caregiver burden.