Multiple Sclerosis Journal

Anti-oxidant compounds that are found in over-the-counter (OTC) supplements and foods are gaining interest as treatments for multiple sclerosis (MS). They are widely used by patients, sometimes without a clear evidence base.

We conducted a systematic review of animal and clinical research to determine the evidence for the benefits of OTC anti-oxidants in MS.

Using predefined criteria, we searched key databases. Two authors scrutinized all studies against inclusion/exclusion criteria, assessed study risk-of-bias and extracted results.

Of the 3507 titles, 145 met criteria and included compounds, α(alpha)-lipoic acid (ALA), anti-oxidant vitamins, Ginkgo biloba, quercetin, resveratrol and epigallocatechin-3-gallate (ECGC). The strongest evidence to support OTC anti-oxidants was for compounds EGCG and ALA in animal models; both consistently showed anti-inflammatory/anti-oxidant effects and reduced neurological impairment. Only vitamin E, Ginkgo biloba and ALA were examined for efficacy in pilot clinical trials with either conflicting evidence or evidence of no benefit.

OTC anti-oxidants EGCG and ALA show the most consistent benefit, however only in preclinical studies. There is no evidence that they alter MS relapses or progression. Future work should focus on testing more of these therapies for clinical efficacy before recommending them to MS patients.

Single nucleotide polymorphisms (SNPs) near SOCS1 are associated with multiple sclerosis (MS), but the most important SNPs in the area and mechanisms by which they influence the disease are unknown.

A haplotype-tagging association study was performed covering 60.5kbp around SOCS1, and the index SNP was validated in a total of 2292 individuals. mRNA expression of SOCS1 and nearby genes was measured in MS patients with different disease courses and healthy controls. SOCS1 protein expression was studied by flow cytometry in a separate cohort of patients and controls. Differentiation and maturation of monocyte-derived dendritic cells (moDCs) were also studied.

One SNP, rs423674, reached genome-wide significance. No genotype-specific mRNA expression differences were seen, but, by flow cytometry, significant interactions were observed between genotypes for rs423674 and disease activity (relapse or remission) in B cells and regulatory T cells. Furthermore, homozygotes for the risk allele (GG) showed higher levels of CD1a and CD86 than carriers of the protective allele (GT) in immature moDCs and a greater increase of HLA-DR+ cell percentage than GT heterozygotes upon maturation.

rs423674, or its genetic proxies, may influence MS risk by modulating SOCS1 expression in a cell-specific manner and by influencing dendritic cell function.

Acquired demyelinating syndromes (ADS) in children are a group of distinct first immune-mediated demyelinating events of the central nervous system (CNS). Predictive biomarkers for future diagnosis are lacking. A putative target antigen is myelin oligodendrocyte glycoprotein (MOG). We analyzed the presence of MOG antibodies in a cohort of ADS patients in The Netherlands.

Using a cell-based assay, we analyzed 117 children with ADS from a nationwide cohort, whom were divided into five groups: optic neuritis (ON; n = 20), transverse myelitis (TM; n = 7), other monofocal ADS (n = 22), polyfocal ADS without encephalopathy (n = 44) and polyfocal ADS with encephalopathy (n = 24). Additionally, we tested children with other neurological diseases (OND; n = 13), healthy children (n = 31) and adult polyfocal ADS plus encephalopathy (ADEM) patients (n = 29).

We found that 21 of the 117 children with ADS tested anti-MOG seropositive (18%). The group of patients with ADEM had the highest prevalence of anti-MOG seropositivity (42% versus 18% in the non-encephalopathic polyfocal ADS patients). Although 47 ADS children had a final diagnosis of multiple sclerosis (MS), in only one of them were MOG antibodies detected (2%), with only borderline positivity. Only 1 out of the 29 adult ADEM patients tested anti-MOG seropositive.

MOG antibodies are strongly skewed towards ADS children that present with an ADEM-like disease onset. The presence of such antibodies pleads against a future diagnosis of MS.

In multiple sclerosis (MS), disturbed T-cell homeostasis affects both conventional CD4⁺ T cells (Tcon) and regulatory T cells (Treg). Functionally, this is linked to a loss of Treg-suppressive properties. Concerns exist as to whether fingolimod might further aggravate Treg dysfunction by inhibiting thymic egress and, thus, promoting premature immunosenescence.

The objective of this paper is to investigate whether fingolimod, by sequestration of developing cells in the thymus, might deteriorate numeric and/or functional disequilibrium of T-cell subtypes.

We assessed numbers and phenotypes of blood Tcon and Treg in 74 MS patients treated with fingolimod and in 37 healthy donors. Treg and Tcon were also analyzed for immunoreactivity, suppressive function, sphingosine-1-phosphate-triggered (S1P) trafficking, and S1P-receptor expression. This was complemented by assessing surrogate markers of thymic T-cell development, including frequencies of cells expressing T-cell receptors (TCR) of dual specificity, and TCR diversity in Treg.

Fingolimod did not negatively affect naive T-cell phenotypes or markers of thymic T-cell development. By reducing CCR7-expressing Tcon, fingolimod increased relative proportions of Treg. As a result of this shift, fewer proliferative CCR7⁻ Tcon became enriched and Treg-dysfunction was indirectly reversed.

These observations argue against harmful interference of fingolimod with thymic T-cell output that, particularly in pediatric MS, might possibly counteract its beneficial effects.

Accumulating data highlight proinflammatory processes leading to MS relapses. Whether anti-inflammatory mechanisms are concomitantly activated is unclear. The ectonucleotidase CD39 has been described as a novel T regulatory cell (Treg) marker. The purpose of this study was to explore whether regulatory mechanisms are activated during MS relapses and reinforced by intravenous methylprednisolone (ivMP).

Blood samples were collected from stable and relapsing MS patients and healthy controls. We used FOXP3 methylation-specific qPCR and CD4⁺CD25^highFOXP3⁺ analysis to quantify Tregs. Cytokine mRNA expression levels were measured in peripheral blood mononuclear cells (PBMCs) and in CD4⁺ T cells. CD39 expression was determined by flow cytometry in monocytes, NK, T and B cells. CD39 enzymatic activity was assessed by ATP luminometry.

The proportion of Tregs was similar in relapsing MS patients and healthy controls. CD39 mRNA level was higher in PBMCs of relapsing MS patients than in controls. The proportion of CD39-expressing Tregs was higher in MS patients. IvMP decreased the overall proportion of Tregs while it increased CD39 mRNA levels, the proportions of CD39-expressing Tregs and monocytes as well as CD39 ectonucleotidase activity.

Our data suggest that immunoregulatory mechanisms are ongoing in MS patients, particularly during relapses, and strengthened by ivMP.

Impaired manual dexterity is frequent and disabling in patients with multiple sclerosis (MS), affecting activities of daily living (ADL) and quality of life.

We aimed to evaluate the effectiveness of a standardized, home-based training program to improve manual dexterity and dexterity-related ADL in MS patients.

This was a randomized, rater-blinded controlled trial. Thirty-nine MS patients acknowledging impaired manual dexterity and having a pathological Coin Rotation Task (CRT), Nine Hole Peg Test (9HPT) or both were randomized 1:1 into two standardized training programs, the dexterity training program and the theraband training program. Patients trained five days per week in both programs over a period of 4 weeks. Primary outcome measures performed at baseline and after 4 weeks were the CRT, 9HPT and a dexterous-related ADL questionnaire. Secondary outcome measures were the Chedoke Arm and Hand Activity Inventory (CAHAI-8) and the JAMAR test.

The dexterity training program resulted in significant improvements in almost all outcome measures at study end compared with baseline. The theraband training program resulted in mostly non-significant improvements.

The home-based dexterity training program significantly improved manual dexterity and dexterity-related ADL in moderately disabled MS patients. Trial Registration NCT01507636.

Patients with multiple sclerosis (MS) are at increased risk of reduced bone mineral density (BMD). A contributing factor might be treatment with high-dose glucocorticoids (GCs).

The objective of this paper is to assess bone mass in patients with MS and evaluate the importance of short-term, high-dose GC treatment and other risk factors that affect BMD in patients with MS.

A total of 260 patients with MS received short-term high-dose GC treatment and had their BMD measured by dual x-ray absorptiometry. BMD was compared to a healthy age-matched reference population (Z-scores). Data regarding GCs, age, body mass index (BMI), serum 25(OH)D, disease duration and severity were collected retrospectively and analysed in a multiple linear regression analysis to evaluate the association between each risk factor and BMD.

Osteopenia was present in 38% and osteoporosis in 7% of the study population. Mean Z-score was significantly below zero, indicating a decreased BMD in our MS patients. Multiple linear regression analysis showed no significant association between GCs and BMD. In contrast, age, BMI and disease severity were independently associated with both lumbar and femoral BMD.

Reduced BMD was prevalent in patients with MS. GC treatment appears not to be the primary underlying cause of secondary osteoporosis in MS patients.

There has been limited research on upper limb dysfunction in people with multiple sclerosis (PwMS).

The objective of this paper is to study unilateral and bilateral upper limb dysfunction at different International Classification of Functioning (ICF) levels according to overall disability in PwMS.

A total of 105 PwMS (16 with EDSS<4 (mild); 17 with EDSS 4–5.5 (moderate); 37 with EDSS 6–6.5 (severe); 35 with EDSS>6.5 (severe non-ambulant)) were recruited from two rehabilitation centers and assessed in a cross-sectional study.

The whole sample showed a diminished sensory function (median (first/third interquartile)) score of 3 (2/3) on the Monofilament Test and a reduced strength 91 (76/100) points on the Motricity Index (Body-Function level). Sensory dysfunction did not increase with higher EDSS while strength decreased from 100 (86/100) in the mild subgroups to 91 (80/100) points in the severe subgroup. All showed diminished dexterity, scoring 0.28 peg/s (0.17/0.35) on the Nine-Hole Peg Test (NHPT) (activity level). Score was better for the mild (0.38 (0.35/0.46)) peg/s compared to the severe subgroup (0.28 (0.17/0.35)). Sixty-eight percent, 44% and 75% of PwMS showed bilateral disorders in sensation, strength and dexterity, respectively. The Community Integration Questionnaire (participation level) showed a 35% reduction in home activities, even among PwMS with EDSS<4.

This study showed uni-/bilateral upper limb abnormalities at all ICF levels increasing with the overall disability.

This study examined the influence of processing speed (PS) on benefit from treatment with the modified Story Memory Technique^© (mSMT), a behavioral intervention shown to improve new learning and memory in multiple sclerosis (MS).

This double-blind, placebo-controlled, randomized clinical trial included 85 participants with clinically definite MS, 45 assigned to the treatment group and 40 to the placebo-control group. Participants completed baseline and follow-up neuropsychological assessment. The present study represents a post-hoc analysis to examine the role of PS on treatment efficacy.

The treatment group showed a significantly improved CVLT learning slope relative to the placebo group post-treatment, after co-varying PS performance. SDMT performance was a significant predictor of benefit from mSMT treatment, beyond group assignment. Post-hoc analysis indicated a significant correlation between the SDMT and overall cognition, indicating that the SDMT may be serving as a proxy for overall cognitive impairment.

Performance on measures of cognitive dysfunction aside from learning and memory impact the benefit of mSMT treatment. While the current study focused on PS as a critical factor, PS may be serving as a marker for generalized cognitive dysfunction. Implications for cognitive rehabilitation in MS are discussed.© Kessler Foundation Inc. All rights reserved.

Spasticity is an extremely common, distressing and disabling symptom of multiple sclerosis. Limited data suggest the associated health care costs correlate with increasing severity and place a high economic burden on individuals, health care systems and society.

The aim of this study was to quantify the impact of multiple sclerosis spasticity on health care resources and the associated costs at different levels of severity in people with multiple sclerosis in the United Kingdom.

An online survey was carried out to understand the resources used in the management of spasticity in multiple sclerosis. The questionnaire asked health care specialists to estimate their involvement and the resource use associated with different levels of spasticity, and the survey outputs were used to derive the resource costs.

The level and cost of care substantially increased with the degree of spasticity. Key factors contributing to high annual costs per patient were home care, hospital admissions and high-cost items, such as hospital beds.

Based on the survey results, it can be assumed that managing spasticity early and effectively could result in substantial cost savings, in addition to the improvements in health-related quality of life.

Pharmaceutical industry financial support of physicians, physician practices, and academic departments involved in multicenter industry-sponsored clinical trials of novel therapeutic agents is a relatively new and infrequently acknowledged source of potential physician conflict of interest. Detailed disclosure of these relationships to study participants is not uniformly a part of informed consent and documentation practices.

To understand attitudes of patients with multiple sclerosis concerning disclosure of potential physician–industry conflicts of interest created by clinical trials and how such disclosures may influence study participation

An anonymous online instrument was developed.

597 people with multiple sclerosis participated in the study. The study found that detailed disclosure of conflicts of interest is important to potential participants in industry-sponsored clinical trials for multiple sclerosis therapies and that the presence of these conflicts of interest may influence patients’ decisions to participate in these studies.

Findings from this study support a call for uniform guidelines regarding disclosure of physician–industry relationships to prospective research participants for industry-sponsored clinical trials.

Children with untreated biotinidase deficiency can experience variable symptoms depending on their age of presentation. Older children and adolescents can exhibit predominant neurological deficits including para- or tetraparesis and vision loss.

We report the first case of delayed-onset biotinidase deficiency in a young adult.

A 22-year-old man presented with a disabling extensive myelopathy and bilateral optic neuropathy which mimicked the findings of a (seronegative) neuromyelitis optica. Imaging investigations were characterized by an MRI T2 hyper-intensity involving the spinal cord, the optic nerves, the fornix and the mammillar bodies, together with an increased ¹⁸F-FDG uptake on positron emission tomography. He was ultimately shown to have profound biotinidase deficiency due to a novel missense mutation and was partly improved by oral biotin therapy.

This individual exemplifies the need to include biotinidase deficiency in the differential diagnosis of patients with extensive myelopathy and/or bilateral optic neuropathy and argues for newborn screening for the disorder.