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Lower serum vitamin D levels are associated with a higher relapse risk in multiple sclerosis

Objective: There is increasing evidence that vitamin D can be protective against the development of multiple sclerosis (MS), but it may also be beneficial for the clinical course of the disease. Our objective was to prospectively investigate if 25-hydroxy-vitamin D (25-OH-D) levels are associated with exacerbation risk in MS in a study with frequent serum measurements. Methods: This was a prospective longitudinal study in 73 patients with relapsing-remitting MS. Blood samples for 25-OH-D measurements were taken every 8 weeks. Associations between 25-OH-D levels and exacerbation rates were assessed using Poisson regression (generalized estimating equations) with the individual serum levels as time-dependent variable. Results: During follow-up (mean 1.7 years), 58 patients experienced a total of 139 exacerbations. Monthly moving averages of 25-OH-D levels were categorized into low (<50 nmol/L), medium (50–100 nmol/L), and high (>100 nmol/L) levels. Exacerbation risk decreased significantly with higher serum vitamin D levels: respective relative exacerbation rates for the medium and high-level category as compared to the low-level category were 0.7 and 0.5 (p value for trend: p = 0.007). The association between 25-OH-D concentrations and exacerbation rate was log linear without a threshold. With each doubling of the serum 25-OH-D concentration the exacerbation rate decreased by 27% (95% confidence interval 8%–42%, p = 0.008). Conclusions: Our finding that higher vitamin D levels are associated with decreased exacerbation risk in relapsing-remitting MS suggests a beneficial effect of vitamin D on disease course in MS. However, the possibility of reverse causality cannot be ruled out completely. Randomized intervention studies are therefore needed to investigate the effect of vitamin D supplementation in MS.

Serum neurofilament light chain levels are increased in patients with a clinically isolated syndrome

Background Neurofilament light chain (NfL) represents a promising biomarker for axonal injury. We present the first exploratory study on serum NfL in patients with a clinically isolated syndrome (CIS) and healthy controls. Methods We investigated serum NfL levels in 100 patients with CIS with a short conversion interval to clinically definite multiple sclerosis (MS) (fast converters (FC), median (IQR) conversion time: 110 days (79–139)); 98 patients with non-converting CIS (non-converters (NC), follow-up: 6.5 years (5.3–7.9)); and 92 healthy controls. Results NfL levels were higher in FC (24.1 pg/mL (13.5–51.8)) and NC (19.3 pg/mL (13.6–35.2)) than in healthy controls (7.9 pg/mL (5.6–17.2)) (OR=5.85; 95% CI 2.63 to 13.02; p=1.5×10−5 and OR=7.03; 95% CI 2.85 to 17.34; p=2.3×10−5, respectively). When grouping FC and NC, increased serum NfL concentration was also associated with increasing numbers of T2 hyperintense MRI lesions (OR=2.36; 95% CI 1.21 to 4.59; p=0.011), gadolinium-enhancing lesions (OR=2.69; 95% CI 1.13 to 6.41; p=0.026) and higher disability scores (OR=2.54; 95% CI 1.21 to 5.31; p=0.013) at CIS diagnosis. Conclusions If replicated in future studies, serum NfL may represent a reliable and easily accessible biomarker of early axonal damage in CIS and MS.

Fatigue at time of CIS is an independent predictor of a subsequent diagnosis of multiple sclerosis

Objective Fatigue is a common, disabling symptom of multiple sclerosis (MS), but little is known about fatigue in patients with clinically isolated syndrome (CIS), often the presenting symptom of MS. We aimed to investigate the prevalence and severity of fatigue in patients with CIS, and its association with a diagnosis of clinically definite MS (CDMS). Methods 127 patients were consecutively included in our ongoing prospective CIS study. At baseline, clinical, demographic, laboratory and MRI data were collected, and fatigue severity was assessed using Krupps Fatigue Severity Scale (FSS); fatigue was defined as FSS≥5.0. Fatigue scores were compared with scores of 113 healthy controls and with scores from the literature. The association of fatigue with CDMS was calculated using Cox regression models. Results The mean FSS of patients with CIS was 4.3, similar to MS patients, and significantly higher than that of healthy individuals (p<0.001). Fatigue prevalence in patients with CIS (46.5%) was significantly higher than in controls (p<0.001). Fifty-two patients (40.9%) reached CDMS during follow-up. Fatigue was associated with a diagnosis of CDMS in univariate analysis (HR 2.6, 95% CI 1.5 to 4.6) and in multivariate analysis correcting for sex, age, neuroanatomical localisation of CIS, 25-OH-vitamin D, anxiety, depression, MRI dissemination in space and gadolinium enhancement (HR 4.5, 95% CI 1.9 to 10.6). Conclusions Already at the stage of CIS, fatigue is a very common symptom, with a severity similar to fatigue in MS patients. This fatigue seems unrelated to the type or severity of the attack. Importantly, we found that fatigue was an independent predictor of a subsequent diagnosis of MS.

Recent gains in clinical multiple sclerosis research.

Multiple sclerosis (MS) is a common neurological disease mainly affecting young people. Around the world, over 2.5 million people suffer from this central nervous system (CNS) disorder. Although the exact disease mechanism is not completely clear, it is known that both environmental and genetic factors influence the development of MS. Here we aim to summarize a few major highlights of recent progress that have been made in clinical MS research. A genetic predisposition in combination with Epstein-Barr virus infection seems to be essential to get MS. Recently more than 50 susceptibility genetic loci for MS have been described. MS prevalence has a latitudinal gradient indicating that sunlight exposure and therefore vitamin D are important contributors to MS risk. Several studies found an inverse association between MS prevalence and serum vitamin D levels. In most cases, MS starts with an acute episode involving one or more sites of the CNS. The role of the recently revised McDonald Diagnostic Criteria for the diagnosis of MS, which sometimes allow the diagnosis after a first attack, is discussed. Most patients with MS suffer from exacerbations and remissions of neurological deficits: relapsing-and remitting MS. With time, the majority of these patients enter a disease phase characterized by continuous, irreversible neurological decline; this is called secondary progressive MS. In 10-20% of patients, the disease is progressive from onset. Life expectancy of patients after diagnosis with MS is around 35 years, and MS patients die 5-10 years earlier than the general population. A substantial percentage of MS patients have their first attack during childhood. Clinics of childhood-onset MS versus adult-onset are explained, as are diagnostics, differential diagnoses and therapeutic options for children with MS. Also another demyelinating disease of the CNS, neuromyelitis optica (NMO) is highlighted. Since NMO has been considered as a variant of MS and also has been misdiagnosed as MS, recent insights in the pathology of NMO are explained.

Application of the 2010 revised criteria for the diagnosis of multiple sclerosis to patients with clinically isolated syndromes

Recently, the McDonald criteria for the diagnosis of multiple sclerosis (MS) have been revised, with the aims to diagnose earlier and to simplify the use of brain MRI. To validate the 2010 revised criteria they were applied to a cohort of patients with clinically isolated syndromes (CIS).

No evidence for an association of osteopontin plasma levels with disease activity in multiple sclerosis

1. UK Multiple Sclerosis Specialist Nurse Association (UKMSSNA). Multiple sclerosis specialist nurses: Adding value and delivering targets. UKMSSNA, 2006; Ledbury, UK. 2. Nuffield Trust. Trends in emergency admission 2004–9: Is greater efficiency breeding inefficiency? Nuffield Trust, 2010; London, UK. 3. Health and Social Care Information Centre. Hospital episode statistics, www.hesonline.nhs.uk/Ease/servlet/ContentServ er?siteID=1937&categoryID=202 (2012, accessed August 2012).

The influence of vitamin D on postpartum relapse and quality of life in pregnant multiple sclerosis patients.

In relapsing−remitting MS patients, lower serum vitamin D concentrations are associated with higher relapse risk. In a number of conditions, low vitamin D has been associated with fatigue. Pregnant women are at particular risk for vitamin D insufficiency. Our objective was to investigate whether vitamin D status is associated with postpartum relapse and quality of life during pregnancy.

Vitamin A is not associated with exacerbations in multiple sclerosis

BACKGROUND Vitamin A is a multifunctional vitamin that can inhibit the formation of Th17 cells, which are probably involved in the development of relapses in MS. Furthermore, it promotes Treg formation. Therefore, vitamin A can be hypothesized to be lower in patients than in healthy controls, and to decrease relapse risk in relapsing-remitting MS (RRMS) patients. OBJECTIVE To compare vitamin A levels in MS patients and controls, and to investigate whether vitamin A levels are associated with relapse risk. METHODS In a case-control study all-trans-retinol levels were compared between 31 RRMS patients and 29 matched controls. In a prospective longitudinal study in 73 RRMS patients, serum samples for all-trans-retinol measurements were taken every eight weeks. Associations between all-trans-retinol concentrations and relapse rates were calculated using Poisson regression with the individual serum levels as time-dependent variable. Associations between vitamin A and vitamin D were calculated. RESULTS Mean vitamin A levels were lower in patients (2.16μmol/l) than in controls (2.44μmol/l) but with borderline significance (p=0.05). In the longitudinal study, during follow-up (mean 1.7 years), 58 patients experienced a total of 139 relapses. Monthly moving averages of all-trans retinol levels were categorized into tertiles: a low (<2.9μmol/l), medium (2.9-3.7μmol/l) and high level (>3.7μmol/l). Relapse rates were not associated with serum all-trans retinol levels (p>0.2), in univariate nor in multivariate analysis. Serum concentrations of all-trans-retinol and 25-OH-vitamin D were positively correlated, although this correlation was weak (r=0.15). CONCLUSION We did not find evidence for a role for vitamin A in the disease course of RRMS. We did find an association between vitamin A and D levels in the RRMS patients, possibly explained by dietary products that contain both fat-soluble vitamins.

Soluble CD27 Levels in Cerebrospinal Fluid as a Prognostic Biomarker in Clinically Isolated Syndrome

Importance There is a growing number of therapies that could be administered after the first symptom of central nervous system demyelination. These drugs can delay multiple sclerosis (MS) diagnosis and slow down future disability. However, treatment of patients with benign course may not be needed; therefore, there is a need for biomarkers to predict long-term prognosis in patients with clinically isolated syndrome (CIS). Objective To investigate whether the T-cell activation marker soluble CD27 (sCD27) measured in cerebrospinal fluid of patients at time of a first attack is associated with a subsequent diagnosis of MS and a higher relapse rate. Design, Setting, and Participants This prospective study included 77 patients with CIS between March 2002 and May 2015 in a tertiary referral center for multiple sclerosis, in collaboration with several regional hospitals. Patients with CIS underwent a lumbar puncture and magnetic resonance imaging scan within 6 months after first onset of symptoms. Main Outcomes and Measures Soluble CD27 levels were determined in cerebrospinal fluid using a commercially available enzyme-linked immunosorbent assay. Cox regression analyses was used to calculate univariate and multivariate hazard ratios for MS diagnosis. Association between sCD27 levels and relapse rate was assessed using a negative binomial regression model. Results Among 77 patients with CIS, 50 were female (79.5%), and mean (SD) age was 32.7 (7.4) years. Mean (SD) age in the control individuals was 33.4 (9.5) years, and 20 were female (66.7%).Patients with CIS had higher cerebrospinal fluid sCD27 levels than control individuals (geometric mean, 31.3 U/mL; 95% CI, 24.0-40.9 vs mean, 4.67 U/mL; 95% CI, 2.9-7.5; P < .001). During a mean (SD) follow-up of 54.8 (35.1) months, 39 of 77 patients (50.6%) were diagnosed as having MS. In a model adjusted for magnetic resonance imaging and cerebrospinal fluid measurements, sCD27 levels were associated with a diagnosis of MS (hazard ratio, 2.4 per 100 U/mL increase in sCD27 levels; 95% CI, 1.27-4.53; P = .007). Additionally, patients with MS with high sCD27 levels (median, >31.4 U/mL) at the time of CIS had a 5.5 times higher annualized relapse rate than patients with low sCD27 levels (annualized relapse rate, 0.06 vs 0.33; P = .02). Conclusions and Relevance Soluble CD27 in cerebrospinal fluid of patients with CIS was associated with MS diagnosis and a high relapse rate. Therefore, sCD27 is an activation molecule directly related to the immunopathology of the disease and is a potential clinical marker to help in treatment decisions after a first attack of suspected MS.

Regulator of oligodendrocyte maturation, miR-219, a potential biomarker for MS

BackgroundMultiple sclerosis (MS) is a demyelinating and degenerative disease of the central nervous system. Normally, demyelination is followed by remyelination, which requires repopulation of a demyelinated area by oligodendrocyte precursor cells. Although large numbers of precursor cells are present in MS lesions, remyelination often fails, in part by the inability of precursor cells to differentiate into mature myelin-forming cells. In mouse and rat, miR-219 is required for this differentiation. Previously, we identified decreased miR-219 expression in tissue of MS patients compared to controls. Cell-free miRNAs have been detected in many different body fluids including cerebrospinal fluid (CSF) and may reflect disease processes going on in the central nervous system. This prompted us to investigate the biomarker performance of CSF miR-219 for MS diagnosis.MethodsQuantitative PCR was performed measuring miR-219 levels in CSF of MS patients and controls in three independent cohorts.ResultsAll three cohorts of MS patients and controls revealed that absence of miR-219 detection in CSF is consistently associated with MS.ConclusionsWe have been able to identify and validate absence of miR-219 detection in CSF of MS patients compared to controls, suggesting that it may emerge as a candidate biomarker for MS diagnosis.