Multiple Sclerosis Journal

Epidemiological findings suggest a relationship between multiple sclerosis (MS) and cardiovascular disease (CVD) risk factors, although the nature of this relationship is not well understood.

We used genome-wide association study (GWAS) data to identify shared genetic factors (pleiotropy) between MS and CVD risk factors.

Using summary statistics from a large, recent GWAS (total n > 250,000 individuals), we investigated overlap in single nucleotide polymorphisms (SNPs) associated with MS and a number of CVD risk factors including triglycerides (TG), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, body mass index, waist-to-hip ratio, type 2 diabetes, systolic blood pressure, and C-reactive protein level.

Using conditional enrichment plots, we found 30-fold enrichment of MS SNPs for different levels of association with LDL and TG SNPs, with a corresponding reduction in conditional false discovery rate (FDR). We identified 133 pleiotropic loci outside the extended major histocompatibility complex with conditional FDR < 0.01, of which 65 are novel. These pleiotropic loci were located on 21 different chromosomes. Our findings point to overlapping pathobiology between clinically diagnosed MS and cardiovascular risk factors and identify novel common variants associated with increased MS risk.

Glycosylation alterations have been associated with the development of several human diseases and their animal models, including multiple sclerosis.

We aimed to determine whether immunoglobulin G galactosylation might be changed in multiple sclerosis.

Immunoglobulin G was isolated from serum and cerebrospinal fluid of patients with multiple sclerosis or viral meningitis and control patients without history of inflammatory or autoimmune disease. A lectin-based assay was used to investigate potential galactosylation modifications of immunoglobulin G.

Galactosylation of immunoglobulin G isolated from cerebrospinal fluid of control patients was found to be age- and gender-dependent. In addition, immunoglobulin G galactosylation was significantly altered in cerebrospinal fluid but not in serum of multiple sclerosis patients. Furthermore, this modification was correlated with an active progression of multiple sclerosis. Finally, the loss of galactosyl moieties was not simply associated with inflammation as no such change was detected in viral meningitis patients characterized by brain inflammation.

Using diffusion tensor imaging (DTI), it was previously found that demyelinated gray matter (GM) lesions have increased fractional anisotropy (FA) when compared to normal-appearing gray matter (NAGM) in multiple sclerosis (MS). The biological substrate underlying this FA change is so far unclear; both neurodegenerative changes and microglial activation have been proposed as causal contributors.

To test the proposed hypothesis that microglia activation is responsible for increased FA in cortical GM lesions.

We investigated post-mortem cortical DTI changes in hemispheric, coronally cut sections and investigated the underlying histopathology using immunohistochemistry.

Overall, there were few activated microglia/macrophages, and no difference between GM lesions and NAGM was observed. However, cell density was increased in GM lesions compared to NAGM (309.67 ± standard deviation (SD) 124.44 vs 249.95 ± SD 56.75, p = 0.002).

FA increase was not due to lesional and non-lesional differences in microglia activation and/or proliferation. We found an increase in general cellular density without a notable difference in cellular size, that is, tissue compaction, as a possible alternative explanation.

The transparent ocular structure enables quantitative analysis of microvasculature of retina, a neuronal tissue affected by multiple sclerosis (MS).

The aim of this study was to determine whether the retinal blood flow velocity and flow volume at the macula are impaired in patients with relapsing remitting multiple sclerosis (RRMS).

A total of 17 RRMS patients and 17 age- and gender-matched healthy subjects were assessed. A retinal function imager was used to measure the blood flow velocity of retinal arterioles and venules and to calculate the total perifoveal blood flow volume.

The blood flow velocities of the retinal arterioles (3.34 ± 0.89 mm/s) and venules (2.61 ± 0.6 mm/s) were significantly lower in MS patients than normal subjects (arteriole: 4.10 ± 0.87 mm/s; venule: 3.22 ± 0.65 mm/s, both p = 0.01). In addition, the total perifoveal blood flow volume in arterioles (3.74 ± 1.64 nL/s) and venules (3.81 ± 1.60 nL/s) were significantly lower in MS patients than in normal subjects (arteriole: 4.87 ± 1.41 nL/s, p = 0.02; venule: 4.71 ± 1.64 nL/s, p = 0.04).

The impaired retinal microcirculation in RRMS patients indicates microvascular dysfunction in MS.

Myelin oligodendrocyte glycoprotein (MOG) antibodies have been described in children with acute disseminated encephalomyelitis (ADEM), recurrent optic neuritis, neuromyelitis optica spectrum disorders and more recently in children with multiphasic disseminated encephalomyelitis (MDEM).

To delineate the clinical, cerebrospinal fluid (CSF) and radiological features of paediatric MDEM with MOG antibodies.

Clinical course, serum antibodies, CSF, magnetic resonance imaging (MRI) studies and outcome of paediatric MDEM patients were reviewed.

A total of 8 children with two or more episodes of ADEM were identified from a cohort of 295 children with acute demyelinating events. All children had persisting MOG antibodies (median titre: 1:1280). All ADEM episodes included encephalopathy, polyfocal neurological signs and a typical MRI. Apart from ADEM episodes, three children had further clinical attacks without encephalopathy. Median age at initial presentation was 3 years (range: 1–7 years) and median follow-up 4 years (range: 1–8 years). New ADEM episodes were associated with new neurological signs and new MRI lesions. Clinical outcome did range from normal (four of the eight) to mild or moderate impairment (four of the eight). A total of four children received monthly immunoglobulin treatment during the disease course.

Children with MDEM and persisting MOG antibodies constitute a distinct entity of relapsing demyelinating events and extend the spectrum of MOG antibody–associated diseases.

Although many individuals with multiple sclerosis (MS) experience depression, there are no studies on the frequency and effect of peripartum depression among parents with MS.

To examine the frequency of peripartum depression in individuals with MS and its potential association with children’s psychiatric disorders.

We conducted a cohort study in British Columbia, Canada, using linked health databases, of parents with MS and their children, and age-matched unaffected parent–child dyads. The diagnosis of peripartum depression, MS and psychiatric disorders in children was based on information from hospital admission, physician visit and drug prescription claims.

Peripartum depression was significantly more common among MS parents (n = 360) versus unaffected (n = 1207) parents (25.8% vs 18.5%, p value 0.02), especially among MS affected fathers versus unaffected fathers (25.7% vs 10.2%, p value < 0.001). The incidence of psychiatric disorders in children was 3.3 and 2.7 per 100 child-years among children with and without an MS parent, respectively. The rate of psychiatric disorders was significantly higher in children with an MS parent (vs without, hazard ratio (HR): 1.34; 95% confidence interval (CI): 1.03–1.74) and among children with parents who had peripartum depression (HR: 1.87; 95% CI: 1.36–2.55).

Parental MS is associated with a higher risk of peripartum depression and increases the risk of psychiatric disorders in children.

It is unclear whether fatigue is a consequence or a predictive trait of disease worsening.

To investigate the predictive value of fatigue toward conversion to confirmed moderate–severe disability in patients with relapsing-remitting multiple sclerosis (RRMS).

We retrospectively selected from the Comprehensive Longitudinal Investigations in MS at the Brigham and Women’s Hospital (CLIMB) study cohort RRMS patients who converted to confirmed (⩾2 years) Expanded Disability Status Scale (EDSS) score ⩾3 within a follow-up period ⩾3 years. We contrasted the Modified Fatigue Impact Scale (MFIS) score of 33 converters, obtained at least 1 year before conversion to EDSS ⩾3, with that of 33 non-converter RRMS patients matched for baseline characteristics.

Total MFIS score was higher in converter versus non-converter MS patients (median 37 vs 13; p < 0.0001). EDSS and Center for Epidemiological Studies Depression scale (CES-D) scores were also higher in the converters (median EDSS 1.5 vs 0, p < 0.0001; median CES-D 30 vs 24, p < 0.0001) and were both associated with MFIS score (EDSS: rho = 0.42, p = 0.0005; CES-D: rho = 0.72, p < 0.0001). After adjusting for EDSS and CES-D in multivariate analysis, MFIS remained a significant predictor of subsequent conversion to confirmed EDSS ⩾3.

Fatigue is a promising indicator of risk for conversion to confirmed moderate–severe disability in RRMS patients.

To compare the frequency and pattern of cognitive impairment (CI) between patients with neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS).

A total of 82 NMOSD patients, 58 MS patients, and 45 healthy controls (HCs) underwent a neuropsychological assessment.

CI was observed in 29% of NMOSD and 50% of MS patients (p < 0.001); CI was considered present if a patient scored lower than the fifth percentile compared with HCs in at least three domains. A lower frequency of CI was consistently found when CI was indicated by at least two failed tests (p < 0.001). MS patients performed worse than did NMOSD patients on verbal learning and verbal and visual memory tests. Levels of education and depression and the interval from disease onset to treatment were associated with a negative influence on cognition in patients with NMOSD.

CI in patients with NMOSD may be not as common as in patients with MS. MS patients exhibited severe impairment, particularly on learning and memory tests, compared with NMOSD patients. Differential prevalence and patterns of CI between NMOSD and MS patients suggest that the two diseases have different mechanisms of brain injury.

Multiple sclerosis (MS) is associated with considerable morbidity and serious disability, but little is known of the long-term impact of the disease on work ability.

To assess sick leave (short-term absence) and disability pension (long-term absence) before and after diagnosis of MS.

Patients with MS in Sweden were identified in a nationwide disease-specific register and matched with general population controls. Sick leave and disability pension were measured before and after index (i.e. the MS diagnosis date).

The final sample comprised 6092 patients and 60,345 controls (mean age 39 years; 70% female). The mean annual prevalence of sick leave ranged from 12% the first year after index to 23% after 11 years among patients and from 13% to 13% among controls. Corresponding estimates for disability pension were 12% and 55% for patients and 7% and 9% for controls. Significant differences in sick leave were observed up to 15 years before index and 3 years for disability pension.

Patients with MS in Sweden have elevated levels of sick leave and disability pension up to 15 years before disease diagnosis. Our results highlight the burden of disease on affected patients and society and underscore the substantial unmet medical need.

The Multiple Sclerosis Walking Scale-12 (MSWS-12) measures walking ability from the patients’ perspective. We examined the quality of the MSWS-12 using an item response theory model, the graded response model (GRM).

A total of 625 unique Dutch multiple sclerosis (MS) patients were included. After testing for unidimensionality, monotonicity, and absence of local dependence, a GRM was fit and item characteristics were assessed. Differential item functioning (DIF) for the variables gender, age, duration of MS, type of MS and severity of MS, reliability, total test information, and standard error of the trait level (θ) were investigated.

Confirmatory factor analysis showed a unidimensional structure of the 12 items of the scale, explaining 88% of the variance. Item 2 did not fit into the GRM model. Reliability was 0.93. Items 8 and 9 (of the 11 and 12 item version respectively) showed DIF on the variable severity, based on the Expanded Disability Status Scale (EDSS). However, the EDSS is strongly related to the content of both items.

Our results confirm the good quality of the MSWS-12. The trait level (θ) scores and item parameters of both the 12- and 11-item versions were highly comparable, although we do not suggest to change the content of the MSWS-12.

Cognitive and motor abilities in multiple sclerosis (MS) are typically quantified using reliable, consensus standard tests validated in the MS population. While these performance measures are associated with vocational disability in parametric analyses, translation of raw scores into anchors reflecting clinically relevant, functional impairment requires further research.

To examine performance-based motor and cognitive outcomes among definitive anchors that designate varying degrees of functional impairment, thereby establishing benchmarks for score interpretation.

We evaluated MS patients and healthy controls, all undergoing a brief test battery. Outcomes were derived from the MS Functional Composite (MSFC) and the Brief International Cognitive Assessment for MS (BICAMS). Functional impairment anchors were (1) disability benefits, (2) employed with negative work events, and (3) employed without problems.

All measures yielded statistically significant differences across all levels of work status, after accounting for the effects of age and education. Benchmark values distinguished the functional impairment groups. When evaluated in combination, the Timed 25-Foot Walk and the Symbol Digit Modalities Test were the most robust predictors of functional decline.

We have established benchmark scores for popular motor and cognitive tests that are associated with specific degrees of impairment in work status.

No molecular marker can monitor disease progression and treatment efficacy in multiple sclerosis (MS). Circulating microparticles represent a potential snapshot of disease activity at the blood brain barrier.

To profile plasma microparticles by flow cytometry in MS and determine how fingolimod could impact endothelial microparticles production.

In non-treated MS patients compared to healthy and fingolimod-treated patients, endothelial microparticles were higher, while B-cell-microparticle numbers were lower. Fingolimod dramatically reduced tumour necrosis factor (TNF)-induced endothelial microparticle release in vitro.

Fingolimod restored dysregulated endothelial and B-cell-microparticle numbers, which could serve as a biomarker in MS.

The appearance of solid tumors und lymphomas during treatment with fingolimod was observed in studies and has been described in case reports.

To report a case of primary cutaneous CD30(+) anaplastic large-cell T-cell lymphoma during treatment of multiple sclerosis (MS) with fingolimod.

Case study.

Our patient developed a lymphoma a few weeks after initialization of therapy with fingolimod; 5 weeks after discontinuation of treatment the lesions resolved.

Causality of fingolimod is indicated by the fact that the skin lesions appeared after commencement of treatment and resolved after discontinuation of therapy. This case serves as a reminder of the potential side effects of fingolimod.